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## **Meet the editor**

Dr Jácome Bruges Armas is a Senior Specialist in Internal Medicine and is currently the Director of the Genetics and Arthritis Research Group (GARG) at the Institute for Molecular and Cell Biology (IBMC), University of Porto, PortugaL. He is also the Director of the Epidemiology and Molecular Biology Service (SEEBMO) at the Hospital de Santo Espirito de Angra do Heroismo,

Terceira Island, The Azores, Portugal. His research interests are mainly the epidemiology and molecular genetics of Spondyloarthritis (SpA), Diffuse Idiopathic Skeletal Hyperostosis (DISH), and Chondrocalcinosis (CC). He is a member of several scientific organizations and a member of the editorial board of several scientific journals.

Contents

**Preface IX** 

Jeanette Wolf

Chapter 2 **Ankylosing Apondylitis** 

and Peter Revington

Chapter 3 **Bone Mineral Density Changes** 

and Irena Butrimienė

**Part 2 HLA and Non-MHC Genes,** 

Wen-Chan Tsai

Chapter 4 **Surgical Treatment After Spinal Trauma** 

Chapter 5 **HLA-B27 and Ankylosing Spondylitis 73** 

Chapter 6 **Humoral Immune Response to** *Salmonella*

**Part 1 Clinical Manifestations, Bone Density** 

Chapter 1 **Clinical Features of Ankylosing Spondylitis 3** 

**of Temporomandibular Joint (TMJ) 15**  Raveendra Manemi, Rooprashmi Kenchangoudar

**in Patients with Spondyloarthropathies 27** 

**in Patients with Ankylosing Spondylitis 55** 

George Machairas, Pavlos Katonis and George Sapkas

**Antigens and Polymorphisms in Receptors for** 

Ma. de Jesús Durán-Avelar, Norberto Vibanco-Pérez,

**Immune Response, and Gene Expression Studies 71** 

**the Fc of IgG in Patients with Ankylosing Spondylitis 85** 

Angélica N. Rodríguez-Ocampo, Juan Manuel Agraz-Cibrian, Salvador Peña-Virgen and José Francisco Zambrano-Zaragoza

Stamatios A. Papadakis, Konstantinos Kateros, Spyridon Galanakos,

Lina Vencevičienė, Rimantas Vencevičius

**Measurements and Axial Fractures Treatment 1** 

### Contents

#### **Preface XI**



### Preface

Ankylosing Spondylitis (AS) was first described possibly at the end of the XVII century by Buckley (1931) and Connor, but it was only recognized after the radiologic descriptions of Bechterew, Strumpell and Marie, during the XIX century. In 1964 the American Rheumatism Association classified AS as a distinct disease. About forty years ago (1973), Schlosstein and Brewerton published simultaneously but independently the association of AS with the Class I allele B\*27.

Since then, AS has been the target of intense research and an enormous amount of information has been gathered about this disease. Now it is known that AS is one of a group of several diseases known as Spondyloarthritis (SpA): AS, reactive arthritis, unspecified spondyloarthritis, psoriatic arthritis, and entheropathic arthritis.

Also, during the last ten years research has been focused on the understanding of the molecular and cellular processes involved in AS pathogenesis. Genome Wide Association Studies (GWAS) were followed by other studies using candidate genes which allowed the identification of non-HLA genes associated with AS susceptibility.

The more detailed knowledge of the molecular and cellular mechanisms, and the identification of biomarkers and their signaling pathways, contributed to the development of anti-TNFα and anti-IL6 molecules which are highly effective in the treatment of AS. These drugs radically changed the treatment of SpA and improved significantly the quality of life of the patients. With the deeper knowledge of the cellular mechanisms of AS, further therapeutic improvements will follow.

In this book, we have tried through original research and revised chapters, to update the clinical and molecular knowledge of AS and SpA.

The chapters in the first section, "*Clinical Manifestations, Bone Density Measurements and Axial Fractures Treatment",* cover general and more specific clinical aspects of SpA. Spinal and axial joints are affected in AS, but the hallmark of this disease is the axial aggression, sometimes restricted to the sacroiliac joint, better characterized in the early stages by MRI. Peripheral joints may be involved in 30% of cases, and the earlier

#### X Preface

involvement of these joints may be an indicator of a more aggressive disease. Extraarticular manifestations are quite common in AS, namely enthesitis, acute anterior uveitis (AUU), cardiac involvement, pulmonary fibrosis, and secondary renal amyloidosis. Psoriatic arthritis has several subgroups and the sub-classification of this disease may be difficult even for the rheumatologist. Up to 50% of AS patients may have gut inflammation when examined by colonoscopy, and SpA may be found in 1- 12% of patients with Crohn`s Disease and Ulcerative Colitis, with higher incidence of peripheral arthritis; sacroiliitis may occur asymptomatic or with typical symptoms. Reactive arthritis tends to be more aggressive and as a longer duration in HLA-B\*27 positive cases (50%). Asymmetrical acute peripheral arthritis, enthesitis, acute sacroiliitis, urogenital inflammation, and ocular manifestations are common and may last several months to two years. The importance of clinical measurements to evaluate pain, morning stiffness, and functional ability is well evaluated with the BASDAI and BASFI questionnaires. Several measurements may be used by the clinician, to check and control spinal function and flexibility.

Preface XI

anterior and posterior ligaments are more thoroughly ossified and resistant in the thoracic and lumbar spine. Shearing fractures are the most unstable type of fractures and serious complications are: severe neurological symptoms, haemothorax, or the rupture of the aorta. Standard radiographs are inadequate to evaluate shearing fractures due to osteoporosis and the position of the shoulders, and diagnosis may be difficult due to pre-existing spinal alterations. The approach to treatment depends on the type of injury, degree of spinal instability, and neurological status of the patient. The operative treatment of these injuries is effective. Stabilization of fractures is better performed with anterior and posterior support of the spine, but because of frequent associated cardiovascular and pulmonary morbidities, this approach is not always

The second section "*HLA and non-MHC genes, Immune Response, and Gene Expression Studies"* is dedicated to the molecular and immunological processes of AS. HLA-B\*27 is a unique HLA Class I molecule: anchoring peptides in the binding grove of B pocket must have an arginine at the P2, and the free thiol Cys67 residue made B\*27 easy to form homodimers in the extracellular domain. Twin studies suggest that the HLA-B\*27 accounts for more than 50% of AS susceptibility. Until July 2011, 82 subtypes were described based on nucleotide differences. HLA-B\*27:05 is the ancestral and most prevalent subtype in the majority of world populations. Several subtypes are clearly disease associated, but B\*27:06 and B\*27:09 have been reported not to be associated with AS and may have a protective role. According to some authors the level of B27 mRNA may correlate with disease activity and several theories have tried to explain the disease pathogenesis: molecular mimicry and arthritogenic peptides, free heavy chain, and unfolded protein response were

The second chapter in this section deals with the possibility that infectious agents may have an important role as triggering factors for some autoimmune diseases like AS. Previous work reported humoral immune responses to bacteria such as *Klebsiella pneumonia*, *Salmonella typhimurium, Shigella flexneri, Yersinia enterocolitica,* and *Campylobacter jejuni*. The authors reported that the 30 kDa band (p30) from *S. typhimurium* could be differentially recognized by the immune response in AS patients. In this chapter the authors have investigated whether the p30 antigen recognized by AS patients is specific to *S. typhimurium,* or if it can be found in another serovar of salmonella enterica. Twenty eight AS patients and 28 healthy controls were investigated to analyze the IgG and IgA humoral immune response against Salmonella enterica serovar enteritidis by western-blot. The immune response against *S. typhimurium* appears to be strain specific; patients with AS produce IgG3 antibodies against the p30 of *S. typhimurium* in contrast to healthy controls. The authors also hypothesized that the relationship between the humoral response and the pathogenesis of the disease could be due to Fc�R polymorphisms of IgG. The authors suggest a link between humoral immune response in a susceptible individual and

possible.

considered main streams of hypothesis.

Fc�RIII-150-VV.

The chapter on the incidence, clinical features, pathophysiology, signs, symptoms, and current management of the Temporomandibular Joint (TMJ), reviews how AS affects this joint. TMJ is involved in 4% to 32% of cases, and ranges from mild disease to ankylosis which is exceptional. The non-surgical treatment of TMJ in AS is the most effective way of managing over 80% of patients. Non-pharmacological treatment includes fabrication of intra oral splints, physiotherapy, and patient education. The pharmacological treatment includes NSAIDS, Coxibs, corticosteroids, and anti-TNF agents. The surgical treatment – injection of steroids, joint lavage and total joint replacement -, is indicated in patients with marked trismus, or in cases of the failure of other non-surgical therapies.

The third chapter in this section is dedicated to bone mineral density (BMD) changes in patients with SpA. BMD has been investigated mainly in patients with AS. The authors investigated BMD changes in AS and in other diseases belonging to the SpA group – ReA (Reactive Arthritis), PsA (Psoriatic Arthritis), EnA (Entheropathic Arthritis) - to assess the relationship between changes in BMD and specific diseaserelated variables like duration, physical disability and immobility, activity of the disease, and medications. The results were also compared with a group of patients with Rheumatoid Arthritis (RA) and healthy people. Several conclusions were obtained but possibly the most relevant are: 1) BMD was identical between patients with SpA and RA; 2) Similar changes were found in patients from the various SpA groups.

The fourth and last chapter in this section is dedicated to surgical treatment in patients with AS. Patients with AS may undergo a fracture with minimal or no history of trauma, and the fracture should be considered as a high-risk injury. New back pain in AS patients should be assumed to be caused by a fracture until proven otherwise. The cervical spine is the most frequent fracture site (75%, C6-C7 and C7-D1) because the anterior and posterior ligaments are more thoroughly ossified and resistant in the thoracic and lumbar spine. Shearing fractures are the most unstable type of fractures and serious complications are: severe neurological symptoms, haemothorax, or the rupture of the aorta. Standard radiographs are inadequate to evaluate shearing fractures due to osteoporosis and the position of the shoulders, and diagnosis may be difficult due to pre-existing spinal alterations. The approach to treatment depends on the type of injury, degree of spinal instability, and neurological status of the patient. The operative treatment of these injuries is effective. Stabilization of fractures is better performed with anterior and posterior support of the spine, but because of frequent associated cardiovascular and pulmonary morbidities, this approach is not always possible.

X Preface

and control spinal function and flexibility.

other non-surgical therapies.

groups.

involvement of these joints may be an indicator of a more aggressive disease. Extraarticular manifestations are quite common in AS, namely enthesitis, acute anterior uveitis (AUU), cardiac involvement, pulmonary fibrosis, and secondary renal amyloidosis. Psoriatic arthritis has several subgroups and the sub-classification of this disease may be difficult even for the rheumatologist. Up to 50% of AS patients may have gut inflammation when examined by colonoscopy, and SpA may be found in 1- 12% of patients with Crohn`s Disease and Ulcerative Colitis, with higher incidence of peripheral arthritis; sacroiliitis may occur asymptomatic or with typical symptoms. Reactive arthritis tends to be more aggressive and as a longer duration in HLA-B\*27 positive cases (50%). Asymmetrical acute peripheral arthritis, enthesitis, acute sacroiliitis, urogenital inflammation, and ocular manifestations are common and may last several months to two years. The importance of clinical measurements to evaluate pain, morning stiffness, and functional ability is well evaluated with the BASDAI and BASFI questionnaires. Several measurements may be used by the clinician, to check

The chapter on the incidence, clinical features, pathophysiology, signs, symptoms, and current management of the Temporomandibular Joint (TMJ), reviews how AS affects this joint. TMJ is involved in 4% to 32% of cases, and ranges from mild disease to ankylosis which is exceptional. The non-surgical treatment of TMJ in AS is the most effective way of managing over 80% of patients. Non-pharmacological treatment includes fabrication of intra oral splints, physiotherapy, and patient education. The pharmacological treatment includes NSAIDS, Coxibs, corticosteroids, and anti-TNF agents. The surgical treatment – injection of steroids, joint lavage and total joint replacement -, is indicated in patients with marked trismus, or in cases of the failure of

The third chapter in this section is dedicated to bone mineral density (BMD) changes in patients with SpA. BMD has been investigated mainly in patients with AS. The authors investigated BMD changes in AS and in other diseases belonging to the SpA group – ReA (Reactive Arthritis), PsA (Psoriatic Arthritis), EnA (Entheropathic Arthritis) - to assess the relationship between changes in BMD and specific diseaserelated variables like duration, physical disability and immobility, activity of the disease, and medications. The results were also compared with a group of patients with Rheumatoid Arthritis (RA) and healthy people. Several conclusions were obtained but possibly the most relevant are: 1) BMD was identical between patients with SpA and RA; 2) Similar changes were found in patients from the various SpA

The fourth and last chapter in this section is dedicated to surgical treatment in patients with AS. Patients with AS may undergo a fracture with minimal or no history of trauma, and the fracture should be considered as a high-risk injury. New back pain in AS patients should be assumed to be caused by a fracture until proven otherwise. The cervical spine is the most frequent fracture site (75%, C6-C7 and C7-D1) because the The second section "*HLA and non-MHC genes, Immune Response, and Gene Expression Studies"* is dedicated to the molecular and immunological processes of AS. HLA-B\*27 is a unique HLA Class I molecule: anchoring peptides in the binding grove of B pocket must have an arginine at the P2, and the free thiol Cys67 residue made B\*27 easy to form homodimers in the extracellular domain. Twin studies suggest that the HLA-B\*27 accounts for more than 50% of AS susceptibility. Until July 2011, 82 subtypes were described based on nucleotide differences. HLA-B\*27:05 is the ancestral and most prevalent subtype in the majority of world populations. Several subtypes are clearly disease associated, but B\*27:06 and B\*27:09 have been reported not to be associated with AS and may have a protective role. According to some authors the level of B27 mRNA may correlate with disease activity and several theories have tried to explain the disease pathogenesis: molecular mimicry and arthritogenic peptides, free heavy chain, and unfolded protein response were considered main streams of hypothesis.

The second chapter in this section deals with the possibility that infectious agents may have an important role as triggering factors for some autoimmune diseases like AS. Previous work reported humoral immune responses to bacteria such as *Klebsiella pneumonia*, *Salmonella typhimurium, Shigella flexneri, Yersinia enterocolitica,* and *Campylobacter jejuni*. The authors reported that the 30 kDa band (p30) from *S. typhimurium* could be differentially recognized by the immune response in AS patients. In this chapter the authors have investigated whether the p30 antigen recognized by AS patients is specific to *S. typhimurium,* or if it can be found in another serovar of salmonella enterica. Twenty eight AS patients and 28 healthy controls were investigated to analyze the IgG and IgA humoral immune response against Salmonella enterica serovar enteritidis by western-blot. The immune response against *S. typhimurium* appears to be strain specific; patients with AS produce IgG3 antibodies against the p30 of *S. typhimurium* in contrast to healthy controls. The authors also hypothesized that the relationship between the humoral response and the pathogenesis of the disease could be due to Fc�R polymorphisms of IgG. The authors suggest a link between humoral immune response in a susceptible individual and Fc�RIII-150-VV.

Other HLA genes have been associated with AS susceptibility, like HLA-B\*60 and HLA-DRB1 alleles. A recent publication involving a Spanish/Portuguese cohort reports the association with HLA-DPA1 and HLA-DPB1 alleles and AS. GWAS supported the presence of non-MHC susceptibility genes and further studies narrow down the chromosome areas first identified. ERAP1 (5q15) and IL23R (1p31.3) are the most consistently non-MHC associated genes to AS. ERAP1 is a MHC class I dependent aminopeptidase, and plays a major role in peptide trimming for presentation at the cell surface. Recently it was shown that HLA-B\*27 positive and negative AS cases differ in association with ERAP1, suggesting that the mechanism by which B\*27 induces AS involves aberrant presentation or handling of peptides. IL23R is a member of the haemopoietin receptor family, and genetic variants of this gene have been reported in association with other autoimmune diseases such as inflammatory bowel disease (IBD), psoriasis, and systemic sclerosis. The association of several IL23R SNPs with AS was first reported by the Consortium WTCCC/TASC in 2007 and, since then, it has been replicated in several populations. The attributable risk for this gene was calculated to be 9%. KIF21B belongs to a family of kinesin motor proteins and was recently found with a strong association to AS in caucasians. Several other genes are suggestively associated with the AS: IL-1 gene cluster, ANTXR2, TNFSF15, TNFRSF1A, and TRADD.

Preface XIII

**Dr Jacome Bruges-Armas** 

Portugal

Hospital of the Holy Spirit, The Azores,

I am very grateful to all authors for their contribution to this textbook. I sincerely hope that this volume *Clinical and Molecular Advances in Ankylosing Spondylitis* may help to clarify some aspects of the disease contributing to a better understanding of AS

pathogenesis.

The last chapter of this book explains the recent advances in molecular biology using microarray-based genotyping and expressing assays which are ideal to investigate diseases with underlying complex genetic causes. Microarray expression technology, together with the most recent bioinformatics platforms, can be used for the detection and quantification of differentially expressed genes but, according to the authors, the success of the experiences greatly depends on whether the hypothesis and rationale have been formulated through a clearly delineated question. Although significant inter-individual variations on gene expression may occur, recent studies have been focused on the investigation of gene expression patterns in peripheral blood to identify systemic markers of the disease. Seven papers published since 2007 uncovered pathways and potential biomarkers which may be useful for diagnosis and treatment prediction on SpA. Consistent expression changes in genes such as TLRs, NLRP2 and CLEC4D supports the importance of innate immune mechanisms in AS pathogenesis. Other expression profiles include a pro-inflammatory signature in uSpA and AS, a decreased immune responsiveness and immunosuppressive phenotypes, and two bone remodeling signatures with over-expression of PCSK6, FREMEN1, and catenin alpha-like 1 (CTNNAL1) genes in SpA patients or downregulation of SPOCK2, EP300 and PPP2R1A in AS patients, which are possible mediators in the ossification process. A promising biomarker for early diagnostic of SpA is a member of the family of regulators of G protein signaling (RGS1), although not confirmed in all studies to date. The identification of biomarkers of treatment response to biologic therapies may enable the more appropriate therapy to be chosen, contributing to a patient-specific personalized medicine. LIGHT, RUNX2, and the CX3CL1-CC3CR1 complex may be considered for treatment response in SpA patients.

Preface XIII

I am very grateful to all authors for their contribution to this textbook. I sincerely hope that this volume *Clinical and Molecular Advances in Ankylosing Spondylitis* may help to clarify some aspects of the disease contributing to a better understanding of AS pathogenesis.

XII Preface

TNFSF15, TNFRSF1A, and TRADD.

considered for treatment response in SpA patients.

Other HLA genes have been associated with AS susceptibility, like HLA-B\*60 and HLA-DRB1 alleles. A recent publication involving a Spanish/Portuguese cohort reports the association with HLA-DPA1 and HLA-DPB1 alleles and AS. GWAS supported the presence of non-MHC susceptibility genes and further studies narrow down the chromosome areas first identified. ERAP1 (5q15) and IL23R (1p31.3) are the most consistently non-MHC associated genes to AS. ERAP1 is a MHC class I dependent aminopeptidase, and plays a major role in peptide trimming for presentation at the cell surface. Recently it was shown that HLA-B\*27 positive and negative AS cases differ in association with ERAP1, suggesting that the mechanism by which B\*27 induces AS involves aberrant presentation or handling of peptides. IL23R is a member of the haemopoietin receptor family, and genetic variants of this gene have been reported in association with other autoimmune diseases such as inflammatory bowel disease (IBD), psoriasis, and systemic sclerosis. The association of several IL23R SNPs with AS was first reported by the Consortium WTCCC/TASC in 2007 and, since then, it has been replicated in several populations. The attributable risk for this gene was calculated to be 9%. KIF21B belongs to a family of kinesin motor proteins and was recently found with a strong association to AS in caucasians. Several other genes are suggestively associated with the AS: IL-1 gene cluster, ANTXR2,

The last chapter of this book explains the recent advances in molecular biology using microarray-based genotyping and expressing assays which are ideal to investigate diseases with underlying complex genetic causes. Microarray expression technology, together with the most recent bioinformatics platforms, can be used for the detection and quantification of differentially expressed genes but, according to the authors, the success of the experiences greatly depends on whether the hypothesis and rationale have been formulated through a clearly delineated question. Although significant inter-individual variations on gene expression may occur, recent studies have been focused on the investigation of gene expression patterns in peripheral blood to identify systemic markers of the disease. Seven papers published since 2007 uncovered pathways and potential biomarkers which may be useful for diagnosis and treatment prediction on SpA. Consistent expression changes in genes such as TLRs, NLRP2 and CLEC4D supports the importance of innate immune mechanisms in AS pathogenesis. Other expression profiles include a pro-inflammatory signature in uSpA and AS, a decreased immune responsiveness and immunosuppressive phenotypes, and two bone remodeling signatures with over-expression of PCSK6, FREMEN1, and catenin alpha-like 1 (CTNNAL1) genes in SpA patients or downregulation of SPOCK2, EP300 and PPP2R1A in AS patients, which are possible mediators in the ossification process. A promising biomarker for early diagnostic of SpA is a member of the family of regulators of G protein signaling (RGS1), although not confirmed in all studies to date. The identification of biomarkers of treatment response to biologic therapies may enable the more appropriate therapy to be chosen, contributing to a patient-specific personalized medicine. LIGHT, RUNX2, and the CX3CL1-CC3CR1 complex may be

**Dr Jacome Bruges-Armas**  Hospital of the Holy Spirit, The Azores, Portugal

**Part 1** 

**Clinical Manifestations, Bone Density** 

**Measurements and Axial Fractures Treatment** 

## **Part 1**

**Clinical Manifestations, Bone Density Measurements and Axial Fractures Treatment** 

**1** 

Jeanette Wolf

*Wilhelminenspital* 

*Vienna Austria* 

*5th Dep. of Inner Medicine* 

**Clinical Features of Ankylosing Spondylitis** 

Ankylosing spondylitis is an inflammatory rheumatic disease, its cause is yet unknown, a cross-reactivity of antibodies against germs and HLA-B27 is discussed, but not yet proven. Ankylosing spondylitis belongs to the group of seronegative spondyloarthritides (Moll J, Haslock I, Mac Rae IF, Wright V) (Wright V), there is a strong linkage to HLA-B27. Its prevalence lies between 0.1% and 1% with a male predominance of 2-3: 1, the onset of disease lies between 20 and 40 years, very seldom above the age of 45 (Wolf J, Fasching P). So women are less frequently concerned, and the illness tends to take a milder course (Sieper J, Braun J, Rudwaleit M, Boonen A, Zink A) (Gladman DD). On the other hand this puts women to a disadvantage, as the disease is less easily detected, leading to an even

General symptoms include morning stiffness of more than 60 minutes, fatigue, sometimes even slightly elevated temperature, but the main initial symptom is low back pain at night and in the morning. All patients with low back pain should be questioned about a positive family history concerning rheumatic diseases, as the risk of developing this illness is higher in patients where family members already have been diagnosed with ankylosing spondylitis. This of course suggests a certain genetic disposition, especially if HLA-B27 is

As a systemic inflammatory disease it is not restricted to a single organ or part of the body.

The first symptoms of this disease are usually a low back pain with its peak at night and in the morning and morning stiffness, which can last for hours. Both symptoms get better with exercise, back pain can worsen with inactivity. Some patients show only a partial involvement of the spine, in others the whole spine is involved. The physician always should examine the patient´s back by patting it gently with one fist, starting at the cervical spine all the way down to the sacrum, asking the patient, if and which part of the spine is

The disease is caused by chronic inflammation of the spinal joints and entheses, proliferative synovitis and central cartilage fusion, which can lead to total destruction and ankylosis of

The following subchapters will deal with the different manifestations of this disease.

**1. Introduction** 

**2. Spinal manifestations** 

painful during this examination.

longer interval between disease onset and treatment.

involved (Van der Linden SM, Valkenburg HA, De Jongh BM, Cats A).

### **Clinical Features of Ankylosing Spondylitis**

#### Jeanette Wolf

*5th Dep. of Inner Medicine Wilhelminenspital Vienna Austria* 

#### **1. Introduction**

Ankylosing spondylitis is an inflammatory rheumatic disease, its cause is yet unknown, a cross-reactivity of antibodies against germs and HLA-B27 is discussed, but not yet proven. Ankylosing spondylitis belongs to the group of seronegative spondyloarthritides (Moll J, Haslock I, Mac Rae IF, Wright V) (Wright V), there is a strong linkage to HLA-B27. Its prevalence lies between 0.1% and 1% with a male predominance of 2-3: 1, the onset of disease lies between 20 and 40 years, very seldom above the age of 45 (Wolf J, Fasching P). So women are less frequently concerned, and the illness tends to take a milder course (Sieper J, Braun J, Rudwaleit M, Boonen A, Zink A) (Gladman DD). On the other hand this puts women to a disadvantage, as the disease is less easily detected, leading to an even longer interval between disease onset and treatment.

General symptoms include morning stiffness of more than 60 minutes, fatigue, sometimes even slightly elevated temperature, but the main initial symptom is low back pain at night and in the morning. All patients with low back pain should be questioned about a positive family history concerning rheumatic diseases, as the risk of developing this illness is higher in patients where family members already have been diagnosed with ankylosing spondylitis. This of course suggests a certain genetic disposition, especially if HLA-B27 is involved (Van der Linden SM, Valkenburg HA, De Jongh BM, Cats A).

As a systemic inflammatory disease it is not restricted to a single organ or part of the body. The following subchapters will deal with the different manifestations of this disease.

#### **2. Spinal manifestations**

The first symptoms of this disease are usually a low back pain with its peak at night and in the morning and morning stiffness, which can last for hours. Both symptoms get better with exercise, back pain can worsen with inactivity. Some patients show only a partial involvement of the spine, in others the whole spine is involved. The physician always should examine the patient´s back by patting it gently with one fist, starting at the cervical spine all the way down to the sacrum, asking the patient, if and which part of the spine is painful during this examination.

The disease is caused by chronic inflammation of the spinal joints and entheses, proliferative synovitis and central cartilage fusion, which can lead to total destruction and ankylosis of

Clinical Features of Ankylosing Spondylitis 5

Fig. 1. Syndesmophytes.

these joints. Fibroblast proliferation on the other hand leads to increased ossification creating syndesmophytes (Figure 1) between the vertebral bodies and later on bamboo spine (Figure 2). These cause an irreversible loss of spinal flexibility and movement, resulting in the typical habitus still to be seen in older patients with a long disease duration due to significantly enhanced kyphosis of the thoracic part of the spine and loss of lordosis of the lumbal spine, finally making it impossible for the patient to bend any part of his spine.

Inflammation can also be found in the intervertebral disks resulting in discitis and spondylitis, which can be seen as narrowing of the intervertebral space and destruction of the adjacent cover plates. Seldom synovitis and osteitis can be found in the atlantoaxial area leading to erosions and destruction of the lateral atlantoaxial joint. At the worst the joint is destabilized, this may cause cord compression and neurological loss of function.

The costovertebral and costotransverse joints are quite commonly affected, being causal to reduced chest expansion and decreased vital capacity of the lungs.

In some patients ankylosing spondylitis is restricted exclusively to an affection of the sacroiliac articulation (sacroiliitis), best shown by MRI, as it causes bone marrow edema and cartilage changes. X-ray takes a long time to reveal this arthritis, because there only bone destruction and ankylosis are visible, these are not seen in the early stages of the disease. In the end sacroiliitis can lead to total destruction and ankylosis of the sacroiliacal joint, then of course it is clearly visible in x-ray (Figure 3). Active sacroiliitis can lead to local pressure pain and pain associated with movements of the pelvis.

Finally kyphosis of the thoracic spine, obliteration of the lumbal lordosis and forward stoop of the neck occur, these signs are irreversible. Due to osteoporosis even minor trauma may result in spinal fractures, causing a rapid and significant increase in pain. Fracture fragments can be dislocated and lead to cord compression.

#### **3. Peripheral joints**

Almost half of the patients experience arthritis in the hips or the shoulders. Up to 30% of the patients suffer from small joint involvement with swelling, pain and stiffness in the inflamed joints. Often these appear as asymmetrical oligoarthritis. Usually they are nonerosive, but deformity and consequently destruction of the hips have been seen. An early involvement of peripheral joints can be an indicator of a more aggressive progress. Peripheral joint involvement can occur at any stage of the disease (Sieper J, Braun J, Rudwaleit M, Boonen A, Zink A) (Gladman DD).

#### **4. Extra- articular manifestations**

Quite common there is an involvement of the enthesis, meaning the insertion of tendons, ligaments and capsules into the bone. These inflammatory changes are referred to as enthesitis (Francois RJ, Braun J, Khan MA). Any enthesis may be concerned, but most frequently an enthesitis of the Achilles tendon is found. Enthesitis causes pain, swelling and thickening as well as loss of function, it can occur all of a sudden, but is found quite often as a chronic inflammation, which can finally lead to rupture of the tendon. Arthritis of the adjacent joint has also been described, enthesitis is presumed to be the starting point of joint inflammation (McGonagle D, Gibbon W, Emery P)

these joints. Fibroblast proliferation on the other hand leads to increased ossification creating syndesmophytes (Figure 1) between the vertebral bodies and later on bamboo spine (Figure 2). These cause an irreversible loss of spinal flexibility and movement, resulting in the typical habitus still to be seen in older patients with a long disease duration due to significantly enhanced kyphosis of the thoracic part of the spine and loss of lordosis of the lumbal spine, finally making it impossible for the patient to bend any part of his spine.

Inflammation can also be found in the intervertebral disks resulting in discitis and spondylitis, which can be seen as narrowing of the intervertebral space and destruction of the adjacent cover plates. Seldom synovitis and osteitis can be found in the atlantoaxial area leading to erosions and destruction of the lateral atlantoaxial joint. At the worst the joint is

The costovertebral and costotransverse joints are quite commonly affected, being causal to

In some patients ankylosing spondylitis is restricted exclusively to an affection of the sacroiliac articulation (sacroiliitis), best shown by MRI, as it causes bone marrow edema and cartilage changes. X-ray takes a long time to reveal this arthritis, because there only bone destruction and ankylosis are visible, these are not seen in the early stages of the disease. In the end sacroiliitis can lead to total destruction and ankylosis of the sacroiliacal joint, then of course it is clearly visible in x-ray (Figure 3). Active sacroiliitis can lead to local pressure

Finally kyphosis of the thoracic spine, obliteration of the lumbal lordosis and forward stoop of the neck occur, these signs are irreversible. Due to osteoporosis even minor trauma may result in spinal fractures, causing a rapid and significant increase in pain. Fracture

Almost half of the patients experience arthritis in the hips or the shoulders. Up to 30% of the patients suffer from small joint involvement with swelling, pain and stiffness in the inflamed joints. Often these appear as asymmetrical oligoarthritis. Usually they are nonerosive, but deformity and consequently destruction of the hips have been seen. An early involvement of peripheral joints can be an indicator of a more aggressive progress. Peripheral joint involvement can occur at any stage of the disease (Sieper J, Braun J,

Quite common there is an involvement of the enthesis, meaning the insertion of tendons, ligaments and capsules into the bone. These inflammatory changes are referred to as enthesitis (Francois RJ, Braun J, Khan MA). Any enthesis may be concerned, but most frequently an enthesitis of the Achilles tendon is found. Enthesitis causes pain, swelling and thickening as well as loss of function, it can occur all of a sudden, but is found quite often as a chronic inflammation, which can finally lead to rupture of the tendon. Arthritis of the adjacent joint has also been described, enthesitis is presumed to be the starting point of joint

destabilized, this may cause cord compression and neurological loss of function.

reduced chest expansion and decreased vital capacity of the lungs.

pain and pain associated with movements of the pelvis.

fragments can be dislocated and lead to cord compression.

Rudwaleit M, Boonen A, Zink A) (Gladman DD).

inflammation (McGonagle D, Gibbon W, Emery P)

**4. Extra- articular manifestations** 

**3. Peripheral joints** 

Fig. 1. Syndesmophytes.

Clinical Features of Ankylosing Spondylitis 7

Up to 40% of all patients suffer from acute anterior uveitis at least once in their lifetime (Rosenbaum JT). Uveitis occurs usually unilateral, symptoms include pain, redness, reduced sight, photophobia, grittiness, myosis and increased lacrimation. It is self-limiting, but tends to reoccur. Untreated it may lead to complications like synechia and cataract. Patients have to be advised to see a doctor immediately after onset of the above mentioned symptoms.

Another extra-articular manifestation is aortitis and/or aortic regurgitation. Approximately 9% of ankylosing spondylitis patients are concerned. Aortitis can be seen in echocardiography showing thickening of the aortic wall and dilatation of the aortic root, thickening of the aortic valves causing aortic insufficiency (2-10% of the patients). 1-9% acquire a complete heart block, mainly located in the atrioventricular node (Bergfeldt L).

The lungs are usually only concerned indirectly because of involvement of the costovertebral and costotransverse joints and therefore reduction of chest expansion leading to reduced vital capacity. This can be detected by pulmonary function testing. But pulmonary participation like upper lobe fibrosis and pleural thickening has been described, these can be detected by high-resolution computed tomography (Maghraoui AE, Chaouir S, Abid A et al) (Souza AS, Muller NL, Marchiori E, Soares-Souza LV). These findings are

4-9% of the patients develop a secondary renal amyloidosis as part of the autoimmune disease, yet primarily, renal involvement is rather uncommon in ankylosing spondylitis. Renal amyloidosis may occur in patients with long disease duration (Nabokov AV,

Due to chronic pain, patients with ankylosing spondylitis often depend upon painkillers. Especially non-steroidal anti-inflammatory drugs (NSAIDs) are prescribed, as these agents

usually clinically asymptomatic, yet fibrosis tends to progress over time.

Fig. 3. Ankylosis caused by sacroiliits.

Shabunin MA, Smirnov AV).

Fig 2. Bamboo stick.

Fig 2. Bamboo stick.

Fig. 3. Ankylosis caused by sacroiliits.

Up to 40% of all patients suffer from acute anterior uveitis at least once in their lifetime (Rosenbaum JT). Uveitis occurs usually unilateral, symptoms include pain, redness, reduced sight, photophobia, grittiness, myosis and increased lacrimation. It is self-limiting, but tends to reoccur. Untreated it may lead to complications like synechia and cataract. Patients have to be advised to see a doctor immediately after onset of the above mentioned symptoms.

Another extra-articular manifestation is aortitis and/or aortic regurgitation. Approximately 9% of ankylosing spondylitis patients are concerned. Aortitis can be seen in echocardiography showing thickening of the aortic wall and dilatation of the aortic root, thickening of the aortic valves causing aortic insufficiency (2-10% of the patients). 1-9% acquire a complete heart block, mainly located in the atrioventricular node (Bergfeldt L).

The lungs are usually only concerned indirectly because of involvement of the costovertebral and costotransverse joints and therefore reduction of chest expansion leading to reduced vital capacity. This can be detected by pulmonary function testing. But pulmonary participation like upper lobe fibrosis and pleural thickening has been described, these can be detected by high-resolution computed tomography (Maghraoui AE, Chaouir S, Abid A et al) (Souza AS, Muller NL, Marchiori E, Soares-Souza LV). These findings are usually clinically asymptomatic, yet fibrosis tends to progress over time.

4-9% of the patients develop a secondary renal amyloidosis as part of the autoimmune disease, yet primarily, renal involvement is rather uncommon in ankylosing spondylitis. Renal amyloidosis may occur in patients with long disease duration (Nabokov AV, Shabunin MA, Smirnov AV).

Due to chronic pain, patients with ankylosing spondylitis often depend upon painkillers. Especially non-steroidal anti-inflammatory drugs (NSAIDs) are prescribed, as these agents

Clinical Features of Ankylosing Spondylitis 9

Neurological symptoms are caused by complications of long-ongoing disease. Due to osteoporosis spinal fractures may occur, leading to suddenly increasing back pain in the afflicted region. If a fracture fragment is dislocated, it may injure the spinal cord and subsequently cause neurological symptoms. The cauda equina syndrome is evoked by dural ectasia, usually a late manifestation of the illness (Ahn NU, Ahn UM, Nallamshetty L, Springer BD, Buchowski JM), leading to sensory and / or motor loss of function and finally sphincter dysfunction. Patients may also develop pain in the rectum or the lower limbs. Atlantoaxial subluxation on the other hand may cause neurological symptoms in one or both arms. 2% of all patients with ankylosing spondylitis are concerned, but not all of them show signs of cord compression (Chou LW, Lo SF, Kao MJ, Jim YF, Cho DY). Subluxation may be caused by transverse or posterior longitudinal ligament damage or local atlantodental synovitis as well as somatic stress caused by increased kyphosis of the cervical

**6. Ankylosing spondylitis and other seronegative spondyloarthritides** 

peripheral arthritis caused by ankylosing spondylitis.

Ankylosing spondylitis belongs to the group of seronegative spondyloarthritides together with psoriatic arthritis, reactive arthritis and unspecified spondyloarthritis. They all lack rheumatoid factor, thus being seronegative. Ankylosing spondylitis has also been seen in combination with psoriatic arthritis or enteropathic arthropathies like Crohn´s Disease and

Peripheral asymmetrical arthritis is seen in approximately 50% of patients with psoriatic arthritis. As this disease can also include axial manifestations, a thorough skin examination has to be done in any patient with low back pain. 20 to 40% of patients with psoriatic arthritis suffer from sacroiliitis (Gladman DD, Shuckett R, Russell ML et al) (Torre Alonso JC, Rodriguez Perez A, Arribas Castrillo JM et al). There is also a tendency of cervical spine involvement and asymmetrical affliction (Jenkinson T, Armas J, Evison G et al). Psoriatic arthritis can cause monoarthritis, dactylitis, asymmetrical oligoarthritis and enthesitis, up to 25% of patients with psoriatic arthritis are HLA-B27 positive, but in patients with spinal inflammation up to 70% are HLA-B27 positive. On the other hand, there are patients who show no or only minimal skin affection at the onset of arthritis, making it even more difficult to find the right diagnosis. The transition between these two diseases is gradual and can differ greatly between two individuals. Some patients show definite signs and symptoms of ankylosing spondylitis with only marginal involvement of the skin and peripheral joints, others mainly present skin and joint affections with only little back pain. In these cases, it is quite easy to diagnose ankylosing spondylitis in combination with psoriasis or psoriatic arthritis with axial manifestations. But other individuals are not as easily diagnosed, especially if all symptoms are equally strong or weak or if there is no skin involvement at all. So sometimes it can be difficult even for the rheumatologist to differentiate between these two diseases. Yet this is of importance concerning the choice of treatment: while psoriatic arthritis can be treated with Disease Modifying Anti-Rheumatic Drugs (DMARDs) like Methotrexate or Leflunomide, these agents have no effect on

Spondyloarthritis can be found in both Crohn´s Disease and ulcerative colitis. The incidence lies at 1-12%. Up to 50% of the patients also develop peripheral arthritis. Both are autoimmune diseases, yet the pathogenesis is still largely unclear. Peripheral arthritis can

spine.

ulcerative colitis.

reduce pain, but also inflammation itself. Long-term intake of this medication is generally recommended, as trials have shown a significantly better effect on pain in comparison to placebo (Dougados M, Dijkmans B, Kan M, Maksymowych W, Van der Linden S, Brandt J) (Van der Heijde D, Baraf HS, Ramos-Remus C et al). Some studies even reported a decrease of spinal ossification, if the drug was taken on a regular basis (Boersma JW) (Wanders A, Van der Heijde D, Landewe R et al). On the other hand, NSAID induced nephropathy can occur in older patients with a longer disease duration and after several weeks or months of NSAID use, independent of the primal medical cause for painkillers. NSAIDs have to be discontinued in these cases. However, renal parameters should be checked on a regular basis in all patients with ankylosing spondylitis.

In up to half of the patients osteoporosis can be found, yet DEXA can be falsified by syndesmophytes, creating the impression of a higher bone density. Bone fracture caused by even minor traumatic events can lead to a sudden increase of pain. The same applies to fractures of the syndesmophytes themselves. Most frequently fractures of the cervical spine are observed, followed by the thoracolumbar region (Feldtkeller E, Vosse D, Geusens P, Van der Linden S). Osteoporosis may be induced by an imbalance between osteoblasts and osteoclasts in favour of the osteoclasts (Obermayer-Pietsch BM, Lange U, Tauber G et al). Decreased mobility may also play its part in the development of osteoporosis.

#### **5. Disease impact**

Fatigue and sleeping disorders are quite common in patients with ankylosing spondylitis (Jones SD, Koh WH, Steiner A, Garrett SL, Calin A) (Hultgren S, Broma JE, Gudbjornsson B, Hetta J, Lindqvist U), they can even lead to depression (Barlow JH, Macey SJ, Struthers GR) as well as reduced fitness and working capacity. Fatigue is a typical symptom of ankylosing spondylitis, therefore it has been included in the BASDAI, a patient´s questionnaire (Garrett S, Jenkinson T, Kennedy LG, Whitelock H, Gaisford P, Calin A). It seems to correlate with disease activity (Günaydin R, Göksel Karatepe A, Cesmeli N, Kaya T) and aggravates the difficulties patients already experience in daily life activities due to pain and reduced mobility. Sleep disturbance is caused by low back pain that typically begins at night and keeps the patient from having a restful sleep, but also by depression and anxiety. The combination of chronic disease, chronic pain and ensuing disability can lead to depression, for the patient is no longer able to perform activities of daily life the way he or she wishes to and may not be able to work full-time or even fears to lose his or her job because of reduced mobility and flexibility. Ankylosing spondylitis has a highly individual disease course and duration, some patients show only minor symptoms and restrictions, while others suffer very badly. Work disability is higher in patients with longer disease duration, inflammation of peripheral joints, lower level of education, high pain levels and physically straining jobs. Patients with long disease duration and difficult to treat back pain are more prone to develop depression than patients with no or only light pain and symptoms (Baysal O, Durmus B, Ersoy Y, Altay Z, Senel K, Nas K, Ugur M, Kaya A, Gür A, Erdal A, Ardicoglu O, Tekeoglu I Cevik R, Yildirim K, Kamnli A, Sarac AJ, Karatay S Ozgocmen S). The degree of disease activity also seems to correlate with anxiety and health status. Patients with higher disease activity scores were more anxious and more depressed (Martindale J, Smith J, Sutton CJ, Grennan D, Goodacre L, Goodacre JA).

reduce pain, but also inflammation itself. Long-term intake of this medication is generally recommended, as trials have shown a significantly better effect on pain in comparison to placebo (Dougados M, Dijkmans B, Kan M, Maksymowych W, Van der Linden S, Brandt J) (Van der Heijde D, Baraf HS, Ramos-Remus C et al). Some studies even reported a decrease of spinal ossification, if the drug was taken on a regular basis (Boersma JW) (Wanders A, Van der Heijde D, Landewe R et al). On the other hand, NSAID induced nephropathy can occur in older patients with a longer disease duration and after several weeks or months of NSAID use, independent of the primal medical cause for painkillers. NSAIDs have to be discontinued in these cases. However, renal parameters should be checked on a regular

In up to half of the patients osteoporosis can be found, yet DEXA can be falsified by syndesmophytes, creating the impression of a higher bone density. Bone fracture caused by even minor traumatic events can lead to a sudden increase of pain. The same applies to fractures of the syndesmophytes themselves. Most frequently fractures of the cervical spine are observed, followed by the thoracolumbar region (Feldtkeller E, Vosse D, Geusens P, Van der Linden S). Osteoporosis may be induced by an imbalance between osteoblasts and osteoclasts in favour of the osteoclasts (Obermayer-Pietsch BM, Lange U, Tauber G et al).

Fatigue and sleeping disorders are quite common in patients with ankylosing spondylitis (Jones SD, Koh WH, Steiner A, Garrett SL, Calin A) (Hultgren S, Broma JE, Gudbjornsson B, Hetta J, Lindqvist U), they can even lead to depression (Barlow JH, Macey SJ, Struthers GR) as well as reduced fitness and working capacity. Fatigue is a typical symptom of ankylosing spondylitis, therefore it has been included in the BASDAI, a patient´s questionnaire (Garrett S, Jenkinson T, Kennedy LG, Whitelock H, Gaisford P, Calin A). It seems to correlate with disease activity (Günaydin R, Göksel Karatepe A, Cesmeli N, Kaya T) and aggravates the difficulties patients already experience in daily life activities due to pain and reduced mobility. Sleep disturbance is caused by low back pain that typically begins at night and keeps the patient from having a restful sleep, but also by depression and anxiety. The combination of chronic disease, chronic pain and ensuing disability can lead to depression, for the patient is no longer able to perform activities of daily life the way he or she wishes to and may not be able to work full-time or even fears to lose his or her job because of reduced mobility and flexibility. Ankylosing spondylitis has a highly individual disease course and duration, some patients show only minor symptoms and restrictions, while others suffer very badly. Work disability is higher in patients with longer disease duration, inflammation of peripheral joints, lower level of education, high pain levels and physically straining jobs. Patients with long disease duration and difficult to treat back pain are more prone to develop depression than patients with no or only light pain and symptoms (Baysal O, Durmus B, Ersoy Y, Altay Z, Senel K, Nas K, Ugur M, Kaya A, Gür A, Erdal A, Ardicoglu O, Tekeoglu I Cevik R, Yildirim K, Kamnli A, Sarac AJ, Karatay S Ozgocmen S). The degree of disease activity also seems to correlate with anxiety and health status. Patients with higher disease activity scores were more anxious and more depressed (Martindale J, Smith J, Sutton

Decreased mobility may also play its part in the development of osteoporosis.

basis in all patients with ankylosing spondylitis.

CJ, Grennan D, Goodacre L, Goodacre JA).

**5. Disease impact** 

Neurological symptoms are caused by complications of long-ongoing disease. Due to osteoporosis spinal fractures may occur, leading to suddenly increasing back pain in the afflicted region. If a fracture fragment is dislocated, it may injure the spinal cord and subsequently cause neurological symptoms. The cauda equina syndrome is evoked by dural ectasia, usually a late manifestation of the illness (Ahn NU, Ahn UM, Nallamshetty L, Springer BD, Buchowski JM), leading to sensory and / or motor loss of function and finally sphincter dysfunction. Patients may also develop pain in the rectum or the lower limbs. Atlantoaxial subluxation on the other hand may cause neurological symptoms in one or both arms. 2% of all patients with ankylosing spondylitis are concerned, but not all of them show signs of cord compression (Chou LW, Lo SF, Kao MJ, Jim YF, Cho DY). Subluxation may be caused by transverse or posterior longitudinal ligament damage or local atlantodental synovitis as well as somatic stress caused by increased kyphosis of the cervical spine.

#### **6. Ankylosing spondylitis and other seronegative spondyloarthritides**

Ankylosing spondylitis belongs to the group of seronegative spondyloarthritides together with psoriatic arthritis, reactive arthritis and unspecified spondyloarthritis. They all lack rheumatoid factor, thus being seronegative. Ankylosing spondylitis has also been seen in combination with psoriatic arthritis or enteropathic arthropathies like Crohn´s Disease and ulcerative colitis.

Peripheral asymmetrical arthritis is seen in approximately 50% of patients with psoriatic arthritis. As this disease can also include axial manifestations, a thorough skin examination has to be done in any patient with low back pain. 20 to 40% of patients with psoriatic arthritis suffer from sacroiliitis (Gladman DD, Shuckett R, Russell ML et al) (Torre Alonso JC, Rodriguez Perez A, Arribas Castrillo JM et al). There is also a tendency of cervical spine involvement and asymmetrical affliction (Jenkinson T, Armas J, Evison G et al). Psoriatic arthritis can cause monoarthritis, dactylitis, asymmetrical oligoarthritis and enthesitis, up to 25% of patients with psoriatic arthritis are HLA-B27 positive, but in patients with spinal inflammation up to 70% are HLA-B27 positive. On the other hand, there are patients who show no or only minimal skin affection at the onset of arthritis, making it even more difficult to find the right diagnosis. The transition between these two diseases is gradual and can differ greatly between two individuals. Some patients show definite signs and symptoms of ankylosing spondylitis with only marginal involvement of the skin and peripheral joints, others mainly present skin and joint affections with only little back pain. In these cases, it is quite easy to diagnose ankylosing spondylitis in combination with psoriasis or psoriatic arthritis with axial manifestations. But other individuals are not as easily diagnosed, especially if all symptoms are equally strong or weak or if there is no skin involvement at all. So sometimes it can be difficult even for the rheumatologist to differentiate between these two diseases. Yet this is of importance concerning the choice of treatment: while psoriatic arthritis can be treated with Disease Modifying Anti-Rheumatic Drugs (DMARDs) like Methotrexate or Leflunomide, these agents have no effect on peripheral arthritis caused by ankylosing spondylitis.

Spondyloarthritis can be found in both Crohn´s Disease and ulcerative colitis. The incidence lies at 1-12%. Up to 50% of the patients also develop peripheral arthritis. Both are autoimmune diseases, yet the pathogenesis is still largely unclear. Peripheral arthritis can

Clinical Features of Ankylosing Spondylitis 11

As these two tests have to be filled out by the patient, they are very useful to evaluate how the patient is feeling overall and faring at work and at home. They can be redone at every

There are several easy to do measurements for the spine that can be evaluated at any visit and by every physician (Van der Heijde D, Bellamy N, Calin A, Dougados M, Khan MA, Van der Linden S). These examinations are important to check and control spinal function and flexibility, as ankylosing spondylitis is characterized by increasing ankylosis and loss of spinal flexibility and mobility. The rheumatologist can use these measurements to check on a possible progress of the illness or the success of an ongoing therapy. They can be easily done and redone at any given time. All that is necessary is a measuring tape and a pen.

The first test is called Schober (Schober P) (Viitanen JV, Heikkila S, Kokko ML, Kautiainen H). This gives evidence about the lumbal spine flexion. The patient has to stand straight, a sign is made over the spine at the height of the posterior superior iliac spines, a second sign 10 cm above the first (Figure 4). Then the patient has to bend forward with locked knees as far as possible, and the distance between the two marks is measured. A healthy and flexible lumbal spine shows an increase of this distance of at least 5 cm. An increase of 4 cm or less

A variation of the Schober test is the modified Schober test. When using the modified Schober test another mark is set 5 cm below the posterior superior iliac spines, then the distance between this point and the one 15 cm above is measured. There should be a

Lateral lumbar flexion can also be tested. The patient leans against the wall placing his or her hands to the side of his legs. The end of the middle finger is marked, then the patient is asked to bend laterally with straight knees towards the marked side as far as possible. The difference between start and endpoint of the middle finger is measured. A distance of more

The next test is called Ott. Here the flexibility of the thoracic spine is measured. Once again, the patient has to stand upright. The seventh cervical spine is marked, then the second mark is applied 30 cm below the first one. Then the patient has to bend forward again as far as possible, and once again the distance between the two marks is measured. The distance should increase at least to 33 cm in order to show a normal movement of the thoracic spine. Then the patient should stand against the wall, heels and shoulders touching the wall. The patient is asked to move his head backwards, until his occiput touches the wall (Heuft-Dorenbosch L, Vosse D, Landewe R, Spoorenberg A, Dougados M). Patients with decreased cervical movement are not able to do so, in this case the distance between the back of the head and the wall is measured. Any distance is pathological. Next the patient is asked to move his chin towards his breast, thus measuring the ventral flexibility of the cervical spine. The chin should touch the breast, any measurable distance is an indication for reduced

Next one can also measure the distance between fingertips and floor. In this case the patient has to bend his back forward with unbent knees as far as possible, until the fingertips touch the floor. This test is a general test of spinal flexion, but untrained people or patients with non-inflammatory diseases like spondylosis deformans or discopathy are quite often not

correlates with a restriction of movement of the lumbal spine.

difference of 20 cm at least (Mcrae IF, Wright V).

than 10 cm means normal lateral flexibility.

agility of the cervical spine.

able to reach the floor as well.

visit to check, if there is an improvement or worsening of symptoms and mobility.

appear before the onset of bowel symptoms, causing acute, but self-limiting attacks of monoarthritis or asymmetrical oligoarthritis as well as chronic arthritis. Hips and shoulders are less frequently affected as in ankylosing arthritis. A flare of the bowel disease can be accompanied by another flare of arthritis. Enthesitis of the Achilles tendon has been reported. Sacroiliitis can occur asymptomatic or with the typical signs of low back pain, stiffness and reduction of spinal mobility. Spondylitis is independent of gut flares. Up to 50% of patients with ankylosing spondylitis on the other hand are diagnosed with gut inflammation when examined by colonoscopy (De Kaiser F, Baeten D, Van De Bosch F et al).

Reactive arthritis is another disease belonging to the group of seronegative spondyloarthritides and usually leads to asymmetrical peripheral arthritis lasting for several months up to one or two years. Acute inflammation, swelling and pain of the joints, dactylitis and enthesitis are the main symptoms. Any joint can be affected, but most commonly knees, ankles and metatarsophalangeal joints. Later on, osteoarthritis may develop in formerly affected joints. Patients also suffer from fatigue, fever and malaise. Low back pain is rather common in these patients, caused by acute sacroiliitis, enthesitis and muscle tension. Spondylitis and sacroiliitis tend to be asymmetrical, but normally they do not lead to spinal fusion and ankylosis. There is a correlation between reactive arthritis, HLA-B27 and a previous infection (Khan MA) (Silman AJ, Hochberg MD), yet no germ can be found in any of the affected joints. Skin and mucous membrane lesions, sterile urogenital inflammation, sterile conjunctivitis, but also acute anterior uveitis and keratitis may occur (Saari KM). As ocular manifestations tend to reoccur, patients have to be advised to see an ophthalmologist immediately upon onset of ocular symptoms. X-ray will not be very helpful in acute sacroiliitis, but it can help to detect signs of previous sacroiliac inflammation. Back pain may persist even after disappearance of arthritis. In some patients ankylosing spondylitis subsequently evolves, but it is unclear whether reactive arthritis is the predecessor or if this is just a coincidence. Reactive arthritis tends to show a more aggressive and longer disease course when HLA-B27 positive, but at least 50% are HLA-B27 negative, so it should not be tested on a regular basis, as the result could be misleading.

#### **7. Clinical measurements for ankylosing spondylitis**

In order to evaluate pain, morning stiffness and functional ability two different questionnaires have been developed: the BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) and the BASFI (Bath Ankylosing Spondylitis Functional Index). Both are questionnaires that have to be completed by the patient.

The BASDAI (Garrett S, Jenkinson T, Kennedy LG, Whitelock H, Gaisford P, Calin A) consists of 6 questions, they deal with fatigue, pain and morning stiffness during the last week. The questions have to be answered on a scale from 0 to 10. The patient has to tick the box with the appropriate number. 0 means no fatigue / pain / morning stiffness at all, 10 would be the worst possible case.

The BASFI (Calin A, Garrett S, Whitelock H et al) is meant to evaluate functional impairment. 10 questions are asked about the patient´s ability to dress, to bend forward, to reach up, to stand up, use the stairs, do physical labour, sports and a full day´s activities. Once again a scale from 0 to 10 is used. 0 means no problems at all, 10 means that the patient is not able to perform these activities.

appear before the onset of bowel symptoms, causing acute, but self-limiting attacks of monoarthritis or asymmetrical oligoarthritis as well as chronic arthritis. Hips and shoulders are less frequently affected as in ankylosing arthritis. A flare of the bowel disease can be accompanied by another flare of arthritis. Enthesitis of the Achilles tendon has been reported. Sacroiliitis can occur asymptomatic or with the typical signs of low back pain, stiffness and reduction of spinal mobility. Spondylitis is independent of gut flares. Up to 50% of patients with ankylosing spondylitis on the other hand are diagnosed with gut inflammation when examined by colonoscopy (De Kaiser F, Baeten D, Van De Bosch F et al). Reactive arthritis is another disease belonging to the group of seronegative spondyloarthritides and usually leads to asymmetrical peripheral arthritis lasting for several months up to one or two years. Acute inflammation, swelling and pain of the joints, dactylitis and enthesitis are the main symptoms. Any joint can be affected, but most commonly knees, ankles and metatarsophalangeal joints. Later on, osteoarthritis may develop in formerly affected joints. Patients also suffer from fatigue, fever and malaise. Low back pain is rather common in these patients, caused by acute sacroiliitis, enthesitis and muscle tension. Spondylitis and sacroiliitis tend to be asymmetrical, but normally they do not lead to spinal fusion and ankylosis. There is a correlation between reactive arthritis, HLA-B27 and a previous infection (Khan MA) (Silman AJ, Hochberg MD), yet no germ can be found in any of the affected joints. Skin and mucous membrane lesions, sterile urogenital inflammation, sterile conjunctivitis, but also acute anterior uveitis and keratitis may occur (Saari KM). As ocular manifestations tend to reoccur, patients have to be advised to see an ophthalmologist immediately upon onset of ocular symptoms. X-ray will not be very helpful in acute sacroiliitis, but it can help to detect signs of previous sacroiliac inflammation. Back pain may persist even after disappearance of arthritis. In some patients ankylosing spondylitis subsequently evolves, but it is unclear whether reactive arthritis is the predecessor or if this is just a coincidence. Reactive arthritis tends to show a more aggressive and longer disease course when HLA-B27 positive, but at least 50% are HLA-B27 negative,

so it should not be tested on a regular basis, as the result could be misleading.

In order to evaluate pain, morning stiffness and functional ability two different questionnaires have been developed: the BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) and the BASFI (Bath Ankylosing Spondylitis Functional Index). Both are

The BASDAI (Garrett S, Jenkinson T, Kennedy LG, Whitelock H, Gaisford P, Calin A) consists of 6 questions, they deal with fatigue, pain and morning stiffness during the last week. The questions have to be answered on a scale from 0 to 10. The patient has to tick the box with the appropriate number. 0 means no fatigue / pain / morning stiffness at all, 10

The BASFI (Calin A, Garrett S, Whitelock H et al) is meant to evaluate functional impairment. 10 questions are asked about the patient´s ability to dress, to bend forward, to reach up, to stand up, use the stairs, do physical labour, sports and a full day´s activities. Once again a scale from 0 to 10 is used. 0 means no problems at all, 10 means that the patient

**7. Clinical measurements for ankylosing spondylitis** 

questionnaires that have to be completed by the patient.

would be the worst possible case.

is not able to perform these activities.

As these two tests have to be filled out by the patient, they are very useful to evaluate how the patient is feeling overall and faring at work and at home. They can be redone at every visit to check, if there is an improvement or worsening of symptoms and mobility.

There are several easy to do measurements for the spine that can be evaluated at any visit and by every physician (Van der Heijde D, Bellamy N, Calin A, Dougados M, Khan MA, Van der Linden S). These examinations are important to check and control spinal function and flexibility, as ankylosing spondylitis is characterized by increasing ankylosis and loss of spinal flexibility and mobility. The rheumatologist can use these measurements to check on a possible progress of the illness or the success of an ongoing therapy. They can be easily done and redone at any given time. All that is necessary is a measuring tape and a pen.

The first test is called Schober (Schober P) (Viitanen JV, Heikkila S, Kokko ML, Kautiainen H). This gives evidence about the lumbal spine flexion. The patient has to stand straight, a sign is made over the spine at the height of the posterior superior iliac spines, a second sign 10 cm above the first (Figure 4). Then the patient has to bend forward with locked knees as far as possible, and the distance between the two marks is measured. A healthy and flexible lumbal spine shows an increase of this distance of at least 5 cm. An increase of 4 cm or less correlates with a restriction of movement of the lumbal spine.

A variation of the Schober test is the modified Schober test. When using the modified Schober test another mark is set 5 cm below the posterior superior iliac spines, then the distance between this point and the one 15 cm above is measured. There should be a difference of 20 cm at least (Mcrae IF, Wright V).

Lateral lumbar flexion can also be tested. The patient leans against the wall placing his or her hands to the side of his legs. The end of the middle finger is marked, then the patient is asked to bend laterally with straight knees towards the marked side as far as possible. The difference between start and endpoint of the middle finger is measured. A distance of more than 10 cm means normal lateral flexibility.

The next test is called Ott. Here the flexibility of the thoracic spine is measured. Once again, the patient has to stand upright. The seventh cervical spine is marked, then the second mark is applied 30 cm below the first one. Then the patient has to bend forward again as far as possible, and once again the distance between the two marks is measured. The distance should increase at least to 33 cm in order to show a normal movement of the thoracic spine.

Then the patient should stand against the wall, heels and shoulders touching the wall. The patient is asked to move his head backwards, until his occiput touches the wall (Heuft-Dorenbosch L, Vosse D, Landewe R, Spoorenberg A, Dougados M). Patients with decreased cervical movement are not able to do so, in this case the distance between the back of the head and the wall is measured. Any distance is pathological. Next the patient is asked to move his chin towards his breast, thus measuring the ventral flexibility of the cervical spine. The chin should touch the breast, any measurable distance is an indication for reduced agility of the cervical spine.

Next one can also measure the distance between fingertips and floor. In this case the patient has to bend his back forward with unbent knees as far as possible, until the fingertips touch the floor. This test is a general test of spinal flexion, but untrained people or patients with non-inflammatory diseases like spondylosis deformans or discopathy are quite often not able to reach the floor as well.

Clinical Features of Ankylosing Spondylitis 13

Baysal O, Durmus B, Ersoy Y, Altay Z, Senel K, Nas K, Ugur M, Kaya A, Gür A, Erdal A,

Boersma JW: Retardation of ossification o the lumbar vertebral column in ankylosing spondylitis by means of phenybutazone. Scand J Rheumatol 1976: (5)1:60-64 Calin A, Garrett S, Whitelock H et al: A new approach to defining functional ability in

Chou LW, Lo SF, Kao MJ, Jim YF, Cho DY: Ankylosing spondylitis manifested by

De Kaiser F, Baeten D, Van De Bosch F et al : Gut inflammation and spondyloarthropathies.

Dougados M, Dijkmans B, Kan M, Maksymowych W, Van der Linden S, Brandt J:

Feldtkeller E, Vosse D, Geusens P, Van der Linden S: Prevalence and annual incidence of

Francois RJ, Braun J, Khan MA : Entheses and enthesitis: a histopathologic rewiew and relevance to spondyloarthritis. Curr Opin Rheuamtol 2001; 13: 255-264 Garrett S, Jenkinson T, Kennedy LG, Whitelock H, Gaisford P, Calin A: A new approach to

Gladman DD, Shuckett R, Russell ML et al: Psoriatic arthritis (PSA) – an analysis of 220

Gladman DD: Clinical aspects of the spondyloarthropathies. Am J Med Sci 1998; 316: 234-

Günaydin R, Göksel Karatepe A, Cesmeli N, Kaya T: Fatigue in patients with ankylosing

Heuft-Dorenbosch L, Vosse D, Landewe R, Spoorenberg A, Dougados M: Measurement of

Hultgren S, Broma JE, Gudbjornsson B, Hetta J, Lindqvist U: Sleep disturbances in

Jenkinson T, Armas J, Evison G et al : The cervical spine in psoriatic arthritis: a clinical and

Jones SD, Koh WH, Steiner A, Garrett SL, Calin A: Fatigue in ankylosing spondylitis : its

Maghraoui AE, Chaouir S, Abid A et al: Lung findings on thoracic high-resolution

Bergfeldt L: HLA-B27- associated cardiac disease. Ann Intern Med 1997; 127: 621-629

Functional Index. J Rheumatol 1994; 21: 2281-2285

Disease Activity Index. J Rheumatol 1994; 21: 2286-2291

disturbance. Clin Rheumatol 209 Sep; 28(9): 1045-51

implications. Scand J Rheumatol 2000; 29: 365-369

radiological study. Br J Rheumatol 1994; 33: 255-259

Khan MA, ed: Spondyloarthropathies. Rheum Dis Clin N Amer 1992, 18:1-276

tragus-to-wall distance. J Rheumatol 2004; 31: 1779-1784

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patients. Q J Med 1987; 238: 127-141

952-955

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238

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Ardicoglu O, Tekeoglu I Cevik R, Yildirim K, Kamnli A, Sarac AJ, Karatay S Ozgocmen S: Relationship between psychological status and disease activity and quality of life in ankylosing spondylitis. Rheumatol Int 201 Jun; 31(6): 795-800

ankylosing spondylitis: the development of the Bath Ankylosing Spondylitis

spontaneous anterior atlantoaxial subluxation. Am J Phys Med Rehabil 2002; 81:

Conventional treatments for ankylosing spondylitis. Ann Rheum Dis 2002;

vertebral fractures in patients with ankylosing spondylitis. Rheumatol Int 2005; 26:

defining disease status in ankylosing spondylitis: the Bath Ankylosing Spondylitis

spondylitis: relationships with disease-specific variables, depression and sleep

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outpatients with ankylosing spondylitis: a questionnaire study with gender

prevalence and relationship to disease activity, sleep and other factors. J Rheumatol

computed tomography in patients with ankylosing spondylitis. Correlations with disease duration, clinical findings ad pulmonary function testing. Clin Rheumatol

Another easy but very important test is the measurement of chest expansion. Chest circumference is measured at the height of the forth intercostal space in expiration, then in maximum inspiration. Normally there is a difference of 5 cm or more. Decreased chest expansion in patients with ankylosing spondylitis can lead to breath shortness, reduced exercise tolerance and reduced vital capacity of the lungs. Patients with a reduced chest expansion should be checked regularly by pulmonary function testing.

Fig. 4. Schober test.

#### **8. Conclusion**

Ankylosing spondylitis is a chronic inflammatory rheumatic disease. This disease – as all inflammatory rheumatic diseases – shows a great variability and individuality concerning symptoms, progress and outcome and is not limited to axial manifestation and affliction of the entheses, but may also involve peripheral joints, inner organs like the heart, lungs, kidneys and eyes and is associated with fatigue and depression.

So it can be quite difficult even for the rheumatologist to find the right diagnosis from the start. So every doctor should keep in mind to send each patient with low back pain during the night and in the morning , morning stiffness and reduced flexibility of the spine to a rheumatologist.

#### **9. References**


Another easy but very important test is the measurement of chest expansion. Chest circumference is measured at the height of the forth intercostal space in expiration, then in maximum inspiration. Normally there is a difference of 5 cm or more. Decreased chest expansion in patients with ankylosing spondylitis can lead to breath shortness, reduced exercise tolerance and reduced vital capacity of the lungs. Patients with a reduced chest

Ankylosing spondylitis is a chronic inflammatory rheumatic disease. This disease – as all inflammatory rheumatic diseases – shows a great variability and individuality concerning symptoms, progress and outcome and is not limited to axial manifestation and affliction of the entheses, but may also involve peripheral joints, inner organs like the heart, lungs,

So it can be quite difficult even for the rheumatologist to find the right diagnosis from the start. So every doctor should keep in mind to send each patient with low back pain during the night and in the morning , morning stiffness and reduced flexibility of the spine to a

Ahn NU, Ahn UM, Nallamshetty L, Springer BD, Buchowski JM: Cauda equina syndrome

after medical and surgical treatments. J Spinal Disord 2001; 14: 427-433 Barlow JH, Macey SJ, Struthers GR: Gender, depression and ankylosing spondylitis.

in ankylosing spondylitis (the CES – AS syndrome): meta-analysis of outcomes

kidneys and eyes and is associated with fatigue and depression.

Arthritis Care Res 1993; 6; 45-51

expansion should be checked regularly by pulmonary function testing.

Fig. 4. Schober test.

**8. Conclusion** 

rheumatologist.

**9. References** 


**2** 

*UK* 

**Ankylosing Apondylitis** 

*1Dept. of Oral and Maxillofacial Surgery,* 

*2Dept. of Oral and Maxillofacial Surgery* 

*North Bristol NHS Trust, Bristol* 

**of Temporomandibular Joint (TMJ)** 

*Gloucestershire Royal Hospitals NHS Trust, Gloucester,* 

Raveendra Manemi1, Rooprashmi Kenchangoudar1 and Peter Revington2

The ankylosing spondylitis (AS) (Bechterew's disease) is a chronic inflammatory rheumatoid disease with predilection in the axial structures. Often the first clinical indication of the condition is lumbo-sacral pain and discomfort with limited range of motion. The prevalence in Caucasian population is 1-2% with slight male predominance [1, 31, and 32]. Peak age of onset is between 20–30 years, with an average 5–6-year delay in diagnosis reported in the literature. A familial tendency has been strongly suggested by recent evidence. Immunologic activity is suggested by the presence of histocompatibility antigen HLA-B27 (in more than 90 percent of patients with this disease) and circulating

The disease course, although highly variable, will progress to severe disability in one third of patients. Progressive synovial changes eventually involve all of the axial joints including the temporomandibular joint [2]. Literature shows the temporomandibular joint (TMJ) is involved in 4% to 32% of cases [1, 31, and 32]. The severity of the disease may range from sore TMJ to complete ankylosis leading to restricted mouth opening. Ankylosis of the TMJ is exceptional; the involvement of TMJ has not been very well investigated. This chapter describes the incidence, clinical features, pathophysiology, signs, symptoms and current

The Temporo-Mandibular joint (TMJ) is the joint of the jaw and is frequently referred to as TMJ [3]. There are two TMJs, one on either side, working in unison. The name is derived from the two bones which form the joint: the upper temporal bone which is part of the cranium (skull), and the lower jaw bone called the mandible. The unique feature of the TMJs is the articular disc. The disc is composed of fibrocartilagenous tissue (like the firm and flexible elastic cartilage of the ear) which is positioned between the two bones that form the joint. The TMJs are one of the only synovial joints in the human body with an articular disc, another being the sternoclavicular joint. The disc divides each joint into two. The lower joint compartment formed by the mandible and the articular disc is involved in rotational

**1. Introduction** 

immune complexes.

**2. Anatomy of TMJ** 

management of TMJ ankylosing spondylitis


### **Ankylosing Apondylitis of Temporomandibular Joint (TMJ)**

Raveendra Manemi1, Rooprashmi Kenchangoudar1 and Peter Revington2 *1Dept. of Oral and Maxillofacial Surgery, Gloucestershire Royal Hospitals NHS Trust, Gloucester, 2Dept. of Oral and Maxillofacial Surgery North Bristol NHS Trust, Bristol* 

*UK* 

#### **1. Introduction**

14 Clinical and Molecular Advances in Ankylosing Spondylitis

Martindale J, Smith J, Sutton CJ, Grennan D, Goodacre L, Goodacre JA: Disease and

McGonagle D, Gibbon W, Emery P: Classification of inflammatory arthritis by enthesitis.

Nabokov AV, Shabunin MA, Smirnov AV: Renal involvement in ankylosing spondylitis

Obermayer-Pietsch BM, Lange U, Tauber G et al: Vitamin D receptor initiation codon

Rosenbaum JT: Characterization of uveitis associated with spondyloarthritis. J Rheumatol

Saari KM: The eye and reactive arthritis. In: Toivanen A, Toivanen P, eds: Reactive Arthritis.

Schober P: The lumbar vertebral column in backache. Munchener Medizinisch

Sieper J, Braun J, Rudwaleit M, Boonen A, Zink A: Ankylosing spondylitis: an overview. An

Silman AJ, Hochberg MD: Epidemiology of Rheumatic Diseases. Oford: Oxford University

Souza AS, Muller NL, Marchiori E, Soares-Souza LV: Pulmonary abnormalities in

Torre Alonso JC, Rodriguez Perez A, Arribas Castrillo JM et al: Psoriatic arthritis (PA): a

Van der Heijde D, Baraf HS, Ramos-Remus C et al: Evaluation of the efficacy of etoricoxib in

Van der Heijde D, Bellamy N, Calin A, Dougados M, Khan MA, Van der Linden S:

Ankylosing Spondylitis Working Group. J Rheumatol 1997; 24: 2225-2229 Van der Linden SM, Valkenburg HA, De Jongh BM, Cats A: The risk of developing

Viitanen JV, Heikkila S, Kokko ML, Kautiainen H: Clinical assessment of spinal mobility

Wanders A, Van der Heijde D, Landewe R et al: Nonsteroidal antiinflammatory drugs

Wolf J, Fasching P: Ankylosing spondylitis: Wien Med Wochenschr; 2010 May; 160(9-10):

Wright V: Seronegative polyarthritis. Amsterdam:North Holland Publishing Company: 1976

randomized clinical trial. Arthritis Rheum 2005: 52(6): 1756-1765

ankylosing spondylitis: inspiratory and expiratory high-resolution CT findings in

clinical, immunological and radiological study of 180 patients. Br J Rheumatol 1991;

ankylosing spondylitis: results of a fifty-two-week, randomized, controlled study.

Preliminary core sets for endpoints in ankylosing spondylitis. Assessments in

ankylosing spondylitis in HLA-B27 positive individuals. A comparison of relatives of spondylitis patients with the general population. Arthritis Rheum 1984: 27: 241-

measurements in ankylosing spondylis: a compact set for follow-up and trials?.

reduce radiographic progression in patients with ankylosing spondylitis: a

Mcrae IF, Wright V: Measurement of back movement. Ann Rheum Dis 1969; 28: 584-589 Moll J, Haslock I, Mac Rae IF, Wright V: Association between ankylosing spondylitis,

(Bechterew´s disease). Nephrol Dial Transplant 1996: 11: 1172-1175

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spondylitis. Osteoporosis Int 2003; 14: 995-1000

17 patients. J Thorac Imaging 2004; 19: 259-263

psychological status in ankylosing spondylitis. Rheumatology (Oxford) 2006 Oct;

psoriatic arthritis, Reiter´s syndrome, the intestinal arthropathies and Becet

polymorphism, bone density and inflammatory activity of patients with ankylosing

The ankylosing spondylitis (AS) (Bechterew's disease) is a chronic inflammatory rheumatoid disease with predilection in the axial structures. Often the first clinical indication of the condition is lumbo-sacral pain and discomfort with limited range of motion. The prevalence in Caucasian population is 1-2% with slight male predominance [1, 31, and 32]. Peak age of onset is between 20–30 years, with an average 5–6-year delay in diagnosis reported in the literature. A familial tendency has been strongly suggested by recent evidence. Immunologic activity is suggested by the presence of histocompatibility antigen HLA-B27 (in more than 90 percent of patients with this disease) and circulating immune complexes.

The disease course, although highly variable, will progress to severe disability in one third of patients. Progressive synovial changes eventually involve all of the axial joints including the temporomandibular joint [2]. Literature shows the temporomandibular joint (TMJ) is involved in 4% to 32% of cases [1, 31, and 32]. The severity of the disease may range from sore TMJ to complete ankylosis leading to restricted mouth opening. Ankylosis of the TMJ is exceptional; the involvement of TMJ has not been very well investigated. This chapter describes the incidence, clinical features, pathophysiology, signs, symptoms and current management of TMJ ankylosing spondylitis

#### **2. Anatomy of TMJ**

The Temporo-Mandibular joint (TMJ) is the joint of the jaw and is frequently referred to as TMJ [3]. There are two TMJs, one on either side, working in unison. The name is derived from the two bones which form the joint: the upper temporal bone which is part of the cranium (skull), and the lower jaw bone called the mandible. The unique feature of the TMJs is the articular disc. The disc is composed of fibrocartilagenous tissue (like the firm and flexible elastic cartilage of the ear) which is positioned between the two bones that form the joint. The TMJs are one of the only synovial joints in the human body with an articular disc, another being the sternoclavicular joint. The disc divides each joint into two. The lower joint compartment formed by the mandible and the articular disc is involved in rotational

Ankylosing Apondylitis of Temporomandibular Joint (TMJ) 17

Fig. 2. Lateral view of TMJ (Courtesy: Gray's anatomy).

Fig. 3. Sagittal section of the articulation of the mandible. (Courtesy: Gray's anatomy).

movement—this is the initial movement of the jaw when the mouth opens. The upper joint compartment formed by the articular disk and the temporal bone is involved in translational movement—this is the secondary gliding motion of the jaw as it is opened widely.

The part of the mandible which mates to the under-surface of the disc is the condyle and the part of the temporal bone which mates to the upper surface of the disk is the glenoid (or mandibular) fossa.

#### Fig. 1.

The TMJ is a hinge and gliding joint and is the most constantly used joint in the body. The round upper end of the lower jaw, or the movable portion of the joint, is called the condyle; the socket is called the articular fossa. Between the condyle and the fossa is a disk made of cartilage that acts as a cushion to absorb stress and allows the condyle to move easily when the mouth opens and closes.

#### **3. Pathophysiology**

Ankylosing spondylitis (AS) is a systemic rheumatic disease, meaning it affects the entire body. Approximately 90% of AS patients express the HLA-B27 genotype, meaning there is a strong genetic association. However, only 5% of individuals with the HLA-B27 genotype contract the disease. Tumor necrosis factor-alpha (TNF α) and Interleukin-1(IL-1) are also implicated in ankylosing spondylitis. Autoantibodies specific for AS have not been identified. Antineutrophil cytoplasmic antibodies (ANCA) are associated with AS, but do not correlate with disease severity.

TMJ involvement in patients with ankylosing spondylitis has been described previously in very few journals[16] Its reported frequency varies from 1% to 35%, depending on the diagnostic criteria, the population studied, and the tools used to assess TMJ involvement[17]. However, the majority of the reports included patients with long lasting ankylosing spondylitis from tertiary care centres, and while they focus on TMJ involvement, little information on the characteristics of the ankylosing spondylitis is given.

movement—this is the initial movement of the jaw when the mouth opens. The upper joint compartment formed by the articular disk and the temporal bone is involved in translational

The part of the mandible which mates to the under-surface of the disc is the condyle and the part of the temporal bone which mates to the upper surface of the disk is the glenoid (or

The TMJ is a hinge and gliding joint and is the most constantly used joint in the body. The round upper end of the lower jaw, or the movable portion of the joint, is called the condyle; the socket is called the articular fossa. Between the condyle and the fossa is a disk made of cartilage that acts as a cushion to absorb stress and allows the condyle to move easily when

Ankylosing spondylitis (AS) is a systemic rheumatic disease, meaning it affects the entire body. Approximately 90% of AS patients express the HLA-B27 genotype, meaning there is a strong genetic association. However, only 5% of individuals with the HLA-B27 genotype contract the disease. Tumor necrosis factor-alpha (TNF α) and Interleukin-1(IL-1) are also implicated in ankylosing spondylitis. Autoantibodies specific for AS have not been identified. Antineutrophil cytoplasmic antibodies (ANCA) are associated with AS, but do

TMJ involvement in patients with ankylosing spondylitis has been described previously in very few journals[16] Its reported frequency varies from 1% to 35%, depending on the diagnostic criteria, the population studied, and the tools used to assess TMJ involvement[17]. However, the majority of the reports included patients with long lasting ankylosing spondylitis from tertiary care centres, and while they focus on TMJ involvement,

little information on the characteristics of the ankylosing spondylitis is given.

movement—this is the secondary gliding motion of the jaw as it is opened widely.

mandibular) fossa.

Fig. 1.

the mouth opens and closes.

not correlate with disease severity.

**3. Pathophysiology** 

Fig. 2. Lateral view of TMJ (Courtesy: Gray's anatomy).

Fig. 3. Sagittal section of the articulation of the mandible. (Courtesy: Gray's anatomy).

Ankylosing Apondylitis of Temporomandibular Joint (TMJ) 19

Radiographic findings in TMJ depend on the etiology, in cases of AS, rheumatoid arthritis and seronegative spondyloarthropathies, plain films show erosions, osteophytes, subchondral bony sclerosis, and condylar-glenoid fossa remodeling[1].It is diffcult to to differntiate AS of TMJ with other degenarative conditions affecting this joint as there is significant correlation between the radilogical findings of AS and other degenarative disorders[19]CT scans can explore both bony structures and muscular soft tissues. Of interest, there is utility with cone beam computed tomography (CBCT). The patient is scanned with the mouth open and closed. Specifically, CBCT can aid in the diagnosis of this

Magnetic resonance imaging (MRI) is now clearly established as a sensitive and specific tool to detect sacroiliitis [20] but minimal literature found on MRI sensitivity of TMJs in AS hence MRI should be used as the study of choice if TMJ articular or meniscal pathology is

Diagnostic arthroscopy is an invasive diagnostic approach and should be used mainly in patients suffering from internal TMJ derangements recalcitrant to conservative

condition along with history and physical examination.

suspected and an endoscopic or surgical procedure is contemplated.

measures.TMJ can be approached via pre auricular incisions.

Fig. 5.

Fig. 4. CT scan shows complete ankylosis of bilateral TMJs in AS (marked areas showing reduced joint space and fusion of condylar head with glenoid fossa).

#### **4. Signs and symptoms [4, 18]**


#### **5. Diagnosis**

This problem is diagnosed through a combination of clinical history, examination, imaging and the finding of HLA-B27 in the blood.

#### Fig. 5.

18 Clinical and Molecular Advances in Ankylosing Spondylitis

Fig. 4. CT scan shows complete ankylosis of bilateral TMJs in AS (marked areas showing

Chronic pain in the muscles of mastication described as a dull ache, typically unilateral

Headache and/or neck ache: In some cases, patients may complain of headache without

Limitation of jaw opening (normal range is at least 40 mm as measured from lower to

This problem is diagnosed through a combination of clinical history, examination, imaging

reduced joint space and fusion of condylar head with glenoid fossa).

Pain may radiate to the ear and jaw and is worsened with chewing

upper anterior teeth) worsens as the disease progresses.

**4. Signs and symptoms [4, 18]** 

 Clicking or popping in the TMJ Tenderness to palpation of the TMJ

and the finding of HLA-B27 in the blood.

**5. Diagnosis** 

may become bilateral in later stages.

 Associated neck, shoulder, and back pain Increasing pain over the course of the day

localized pain in the temporomandibular joint. A bite that feels uncomfortable or different from usual Radiographic findings in TMJ depend on the etiology, in cases of AS, rheumatoid arthritis and seronegative spondyloarthropathies, plain films show erosions, osteophytes, subchondral bony sclerosis, and condylar-glenoid fossa remodeling[1].It is diffcult to to differntiate AS of TMJ with other degenarative conditions affecting this joint as there is significant correlation between the radilogical findings of AS and other degenarative disorders[19]CT scans can explore both bony structures and muscular soft tissues. Of interest, there is utility with cone beam computed tomography (CBCT). The patient is scanned with the mouth open and closed. Specifically, CBCT can aid in the diagnosis of this condition along with history and physical examination.

Magnetic resonance imaging (MRI) is now clearly established as a sensitive and specific tool to detect sacroiliitis [20] but minimal literature found on MRI sensitivity of TMJs in AS hence MRI should be used as the study of choice if TMJ articular or meniscal pathology is suspected and an endoscopic or surgical procedure is contemplated.

Diagnostic arthroscopy is an invasive diagnostic approach and should be used mainly in patients suffering from internal TMJ derangements recalcitrant to conservative measures.TMJ can be approached via pre auricular incisions.

Ankylosing Apondylitis of Temporomandibular Joint (TMJ) 21

and behavioural therapy have, however, been shown to be beneficial for other outcomes such as motivation and anxiety. Patient associations and self help groups have not been

The pharmacological management of AS of TMJ is essentially same as general management of AS which include Nonsteroidal Anti-inflammatory Drugs (NSAIDs), Coxibs, and Corticosteroids. Literature also shows use of Disease-Modifying Antirheumatic Drugs (DMRDs) and anti-tumour necrosis factor (TNF) agents are recommended in the case of NSAID failure. There is insufficient evidence to support or not support the effectiveness of the reported drugs for the management of pain due TMD (Temporo-Mandibular Disorders). There is a need for high quality RCTs to derive evidence of the effectiveness of pharmacological interventions to treat pain associated with TMD [23] However it has been noticed that most patients respond well to medications given to reduce pain and inflammation, combined with mouth opening exercises to maintain adequate mouth

The surgical management is indicated in patients with marked trismus (decreased mouth opening) and in case of failure of other non surgical modalities. The surgical treatment may include injection of steroid, joint lavage and total joint replacement. TMJ intra-articular steroid injections use 0.5-1ml of Triamcinolone acetate or methyl prednilosone which is mixed with normal saline. These injections can be performed under local anaesthesia or general anaesthesia. Many patients reported quick relief of symptoms from steroid

Total joint replacement is considered as a last resort if the other treatment modalities fail. The first TMJ total joint replacement was performed about twenty years ago [26]. The principles, which were learned in total hip and knee replacement, have been successfully applied to the TMJ. Prosthetic replacement of the TMJ is a procedure that has undergone a technological revolution over the last decade. In spite of the high frequency of TMJ involvement, ankylosis secondary to AS seems to seldom ensue, and relatively few patients develop such severe degenerative TMJ disease that they require total joint replacement. This is reflected in the paucity of literature on the topic, with approximately 11 cases reported

However, when the TMJ ankylosis occurs, it is an extremely disabling affliction that causes problems with mastication, digestion, speech, appearance, and access to routine dentistry. It also has an impact on the psychological development of the patient with concerns related to an inability to open the mouth. Therefore, in patients with ankylosing spondylitis, the total replacement of the TMJ with an alloplastic joint system has become the treatment of choice. These allow closer reproduction of the natural anatomy, avoids donor site morbidity, decreases the risk of reankylosis, and reduces operation time. Furthermore, they allow for immediate physiotherapy and rehabilitation with consequent increased benefit to the

opening and strengthen muscles of mastication to counteract possible ankylosis.

studied for their effect on pain or functional outcomes.

**8. The pharmacological management** 

**9. The surgical management** 

injections [24, 25] and joint lavage.

patient. [28].

worldwide involving the TMJs bilaterally [8, 26, and 27].

#### **6. Management**

The treatment modalities mainly aim for relief of the symptoms and may be to prevent the progression of the disease [21]. The management of AS includes non-pharmacological, pharmacological, invasive and surgical interventions that should be tailored to each patient's disease manifestations, current symptoms, clinical findings and prognostic indicators [22]. The non-surgical treatment of temporomandibular disorder secondary to AS continues to be the most effective way of managing over 80 per cent of patients who present with symptoms of temporomandibular pain and dysfunction. Non-steroidal antiinflammatory drugs (NSAIDs) are recommended as first-line pharmacological treatment**.** 

### **7. Non-pharmacological treatment**

Non-pharmacological treatment of AS includes fabrication of intra-oral splint,physiothery and patient education.The most recent systematic review of physiotherapy for AS reviewed six randomised controlled trials (RCTs), showing that home exercise improved function in the short term compared with no intervention.

**Fabrication and insertion of an Intra-oral Orthotic (also known as splint or bite-gaurd):** The purpose of these Orthotics, which may be fitted to either the upper or lower jaws, and in some cases to both, is to re-position the condyle head in the joint space to a more normal position, thereby relieving the stresses, and pressures, being placed on the tissues of the joints, and their related supporting structures allowing them to heal.

**Physiotherapy Therapy:** These treatments might include Ultra-sound, TENS (transcutaneous electrical nerve stimulation) and home exercises.

Ultrasound therapy is part of a physical therapy treatment using sound waves at a remarkably exorbitant frequency to penetrate the skin deep to the soft tissue of painful area. It involves employing a hand held probe provided a rounded make every effort which is attached to an ultrasound machine. A gel would be rubbed onto the skin and the probe head will be moved over the affected area in small circular movements. The high-frequency (ultrasonic) waves are produced by vibration on the run of the probe. The waves travel with the skin bringing about vibration to the tissue in the affected area. The vibration causes a heating up of the tissue that has a beneficial effect on the TMJ. The ultrasound therapy is safe when administered by a professional or person who has had training as it can have its dangers of skin burns.

TENS in which a low voltage, low amperage current is applied to the preauricular region which is to relax the masticatory muscles, which are in a state of hyperactivity, fatigue or in spasm secondary to pain. It is like an electronic massage of the facial muscles.

In exercise rehabilitation program, patient has to roll back the tongue to touch the roof of the mouth and asked to open and close the jaw by holding the tongue in same position. In another technique patient is asked to slowly open and close the mouth by keeping the palm of the hand against chin with gentle pressure. These exercises mainly aid in improving the mouth opening and to strengthen the muscles of mastication and TMJ ligaments.

**Patient education**: has been shown to have short term benefit for function in AS in one controlled trial. There are no studies examining the effect of education on pain. Education

The treatment modalities mainly aim for relief of the symptoms and may be to prevent the progression of the disease [21]. The management of AS includes non-pharmacological, pharmacological, invasive and surgical interventions that should be tailored to each patient's disease manifestations, current symptoms, clinical findings and prognostic indicators [22]. The non-surgical treatment of temporomandibular disorder secondary to AS continues to be the most effective way of managing over 80 per cent of patients who present with symptoms of temporomandibular pain and dysfunction. Non-steroidal antiinflammatory drugs (NSAIDs) are recommended as first-line pharmacological treatment**.** 

Non-pharmacological treatment of AS includes fabrication of intra-oral splint,physiothery and patient education.The most recent systematic review of physiotherapy for AS reviewed six randomised controlled trials (RCTs), showing that home exercise improved function in

**Fabrication and insertion of an Intra-oral Orthotic (also known as splint or bite-gaurd):** The purpose of these Orthotics, which may be fitted to either the upper or lower jaws, and in some cases to both, is to re-position the condyle head in the joint space to a more normal position, thereby relieving the stresses, and pressures, being placed on the tissues of the

**Physiotherapy Therapy:** These treatments might include Ultra-sound, TENS

Ultrasound therapy is part of a physical therapy treatment using sound waves at a remarkably exorbitant frequency to penetrate the skin deep to the soft tissue of painful area. It involves employing a hand held probe provided a rounded make every effort which is attached to an ultrasound machine. A gel would be rubbed onto the skin and the probe head will be moved over the affected area in small circular movements. The high-frequency (ultrasonic) waves are produced by vibration on the run of the probe. The waves travel with the skin bringing about vibration to the tissue in the affected area. The vibration causes a heating up of the tissue that has a beneficial effect on the TMJ. The ultrasound therapy is safe when administered by a professional or person who has had training as it can have its

TENS in which a low voltage, low amperage current is applied to the preauricular region which is to relax the masticatory muscles, which are in a state of hyperactivity, fatigue or in

In exercise rehabilitation program, patient has to roll back the tongue to touch the roof of the mouth and asked to open and close the jaw by holding the tongue in same position. In another technique patient is asked to slowly open and close the mouth by keeping the palm of the hand against chin with gentle pressure. These exercises mainly aid in improving the

**Patient education**: has been shown to have short term benefit for function in AS in one controlled trial. There are no studies examining the effect of education on pain. Education

spasm secondary to pain. It is like an electronic massage of the facial muscles.

mouth opening and to strengthen the muscles of mastication and TMJ ligaments.

**6. Management** 

dangers of skin burns.

**7. Non-pharmacological treatment** 

the short term compared with no intervention.

joints, and their related supporting structures allowing them to heal.

(transcutaneous electrical nerve stimulation) and home exercises.

and behavioural therapy have, however, been shown to be beneficial for other outcomes such as motivation and anxiety. Patient associations and self help groups have not been studied for their effect on pain or functional outcomes.

#### **8. The pharmacological management**

The pharmacological management of AS of TMJ is essentially same as general management of AS which include Nonsteroidal Anti-inflammatory Drugs (NSAIDs), Coxibs, and Corticosteroids. Literature also shows use of Disease-Modifying Antirheumatic Drugs (DMRDs) and anti-tumour necrosis factor (TNF) agents are recommended in the case of NSAID failure. There is insufficient evidence to support or not support the effectiveness of the reported drugs for the management of pain due TMD (Temporo-Mandibular Disorders). There is a need for high quality RCTs to derive evidence of the effectiveness of pharmacological interventions to treat pain associated with TMD [23] However it has been noticed that most patients respond well to medications given to reduce pain and inflammation, combined with mouth opening exercises to maintain adequate mouth opening and strengthen muscles of mastication to counteract possible ankylosis.

#### **9. The surgical management**

The surgical management is indicated in patients with marked trismus (decreased mouth opening) and in case of failure of other non surgical modalities. The surgical treatment may include injection of steroid, joint lavage and total joint replacement. TMJ intra-articular steroid injections use 0.5-1ml of Triamcinolone acetate or methyl prednilosone which is mixed with normal saline. These injections can be performed under local anaesthesia or general anaesthesia. Many patients reported quick relief of symptoms from steroid injections [24, 25] and joint lavage.

Total joint replacement is considered as a last resort if the other treatment modalities fail. The first TMJ total joint replacement was performed about twenty years ago [26]. The principles, which were learned in total hip and knee replacement, have been successfully applied to the TMJ. Prosthetic replacement of the TMJ is a procedure that has undergone a technological revolution over the last decade. In spite of the high frequency of TMJ involvement, ankylosis secondary to AS seems to seldom ensue, and relatively few patients develop such severe degenerative TMJ disease that they require total joint replacement. This is reflected in the paucity of literature on the topic, with approximately 11 cases reported worldwide involving the TMJs bilaterally [8, 26, and 27].

However, when the TMJ ankylosis occurs, it is an extremely disabling affliction that causes problems with mastication, digestion, speech, appearance, and access to routine dentistry. It also has an impact on the psychological development of the patient with concerns related to an inability to open the mouth. Therefore, in patients with ankylosing spondylitis, the total replacement of the TMJ with an alloplastic joint system has become the treatment of choice. These allow closer reproduction of the natural anatomy, avoids donor site morbidity, decreases the risk of reankylosis, and reduces operation time. Furthermore, they allow for immediate physiotherapy and rehabilitation with consequent increased benefit to the patient. [28].

Ankylosing Apondylitis of Temporomandibular Joint (TMJ) 23

Fig. 7. Postero-Anterior (PA) mandible view showing total TMJ replacement using TMJ

sparsely populated with cases of true ankylosis of TMJ secondary to AS.

he found 124 patients (16.5%). forestier et al (1951) found TMJ involvement in 6% of 200 patients. Nagel (1968) reviewed 1000 patients in which TMJ involvement was only 1%. [17] Due disparity in clinical and radiological signs suggests that the TMJ rarely seems to be a severe problem for AS patients. It is felt that most TMJ symptoms may be secondary to muscle spasm, occlusal factors, and postural imbalance [34], and the literature is only

In conclusion we recommend routine clinical examinations of TMJ in patients with AS to detect rare complications like severe trismus and ankylosis. Both pharmacological and non pharmacological modalities are found to be effective in the treatment of AS of TMJ

concepts prostheses.

**11. Conclusion** 

TMJ concepts prosthesis (formerly Techmedica) has up to 17 years follow-up with 90% success rates [29]. These are computer-aided design/computer-aided manufacture (CAD/CAM) custom-made prostheses constructed on a stereolithographic model following a 3D CT scan. The glenoid fossa component is constructed from titanium mesh bonded to the articular surface of high-molecular-weight polyethylene. The condylar component head is cobalt-chrome alloy, and the remainder of the body is titanium and is secured to the ramus of the mandible by screws. Lorenz also makes a stock prosthesis with similar components to the TMJ concepts prosthesis. Whichever operative strategy is employed, it is important to note that these techniques all rely on aggressive postoperative physiotherapy to maintain optimal results [28].

Fig. 6. Dental panoramic view showing bilateral TMJ replacement with TMJ prostheses in AS patient.

#### **10. Discussion**

Ankyolosing spondylitis has the tendency to involve fibro cartilaginous structures such as symphysis pubis, intervertibral discs, sternomanubrial and sternoclavicular joints. The involvement of TMJ has not been very well investigated and its incidence is disputed. Former studies have reported the involvement of the TMJ in AS between 4% and 32%. However, these studies were either only radiological [31] or used only insufficient clinical [32] or radiological [33] examination methods. Ehrlich (1930) reported on 753 cases, where

TMJ concepts prosthesis (formerly Techmedica) has up to 17 years follow-up with 90% success rates [29]. These are computer-aided design/computer-aided manufacture (CAD/CAM) custom-made prostheses constructed on a stereolithographic model following a 3D CT scan. The glenoid fossa component is constructed from titanium mesh bonded to the articular surface of high-molecular-weight polyethylene. The condylar component head is cobalt-chrome alloy, and the remainder of the body is titanium and is secured to the ramus of the mandible by screws. Lorenz also makes a stock prosthesis with similar components to the TMJ concepts prosthesis. Whichever operative strategy is employed, it is important to note that these techniques all rely on aggressive postoperative physiotherapy

Fig. 6. Dental panoramic view showing bilateral TMJ replacement with TMJ prostheses in

Ankyolosing spondylitis has the tendency to involve fibro cartilaginous structures such as symphysis pubis, intervertibral discs, sternomanubrial and sternoclavicular joints. The involvement of TMJ has not been very well investigated and its incidence is disputed. Former studies have reported the involvement of the TMJ in AS between 4% and 32%. However, these studies were either only radiological [31] or used only insufficient clinical [32] or radiological [33] examination methods. Ehrlich (1930) reported on 753 cases, where

to maintain optimal results [28].

AS patient.

**10. Discussion** 

Fig. 7. Postero-Anterior (PA) mandible view showing total TMJ replacement using TMJ concepts prostheses.

he found 124 patients (16.5%). forestier et al (1951) found TMJ involvement in 6% of 200 patients. Nagel (1968) reviewed 1000 patients in which TMJ involvement was only 1%. [17]

Due disparity in clinical and radiological signs suggests that the TMJ rarely seems to be a severe problem for AS patients. It is felt that most TMJ symptoms may be secondary to muscle spasm, occlusal factors, and postural imbalance [34], and the literature is only sparsely populated with cases of true ankylosis of TMJ secondary to AS.

#### **11. Conclusion**

In conclusion we recommend routine clinical examinations of TMJ in patients with AS to detect rare complications like severe trismus and ankylosis. Both pharmacological and non pharmacological modalities are found to be effective in the treatment of AS of TMJ

Ankylosing Apondylitis of Temporomandibular Joint (TMJ) 25

[17] Manemi R V, Fasanmade A, Revington PJ; Bilateral ankylosis of the jaw treated with

[19] L. Miia J. Helenius , DDS, MB,a Dorrit Hallikainen, MD, DDS,b Ilkka Helenius, MD,

[20] Saeed A. Shaikh, MD, Ankylosing spondylitis: recent breakthroughs in diagnosis and

[21] Mansour.M, Cheema. G.S,Naqw A, Greenspan.A,Ankylosing spondylitis: a

[22] http://www.spine-health.com/conditions/arthritis/ankylosing-spondylitis-physical-

[23] Mujakperuo HR, Watson M, Morrison R, Macfarlane TV; Pharmacological interventions

[26] Speculand B, Hensher R, Powell D, Total prosthetic replacement of the TMJ: experience

[27] Andrew M. Felstead, Peter J. Revington, Surgical management of TMJ Ankylosis in

[28] Roychoudhury A, Parkash H, Trikha A. Functional restoration by gap arthroplasty in

[30] Agarwal A. Preankylosing spondylitis. In: Moll JMH, editor. Ankylosing Spondylitis*.* Edinburgh, UK: Churchill Levingstone; 1980. pp. 69–75 [31] Maes HJ, Dihlmann W. Affection of the temporomandibular joints in spondylitis

[32] Resnick D. Temporomandibular joint involvement in ankylosing spondylitis.

ankylosing spondylitis;*Br J Oral Maxillofac Surg.* 2009 Mar;47(2):159-61.

[18] Vivian Tsai; Rick Kulkarni; Temporomandibular Joint syndrome;

Feb; 36(4):210-23. Epub 2006 Sep 29

therapy-and-exercise.

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[25] S Ringold, et al. *J Rheumatol.* 2008; 35(6):1157-1164

Maxillofacial Surgery*.* 2007;65(6):1140–1148.

Nuklearmedizin*.* 1968;109(4):513–516. [PubMed]

63.

*http://emedicine.medscape.com/article/809598-overview.* Feb 2010

treatment *J Can Chiropr Assoc.* 2007 December; 51(4): 249–260.

total alloplastic replacement using the TMJ concepts system in a patient with

PhD, Clinical and radiographic findings of the TMJ in patients with various rheumatic diseases. *Oral Surg Oral Med Oral Pathol Oral Radiol Endod* 2005; 99:455-

contemporary perspective on diagnosis and treatment. *Semin Arthritis Rheum.* 2007

for pain in patients with temporomandibular disorders. *Cochrane Database Syst* 

with two systems 1988-1997,*The British Journal of Oral & Maxillofacial Surgery 38,*360-

Ankylosing spondylitis, *Int J Rheumatol.* 2011;Published online 2011 March

temporomandibular joint ankylosis a report of 50 cases. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics*.*1999;87(2):166–169 [29] Mercuri LG, Edibam NR, Giobbie-Hurder A. Fourteen-year follow-up of a patient-

fitted total temporomandibular joint reconstruction system. Journal of Oral and

ankylopoeiticaBefall der Temporomandibulargelenke bei der Spondylitis ankylopoetica. Fortschritte auf dem Gebiete der Rontgenstrahlen und der

Comparison with rheumatoid arthritis & psoriasis. Radiology*.* 1974; 112(3):587–

depending on the time and progression. One should have high index of suspicion of TMJ ankylosis in AS for an early detection. This could avoid the need of expensive and technique sensitive joint surgeries. Complementary explorations like joint lavage or arthroscopy should be undertaken in ankylosing spondylitis patients with clinical symptoms suggestive of TMJ lesions in order to establish the diagnosis and initiate treatment and avoid the development of ankylosis forms.

#### **12. References**


depending on the time and progression. One should have high index of suspicion of TMJ ankylosis in AS for an early detection. This could avoid the need of expensive and technique sensitive joint surgeries. Complementary explorations like joint lavage or arthroscopy should be undertaken in ankylosing spondylitis patients with clinical symptoms suggestive of TMJ lesions in order to establish the diagnosis and initiate

[1] M.C. Locher, M. Felder, H.F. Sailer Invovlement of TMJ in Ankylosing spondylitis

[2] Ankylosing Spondylitis affecting TMJ-Case report; *International journal of Oral and* 

[3] Rodríguez-Vázquez JF, et al., JF; Mérida-Velasco, JR; Mérida-Velasco, JA; Jiménez-

[4] Robert.J, R.J.Loiselle TMJ Symptoms and Ankylosing Spondylitis. *JADA* 1972; 83.630-

[5] Miller GA, Page HL Jr, Griffith CR. Temporomandibular joint ankylosis: Review of the

[6] Guralnick WC, Kaban LB. Surgical treatment of mandibular hypomobility. *J. Oral Surg* 

[7] Figueroa AA, Gans BJ, Pruzansky S. Long-term follow-up of mandibular costochondral

[8] Moriconi ES, Popowich LD, Guernsey LH. Alloplastic reconstruction of the

[9] Kaban LB, Perrott DH, Fisher K. A protocol for management of temporomandibular joint ankylosis. *J Oral Maxillofacial Surg* 1990; 48(11): 1145-51; discussion 1152. [10] Mauno Kononen, Bengt Wenneberg: Craniomandibular Disorders in Rheumatoid

[12] Fonseca RJ. Oral and Maxillofacial Surgery: Temporomandibular Disorders.

[13] Ju Seop Song, Kwan Joon-Koh, ankylosing spondilitis associated with bilateral TMJ ankylosis. *Korean Journal of Oral and Maxillofacial Surgery* 2000,30. 217-222. [14] Khan MA. 2002. *Ankylosing spondylitis:* The facts. Oxford University Press. ISBN

[16] Qin L, Long X, Li X, Bilateral fibrous ankylosis of temporomandibular joint associated with ankylosing spondylitis: a case report. *Joint Bone Spine.* 2006 Feb 17;

Arthritis, Psoriatic Arthritis and Ankylosing Spondylitis, *ACTA ODONTOL* 

temporomandibular joint. *Dent Clin North Am* 1986; 30(2): 307-25.

Philadelphia (PA): W.B. Saunders Company; 2000. p. 309-13.

[15] Benazzou S, Maagoul R *Rev Stomatol Chir Maxillofac.* 2005 Nov; 106(5): 08-10.

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[11] Chowk TK, Ng.WL. *Scand J Rheumatology.* 1997; 26(2): 133-4.

(Bechterew's disease) *Journal of Cranio-Maxillofacial Surgery*, Volume 24, Issue 4,

Collado, J (1998). "Anatomical considerations on the discomalleolar ligament". J

literature and report of 2 cases of bilateral involvement. *J Oral Surg* 1975; 33(10):

treatment and avoid the development of ankylosis forms.

August 1996, Pages 205-213

*Anat*. 192 (Pt 4): 617–621.

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0192632825.


**3** 

**Bone Mineral Density Changes in Patients** 

Lina Vencevičienė1, Rimantas Vencevičius2 and Irena Butrimienė<sup>3</sup>

*Reconstructive Surgery; State Research Institute Centre for Innovative Medicine* 

*3Vilnius University, Clinic of Rheumatology, Traumatology, Orthopedics and Plastic and* 

The concept of inflammatory spondyloarthropathies (SpA) as an independent group of diseases was introduced approximately 15-20 years ago, when symptoms distinguishing these diseases from rheumathoid arthritis (RA) were defined precisely. SpA group includes 4 main diseases: ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis (ReA) and enteropathic arthropathies (EnA). Global prevalence of these diseases is .2-3.0 percent. Furthermore, SpA incidence in Lithuania is .64 percent (Adomaviciute et al., 2008). The incidence is higher in close relatives of patients with established human leucocyte antigen B27 (HLA B27). SpA is 2-3 times more common in males than in females ( Khan,

Although SpA and RA ethiology and pathogenesis differ, these immune arthritides are similar in their consequences, principles of diagnostic and treatment. Genetic predisposition to the disease and relation with infectious factors is characteristic to both SpA and RA diseases, however, the true causes remain unclear. It is known that tissue damage in these diseases is caused by reactions governed by immune processes. In addition, RA is the most investigated autoimmune, continuously progressing erosive-destructive poliarthritis. The incidence among adults ranges from .35 to 1.0 percent in various populations whilst in Lithuania it is about .55 percent (Adomavičiūtė et al., 2008). In both SpA and RA clinical outcomes depend primarily on various complications: cardiovascular abnormalities,

Osteoporosis (OP) is a skeletal disease characterized by low bone mineral density (BMD) and poor bone quality that reduces bone strength and increases the risk of fractures. OP is a major public health concern, affecting approximately 200 million individuals worldwide, including a third of women aged 60 to 70 years. Fractures of the hip and spine are associated with increased morbidity and mortality (Johnell et al., 2005). Despite the high prevalence of OP and the availability of effective drugs to reduce the risk of fracture, it is underdiagnosed

**1. Introduction** 

2002; Sieper, 2002).

infections, amyloidosis, osteoporosis.

*1Vilnius University, Clinic of Internal Diseases, Family Medicine,* 

*2Vilnius University, Clinic of Rheumatology, Traumatology,* 

**with Spondyloarthropathies** 

*Orthopedics and Plastic and Reconstructive Surgery* 

*Gerontology and Oncology* 

*Lithuania* 


### **Bone Mineral Density Changes in Patients with Spondyloarthropathies**

Lina Vencevičienė1, Rimantas Vencevičius2 and Irena Butrimienė<sup>3</sup> *1Vilnius University, Clinic of Internal Diseases, Family Medicine, Gerontology and Oncology 2Vilnius University, Clinic of Rheumatology, Traumatology, Orthopedics and Plastic and Reconstructive Surgery 3Vilnius University, Clinic of Rheumatology, Traumatology, Orthopedics and Plastic and Reconstructive Surgery; State Research Institute Centre for Innovative Medicine Lithuania* 

#### **1. Introduction**

26 Clinical and Molecular Advances in Ankylosing Spondylitis

[33] Davidson C, Wojtulewski JA, Bacon PA, Winstock D. Temporo mandibular joint

[34] Crum RJ, Loiselle RJ. Temporomandibular joint symptoms and ankylosing

91. [PubMed]

633. [PubMed]

disease in ankylosing spondylitis.Annals of the Rheumatic Diseases*.* 1975;34(1):87–

spondylitis. The Journal of the American Dental Association*.* 1971;83(3):630–

The concept of inflammatory spondyloarthropathies (SpA) as an independent group of diseases was introduced approximately 15-20 years ago, when symptoms distinguishing these diseases from rheumathoid arthritis (RA) were defined precisely. SpA group includes 4 main diseases: ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis (ReA) and enteropathic arthropathies (EnA). Global prevalence of these diseases is .2-3.0 percent. Furthermore, SpA incidence in Lithuania is .64 percent (Adomaviciute et al., 2008). The incidence is higher in close relatives of patients with established human leucocyte antigen B27 (HLA B27). SpA is 2-3 times more common in males than in females ( Khan, 2002; Sieper, 2002).

Although SpA and RA ethiology and pathogenesis differ, these immune arthritides are similar in their consequences, principles of diagnostic and treatment. Genetic predisposition to the disease and relation with infectious factors is characteristic to both SpA and RA diseases, however, the true causes remain unclear. It is known that tissue damage in these diseases is caused by reactions governed by immune processes. In addition, RA is the most investigated autoimmune, continuously progressing erosive-destructive poliarthritis. The incidence among adults ranges from .35 to 1.0 percent in various populations whilst in Lithuania it is about .55 percent (Adomavičiūtė et al., 2008). In both SpA and RA clinical outcomes depend primarily on various complications: cardiovascular abnormalities, infections, amyloidosis, osteoporosis.

Osteoporosis (OP) is a skeletal disease characterized by low bone mineral density (BMD) and poor bone quality that reduces bone strength and increases the risk of fractures. OP is a major public health concern, affecting approximately 200 million individuals worldwide, including a third of women aged 60 to 70 years. Fractures of the hip and spine are associated with increased morbidity and mortality (Johnell et al., 2005). Despite the high prevalence of OP and the availability of effective drugs to reduce the risk of fracture, it is underdiagnosed

Bone Mineral Density Changes in Patients with Spondyloarthropathies 29

the disease, physical disability and immobility, activity of the disease, medications in use) using noninvasive method of BMD evaluation (dual-energy X-ray absorptiometry (DXA)).

To investigate BMD changes at the lumbar spine and upper part of left and right femur

 To investigate BMD changes at the lumbar spine and upper part of left and right femur in patients with various diseases belonging to SpA group (AS, ReA, PsA, EnA) and in SpA patients with different type of joint lesions (only axial, only peripheral, both axial

To analyse relation between the duration of SpA and BMD changes at the lumbar spine

To evaluate influence of physical disability and immobility on BMD changes in patients

To determine influence of medications in use: glucocorticoids and TNF- blockers on

BMD decrease at the lumbar spine and upper part of left and right femur is similar in

Patients treated in the Department of Rheumatology of Vilnius University Hospital "Santariškių klinikos" in the period of December 2006 to June 2008 were invited to participate in this research. Patients arriving at Vilnius University Hospital "Santariškių klinikos" Family Health Center for the prophylactic examination were invited to take part in the control group of the research. A total of 136 patients with SpA, 104 patients with RA and 114 healthy people (control group) matching inclusion criteria, and not having any exclusion

 People with RA diagnosis established according to rheumatoid arthritis diagnostic criteria of American College of Rheumatology (ARA'87) (diagnosis established by

 Subjects with SpA diagnosis established according to diagnostic criteria approved by European Spondyloarthropathy Study Group (ESSG) (1991) (diagnosis established by

 Subjects signed an *Informed Consent* form approved by Lithuanian bioethics committee. (The permission to perform this investigation was obtained from the Lithuanian

Subjects of control group – healthy individuals (Dougados et al., 1991);

 Impact of various diseases belonging to SpA group on bone mass changes is similar. SpA activity and physical disability and immobility are important prognostic factors for

in groups of patients with SpA, Ra and healthy subjects.

patients with inflammatory joint diseases: SpA and RA.

criteria stated below were involved in the investigation.

Age of subjects ranging from 20 to 75 years;

rheumatologist) ( Arnett et al., 1988);

bioethics committee (No.60; 2006-12-22)).

and upper part of left and right femur.

BMD changes in patients with SpA.

**Objectives of the research** 

and peripheral).

with SpA.

**Statements defended:** 

BMD decrease.

**2.1 Study population** 

**2.2 Inclusion criteria** 

rheumatologist);

**2. Study subjects and methods** 

and undertreated (Feldstein et al., 2003). Patients with immune arthritides, who are at very high risk of fracture, are usually not evaluated for OP. It has been reported that in patients with SpA and RA decreased BMD is being diagnosed at a much younger age (Lane at al., 2002). These patients are affected not only by ordinary OP risk factors but also specific disease factors: activity and course of the disease, its duration, treatment with glucocorticoids (GC) and immunosuppressants, reduced mobility (Gratacos, 1999; Kroot, 2001; Baek, 2005).

Most of the publications analyzing BMD changes are related to RA. It was observed that RA is associated with local and systemic loss of bone mineral density (Sambrook, 1995; Gough, 1994) and also with increased risk of osteoporotic fracture (Cooper et al., 1995). The main factors associating RA and decrease of BMD are activity of the disease, physical disability and immobility, disease duration and use of gliucocorticoids (Dequeker, 1995; Kvien, 2000). According to other work in the field, pathologic fractures of spine vertebrae are more common in patients with SpA than RA (despite the formation of syndesmophytes and ossification of longitudinal ligaments that could probably "protect the spine" in SpA case) (Bessant, 2002; Brand, 2008). It is supposed that in both RA and SpA bone tissue is damaged due to reduced mobility, the activity of the disease and, most importantly, similar reactions caused by immune processes, which are characteristic to these diseases (Illei et al., 2000; Pettit, 2001).

Although in most cases SpA are investigated as a whole group of diseases with common clinical, radiological and genetic features, BMD was investigated mostly in patients with AS. According to other studies, the incident of OP in patients with AS is very different and ranges from 50 to 92% (Mitra, 2000; Capaci, 2003). Too little and controversial data concerning changes of BMD in other diseases belonging to SpA group were published (El Maghraoui, 2004; Speden, 2002).

**Scientific novelty.** This investigation for the first time evaluated and compared BMD at the lumbar spine and upper part of left and right femur in patients with SpA and RA and healthy people. Consistent patterns of BMD changes at the lumbar spine and upper parts of both femurs were assessed in patients with diseases belonging to SpA group (AS, ReA, EnA, PsA) and in SpA patients with various types of joint lesion. Relation between SpA specific factors – duration of the disease, physical disability and immobility, activity of the disease, medications in use and BMD changes at the lumbar spine and upper part of left and right femur was evaluated.

Absolute determination of consistent patterns of BMD changes at the lumbar spine and upper parts of both femurs in patients with various diseases belonging to SpA group (AS, ReA, EnA, PsA) and with various types of joint lesion together with, investigation of distinct clinical risk factors associated with BMD changes in SpA patients would allow to select patients for BMD test precisely, indicate the exact skeleton area for investigation, diagnose changes in bone mass earlier and timely apply effective preventive and/or treatment measures.

Aim of the research – to determine consistent patterns of BMD changes at the lumbar spine and upper part of left and right femur in patients with SpA (AS, ReA, PsA, EnA) and to assess the relation between changes of BMD and specific factors of the disease (duration of the disease, physical disability and immobility, activity of the disease, medications in use) using noninvasive method of BMD evaluation (dual-energy X-ray absorptiometry (DXA)).

#### **Objectives of the research**

28 Clinical and Molecular Advances in Ankylosing Spondylitis

and undertreated (Feldstein et al., 2003). Patients with immune arthritides, who are at very high risk of fracture, are usually not evaluated for OP. It has been reported that in patients with SpA and RA decreased BMD is being diagnosed at a much younger age (Lane at al., 2002). These patients are affected not only by ordinary OP risk factors but also specific disease factors: activity and course of the disease, its duration, treatment with glucocorticoids (GC) and immunosuppressants, reduced mobility (Gratacos, 1999; Kroot,

Most of the publications analyzing BMD changes are related to RA. It was observed that RA is associated with local and systemic loss of bone mineral density (Sambrook, 1995; Gough, 1994) and also with increased risk of osteoporotic fracture (Cooper et al., 1995). The main factors associating RA and decrease of BMD are activity of the disease, physical disability and immobility, disease duration and use of gliucocorticoids (Dequeker, 1995; Kvien, 2000). According to other work in the field, pathologic fractures of spine vertebrae are more common in patients with SpA than RA (despite the formation of syndesmophytes and ossification of longitudinal ligaments that could probably "protect the spine" in SpA case) (Bessant, 2002; Brand, 2008). It is supposed that in both RA and SpA bone tissue is damaged due to reduced mobility, the activity of the disease and, most importantly, similar reactions caused by immune processes, which are characteristic to these diseases (Illei et al., 2000;

Although in most cases SpA are investigated as a whole group of diseases with common clinical, radiological and genetic features, BMD was investigated mostly in patients with AS. According to other studies, the incident of OP in patients with AS is very different and ranges from 50 to 92% (Mitra, 2000; Capaci, 2003). Too little and controversial data concerning changes of BMD in other diseases belonging to SpA group were published (El

**Scientific novelty.** This investigation for the first time evaluated and compared BMD at the lumbar spine and upper part of left and right femur in patients with SpA and RA and healthy people. Consistent patterns of BMD changes at the lumbar spine and upper parts of both femurs were assessed in patients with diseases belonging to SpA group (AS, ReA, EnA, PsA) and in SpA patients with various types of joint lesion. Relation between SpA specific factors – duration of the disease, physical disability and immobility, activity of the disease, medications in use and BMD changes at the lumbar spine and upper part of left and right

Absolute determination of consistent patterns of BMD changes at the lumbar spine and upper parts of both femurs in patients with various diseases belonging to SpA group (AS, ReA, EnA, PsA) and with various types of joint lesion together with, investigation of distinct clinical risk factors associated with BMD changes in SpA patients would allow to select patients for BMD test precisely, indicate the exact skeleton area for investigation, diagnose changes in bone mass earlier and timely apply effective preventive and/or treatment

Aim of the research – to determine consistent patterns of BMD changes at the lumbar spine and upper part of left and right femur in patients with SpA (AS, ReA, PsA, EnA) and to assess the relation between changes of BMD and specific factors of the disease (duration of

2001; Baek, 2005).

Pettit, 2001).

Maghraoui, 2004; Speden, 2002).

femur was evaluated.

measures.


#### **Statements defended:**


#### **2. Study subjects and methods**

#### **2.1 Study population**

Patients treated in the Department of Rheumatology of Vilnius University Hospital "Santariškių klinikos" in the period of December 2006 to June 2008 were invited to participate in this research. Patients arriving at Vilnius University Hospital "Santariškių klinikos" Family Health Center for the prophylactic examination were invited to take part in the control group of the research. A total of 136 patients with SpA, 104 patients with RA and 114 healthy people (control group) matching inclusion criteria, and not having any exclusion criteria stated below were involved in the investigation.

#### **2.2 Inclusion criteria**


Bone Mineral Density Changes in Patients with Spondyloarthropathies 31

In patients with RA the following parameters were assessed: rheumatoid arthritis functional ARA classes; disease activity index DAS 28 and activity of the disease established by

Anthropometric measurements were performed on all patients: height, weight, BMI; laboratory tests: ESR, CRP, calcium blood level, HLA-B27 (in patients with SpA), RF (in patients with RA). Laboratory tests were performed in the Department of Laboratory

In all subjects BMD was measured by dual-energy X-ray absorptiometry (DXA) using osteodensitometer LEXXOS-DMS (software: V6, 20a, version of the year 2006). The anteriorposterior view of lumbar spine (L1-L4 vertebrae) and upper parts of both femurs were examined. BMD data were expressed as g/cm2 and the number of standard deviations from the peak bone mass (T – score), and also the number of standard deviations of any individual result from the age and sex matched population mean (Z – score). Normal ranges were provided by manufacturers of the osteodensitometer. According to ISCD recommendations, BMD deviation was measured as Z-score, since most of the enrolled subjects were males less than 50 years old. Osteodensitometer quality test and measurement error test were performed every morning before work. Indications of the scan of spine vertebrae reference (phantom) fluctuated no more than 2 %, bias of the repeated measurement in spine vertebrae was not higher than 1.5 %, and in the upper part of femur– not higher then 2.1 %. All BMD measurements were performed by the principal

Statistical analysis was performed using SPSS 16 software. Mean (M) and standard deviation (SD) were used to describe quantitative characteristics of the research. Frequencies (n) and percents (%) were used for qualitative characteristics. Depending on applicable assumptions Student's t-test for independent samples was used to compare means of a particular qualitative characteristic of different samples. Analysis of variance ANOVA was used to compare quantitative variables of more than two samples (when variances were unequal Welch test statistics was used). When the hypothesis of the equality of means of two or more groups was rejected, pairwise comparison of this characteristic was additionally used. In that case Tukey HSD Post Hoc test was used. Differences of qualitative characteristics of experimental groups were assessed using Chi square test. Selected level of

To analyze relationship between SpA variables: the duration of disease, physical disability and immobility, activity of the disease and treatment with GC and TNF- blockers and BMD changes linear regression models were developed. Stepwise selection of variables in the linear regression was used. Variables were included in the model when their p was <.05 and excluded when their p was > .10. When strong association between independent variables was observed (e.g., cumulative dose of GC and duration of use (calculated using Spearman correlation coefficient), only one of them was used for calculations. To assess probability that Z-score will be -2 in any site of examined skeleton logistic regression

Diagnostics of Vilnius University Hospital "Santariškių klinikos".

rheumatologist (Arnett et al., 1988).

investigator.

**2.6 Data analysis** 

significance α = .05.

analysis was used.

**2.5 Evaluation of the bone mineral density** 

#### **2.3 Exclusion criteria**


#### **2.4 Research structure**

Primary selection of patients was performed according to patients' medical history and data of clinical investigations (data from the hospital and out-patient records were used under the patients consent). Then, every patient completed one of the three questionnaires depending on the research subgroup he/she belonged to. The following questionnaire data were assessed: socio-demographic data – age, gender, education, profession, work environment; smoking, use of alcohol; bone fractures in subject and his close relatives; previous and current diseases; previously and currently used medications; calcium amount in the diet (mg/d); frequency of physical activities by month (at least 20 minutes physical exercises per day) and the age of the beginning and the end of menstrual cycle in femails.

In patients with SpA and RA: duration of the disease (in months) from the onset of the first symptoms and from the date the diagnosis was established; pain intensity assessment using 10 cm VAS scale; patient's general status assessment using 10 cm VAS scale.

In patients with SpA the following parameters were assessed: disease belonging to SpA group; type of joint lesion: axial, peripheric, both axial and peripheric; physical disability was assessed by completing Health Assessment Questionaire Modified for Spondyloarthropathies (HAQ-S) (Daltroy et al., 1990); immobility was assessed according to Bath Ankylosing Spondylitis Functional Index (BASFI) (Calin et al., 1994) and Bath Ankylosing Spondylitis Patient Global Score (BAS-G) (Jones et al., 1996); assessment of enthesis; movement of spine was assessed according to standardized SpA clinical measurements: lumbar side flexion, modified Schober's test, tragus to wall distance and intermalleolar distance (Jenkinson et al, 1994); activity of the disease according to patients self-assessment using Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (Garrett et al, 1994); activity of the disease evaluated by rheumatologist (Landewe et al, 2004). The linguistic and cultural adaptation of these questionnaires was made during the study. Internal consistency was high for functional and disease activity index (Cronbach alpha>/=0.80) and moderate for the Bath Ankylosing Spondylitis Patient Global Score (Cronbach alpha=0.58). High stability in regard to time was characteristic of all three questionnaires (intraclass correlation coefficient >0.95). A significant association between the separate questions of examined instruments, their joint results and other factors reflecting patient's health was established (Venceviciene et al., 2009).

In patients with RA the following parameters were assessed: rheumatoid arthritis functional ARA classes; disease activity index DAS 28 and activity of the disease established by rheumatologist (Arnett et al., 1988).

Anthropometric measurements were performed on all patients: height, weight, BMI; laboratory tests: ESR, CRP, calcium blood level, HLA-B27 (in patients with SpA), RF (in patients with RA). Laboratory tests were performed in the Department of Laboratory Diagnostics of Vilnius University Hospital "Santariškių klinikos".

#### **2.5 Evaluation of the bone mineral density**

In all subjects BMD was measured by dual-energy X-ray absorptiometry (DXA) using osteodensitometer LEXXOS-DMS (software: V6, 20a, version of the year 2006). The anteriorposterior view of lumbar spine (L1-L4 vertebrae) and upper parts of both femurs were examined. BMD data were expressed as g/cm2 and the number of standard deviations from the peak bone mass (T – score), and also the number of standard deviations of any individual result from the age and sex matched population mean (Z – score). Normal ranges were provided by manufacturers of the osteodensitometer. According to ISCD recommendations, BMD deviation was measured as Z-score, since most of the enrolled subjects were males less than 50 years old. Osteodensitometer quality test and measurement error test were performed every morning before work. Indications of the scan of spine vertebrae reference (phantom) fluctuated no more than 2 %, bias of the repeated measurement in spine vertebrae was not higher than 1.5 %, and in the upper part of femur– not higher then 2.1 %. All BMD measurements were performed by the principal investigator.

#### **2.6 Data analysis**

30 Clinical and Molecular Advances in Ankylosing Spondylitis

Patients with other diseases (renal, liver, thyroid and parathyroid, and cancer)

 Individuals treated with medications (anti-osteoporosis, thyroxin, insulin, anticoagulants, anticonvulsants, hormone replacement therapy, etc.) that may influence bone tissue metabolism, except medications used to treat underlying disease: disease modifiers, TNF-α blockers, GC and non-steroid anti-inflammatory drugs (data obtained

Primary selection of patients was performed according to patients' medical history and data of clinical investigations (data from the hospital and out-patient records were used under the patients consent). Then, every patient completed one of the three questionnaires depending on the research subgroup he/she belonged to. The following questionnaire data were assessed: socio-demographic data – age, gender, education, profession, work environment; smoking, use of alcohol; bone fractures in subject and his close relatives; previous and current diseases; previously and currently used medications; calcium amount in the diet (mg/d); frequency of physical activities by month (at least 20 minutes physical exercises per day) and the age of the beginning and the end of menstrual cycle in

In patients with SpA and RA: duration of the disease (in months) from the onset of the first symptoms and from the date the diagnosis was established; pain intensity assessment using

In patients with SpA the following parameters were assessed: disease belonging to SpA group; type of joint lesion: axial, peripheric, both axial and peripheric; physical disability was assessed by completing Health Assessment Questionaire Modified for Spondyloarthropathies (HAQ-S) (Daltroy et al., 1990); immobility was assessed according to Bath Ankylosing Spondylitis Functional Index (BASFI) (Calin et al., 1994) and Bath Ankylosing Spondylitis Patient Global Score (BAS-G) (Jones et al., 1996); assessment of enthesis; movement of spine was assessed according to standardized SpA clinical measurements: lumbar side flexion, modified Schober's test, tragus to wall distance and intermalleolar distance (Jenkinson et al, 1994); activity of the disease according to patients self-assessment using Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (Garrett et al, 1994); activity of the disease evaluated by rheumatologist (Landewe et al, 2004). The linguistic and cultural adaptation of these questionnaires was made during the study. Internal consistency was high for functional and disease activity index (Cronbach alpha>/=0.80) and moderate for the Bath Ankylosing Spondylitis Patient Global Score (Cronbach alpha=0.58). High stability in regard to time was characteristic of all three questionnaires (intraclass correlation coefficient >0.95). A significant association between the separate questions of examined instruments, their joint results and other factors reflecting

10 cm VAS scale; patient's general status assessment using 10 cm VAS scale.

patient's health was established (Venceviciene et al., 2009).

influencing calcium metabolism or interfering metabolism of bone tissue;

**2.3 Exclusion criteria** 

**2.4 Research structure** 

femails.

Subjects after hip joint replacement;

from medical records and patient interviews); Pregnant women, vegetarians, alcohol addicts.

> Statistical analysis was performed using SPSS 16 software. Mean (M) and standard deviation (SD) were used to describe quantitative characteristics of the research. Frequencies (n) and percents (%) were used for qualitative characteristics. Depending on applicable assumptions Student's t-test for independent samples was used to compare means of a particular qualitative characteristic of different samples. Analysis of variance ANOVA was used to compare quantitative variables of more than two samples (when variances were unequal Welch test statistics was used). When the hypothesis of the equality of means of two or more groups was rejected, pairwise comparison of this characteristic was additionally used. In that case Tukey HSD Post Hoc test was used. Differences of qualitative characteristics of experimental groups were assessed using Chi square test. Selected level of significance α = .05.

> To analyze relationship between SpA variables: the duration of disease, physical disability and immobility, activity of the disease and treatment with GC and TNF- blockers and BMD changes linear regression models were developed. Stepwise selection of variables in the linear regression was used. Variables were included in the model when their p was <.05 and excluded when their p was > .10. When strong association between independent variables was observed (e.g., cumulative dose of GC and duration of use (calculated using Spearman correlation coefficient), only one of them was used for calculations. To assess probability that Z-score will be -2 in any site of examined skeleton logistic regression analysis was used.

Bone Mineral Density Changes in Patients with Spondyloarthropathies 33

determined. It was also established that in both SpA and RA patients mean BMD value in all examined skeletal sites was significantly lower than mean BMD value in control group

**3.3 Homogenicity by BMD changes in patients with various diseases belonging to** 

The second objective of our research was to investigate BMD changes at lumbar spine and upper part of the left and right femur in patients with various diseases belonging to SpA group (AS, ReA, PsA, EnA) and in SpA patients with different type of joint lesions (only

Patients with SpA were allocated to the following subgroups: 54 (39.70%) patients with AS, 33 (24.3%) – with PsA, 29 (21.3%) - with EnA and 20 (14.7%) with ReA. The comparison of

BMD Disease belonging to SpA group p AS (n = 54) PsA (n = 33) EnA (n = 29) ReaA (n = 20) BMDS .885 (.149) .890 (.143) .837 (.075) .870 (.096) .346 BMDL .837 (.125) .845 (.135) .857 (.115) .877 (.094) .632 BMDR .821 (.127) .830 (.131) .858 (.118) .860 (.094) .463 ZS -1.301 (1.023) -1.077 (1.258) -1.631 (.484) -1.298 (.868) .179 ZL -1.282 (.912) -.991 (1.069) -1.157 (.856) -.928 (.965) .392 ZR -1.386 (.933) -1.120 (1.032) -1.158 (.891) -1.040 (.954) .418

Table 2. Comparison of BMD (g/cm2) and Z-score (mean (SD)) between patients with various diseases of spondyloarthropathy group patients with ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis (ReA) and enteropathic arthropathy (EnA). Bone mineral density (BMD) expressed as g/cm2 at spine (BMDS), left femur (BMDL) and right femur (BMDR); BMD expressed as Z-score in spine (ZS), left femur (ZL) and right femur

Data presented in Table 2 do not demonstrate statistically significant BMD differences at lumbar spine and upper parts of the both femurs of patients with AS, PsA, EnA and

Patients with SpA were allocated to three subgroups depending on the type of joint lesion: patients with only axial lesion, only peripheral lesions and patients with both axial and peripheral lesion. Twenty five (18.4%) patients were allocated to the axial lesion group, 20 (14.7%) – to the peripheral lesion group, and both axial and peripheral lesion was diagnosed in 91 (66.9) patients. The comparison of BMD in SpA patients with various joint lesion types showed that there are no significant differences in BMD between subgroups at any

Summarizing data presented in Tables 2 and 3 it might be claimed that no significant differences in BMD mean values were found at any examined sites of the skeleton both comparing patients with various diseases belonging to SpA group and patients with different types of joint lesions. Therefore SpA group could be further analyzed as a

homogeneous group without dividing it into subgroups by diseases.

**spondyloarthropathy group and with various types of joint lesions** 

axial, only peripheral, both axial and peripheral).

BMD value between these groups is presented in Table 2.

subjects.

(ZR).

ReA.

examined sites of the skeleton (Table 3).

#### **3. Results**

#### **3.1 Characteristics of study groups**

Three hundred fifty four subjects were enrolled in this research: 136 (38.4%) patients with SpA, 104 (29.4%) patients with RA and 114 (32.2%) healthy people (control group). The subjects of all groups were similar in BMI, physical activity and family history (all p > .05). No differences in disease activity determined by rheumatologist were observed between RA and SpA patients (p > .516). Subjects' differences in age (SpA patients: M = 42.18 ± 12.92; RA patients: M = 50.09 ± 11.10; p < .001), duration of the disease (SpA patients: M = 112.09 ± 94.54; RA patients: M = 148.49 ± 109.60; p < .007), and gender were determined. There were more males in SpA group compared with RA group (p < .001) and control group (p < .001); there were no differences in the number of males in RA group and control group (p = .119). No significant differences in the proportion of premenopausal and postmenopausal women in research groups were determined. (SpA vs. control group p = .550; SpA vs. RA p = .112; RA vs. control group p = .600).

#### **3.2 BMD comparison in patients with SpA and RA and in control group subjects**

The first objective of our research was to investigate BMD changes at lumbar spine and upper parts of the femurs in groups of patients with SpA, RA and healthy subjects.


BMD values at lumbar spine and upper part of the left and right femur (BMD expressed as g/cm2 and Z-score) are presented in Table 1.

Table 1. Comparison of BMD (g/cm2) and Z-score (mean (SD)) between research groups SpA – patients with spondyloarthropathies; RA – patients with rheumatoid arthritis. Bone mineral density (BMD) expressed as g/cm2 at spine (BMDS), left femur (BMDL) and right femur (BMDR); BMD expressed as Z-score in spine (ZS), left femur (ZL) and right femur (ZR).

In both SpA and RA patients a similar decrease of BMD (expressed as g/cm2 and Z-score, unless otherwise stated) (Table 1) at lumbar spine and upper parts of the both femurs was

Three hundred fifty four subjects were enrolled in this research: 136 (38.4%) patients with SpA, 104 (29.4%) patients with RA and 114 (32.2%) healthy people (control group). The subjects of all groups were similar in BMI, physical activity and family history (all p > .05). No differences in disease activity determined by rheumatologist were observed between RA and SpA patients (p > .516). Subjects' differences in age (SpA patients: M = 42.18 ± 12.92; RA patients: M = 50.09 ± 11.10; p < .001), duration of the disease (SpA patients: M = 112.09 ± 94.54; RA patients: M = 148.49 ± 109.60; p < .007), and gender were determined. There were more males in SpA group compared with RA group (p < .001) and control group (p < .001); there were no differences in the number of males in RA group and control group (p = .119). No significant differences in the proportion of premenopausal and postmenopausal women in research groups were determined. (SpA vs. control group p = .550; SpA vs. RA p = .112;

**3.2 BMD comparison in patients with SpA and RA and in control group subjects** 

upper parts of the femurs in groups of patients with SpA, RA and healthy subjects.

Research groups

SpA (n = 136) RA (n = 104) Control (n = 114)

The first objective of our research was to investigate BMD changes at lumbar spine and

BMD values at lumbar spine and upper part of the left and right femur (BMD expressed as

BMDS .873 (.128) .866 (.125) 1.016 (.121) < .001 3>1 (p <.001)

BMDL .849 (.121) .832 (.131) .998 (.113) < .001 3>1 (p <.001)

BMDR .837 (.122) .825 (.122) .983 (.110) < .001 3>1 (p <.001)

ZS -1.317 (.998) -1.061 (1.096) .045 (.941) < .001 3>1 (p <.001)

ZL -1.133 (.949) -1.014 (1.001) .097 (.842) < .001 3>1 (p <.001)

ZR -1.222 (.952) -1.143 (1.161) -.014 (.838) < .001 3>1 (p <.001)

In both SpA and RA patients a similar decrease of BMD (expressed as g/cm2 and Z-score, unless otherwise stated) (Table 1) at lumbar spine and upper parts of the both femurs was

Table 1. Comparison of BMD (g/cm2) and Z-score (mean (SD)) between research groups SpA – patients with spondyloarthropathies; RA – patients with rheumatoid arthritis. Bone mineral density (BMD) expressed as g/cm2 at spine (BMDS), left femur (BMDL) and right femur (BMDR); BMD expressed as Z-score in spine (ZS), left femur (ZL) and right femur

1 2 3 p Post hoc

3>2 (p <.001)

3>2 (p <.001)

3>2 (p <.001)

3>2 (p <.001)

3>2 (p <.001)

3>2 (p <.001)

**3. Results** 

BMD

(ZR).

**3.1 Characteristics of study groups** 

RA vs. control group p = .600).

g/cm2 and Z-score) are presented in Table 1.

determined. It was also established that in both SpA and RA patients mean BMD value in all examined skeletal sites was significantly lower than mean BMD value in control group subjects.

#### **3.3 Homogenicity by BMD changes in patients with various diseases belonging to spondyloarthropathy group and with various types of joint lesions**

The second objective of our research was to investigate BMD changes at lumbar spine and upper part of the left and right femur in patients with various diseases belonging to SpA group (AS, ReA, PsA, EnA) and in SpA patients with different type of joint lesions (only axial, only peripheral, both axial and peripheral).

Patients with SpA were allocated to the following subgroups: 54 (39.70%) patients with AS, 33 (24.3%) – with PsA, 29 (21.3%) - with EnA and 20 (14.7%) with ReA. The comparison of BMD value between these groups is presented in Table 2.


Table 2. Comparison of BMD (g/cm2) and Z-score (mean (SD)) between patients with various diseases of spondyloarthropathy group patients with ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis (ReA) and enteropathic arthropathy (EnA). Bone mineral density (BMD) expressed as g/cm2 at spine (BMDS), left femur (BMDL) and right femur (BMDR); BMD expressed as Z-score in spine (ZS), left femur (ZL) and right femur (ZR).

Data presented in Table 2 do not demonstrate statistically significant BMD differences at lumbar spine and upper parts of the both femurs of patients with AS, PsA, EnA and ReA.

Patients with SpA were allocated to three subgroups depending on the type of joint lesion: patients with only axial lesion, only peripheral lesions and patients with both axial and peripheral lesion. Twenty five (18.4%) patients were allocated to the axial lesion group, 20 (14.7%) – to the peripheral lesion group, and both axial and peripheral lesion was diagnosed in 91 (66.9) patients. The comparison of BMD in SpA patients with various joint lesion types showed that there are no significant differences in BMD between subgroups at any examined sites of the skeleton (Table 3).

Summarizing data presented in Tables 2 and 3 it might be claimed that no significant differences in BMD mean values were found at any examined sites of the skeleton both comparing patients with various diseases belonging to SpA group and patients with different types of joint lesions. Therefore SpA group could be further analyzed as a homogeneous group without dividing it into subgroups by diseases.

Bone Mineral Density Changes in Patients with Spondyloarthropathies 35

(standard error) Beta p

DAR2 -.124 (.027) -.459 < .001 DAR1 -.066 (.026) -.252 .012 G2 .064 (.023) .231 .006 BMI .005 (.002) .189 .022 constant .773 (.063) < .001

DAR2 -.122 (.022) -.480 < .001 IM2 -.101 (.025) -.290 < .001 BMI .006 (.002) .244 .001 DAR1 -.059 (.021) -.240 .005 Glucocorticoids -.001 (.001) -.141 .045 Constant .783 (.047) < .001

DAR2 -.115 (.022) -.450 < .001 IM2 -.121 (.024) -.347 < .001 BMI .006 (.002) .230 .001 Glucocorticoids -.002 (.001) -.163 .017 DAR1 -.046 (.020) -.185 .025 Constant .775 (.046) < .001

BMI .061 (.015) .313 < .001 DAR2 -.919 (.196) -.441 < .001 DAR1 -.496 (.185) -.247 .008

DAR2 -.922 (.177) -.461 < .001 BMI .072 (.013) .384 < .001 DAR1 -.468 (.165) -.243 .005 Glucocorticoids -.012 (.006) -.146 .042 IM2 -.400 (.199) -.147 .046 Constant -2.399 (.373) < .001

DAR2 -.853 (.178) -.425 < .001 BMI .068 (.013) .360 < .001 IM2 -.550 (.200) -.201 < .001 Glucocorticoids -.013 (.006) -.160 .007 DAR1 -.366 (.166) -.189 .026 Constant -2.414 (.376) < .001

Table 4. Multiple linear regression analysis of BMD (expressed as g/cm2 and Z-score) at different sites of measurement (dependent variable), demographic and disease variables (independent variables). Bone mineral density (BMD) expressed as g/cm2 at spine (BMDS), left femur (BMDL) and right femur (BMDR); BMD expressed as Z-score at spine (ZS), left femur (ZL) and right femur (ZR). IM – intermalleolar distance; DAR - activity of the disease determined by rheumatologist. The coefficient of determination R2 and coefficient of determination corrected by the number of independent variables (R2(adj.)), and p value close to the coefficient of determination is intended to test the hypothesis that regression is absent (hypothesis is discarded when p < .05); standard error determines standard deviation of the coefficient of regression; beta determines coefficient of regression of standardized

first symptoms onset .003 (.001) .252 .003 Glucocorticoids -.019 (.007) -.226 .006 Constant -2.608 (.418) < .001

variable Independent variable Regression coefficient (B)

Duration of the disease from

Dependent

BMDS (R2 =.192; R2 (adj.) = .168; p < .001)

BMDL (R2 =.405; R2 (adj.) = .382; p < .001)

BMDR (R2 =.443; R2 (adj.) = .421; p < .001)

ZS (R2 =.294; R2 (adj.) = .266; p < .001)

ZL (R2 =.388; R2 (adj.) = .365; p < .001)

ZR (R2 =.384 R2 (adj.) = .360; p < .001)

data.


Table 3. Comparison of BMD (g/cm2) and Z-score (mean (SD)) between patients with various types of joint lesions Bone mineral density (BMD) expressed as g/cm2 at spine (BMDS), left femur (BMDL) and right femur (BMDR); BMD expressed as Z-score in spine (ZS), left femur (ZL) and right femur (ZR).

#### **3.4 Variables associated with bone mineral density changes in patients with spondyloarthropathies**

In order to determine variables related to BMD at lumbar spine and upper part of the left and right femur of patients with SpA, 90 models of multiple stepwise linear regression analysis were developed. One of the values of BMD (BMDS, BMDL, BMDR, ZS, ZL, ZR) served as dependent variable, and independent variables were controlled variables: age, gender (when BMD was expressed as g/cm2), BMI, family history of fractures, various diseases belonging to SpA group, type of joint lesions and physical activity. Each time one of the specific SpA factors was involved into the model: duration of the disease calculated from the time of the manifestation of first symptoms and from the time the diagnosis was established; physical disability and immobility indicators: subjective (HAQ-S, BAS-G, BASFI) and objective (spine movement indicators: lumbar side flexion, modified Schober's test, tragus to wall distance and intermalleolar distance); disease activity indicators: BASDAI, ESR, CRP and disease activity determined by rheumatologist; medications in use: glucocorticoids and TNF- blockers. Variables with highest determination coefficients of the equations of multiple stepwise linear regression obtained during the assessment of BMD at lumbar spine and upper part of the left and right femur were selected for the final multiple linear regression analysis:


The summary of the final linear regression analysis model is presented in Table 4. Coding of the categorical variables is presented in Table 5.

Type of joint lesion

BMDS .859 (.158) .846 (.080) .883 (.128) .416 BMDL .836 (.147) .882 (.100) .845 (.117) .391 BMDR .818 (.149) .875 (.103) .833 (.117) .269 ZS -1.427 (1.289) -1.541 (.668) -1.237 (.952) .384 ZL -1.284 (1.122) -.982 (.874) -1.124 (.917) .567 ZR -1.408 (1.142) -1.034 (.874) -1.213 (.913) .421

Peripheric (n = 20)

Table 3. Comparison of BMD (g/cm2) and Z-score (mean (SD)) between patients with various types of joint lesions Bone mineral density (BMD) expressed as g/cm2 at spine (BMDS), left femur (BMDL) and right femur (BMDR); BMD expressed as Z-score in spine

**3.4 Variables associated with bone mineral density changes in patients with** 

In order to determine variables related to BMD at lumbar spine and upper part of the left and right femur of patients with SpA, 90 models of multiple stepwise linear regression analysis were developed. One of the values of BMD (BMDS, BMDL, BMDR, ZS, ZL, ZR) served as dependent variable, and independent variables were controlled variables: age, gender (when BMD was expressed as g/cm2), BMI, family history of fractures, various diseases belonging to SpA group, type of joint lesions and physical activity. Each time one of the specific SpA factors was involved into the model: duration of the disease calculated from the time of the manifestation of first symptoms and from the time the diagnosis was established; physical disability and immobility indicators: subjective (HAQ-S, BAS-G, BASFI) and objective (spine movement indicators: lumbar side flexion, modified Schober's test, tragus to wall distance and intermalleolar distance); disease activity indicators: BASDAI, ESR, CRP and disease activity determined by rheumatologist; medications in use: glucocorticoids and TNF- blockers. Variables with highest determination coefficients of the equations of multiple stepwise linear regression obtained during the assessment of BMD at lumbar spine and upper part of the left and right femur were selected for the final multiple

 Duration of the disease calculated from the time of the manifestation of first symptoms; Indicators of patient's functional status: physical disability and immobility according to HAQ-S questionnaire, and reduction of spine movement assessed by the measurement

The summary of the final linear regression analysis model is presented in Table 4. Coding of

Axial p

Axial and peripheric (n = 91)

BMD

(n = 25)

(ZS), left femur (ZL) and right femur (ZR).

**spondyloarthropathies** 

linear regression analysis:

of intermalleolar distance;

Age, gender (BMD expressed as g/cm2), BMI;

the categorical variables is presented in Table 5.

 Activity of the diseases determined by rheumatologist; Treatment: cumulative doses of glucocorticoids (g).


Table 4. Multiple linear regression analysis of BMD (expressed as g/cm2 and Z-score) at different sites of measurement (dependent variable), demographic and disease variables (independent variables). Bone mineral density (BMD) expressed as g/cm2 at spine (BMDS), left femur (BMDL) and right femur (BMDR); BMD expressed as Z-score at spine (ZS), left femur (ZL) and right femur (ZR). IM – intermalleolar distance; DAR - activity of the disease determined by rheumatologist. The coefficient of determination R2 and coefficient of determination corrected by the number of independent variables (R2(adj.)), and p value close to the coefficient of determination is intended to test the hypothesis that regression is absent (hypothesis is discarded when p < .05); standard error determines standard deviation of the coefficient of regression; beta determines coefficient of regression of standardized data.

Bone Mineral Density Changes in Patients with Spondyloarthropathies 37

patients with the duration of the disease shorter than 100 months; patients with the duration of the disease from 100 to 200 months; and patients with the duration of the disease of more than 200 months. Results of the comparison BMD (expressed as g/cm2 and Z-score) between

BMDL .886 (.100) .804 (.123) .803(.140) < .001 1>2 (p = .002)

BMDR .875 (.096) .795 (.138) .782(.128) < .001 1>2 (p = .002)

ZL -.920 (.893) -1.432 (.947) -1.342(.986) .013 1>2 (p = .021) ZR -1.004 (.878) -1.489 (1.030) -1.491(.922) .011 1>2 (p = .031)

Using analysis of variance (ANOVA) it was established that BMD (expressed as g/cm2 and Z-score) at the both femurs significantly decreased when duration of the disease increased (assessed from the time of first symptoms). BMD at the spine not only decreases with the increase of the duration of disease, but even slightly increases, however, not significantly. We suppose that this is only "false-positive" effect occurred due to spine changes specific to SpA: syndesmophytes, calcification of longitudinal ligaments and calcification intervertebral discs and joint ankylosis in long-term SpA patients, and therefore no significant spine BMD (expressed as g/cm2 and Z-score) differences between these subgroups were established measuring BMD by DXA anterior-posterior view. No significant BMD differences between subgroups of patients allocated according to the duration of the disease assessed from the time of diagnosis were established in any sites of the skeleton (all p > .05. data not shown). According to these data we may assume that the most significant loss of bone mass takes place in the beginning of disease when diagnosis is not established yet. When diagnosis is established, etiopathogenetic treatment starts strongly inhibiting local and systemic inflammation and associated osteoclast activity and demineralization of the bone tissue.

Another variable that allows for the suspected decrease of BMD (expressed as g/cm2 and Zscore) at upper parts of both femurs is decrease in spine movement assessed by the intermalleolar distance. When SpA patients were allocated into subgroups according to standardized levels of limitation of movement, it was noticed that with the decline of spine movement (assessed by the intermalleolar distance) BMD decreased not only at both femurs (expressed as g/cm2 and Z-score), but also at the spine (expressed as g/cm2). The lowest femur BMD (expressed as g/cm2 and Z-score) was determined in SpA patients with severe

limitation of spine movement assessed by the intermalleolar distance (Table 7).

p Post hoc 1 2 3

(n = 26)

1>3 (p = .005)

1>3 (p = .001)

Duration of the disease from the time of first symptoms

(n = 75) 100-200 months (n = 35) > 200 months

BMDS .878 (.105) .852 (.158) .890(.147) .488

ZS -1.311 (.888) -1.468 (1.163) -1.131(1.016) .422

BMD expressed as Z-score in spine (ZS), left femur (ZL) and right femur (ZR).

Table 6. Comparison of BMD (g/cm2) and Z-score (mean (SD)) between patients with various disease duration (assessed from the time of first symptoms). Bone mineral density (BMD) expressed as g/cm2 at spine (BMDS), left femur (BMDL) and right femur (BMDR);

subgroups presented in Table 6.

< 100 months

BMD


Table 5. Coding of the categorical variables in the regression analysis.

The analysis of Table 4 shows that main variable associated with BMD decrease at all examined sites of the skeleton is moderate and high disease activity which was determined by rheumatologist. Higher BMD values at all examined sites of the skeleton are determined by higher BMI of the patients with SpA (positive coefficient of regression). Spine BMD (expressed as Z-score) and both femurs BMD (expressed as g/cm2 and Z-score) are significantly negatively affected by glucocorticoids. This means that higher cumulative glucocorticoid dose is associated with lower BMD at the spine and both femurs. Severe limitation of spine movement, assessed by the intermalleolar distance, is the significant negative variable for BMD changes at the upper part of the left and right femur (expressed as g/cm2 and Z-score). The duration of the disease calculated from the onset of first symptoms was a significant variable associated with the changes in spine BMD (expressed as Z-score). It should be noted that lengthening of the duration of the disease is associated with higher Z-score at the spine (positive coefficient of regression was obtained). Male gender is another causative factor significantly positively affecting spine BMD changes (expressed as g/cm2).

To summarise, it should be stated that the decrease of spine BMD is significantly associated with moderate and high activity of the disease determined by rheumatologist, and with the increase of cumulative dose of glucocorticoids; the decrease of upper part of both femurs BMD is associated with moderate and high activity of the disease determined by rheumatologist, the increase of cumulative dose of glucocorticoids and severe limitation of spine movement assessed by intermalleolar distance. Based on beta coefficients of significant variables it might be stated that the most precise prognostic variable for the decrease of BMD is increasing activity of the disease in patients with SpA determined by rheumatologist.

Analyzing BMD changes dependence from changes of established significant variables subjects of SpA group were allocated into subgroups according to these factors. Allocation was based on literature data and trends of changes of BMD and specific factors established by our research.

In order to clarify how BMD changes with the increase of the disease duration (assessed from the time of first symptoms) we allocated patients with SpA in three subgroups:

The analysis of Table 4 shows that main variable associated with BMD decrease at all examined sites of the skeleton is moderate and high disease activity which was determined by rheumatologist. Higher BMD values at all examined sites of the skeleton are determined by higher BMI of the patients with SpA (positive coefficient of regression). Spine BMD (expressed as Z-score) and both femurs BMD (expressed as g/cm2 and Z-score) are significantly negatively affected by glucocorticoids. This means that higher cumulative glucocorticoid dose is associated with lower BMD at the spine and both femurs. Severe limitation of spine movement, assessed by the intermalleolar distance, is the significant negative variable for BMD changes at the upper part of the left and right femur (expressed as g/cm2 and Z-score). The duration of the disease calculated from the onset of first symptoms was a significant variable associated with the changes in spine BMD (expressed as Z-score). It should be noted that lengthening of the duration of the disease is associated with higher Z-score at the spine (positive coefficient of regression was obtained). Male gender is another causative factor significantly positively affecting spine BMD changes

To summarise, it should be stated that the decrease of spine BMD is significantly associated with moderate and high activity of the disease determined by rheumatologist, and with the increase of cumulative dose of glucocorticoids; the decrease of upper part of both femurs BMD is associated with moderate and high activity of the disease determined by rheumatologist, the increase of cumulative dose of glucocorticoids and severe limitation of spine movement assessed by intermalleolar distance. Based on beta coefficients of significant variables it might be stated that the most precise prognostic variable for the decrease of BMD is increasing activity of the disease in patients with SpA determined by

Analyzing BMD changes dependence from changes of established significant variables subjects of SpA group were allocated into subgroups according to these factors. Allocation was based on literature data and trends of changes of BMD and specific factors established

In order to clarify how BMD changes with the increase of the disease duration (assessed from the time of first symptoms) we allocated patients with SpA in three subgroups:

Variable Coding Gender **G1 G2**  Premonapausal females 0 0 Postmenopausal females 1 0 Males 0 1 Intermalleolar distance **IM1 IM2**  0 – mild limitation of movement 0 0 1 – moderate limitation of movement 1 0 2 – severe limitation of movement 0 1 Activity of the disease determined by rheumatologist **DAR 1 DAR 2**  2 – low activity 0 0 3 – moderate activity 1 0 4 – high activity 0 1

Table 5. Coding of the categorical variables in the regression analysis.

(expressed as g/cm2).

rheumatologist.

by our research.

patients with the duration of the disease shorter than 100 months; patients with the duration of the disease from 100 to 200 months; and patients with the duration of the disease of more than 200 months. Results of the comparison BMD (expressed as g/cm2 and Z-score) between subgroups presented in Table 6.


Table 6. Comparison of BMD (g/cm2) and Z-score (mean (SD)) between patients with various disease duration (assessed from the time of first symptoms). Bone mineral density (BMD) expressed as g/cm2 at spine (BMDS), left femur (BMDL) and right femur (BMDR); BMD expressed as Z-score in spine (ZS), left femur (ZL) and right femur (ZR).

Using analysis of variance (ANOVA) it was established that BMD (expressed as g/cm2 and Z-score) at the both femurs significantly decreased when duration of the disease increased (assessed from the time of first symptoms). BMD at the spine not only decreases with the increase of the duration of disease, but even slightly increases, however, not significantly. We suppose that this is only "false-positive" effect occurred due to spine changes specific to SpA: syndesmophytes, calcification of longitudinal ligaments and calcification intervertebral discs and joint ankylosis in long-term SpA patients, and therefore no significant spine BMD (expressed as g/cm2 and Z-score) differences between these subgroups were established measuring BMD by DXA anterior-posterior view. No significant BMD differences between subgroups of patients allocated according to the duration of the disease assessed from the time of diagnosis were established in any sites of the skeleton (all p > .05. data not shown). According to these data we may assume that the most significant loss of bone mass takes place in the beginning of disease when diagnosis is not established yet. When diagnosis is established, etiopathogenetic treatment starts strongly inhibiting local and systemic inflammation and associated osteoclast activity and demineralization of the bone tissue.

Another variable that allows for the suspected decrease of BMD (expressed as g/cm2 and Zscore) at upper parts of both femurs is decrease in spine movement assessed by the intermalleolar distance. When SpA patients were allocated into subgroups according to standardized levels of limitation of movement, it was noticed that with the decline of spine movement (assessed by the intermalleolar distance) BMD decreased not only at both femurs (expressed as g/cm2 and Z-score), but also at the spine (expressed as g/cm2). The lowest femur BMD (expressed as g/cm2 and Z-score) was determined in SpA patients with severe limitation of spine movement assessed by the intermalleolar distance (Table 7).

Bone Mineral Density Changes in Patients with Spondyloarthropathies 39

Comparison of BMD (expressed as g/cm2 and Z-score) between patients allocated according to cumulative glucocorticoid dose is presented in the Table 8. Analysis of the results using Turkey HSD test demonstrated that between first three groups (untreated patients, patients used < 1g and 1-10g cumulative dose of glucocorticoids) there are no statistically significant differences of BMD (expressed as g/cm2 and Z-score) at the lumbar spine and upper part of the left and right femur. However, differences presented in the Table 8 are caused by the comparison of patients taking a cumulative dose of more than 10 g of glucocorticoids with untreated patients. Summarizing these results it may be said that higher than 10 g cumulative dose of glucocorticoids is associated with the decrease of BMD (expressed as g/cm2 and Z-score) at the upper part of the left and right femur in patients with SpA.

The most important SpA factor associated with the loss of bone mass is the activity of SpA disease. In SpA group there were no patients with inactive disease determined by rheumatologist (score of activity = 1), and therefore patients were allocated into three subgroups according to the activity of disease: 2 – mild activity, 3 moderate activity, 4 – high

BMD Activity of the disease determined by rheumatologist p Post hoc 2 (n = 35) 3 (n = 55) 4 (n = 46)

4<2 (p < .001) 4<3 (p =.015) 3<2 (p = .026)

4<2 (p < .001) 4<3 (p < .001) 3<2 (p = .007)

4<2 (p < .001) 4<3 (p < .001) 3<2 (p = .034)

4<2 (p < .001) 4<3 (p =.025) 3<2 (p = .016)

4<2 (p < .001) 4<3 (p < .001) 3<2 (p = .005)

4<2 (p < .001) 4<3 (p < .001) 3<2 (p = .028)

activity. Comparison BMD between these subgroups presented in the Table 9.

BMDS .937 (.112) .878 (.116) .819 (.133) < .001

BMDL .927 (.093) .865 (.110) .771 (.107) < .001

BMDR .909 (.087) .860 (.109) .754 (.113) < .001

ZS -.809 (.899) -1.301 (.837) -1.722 (1.054) < .001

ZL -.538 (.735) -1.054 (.914) -1.680 (.837) < .001

ZR -.683 (.717) -1.092 (.905) -1.787 (.881) < .001

(ZR); 2 – mild activity, 3 – moderate activity, 3 – high activity.

Table 9. Comparison BMD (g/cm2) and Z-score (mean value (SD)) between SpA patients allocated according to the activity of the disease determined by rheumatologist Bone mineral density (BMD) expressed as g/cm2 at spine (BMDS), left femur (BMDL) and right femur (BMDR); BMD expressed as Z-score in spine (ZS), left femur (ZL) and right femur

Analysis of the comparison data presented in Table 9 demonstrated that disease activity assessment performed by rheumatologist allows to suspect BMD changes in all sites of skeleton. In all analyzed sites (in lumbar spine and both femurs BMD expressed as g/cm2 and Z-score) in patients with lower disease activity (2) BMD was higher in comparison with


Table 7. Comparison of BMD (g/cm2) and Z-score (mean value (SD)) between SpA patients allocated according to the established limitation of spine movement assessed by the intermalleolar distance

Bone mineral density (BMD) expressed as g/cm2 at spine (BMDS), left femur (BMDL) and right femur (BMDR); BMD expressed as Z-score in spine (ZS), left femur (ZL) and right femur (ZR); 0 - mild limitation of movement, 1 – moderate limitation of movement, 2 – severe limitation of movement.

Another significant and clinically important factor associated with BMD changes at the spine and both femurs is cumulative dose of GC. It is not known what cumulative dose of GC or duration of use of these medications become risk factors for the decrease of BMD. Therefore patients were conventionally allocated into 4 subgroups according to the following distribution of cumulative doses: untreated patients (n = 46); patients using cumulative dose of less than 1 g (n = 34) corresponding use of 5 mg/day during up to 6 months; patients using cumulative dose from 1 to 10 g (n = 36) corresponding use of 5 mg/day during up to 5 years; and patients using cumulative dose more than 10 g (n = 20) corresponding use of 5 mg/day longer than 5 years.


Table 8. Comparison of BMD (g/cm2) and Z-score (mean value (SD)) between SpA patients allocated according to the cumulative glucocorticoid dose. Bone mineral density (BMD) expressed as g/cm2 at spine (BMDS), left femur (BMDL) and right femur (BMDR); BMD expressed as Z-score in spine (ZS), left femur (ZL) and right femur (ZR).

BMDS .899 (.112) .857 (.124) .813 (.171) .019 2<0 (p = .024) BMDL .880 (.099) .849 (.116) .730 (.139) < .001 2<0 (p < .001)

BMDR .871 (.100) .840 (.103) .698 (.145) < .001 2<0 (p < .001)

ZL -.980 (.879) -1.145 (.873) -1.692 (1.191) .049 2<0 (p = .009) ZR -1.051 (.885) -1.205 (.794) -1.917 (1.238) .002 2<0 (p < .001)

Table 7. Comparison of BMD (g/cm2) and Z-score (mean value (SD)) between SpA patients allocated according to the established limitation of spine movement assessed by the

Bone mineral density (BMD) expressed as g/cm2 at spine (BMDS), left femur (BMDL) and right femur (BMDR); BMD expressed as Z-score in spine (ZS), left femur (ZL) and right femur (ZR); 0 - mild limitation of movement, 1 – moderate limitation of movement, 2 –

Another significant and clinically important factor associated with BMD changes at the spine and both femurs is cumulative dose of GC. It is not known what cumulative dose of GC or duration of use of these medications become risk factors for the decrease of BMD. Therefore patients were conventionally allocated into 4 subgroups according to the following distribution of cumulative doses: untreated patients (n = 46); patients using cumulative dose of less than 1 g (n = 34) corresponding use of 5 mg/day during up to 6 months; patients using cumulative dose from 1 to 10 g (n = 36) corresponding use of 5 mg/day during up to 5 years; and patients using cumulative dose more than 10 g (n = 20)

p Post hoc 123 4

>10 g (n = 20)

1-10 g (n = 36)

BMDL .881 (.110) .873 (.122) .830 (.106) .769 (.133) .002 4<1 (p = .002)

BMDR .868 (.112) .856 (.113) .827 (.101) .747 (.150) .001 4<1 (p = .001)

ZS -1.320 (.933) -1.097 (.975) -1.361 (.960) -1.602 (1.160) .333 ZL -.871 (.958) -1.076 (.791) -1.270 (.847) -1.586 (1.180) .028 4<1 (p = .024) ZR -.962 (.983) -1.186 (.737) -1.291 (.817) -1.757 (1.226) .017 4<1 (p = .009) Table 8. Comparison of BMD (g/cm2) and Z-score (mean value (SD)) between SpA patients allocated according to the cumulative glucocorticoid dose. Bone mineral density (BMD) expressed as g/cm2 at spine (BMDS), left femur (BMDL) and right femur (BMDR); BMD

expressed as Z-score in spine (ZS), left femur (ZL) and right femur (ZR).

BMDS .869 (.102) .903 (.138) .869 (.126) .844 (.167) .405

Cumulative glucocorticoid dose

0 p Post hoc

2 (n = 19)

2<1 (p < .001)

2<1 (p < .001)

2<1 (p = .014)

4<2 (p = .010)

4<2 (p = .006)

Level of limitation of spine movement

ZS -1.184 (.929) -1.448 (.877) -1.522 (1.370) .234

1 (n = 44)

BMD

intermalleolar distance

BMD

severe limitation of movement.

Untreated (n = 46)

corresponding use of 5 mg/day longer than 5 years.

< 1g (n = 34)

(n = 73)

Comparison of BMD (expressed as g/cm2 and Z-score) between patients allocated according to cumulative glucocorticoid dose is presented in the Table 8. Analysis of the results using Turkey HSD test demonstrated that between first three groups (untreated patients, patients used < 1g and 1-10g cumulative dose of glucocorticoids) there are no statistically significant differences of BMD (expressed as g/cm2 and Z-score) at the lumbar spine and upper part of the left and right femur. However, differences presented in the Table 8 are caused by the comparison of patients taking a cumulative dose of more than 10 g of glucocorticoids with untreated patients. Summarizing these results it may be said that higher than 10 g cumulative dose of glucocorticoids is associated with the decrease of BMD (expressed as g/cm2 and Z-score) at the upper part of the left and right femur in patients with SpA.

The most important SpA factor associated with the loss of bone mass is the activity of SpA disease. In SpA group there were no patients with inactive disease determined by rheumatologist (score of activity = 1), and therefore patients were allocated into three subgroups according to the activity of disease: 2 – mild activity, 3 moderate activity, 4 – high activity. Comparison BMD between these subgroups presented in the Table 9.


Table 9. Comparison BMD (g/cm2) and Z-score (mean value (SD)) between SpA patients allocated according to the activity of the disease determined by rheumatologist Bone mineral density (BMD) expressed as g/cm2 at spine (BMDS), left femur (BMDL) and right femur (BMDR); BMD expressed as Z-score in spine (ZS), left femur (ZL) and right femur (ZR); 2 – mild activity, 3 – moderate activity, 3 – high activity.

Analysis of the comparison data presented in Table 9 demonstrated that disease activity assessment performed by rheumatologist allows to suspect BMD changes in all sites of skeleton. In all analyzed sites (in lumbar spine and both femurs BMD expressed as g/cm2 and Z-score) in patients with lower disease activity (2) BMD was higher in comparison with

Bone Mineral Density Changes in Patients with Spondyloarthropathies 41

Skeletal remodeling in bone growth, maintenance, and repair is tightly regulated by a dynamic interaction between osteoclasts and osteoblasts. Recent advances in immunopathological mechanism of chronic inflammatory rheumatic disease highlighted the altered balance between bone loss and production by inflammation. T cells, natural killers, and cytokines that are involved in inflammatory process may also be responsible for the bone loss (Ritchlin et al., 2003). Many investigators have observed decreased BMD of the whole skeleton and increased femoral and vertebral fracture risk in patients suffering from both RA and SpA in comparison with healthy persons (Lodder, 2004; Huusko, 2001; Grisar, 2002). Up till now BMD changes were not being compared between SpA and RA patients. An interesting observation from our study is that there was no statistically significant difference of BMD in any examined part of skeleton between the two groups of diseases, i.e. RA and SpA but the BMD difference between the control group and RA and SpA groups was statistically significant, the BMD being higher in all examined parts of skeleton of the control group. Analyzing BMD of SpA, RA and control groups the Z-score of the three groups were compared in order to exclude influence of age and gender, known OP risk factors, on BMD. The Z-score in all examined parts was similar for both RA and SpA groups while the Z-score difference in the same parts examined between the control group and both patient groups was statistically significant, the Z-score being higher in the control group. The findings support the hypothesis that inflammatory environment not only in joint synovial tissues but also in bone caused by autoimmune changes in RA and SpA patients induces a lot of molecular changes, RANKL and OPG equilibrium derangement and is one of the causes provoking not only local but also systemic osteoclastogenesis and related bone resorbtion (Suda, 1992; Franck, 2004; Golmia, 2002). The reduced BMD in case of both RA and SpA may also be explained by worsened mobility function (Szejnfeld, 1997; Faus-Riera, 1991), disturbances of calcium and vitamin D metabolism because of intestine injury and

adverse effect of GC on bone tissue (Lange, 2005; Mielants, 1989).

Data on comparison of the BMD between healthy persons and patients diagnosed with SpA are scarce. As it was mentioned above the BMD of SpA patients was mostly investigated in AS. Several researchers have observed decreased BMD in AS patients compared with healthy persons (Will, 1989; Devogelaer, 1992; Sampaio-Barros, 2005). *K. Dheda* and colleagues, having examined 20 PsA patients, have not observed any statistically significant BMD reduction in PsA patients compared with healthy persons either in lumbar spine or in femur (Dheda et al., 2004). On the contrary *B. Frediani* and colleagues have found statistically significant BMD reduction both in vertebra and femur of PsA patients compared with corresponding skeleton parts of the control group (Frediani et al., 2001). Data on statistically significant BMD reduction in entire skeleton of EnA patients compared with the control group was published by several authors. (Frei, 2006; Reffitt, 2003). *J. Grisar* and colleagues investigated bone metabolism markers and BMD of AS, PsA and ReA patients. The investigators found statistically significant BMD decrease in the proximal femur of AS patients compared with PsA patients. There was no statistically significant difference of vertebral BMD of AS patients and both vertebral and proximal femoral BMD of PsA and ReA patients compared with the BMD of the control group. *J. Grisar* and colleagues conclude that in all forms of the above mentioned spondyloarthropathies accelerated resorbtion of bone tissue prevails regardless of the fact that decreased BMD was not

**4. Discussion** 

patients with moderate (3) activity of the disease, and in this group of patients BMD was higher than in patients with high (4) activity of the disease.

#### **3.5 Factors predicting Z-score probability of ≤ - 2.0 at any site of skeleton**

At the last step of the analysis of the results we performed forward stepwise (Wald) logistic regression analysis intended to find out which variables are the most predictive to event causing Z-score probability of - 2 at any site of skeleton. Assigning Z-score - 2.0 as one and Z-score > -2.0 as zero, logistic regression model will predict the probability of the event during which coded variable will obtain valuation of 1; in this case the probability will be designated as *θ*. Z-score of ≤-2.0 at least in one area of skeleton was determined in 43 patients with SpA (31.6 percent of all patients with SpA).

All variables analyzed in this research were entered into a forward stepwise logistic regression model: age, gender, BMI, family history of fractures, disease belonging to SpA group, type of joint lesion and physical activity; duration of the disease assessed from the time of the onset of first symptoms and from the time of the diagnosis; physical disability and immobility indicators: BAS-G, BASFI, HAQ-S, lumbar side flexion, modified Schober's test, tragus to wall distance and intermalleolar distance; indicators of the activity of the disease: ESR, CRP, BASDAI and disease activity determined by rheumatologist; cumulative dose of glucocorticoids and treatment with TNF-α blockers.

The following significant variables for event *θ* remained in the logistic regression model: moderate and high activity of the disease determined by rheumatologist, low BMI and positive family history of fractures. The results of the last step of logistic regression model are presented in Table 10.


Table 10. Logistic regression analysis of the event when Z-score probability at any site of skeleton will be - 2.0 at the analysis of SpA patient data. \* DAR – activity of the disease determined by rheumatologist; coding of variables described in the Table 5.

The analysis demonstrated that correct probabilities for Z-score at any sites of the skeleton were established in 75.7 % of respondents.

#### **4. Discussion**

40 Clinical and Molecular Advances in Ankylosing Spondylitis

patients with moderate (3) activity of the disease, and in this group of patients BMD was

At the last step of the analysis of the results we performed forward stepwise (Wald) logistic regression analysis intended to find out which variables are the most predictive to event causing Z-score probability of - 2 at any site of skeleton. Assigning Z-score - 2.0 as one and Z-score > -2.0 as zero, logistic regression model will predict the probability of the event during which coded variable will obtain valuation of 1; in this case the probability will be designated as *θ*. Z-score of ≤-2.0 at least in one area of skeleton was determined in 43

All variables analyzed in this research were entered into a forward stepwise logistic regression model: age, gender, BMI, family history of fractures, disease belonging to SpA group, type of joint lesion and physical activity; duration of the disease assessed from the time of the onset of first symptoms and from the time of the diagnosis; physical disability and immobility indicators: BAS-G, BASFI, HAQ-S, lumbar side flexion, modified Schober's test, tragus to wall distance and intermalleolar distance; indicators of the activity of the disease: ESR, CRP, BASDAI and disease activity determined by rheumatologist; cumulative

The following significant variables for event *θ* remained in the logistic regression model: moderate and high activity of the disease determined by rheumatologist, low BMI and positive family history of fractures. The results of the last step of logistic regression model

> Coefficient of regression (B), (standard error)

DAR 17.852 <.001 DAR (2) 3.922 (1.091) 13.384 <.001 54.179 DAR (1) 2.610 (1.077) 5.877 .015 13.602 BMI -.156 (.052) 9.025 .003 .856

constant -.528 (1.607) .108 .743 .590

Wald

1.167 (.543) 4.618 .032 3.212

statistics <sup>p</sup>Exp

(B)

**3.5 Factors predicting Z-score probability of ≤ - 2.0 at any site of skeleton** 

higher than in patients with high (4) activity of the disease.

patients with SpA (31.6 percent of all patients with SpA).

dose of glucocorticoids and treatment with TNF-α blockers.

Positive family history of fractures

determined by rheumatologist; coding of variables described in the Table 5.

Table 10. Logistic regression analysis of the event when Z-score probability at any site of skeleton will be - 2.0 at the analysis of SpA patient data. \* DAR – activity of the disease

The analysis demonstrated that correct probabilities for Z-score at any sites of the skeleton

are presented in Table 10.

Indices of the relevance of

*χ2* model compatibility criterion p < .001

*Hosmer* and *Lemeshow χ<sup>2</sup>* compatibility criterion p =

.771

Coefficient of determination: *Negelkerke* R2 = .407

model Regressor\*

were established in 75.7 % of respondents.

Skeletal remodeling in bone growth, maintenance, and repair is tightly regulated by a dynamic interaction between osteoclasts and osteoblasts. Recent advances in immunopathological mechanism of chronic inflammatory rheumatic disease highlighted the altered balance between bone loss and production by inflammation. T cells, natural killers, and cytokines that are involved in inflammatory process may also be responsible for the bone loss (Ritchlin et al., 2003). Many investigators have observed decreased BMD of the whole skeleton and increased femoral and vertebral fracture risk in patients suffering from both RA and SpA in comparison with healthy persons (Lodder, 2004; Huusko, 2001; Grisar, 2002). Up till now BMD changes were not being compared between SpA and RA patients.

An interesting observation from our study is that there was no statistically significant difference of BMD in any examined part of skeleton between the two groups of diseases, i.e. RA and SpA but the BMD difference between the control group and RA and SpA groups was statistically significant, the BMD being higher in all examined parts of skeleton of the control group. Analyzing BMD of SpA, RA and control groups the Z-score of the three groups were compared in order to exclude influence of age and gender, known OP risk factors, on BMD. The Z-score in all examined parts was similar for both RA and SpA groups while the Z-score difference in the same parts examined between the control group and both patient groups was statistically significant, the Z-score being higher in the control group. The findings support the hypothesis that inflammatory environment not only in joint synovial tissues but also in bone caused by autoimmune changes in RA and SpA patients induces a lot of molecular changes, RANKL and OPG equilibrium derangement and is one of the causes provoking not only local but also systemic osteoclastogenesis and related bone resorbtion (Suda, 1992; Franck, 2004; Golmia, 2002). The reduced BMD in case of both RA and SpA may also be explained by worsened mobility function (Szejnfeld, 1997; Faus-Riera, 1991), disturbances of calcium and vitamin D metabolism because of intestine injury and adverse effect of GC on bone tissue (Lange, 2005; Mielants, 1989).

Data on comparison of the BMD between healthy persons and patients diagnosed with SpA are scarce. As it was mentioned above the BMD of SpA patients was mostly investigated in AS. Several researchers have observed decreased BMD in AS patients compared with healthy persons (Will, 1989; Devogelaer, 1992; Sampaio-Barros, 2005). *K. Dheda* and colleagues, having examined 20 PsA patients, have not observed any statistically significant BMD reduction in PsA patients compared with healthy persons either in lumbar spine or in femur (Dheda et al., 2004). On the contrary *B. Frediani* and colleagues have found statistically significant BMD reduction both in vertebra and femur of PsA patients compared with corresponding skeleton parts of the control group (Frediani et al., 2001). Data on statistically significant BMD reduction in entire skeleton of EnA patients compared with the control group was published by several authors. (Frei, 2006; Reffitt, 2003). *J. Grisar* and colleagues investigated bone metabolism markers and BMD of AS, PsA and ReA patients. The investigators found statistically significant BMD decrease in the proximal femur of AS patients compared with PsA patients. There was no statistically significant difference of vertebral BMD of AS patients and both vertebral and proximal femoral BMD of PsA and ReA patients compared with the BMD of the control group. *J. Grisar* and colleagues conclude that in all forms of the above mentioned spondyloarthropathies accelerated resorbtion of bone tissue prevails regardless of the fact that decreased BMD was not

Bone Mineral Density Changes in Patients with Spondyloarthropathies 43

In SpA, especially AS, other potential risk factors for bone loss occur, such as inflammation and mechanical factors -rigidity of the spine resulting in limited mobility and reduced physical activity due to pain and stiffness. Data about these risk factors, high disease activity variables such as ESR, CRP, BASDAI in relation with low BMD levels in different studies are

Acknowledging that high SpA activity is one of the most important risk factors for BMD reduction (Gratacos, 1999; Kim, 2006) and there being no currently standardized indicators of SpA activity we aimed to define which of the accessible disease activity indicators most frequently used in clinical practice might reflect BMD changes in SpA patients. We assessed disease activity on the basis of active disease diagnosis rated by the same rheumatologist, acute inflammatory phase indicators, ESR and CRP, and by subjective patient's evaluation of the disease activity using results of BASDAI questionnaire (Landewe et al., 2004). We found statistically significant association between decreased vertebral and both femoral BMD and moderate or hight SpA activity rated by the rheumatologist. There was no significant correlation between CRB, ESR, BASDAI and BMD changes in the examined

On the contrary, *E. S. Meirelles* and colleagues have found no correlation between disease activity rated by the rheumatologist and BMD changes (Meirelles et al., 1999). *K. Capaci* and colleagues has proved that disease activity rated by physician on the basis of radiological signs of vertebral and hip destruction extent has no influence on the bone mass of AS patients (Capaci et al., 2003). Other authors have made similar conclusions to proving that acute inflammatory phase markers found once do not forecast either progression of radiological signs of SpA or reduction of BMD in different parts of skeleton. (Karberg, 2005; Toussirot, 2001; Muntean, 2011). Nevertheless, *J. Gratacos* and colleagues having carried out a two year perspective study and assessing AS disease activity by ESR, CRP and IL-6 blood concentration found that the subgroup of active disease patients had statistically significant reduction of BMD of femoral neck and lumbar spine but there were no significant BMD changes in the examined parts of the subgroup of non-active disease patients. (Gratacos, 1999). In another study disease activity parameters such as increased CRP and high BASFI and BASMI scores, correlated significantly with low bone mass in femoral neck as well as in lumbar spine (Van der Weijden et al., 2011). However, at the 12-month follow-up study hip bone loss was found to be associated with raised baseline C-reactive protein levels

Based on the previous research, as well as on the results of the present study, we conclude that active course of the disease and pronounced systemic inflammatory process without question has negative influence on BMD by different mechanisms which are insufficiently researched up to this time. We think that the contradiction that exists between our data and presented by other authors about the influence of disease activity on BMD changes may result from the difference in the groups of patients (the other authors mostly studied only AS patients) and methods used to assess disease activity. Furthermore, the role of proinflammatory cytokines might be important for the onset of osteoporosis because increased TNF-alpha levels have been found in patients with AS compared with subjects with noninflammatory back pain, and correlations have been found between disease activity and markers associated with an increased bone metabolism (Lange et al., 2000). We, together with other authors think that cross-sectional laboratory acute inflammatory markers such as

not consistently reported (Karberg, 2005; Gratacos, 1999; Toussirot, 2001).

skeleton parts.

(Haugeberg et al., 2010).

observed in all examined disease patients compared with the control group (Grisar et al., 2002). We have not found any statistically significant BMD difference in AS, PsA, EnA and ReA patients in any part of the skeleton examined.

In our study we tried to define a correlation between BMD changes in lumbar spine and proximal femur and duration of the SpA.The SpA duration was calculated by the two following ways: from manifestation of the first symptoms and from the moment of clinical diagnosis statement. The results revealed that lenghthening disease duration calculated from manifestation of the symptoms is related to vertebral BMD growth and femoral BMD reduction. Agreeing with other authors (Donnelly, 1994; Reid, 1986; Mullaji, 1994), we think that vertebral BMD readings of patients with long disease duration measured by anteriorposterior view of DXA method are merely "deceptive". The lumbar spine often shows misleading high BMD values due to bridging syndesmophytes and ankylosis, which might mask osteoporosis in AS patients with an advanced disease (Donnelly, 1994; Karberg, 2005; Mullaji, 1994; Muntean, 2011).

Our previous investigations showed that SpA patients both with long and short disease duration have statistically significant lower proximal femoral and lumbar vertebral BMD compared with the control group (Venceviciene et al., 2008). Lengthening disease duration calculated from the moment of clinical diagnosis statement had no significant correlation to changes of vertebral and proximal femoral BMD. *R. Will* and colleagues have not found significant difference in the average lumbar vertebral BMD between patients suffering from AS longer than 10 years and the control group (Will et al., 1990). *E. S. Meirelles* and colleagues observed positive correlation between disease duration and changes of proximal femoral and lumbar vertebral BMD (Meirelles et al., 1999). Until now only one study that quantifies the magnitude of osteoporosis in population of early SpA patients is available (Van der Weijden et al., 2011). In this study all patients had a BMD measurement at a median of period 6.6 months after diagnosis. This study showed a high prevalence (47%) of low BMD in both femur and lumbar spine in SpA patients with early disease. In contrast with our study, no significant differences between the two groups with low and normal BMD were found in regard to time since diagnosis and disease duration (median of 6.3 years), counting from the very first symptoms of axial manifestations (Van der Weijden et al., 2011). Unfortunately the above mentioned study has some limitations: the BMD of patients was not compared with healthy persons. More to the point, a BMD and Z-score should be used instead of T-score to assess BMD changes in males under 50 years of age. The fact that low BMD is encountered in a young population with an early disease is very interesting. In most other studies, "early" often refers to patients who have not yet developed ankylosis or other radiological progression signs, or that these studies made use of disease durations as time since diagnosis and then referred to a disease duration of <10 years (Gratacos, 1999; Toussirot, 2001, Will, 1989). The issue of defining disease duration has been often debated in the AS literature. Today, the onset of the first symptoms is considered to be most important criteria (Davis et al., 2006). Taking into account the fact that AS is usually diagnosed 6-8 years after manifestation of the first symptoms we think that the most prominent decrease of the BMD takes place in the early pre-diagnosis period of the disease. Etiopathogenetic treatment begun after diagnosing the disease suppresses local and systematic inflammation and related activity of osteoclasts together with demineralization of the bone tissue.

observed in all examined disease patients compared with the control group (Grisar et al., 2002). We have not found any statistically significant BMD difference in AS, PsA, EnA and

In our study we tried to define a correlation between BMD changes in lumbar spine and proximal femur and duration of the SpA.The SpA duration was calculated by the two following ways: from manifestation of the first symptoms and from the moment of clinical diagnosis statement. The results revealed that lenghthening disease duration calculated from manifestation of the symptoms is related to vertebral BMD growth and femoral BMD reduction. Agreeing with other authors (Donnelly, 1994; Reid, 1986; Mullaji, 1994), we think that vertebral BMD readings of patients with long disease duration measured by anteriorposterior view of DXA method are merely "deceptive". The lumbar spine often shows misleading high BMD values due to bridging syndesmophytes and ankylosis, which might mask osteoporosis in AS patients with an advanced disease (Donnelly, 1994; Karberg, 2005;

Our previous investigations showed that SpA patients both with long and short disease duration have statistically significant lower proximal femoral and lumbar vertebral BMD compared with the control group (Venceviciene et al., 2008). Lengthening disease duration calculated from the moment of clinical diagnosis statement had no significant correlation to changes of vertebral and proximal femoral BMD. *R. Will* and colleagues have not found significant difference in the average lumbar vertebral BMD between patients suffering from AS longer than 10 years and the control group (Will et al., 1990). *E. S. Meirelles* and colleagues observed positive correlation between disease duration and changes of proximal femoral and lumbar vertebral BMD (Meirelles et al., 1999). Until now only one study that quantifies the magnitude of osteoporosis in population of early SpA patients is available (Van der Weijden et al., 2011). In this study all patients had a BMD measurement at a median of period 6.6 months after diagnosis. This study showed a high prevalence (47%) of low BMD in both femur and lumbar spine in SpA patients with early disease. In contrast with our study, no significant differences between the two groups with low and normal BMD were found in regard to time since diagnosis and disease duration (median of 6.3 years), counting from the very first symptoms of axial manifestations (Van der Weijden et al., 2011). Unfortunately the above mentioned study has some limitations: the BMD of patients was not compared with healthy persons. More to the point, a BMD and Z-score should be used instead of T-score to assess BMD changes in males under 50 years of age. The fact that low BMD is encountered in a young population with an early disease is very interesting. In most other studies, "early" often refers to patients who have not yet developed ankylosis or other radiological progression signs, or that these studies made use of disease durations as time since diagnosis and then referred to a disease duration of <10 years (Gratacos, 1999; Toussirot, 2001, Will, 1989). The issue of defining disease duration has been often debated in the AS literature. Today, the onset of the first symptoms is considered to be most important criteria (Davis et al., 2006). Taking into account the fact that AS is usually diagnosed 6-8 years after manifestation of the first symptoms we think that the most prominent decrease of the BMD takes place in the early pre-diagnosis period of the disease. Etiopathogenetic treatment begun after diagnosing the disease suppresses local and systematic inflammation and related activity of osteoclasts together with demineralization

ReA patients in any part of the skeleton examined.

Mullaji, 1994; Muntean, 2011).

of the bone tissue.

In SpA, especially AS, other potential risk factors for bone loss occur, such as inflammation and mechanical factors -rigidity of the spine resulting in limited mobility and reduced physical activity due to pain and stiffness. Data about these risk factors, high disease activity variables such as ESR, CRP, BASDAI in relation with low BMD levels in different studies are not consistently reported (Karberg, 2005; Gratacos, 1999; Toussirot, 2001).

Acknowledging that high SpA activity is one of the most important risk factors for BMD reduction (Gratacos, 1999; Kim, 2006) and there being no currently standardized indicators of SpA activity we aimed to define which of the accessible disease activity indicators most frequently used in clinical practice might reflect BMD changes in SpA patients. We assessed disease activity on the basis of active disease diagnosis rated by the same rheumatologist, acute inflammatory phase indicators, ESR and CRP, and by subjective patient's evaluation of the disease activity using results of BASDAI questionnaire (Landewe et al., 2004). We found statistically significant association between decreased vertebral and both femoral BMD and moderate or hight SpA activity rated by the rheumatologist. There was no significant correlation between CRB, ESR, BASDAI and BMD changes in the examined skeleton parts.

On the contrary, *E. S. Meirelles* and colleagues have found no correlation between disease activity rated by the rheumatologist and BMD changes (Meirelles et al., 1999). *K. Capaci* and colleagues has proved that disease activity rated by physician on the basis of radiological signs of vertebral and hip destruction extent has no influence on the bone mass of AS patients (Capaci et al., 2003). Other authors have made similar conclusions to proving that acute inflammatory phase markers found once do not forecast either progression of radiological signs of SpA or reduction of BMD in different parts of skeleton. (Karberg, 2005; Toussirot, 2001; Muntean, 2011). Nevertheless, *J. Gratacos* and colleagues having carried out a two year perspective study and assessing AS disease activity by ESR, CRP and IL-6 blood concentration found that the subgroup of active disease patients had statistically significant reduction of BMD of femoral neck and lumbar spine but there were no significant BMD changes in the examined parts of the subgroup of non-active disease patients. (Gratacos, 1999). In another study disease activity parameters such as increased CRP and high BASFI and BASMI scores, correlated significantly with low bone mass in femoral neck as well as in lumbar spine (Van der Weijden et al., 2011). However, at the 12-month follow-up study hip bone loss was found to be associated with raised baseline C-reactive protein levels (Haugeberg et al., 2010).

Based on the previous research, as well as on the results of the present study, we conclude that active course of the disease and pronounced systemic inflammatory process without question has negative influence on BMD by different mechanisms which are insufficiently researched up to this time. We think that the contradiction that exists between our data and presented by other authors about the influence of disease activity on BMD changes may result from the difference in the groups of patients (the other authors mostly studied only AS patients) and methods used to assess disease activity. Furthermore, the role of proinflammatory cytokines might be important for the onset of osteoporosis because increased TNF-alpha levels have been found in patients with AS compared with subjects with noninflammatory back pain, and correlations have been found between disease activity and markers associated with an increased bone metabolism (Lange et al., 2000). We, together with other authors think that cross-sectional laboratory acute inflammatory markers such as

Bone Mineral Density Changes in Patients with Spondyloarthropathies 45

In agreement with other authors (Will, 1989; Mullaji, 1994) we have found that frequency of exercise of the patient had no significant influence on BMD changes in the parts of skeleton

Summing up the results it is possible to state that reduction of BMD correlates with disturbances of mobility function that lessens during disease course as demonstrated by the results presented above. On the other hand, comparativelly good spine BMD results are probably "misleading". We as other researchers (Donnelly, 1994; Reid, 1986) support the statement that in the course of the disease, impairment of the spine begins in the form of calcification of longitudinal ligaments and intervertebral discs, formation of syndesmophytes and joint ankylosis. Apparently the decrease in spine mobility caused by

The aim of our study was to clear up whether GC and TNF-α blockers can influence BMD changes for SpA patients. The effect of GC on bone mass of SpA patients is not sufficiently investigated. Some authors are of the opinion that GC cumulative doses is not a factor in the successful prognosis of BMD decrease [Bjarnason, 1997; Habtezion, 2002; Millard, 2001). Several clinical studies have shown that GC in doses of less than 7,5 mg/d does not incite more pronounced bone resorbtion (Bijlsma, 2000; Nishimura, 2000). *O. A. Malysheva* and colleagues have proved that the therapeutic GC dose of 7,5 mg/d has negative influence on BMD when being used longer than 48 weeks (Malysheva et al., 2008). Still A. Savickienė and colleagues have found that duration of GC use and their cumulative dose significantly correlated with lumbar spine BMD reduction in SpA patients (Savickienė et al., 2003). Negative GC influence on bone mass was also described by German researchers having determined that cumulative GC dose negatively correlates with BMD changes and serves as an independent factor for prognosis of BMD reduction in all parts of skeleton (Pollak, 1998;

Considering the fact that GC treatment schemes (dose and duration of presciption) were changed several times we have conditionally divided SpA patients into 4 subgroups according to cumulative GC doses. We have compared BMD among the subgroups. We have not found statistically significant femoral and vertebral BMD difference among the first three subgroups ( patients who have not used GC, used cumulative GC doses of <1g and 1- 10g ). Proximal femoral BMD of patients who used more than 10g of GC was statistically significantly less than BMD of patients who have not used GC. Similar results were obtained by the other group of researchers who proved that only cumulative GC doses exceeding 10 g has significant influence on BMD reduction in all parts of skeleton (Silvennoinen, 1995;

A new group of drugs blocking cytokin TNF- α used for SpA treatment are called TNF- α blocking agents. This drug is effective in reducing disease symptoms, inflammatory processes and joint destruction (Braun, 2002; Brandt, 2000; Baeten, 2001; Breban, 2002 ; Gorman, 2002). It has been shown that TNF-blocking agents not only reduce signs and symptoms of disease activity in SpA, but also arrest hip and spine bone loss (Marzo-Ortega,

We compared BMD readings of patients treated with TNF-α blockers and patients who did not received TNF-α blockers and found no statistically significant BMD difference between the groups in all examined parts of the skeleton. While statistically significant influence of

changes in the spine may be associated with proximal femoral BMD changes.

examined.

De Jong, 2002).

Von Tirpitz, 1993).

2003; Marzo-Ortega, 2005; Demis, 2002).

CRP or ESR and results of BASDAI questionnaire which reflects the main SpA symptoms during the last week can not predict BMD changes (Karberg, 2005; Speden, 2002; Muntean, 2011). Only a physician rheumatologist's assessment of the entire case history including clinical, laboratory, radiological signs and taking regular care of the patient may accurately determine disease activity in the long course of disease activity. Disease activity according to our research data has a significant correlation with bone mass loss both in lumbar vertebral and femoral proximal regions.

We also tried to determine the influence of physical disability and disturbances of mobility function on BMD changes in lumbar vertebral and femoral proximal regions. Like other investigators we have found that patient's mobility function worsens with increasing duration of the illness (Falkenbach, 2002; Wei, 2007; Karatepe, 2005). It is known that SpA standardized indicators of spine mobility correlate with radiological changes such as impairment in sacroiliac joints and spine and the latter is an independent factor for the prediction of femoral BMD changes (Speden et al., 2002). We have established that the decrease of spine mobility determined by the modified Shober test shows possible reduction of femoral BMD. *H. J. Baek* and colleagues, having divided AS patients into two groups by spine flexibility index according to Schober test (correspondingly > 5cm and < 5cm), the group of patients with good mobility and the group of patients with bad mobility, have not found any BMD difference in lumbar spine between the groups while the proximal femoral BMD was statistically significantly lower in the bad mobility group in comparison with the good mobility group (Baek et al., 2005). We have obtained similar results by dividing SpA patients according to tragus-to-wall distance and lumbar lateral flexion measurement, then assessing the decrease in spine flexibility and comparing it's BMD. Statistically significant BMD difference was obtained only in the femur. Differently, the decrease in spine flexibility was determined by intermalleolar distance measurement, showed significant BMD reduction not only in femur but in spine too. We failed to find studies assessing correlation between spine flexibility indices such as lateral flexion, tragus-to-wall distance, intermalleolar distance (measuring spine flexibility in different parts of spine) and BMD changes.

It is worthy to note that many studies assessing mobility and physical disability of SpA patients are being carried out all over the world (Bostan, 2003; Zochling, 2006; Ward, 2002) but the research data about dependence of bone mass changes in different regions of skeleton on physical disability and disturbances of mobility are scarce and controversial. Several scientists insist that disturbances of mobility function have no influence on lowering BMD in AS patients (Mitra, 1999; Maillefert, 2001). *J. Gratacos* and colleagues failed to find the correlation between BMD reduction and the results of HAQ-S questionnaire evaluating physical disability of SpA patients. (Gratacos et al., 1999). Nevertheless *H. Franck* and colleagues found that patients having decreased BMD in different parts of the skeleton had significantly poorer mobility function indices (Schober index and results of BASFI questionnaire) in comparison with the group of patients having normal BMD (Franck et al., 2004). The results of our study however show that lessening of mobility function has no influence on spinal BMD. Changes in femoral BMD are best reflected by the physical disability of SpA patients assessed using HAQ-S questionnaire and disturbances of mobility function assessed by the BASFI questionnaire.

CRP or ESR and results of BASDAI questionnaire which reflects the main SpA symptoms during the last week can not predict BMD changes (Karberg, 2005; Speden, 2002; Muntean, 2011). Only a physician rheumatologist's assessment of the entire case history including clinical, laboratory, radiological signs and taking regular care of the patient may accurately determine disease activity in the long course of disease activity. Disease activity according to our research data has a significant correlation with bone mass loss both in lumbar

We also tried to determine the influence of physical disability and disturbances of mobility function on BMD changes in lumbar vertebral and femoral proximal regions. Like other investigators we have found that patient's mobility function worsens with increasing duration of the illness (Falkenbach, 2002; Wei, 2007; Karatepe, 2005). It is known that SpA standardized indicators of spine mobility correlate with radiological changes such as impairment in sacroiliac joints and spine and the latter is an independent factor for the prediction of femoral BMD changes (Speden et al., 2002). We have established that the decrease of spine mobility determined by the modified Shober test shows possible reduction of femoral BMD. *H. J. Baek* and colleagues, having divided AS patients into two groups by spine flexibility index according to Schober test (correspondingly > 5cm and < 5cm), the group of patients with good mobility and the group of patients with bad mobility, have not found any BMD difference in lumbar spine between the groups while the proximal femoral BMD was statistically significantly lower in the bad mobility group in comparison with the good mobility group (Baek et al., 2005). We have obtained similar results by dividing SpA patients according to tragus-to-wall distance and lumbar lateral flexion measurement, then assessing the decrease in spine flexibility and comparing it's BMD. Statistically significant BMD difference was obtained only in the femur. Differently, the decrease in spine flexibility was determined by intermalleolar distance measurement, showed significant BMD reduction not only in femur but in spine too. We failed to find studies assessing correlation between spine flexibility indices such as lateral flexion, tragus-to-wall distance, intermalleolar distance (measuring spine flexibility in different parts of spine) and BMD

It is worthy to note that many studies assessing mobility and physical disability of SpA patients are being carried out all over the world (Bostan, 2003; Zochling, 2006; Ward, 2002) but the research data about dependence of bone mass changes in different regions of skeleton on physical disability and disturbances of mobility are scarce and controversial. Several scientists insist that disturbances of mobility function have no influence on lowering BMD in AS patients (Mitra, 1999; Maillefert, 2001). *J. Gratacos* and colleagues failed to find the correlation between BMD reduction and the results of HAQ-S questionnaire evaluating physical disability of SpA patients. (Gratacos et al., 1999). Nevertheless *H. Franck* and colleagues found that patients having decreased BMD in different parts of the skeleton had significantly poorer mobility function indices (Schober index and results of BASFI questionnaire) in comparison with the group of patients having normal BMD (Franck et al., 2004). The results of our study however show that lessening of mobility function has no influence on spinal BMD. Changes in femoral BMD are best reflected by the physical disability of SpA patients assessed using HAQ-S questionnaire and disturbances of mobility

vertebral and femoral proximal regions.

function assessed by the BASFI questionnaire.

changes.

In agreement with other authors (Will, 1989; Mullaji, 1994) we have found that frequency of exercise of the patient had no significant influence on BMD changes in the parts of skeleton examined.

Summing up the results it is possible to state that reduction of BMD correlates with disturbances of mobility function that lessens during disease course as demonstrated by the results presented above. On the other hand, comparativelly good spine BMD results are probably "misleading". We as other researchers (Donnelly, 1994; Reid, 1986) support the statement that in the course of the disease, impairment of the spine begins in the form of calcification of longitudinal ligaments and intervertebral discs, formation of syndesmophytes and joint ankylosis. Apparently the decrease in spine mobility caused by changes in the spine may be associated with proximal femoral BMD changes.

The aim of our study was to clear up whether GC and TNF-α blockers can influence BMD changes for SpA patients. The effect of GC on bone mass of SpA patients is not sufficiently investigated. Some authors are of the opinion that GC cumulative doses is not a factor in the successful prognosis of BMD decrease [Bjarnason, 1997; Habtezion, 2002; Millard, 2001). Several clinical studies have shown that GC in doses of less than 7,5 mg/d does not incite more pronounced bone resorbtion (Bijlsma, 2000; Nishimura, 2000). *O. A. Malysheva* and colleagues have proved that the therapeutic GC dose of 7,5 mg/d has negative influence on BMD when being used longer than 48 weeks (Malysheva et al., 2008). Still A. Savickienė and colleagues have found that duration of GC use and their cumulative dose significantly correlated with lumbar spine BMD reduction in SpA patients (Savickienė et al., 2003). Negative GC influence on bone mass was also described by German researchers having determined that cumulative GC dose negatively correlates with BMD changes and serves as an independent factor for prognosis of BMD reduction in all parts of skeleton (Pollak, 1998; De Jong, 2002).

Considering the fact that GC treatment schemes (dose and duration of presciption) were changed several times we have conditionally divided SpA patients into 4 subgroups according to cumulative GC doses. We have compared BMD among the subgroups. We have not found statistically significant femoral and vertebral BMD difference among the first three subgroups ( patients who have not used GC, used cumulative GC doses of <1g and 1- 10g ). Proximal femoral BMD of patients who used more than 10g of GC was statistically significantly less than BMD of patients who have not used GC. Similar results were obtained by the other group of researchers who proved that only cumulative GC doses exceeding 10 g has significant influence on BMD reduction in all parts of skeleton (Silvennoinen, 1995; Von Tirpitz, 1993).

A new group of drugs blocking cytokin TNF- α used for SpA treatment are called TNF- α blocking agents. This drug is effective in reducing disease symptoms, inflammatory processes and joint destruction (Braun, 2002; Brandt, 2000; Baeten, 2001; Breban, 2002 ; Gorman, 2002). It has been shown that TNF-blocking agents not only reduce signs and symptoms of disease activity in SpA, but also arrest hip and spine bone loss (Marzo-Ortega, 2003; Marzo-Ortega, 2005; Demis, 2002).

We compared BMD readings of patients treated with TNF-α blockers and patients who did not received TNF-α blockers and found no statistically significant BMD difference between the groups in all examined parts of the skeleton. While statistically significant influence of

Bone Mineral Density Changes in Patients with Spondyloarthropathies 47

 High and moderate activity of the disease (established by rheumatologist) is associated with the elevated bone resorption at the lumbar spine and upper part of left and right femur. The relation between disease activity (which measured by ESR, CRP level and BASDAI questionnaire) and BMD decrease in any investigated area of skeletal system

 BMD reduction at the lumbar spine and upper parts of both femurs is associated with the decrease of mobility of a SpA patient. Intermalleolar distance is the most precise indicant reflecting the relation between decrease of physical ability and mobility and BMD changes in all investigated areas of skeletal system: at the spine (BMD expressed as g/cm2) and at the upper parts of both femurs (BMD expressed as g/cm2 and Zscore); the lowest BMD at upper parts of both femurs is measured when reduction of

 Significant negative association between cumulative dose of glucocorticoids and BMD changes at the lumbar spine and upper part of left and right femur were observed: BMD at the lumbar spine and upper parts of both femurs decrease with the increase of

Adomaviciute, D; Pileckyte, M; Baranauskaite, A; Morvan, J; Dadoniene, J; Guillemin, F.

*Scand J Rheumatol*, Vol.37, No.2, (March 2008), pp. 113-119, ISSN 0300-9742 Arnett, FC; Edworthy, SM; Bloch, DA; McShane, DJ; Fries, FJ; Cooper, NS; Haeley, LA;

Baek, HJ; Kang, SW; Lee, YJ; Shin, KC; Lee, EB; Yoo, CD; Song, YW. Osteopenia in men with

Baeten, D; Kruithof, E; Van den Bosch, F; Demetter, P; Van Damme, N; Cuvelier, C; De Vos,

Bessant, R; Keat, A. How should clinicians manage osteoporosis in ankylosing spondylitis. *J* 

Bijlsma, JWJ; Jacobs, JWG. Hormonal preservation of bone in rheumatoid arthritis. *Rheum Dis Clin North Am*, Vol.26, No.4, (Nov 2000), pp. 897-910, ISSN 0889-857X

*Rheumatol,* Vol.29, No.7, (July 2002), pp. 1511-1519, ISSN 0315-162X

*Rheumatism,* Vol.31, No.3, (Mar 1988), pp. 315-324, ISSN 0004-3591

Prevalence survey of rheumatoid arthritis and spondyloarthropathy in Lithuania.

Kaplan, SR; Liang, MH; Luthra, HS. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. *Arthritis &* 

mild and severe ankylosing spondylitis. *Rheumatol Int*, Vol.26, No.1, (November

M; Mielants, H; Veys, EM; De Keyser, F. Immunomodulatory effects of anti-tumor necrosis factor alpha therapy on syvinium in spondyloarthropathy: histologic finding in eight patients from opel-label pilot study. *Arthritis Rheum*, Vol.44, No.1,

 In SpA patients BMD changes do not depend on the predominant type of joint lesion. Duration of the disease reflects changes in BMD better when it is calculated not from the time of the establishment of clinical diagnosis, but from the time of onset of first clinical symptoms. Relations between the duration of the disease and BMD changes at the lumbar spine and upper part of left and right femur are different: BMD decreases at the upper parts of both femurs and increases at the spine with longer duration of the

disease.

**6. References** 

was not observed.

spine movement is defined as severe.

cumulative dose of glucocorticoids.

2005), pp. 30-34, ISSN 0172-8172

(Jan 2001), pp. 186-195, ISSN 0004-3591

TNF-α blockers on bone mass was not found it is still not possible to state that these drugs have no positive effect on suppression of bone tissue resorbtion. This cross-sectional study was not designed as an observation of TNF-α blockers effectiveness. On the other hand these drugs are only used to treat SpA of high activity after treatment with other disease modifying drugs and in cases with pronounced joint impairment. On the basis of the results of this study showing statistically significant negative influence of high disease activity on the BMD changes and "deceptive" BMD spine readings conditioned by long disease duration it is possible to assume that these factors could "hide" positive effect on bone caused by the TNF-α blockers. We hope that the further long term longitudinal studies with bigger observational cohort will prove the beneficial effect of TNF-α blockers for not merely reducing local and systemic inflammation but also their positive influence on the bone tissue of SpA patients.

Summing up all the results it is possible to state that only moderate or high SpA activity rated by the rheumatologist and GC cumulative dose are statistically significant specific factors which can predict reduction of BMD of lumbar spine in SpA patients.. It is important to note that the lengthening disease duration counted from the beginning of the first symptoms relates to augmentation of spinal BMD. Reduction of BMD of both proximal femurs was associated with moderate or high SpA activity rated by the rheumatologist, severe reduction of spine flexibility assessed by intermalleolar distance measurement and GC cumulative doses. The BMI is the only significant variable out of all other factors related to spinal and femoral BMD changes. It is necessary to point that increased BMI is related to higher vertebral and femoral BMD readings. The data of this study are in agreement with the data presented by the other authors that low BMI (< 19 kg/m2) is related to possible nutritional deficiencies of vitamin D, calcium and protein and therefore, to BMD reduction (Ravn, 1999; Edelstein, 1993; Cetin, 2001). We have also determined the prognostic factors for SpA patients that need to be included into the group of reduced BMD (when the Z-score is ≤–2.0 in any part of the skeleton). Results of our study show that SpA patients whose disease activity rated by the rheumatologist is moderate or high and who have positive family history of OP fractures have a Z-score of ≤– 2.0 found in any investigated part of the skeleton.

We have proved that SpA disease activity rated by the rheumatologist, spine flexibility assessed by intermalleolar distance measurement, cumulative GC doses, BMI, disease duration measured from the manifestation of symptoms and family history of OP fractures are important for evaluating the risk of BMD reduction for SpA patients. It is valuable for identifying those who should undergo testing for BMD and for what specific region of skeleton, and also for prescribing effective means for prevention and/or treatment.

#### **5. Conclusions**



#### **6. References**

46 Clinical and Molecular Advances in Ankylosing Spondylitis

TNF-α blockers on bone mass was not found it is still not possible to state that these drugs have no positive effect on suppression of bone tissue resorbtion. This cross-sectional study was not designed as an observation of TNF-α blockers effectiveness. On the other hand these drugs are only used to treat SpA of high activity after treatment with other disease modifying drugs and in cases with pronounced joint impairment. On the basis of the results of this study showing statistically significant negative influence of high disease activity on the BMD changes and "deceptive" BMD spine readings conditioned by long disease duration it is possible to assume that these factors could "hide" positive effect on bone caused by the TNF-α blockers. We hope that the further long term longitudinal studies with bigger observational cohort will prove the beneficial effect of TNF-α blockers for not merely reducing local and systemic inflammation but also their positive influence on the bone

Summing up all the results it is possible to state that only moderate or high SpA activity rated by the rheumatologist and GC cumulative dose are statistically significant specific factors which can predict reduction of BMD of lumbar spine in SpA patients.. It is important to note that the lengthening disease duration counted from the beginning of the first symptoms relates to augmentation of spinal BMD. Reduction of BMD of both proximal femurs was associated with moderate or high SpA activity rated by the rheumatologist, severe reduction of spine flexibility assessed by intermalleolar distance measurement and GC cumulative doses. The BMI is the only significant variable out of all other factors related to spinal and femoral BMD changes. It is necessary to point that increased BMI is related to higher vertebral and femoral BMD readings. The data of this study are in agreement with the data presented by the other authors that low BMI (< 19 kg/m2) is related to possible nutritional deficiencies of vitamin D, calcium and protein and therefore, to BMD reduction (Ravn, 1999; Edelstein, 1993; Cetin, 2001). We have also determined the prognostic factors for SpA patients that need to be included into the group of reduced BMD (when the Z-score is ≤–2.0 in any part of the skeleton). Results of our study show that SpA patients whose disease activity rated by the rheumatologist is moderate or high and who have positive family history of OP fractures have a Z-score of ≤–

We have proved that SpA disease activity rated by the rheumatologist, spine flexibility assessed by intermalleolar distance measurement, cumulative GC doses, BMI, disease duration measured from the manifestation of symptoms and family history of OP fractures are important for evaluating the risk of BMD reduction for SpA patients. It is valuable for identifying those who should undergo testing for BMD and for what specific region of

 In patients with spondyloarthropathies BMD (expressed as g/cm2 and Z-score) is the same as in patients with rheumatoid arthritis and is significantly lower in comparison with BMD of healthy subjects measured at the lumbar spine and upper part of left and

 Similar BMD changes at the lumbar spine and upper part of left and right femur are characteristic to SpA patients with various diseases belonging to SpA group.

skeleton, and also for prescribing effective means for prevention and/or treatment.

tissue of SpA patients.

**5. Conclusions** 

right femur.

2.0 found in any investigated part of the skeleton.


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**4** 

*Greece* 

**Surgical Treatment After Spinal Trauma in** 

*2A' Department of Orthopaedics, "G. Gennimatas" General Hospital, Athens,* 

Stamatios A. Papadakis1, Konstantinos Kateros2, Spyridon Galanakos1,

Ankylosing Spondylitis (AS) is a chronic inflammatory disease which is characterized by pain and progressive stiffness and which spinal and sacroiliac joints are mainly affected. It affects mostly males, having a male-to-female ratio approximately 3-4:1 and the onset occur between the 15th and the 35th year of life (Bechterew, 1979; Calin, 1985; van der Linden et

Ankylosing Spondylitis transforms the flexible spinal column into a stiff rod; the stiffened spine cannot bear normal loads in comparison with a healthy spine. In addition, it has been established that bone mineral density loss occurs early in the AS disease course and is associated with inflammation correlated with increased bone resorption (van der Horst-Bruinsma, 2006). The kyphotic deformation of the spine that exists makes the ankylosing and osteoporotic spine susceptible to stress fractures under the impact of small forces and loads (van der Linden et al., 2005). The diffuse paraspinal ossification and inflammatory osteitis of advanced AS creates a fused, brittle spine that is susceptible to fracture (De Peretti et al, 2004; Einsiedel et al, 2006; Hanson and Mirza, 2000; van der Horst-Bruinsma, 2006; Taggard ans Traynelis, 2000;). Patients suffering from AS may undergo a fracture with minimal (Graham and Van Peteghem, 1989; Hanson and Mirza, 2000; Trent et al., 1988; Whang et al, 2009), or even no history of injury (Olerud et al., 1996; Westerveld et al., 2009;

The most frequent site, where a fracture is located is the cervical spine (75%) especially it's lower part, and the cervical-thoracic junction, following by the thoracolumbar junction (T10- L2). The drastic increase in stiffness at the cervicothoracic junction, combined with the lever arm of the fused cervical spine and weight of the head, makes fractures at the C6-C7 and C7- T1 levels most common. The lumbar and thoracic spines are more resistant to fracture because the anterior and posterior longitudinal ligaments are more thoroughly ossified than in the cervical spine. (Bohlman, 1979; Hanson and Mirza, 2000; Osgood et al., 1973; Surin,

**1. Introduction** 

Yau and Chan, 1974).

al., 2005).

**Patients with Ankylosing Spondylitis** 

George Machairas1, Pavlos Katonis3 and George Sapkas4 *1D' Department of Orthopaedics, "KAT" General Hospital, Athens,* 

*3Department of Orthopaedics, University of Crete, Herakleion,* 

*4A' Department of Orthopaedics, University of Athens,* 

*"Attikon" University Hospital, Haidari,* 


### **Surgical Treatment After Spinal Trauma in Patients with Ankylosing Spondylitis**

Stamatios A. Papadakis1, Konstantinos Kateros2, Spyridon Galanakos1, George Machairas1, Pavlos Katonis3 and George Sapkas4 *1D' Department of Orthopaedics, "KAT" General Hospital, Athens, 2A' Department of Orthopaedics, "G. Gennimatas" General Hospital, Athens, 3Department of Orthopaedics, University of Crete, Herakleion, 4A' Department of Orthopaedics, University of Athens, "Attikon" University Hospital, Haidari, Greece* 

#### **1. Introduction**

54 Clinical and Molecular Advances in Ankylosing Spondylitis

von Tirpitz, C; Steder-Neukamm, U; Glas, K; Sander, S; Ring, C; Klaus, J; Reinshagen, M.

Ward, MM. Predictors of the progression of functional disability in patients with ankylosing spondylitis. *J Rheumatol,* Vol.29, No.7, (Jul 2002), pp. 1420-1425, ISSN 0315-162X Wei, JC; Wong, RH; Huang, JH; Yu, CT; Chou, CT; Jan, MS; Tsay, GJ; Chou, MC; Lee, HS.

Will, R; Palmer, R; Bhalla, A; Ring, F; Calin, A. Bone loss as well as bone formation is a

Zochling, J; Braun, J; van der Heijde, D. Assessments in ankylosing spondylitis. *Best Pract Res Clin Rheumatol*, Vol.20, No.3, (Jun 2006), pp. 521-537, ISSN 1521-6942

No.12, (Dec 1993), pp. 1145-1150, ISSN 0044-2771

ISSN 0140-6736

1990), pp. 498-499, ISSN 0263-7103

Osteoporosis in inflammatory bowel disease – results of a survey among members of the German Crohn's and Ulcerative Colitis Association. *Z Gastroenterol*, Vol.41,

Evaluation of internal consistency and re-test reliability of Bath ankylosing spondylitis indices in a large cohort of adult and juvenile spondylitis patients in Taiwan. *Clin Rheumatol*, Vol.26, No.10, (Oct 2007), pp. 1685-1691, ISSN 0770-3198 Will, R; Palmer, R; Bhalla, AK; Ring, F; Calin, A. Osteoporosis in early ankylosing

spondylitis: A primary pathological event? *Lancet*, Vol.2, (Dec 1989), pp. 1483-1485,

feature of progressive ankylosing spondylitis. *Br J Rheumatol*, Vol.29, No.6, (Dec

Ankylosing Spondylitis (AS) is a chronic inflammatory disease which is characterized by pain and progressive stiffness and which spinal and sacroiliac joints are mainly affected. It affects mostly males, having a male-to-female ratio approximately 3-4:1 and the onset occur between the 15th and the 35th year of life (Bechterew, 1979; Calin, 1985; van der Linden et al., 2005).

Ankylosing Spondylitis transforms the flexible spinal column into a stiff rod; the stiffened spine cannot bear normal loads in comparison with a healthy spine. In addition, it has been established that bone mineral density loss occurs early in the AS disease course and is associated with inflammation correlated with increased bone resorption (van der Horst-Bruinsma, 2006). The kyphotic deformation of the spine that exists makes the ankylosing and osteoporotic spine susceptible to stress fractures under the impact of small forces and loads (van der Linden et al., 2005). The diffuse paraspinal ossification and inflammatory osteitis of advanced AS creates a fused, brittle spine that is susceptible to fracture (De Peretti et al, 2004; Einsiedel et al, 2006; Hanson and Mirza, 2000; van der Horst-Bruinsma, 2006; Taggard ans Traynelis, 2000;). Patients suffering from AS may undergo a fracture with minimal (Graham and Van Peteghem, 1989; Hanson and Mirza, 2000; Trent et al., 1988; Whang et al, 2009), or even no history of injury (Olerud et al., 1996; Westerveld et al., 2009; Yau and Chan, 1974).

The most frequent site, where a fracture is located is the cervical spine (75%) especially it's lower part, and the cervical-thoracic junction, following by the thoracolumbar junction (T10- L2). The drastic increase in stiffness at the cervicothoracic junction, combined with the lever arm of the fused cervical spine and weight of the head, makes fractures at the C6-C7 and C7- T1 levels most common. The lumbar and thoracic spines are more resistant to fracture because the anterior and posterior longitudinal ligaments are more thoroughly ossified than in the cervical spine. (Bohlman, 1979; Hanson and Mirza, 2000; Osgood et al., 1973; Surin,

Surgical Treatment After Spinal Trauma in Patients with Ankylosing Spondylitis 57

Fig. 1. Anteroposterior radiograph showing Chance type fracture due to a hyperextension

Fig. 2. Lateral MRI of the same case with a Chance type of fracture at T12-L1 level.

injury at T12-L1 level.

1980; Taggard and Traynelis, 2000; Trent et al., 1988; Westerveld et al., 2009; Yau and Chan, 1974). Disruption of all the three columns of the spine predisposes to displacement and neurological injury (Gelman and Umber, 1978; Rasker et al., 1996).

When a fracture occurs in a patient with AS it should be considered as high-risk injury, especially when it is located in the cervical-thoracic junction of the spine (Fast et al., 1986; Sharma and Mathad, 1988). The most unstable types are shearing fractures. They may have severe neurological symptoms or may lead to haemothorax or rupture of the aorta, which are serious complications (Juric et al., 1990; Sharma and Mathad, 1988). Secondary neurological aggravation may be possible due to displacement of the fractured segments, which happens mainly in hyperextension injuries (Whang et al, 2009). Furthermore, where an interval occurs between trauma and the onset of neurologic signs or worsening of the neurologic picture the formation of an epidural hematoma should be suspected and excluded by means of an MRI scan (Thumbicat et al., 2007). Diagnosis can be difficult due to pre-existing spinal alterations (distortion of the normal spinal anatomy by ectopic bone formation, erosions, sclerosis, disk ossification, vertebral wedging). The standard radiographs are inadequate to fully evaluate shearing fractures due to osteoporosis, and the position of the shoulders (which are usually are located at a higher position). Thus, these fractures can be missed in the first examination and in the later stages, are characterized by vertebral corrosion, collapse and deformity. A misdiagnosed fracture can possibly lead to pseudarthrosis or Andersson lesion.

#### **2. Diagnostic approach and clinical / radiological findings**

The low grade of clinical suspicion makes the diagnosis difficult. The low imaging quality due to osteoporosis and the position of the shoulders (which usually are located in higher position) raise the difficulty level. Shearing fractures are possible to be missed in the first examination. All the available radiological tools should be used in order to validate the diagnosis, particularly when the injury concerns the occipital-cervical, the cervical-thoracic, the thoracolumbar or the lumbar-sacral junctions (Figures 1, 2, 3).

Plain radiographs (face, profile and oblique views) of the injured region may not reveal the fracture, giving only indirect information, such as widening of the disk space and discontinuity of the ossified paraspinal ligaments (Hanson and Mirza, 2000) which unfortunately are not able to set the diagnosis. In later stages these fractures are characterized by vertebral corrosion, collapse and deformity. A misdiagnosed fracture possibly leads to pseudarthrosis.

The neurological disorders may be established at the time of injury but it is not unusual to be established progressively with several days delay. It is not an exaggeration to say, that new back pain in patients with ankylosing spondylitis should be assumed to be caused by a fracture until proven otherwise (Einsiedel et al., 2006; Hanson and Mirza, 2000; Trent et al., 1988). Thus, thorough clinical and radiological assessment should be performed in these patients and should be repeated for the first few weeks, especially if the patient complains for indefinable pain or if neurological disorders are noted. The clinical doctor should always have in mind that the simple radiological evaluation of these injuries may not be able to reveal the fractures from the very first time. CT and MRI are valuable tools in order to reveal these fractures.

1980; Taggard and Traynelis, 2000; Trent et al., 1988; Westerveld et al., 2009; Yau and Chan, 1974). Disruption of all the three columns of the spine predisposes to displacement and

When a fracture occurs in a patient with AS it should be considered as high-risk injury, especially when it is located in the cervical-thoracic junction of the spine (Fast et al., 1986; Sharma and Mathad, 1988). The most unstable types are shearing fractures. They may have severe neurological symptoms or may lead to haemothorax or rupture of the aorta, which are serious complications (Juric et al., 1990; Sharma and Mathad, 1988). Secondary neurological aggravation may be possible due to displacement of the fractured segments, which happens mainly in hyperextension injuries (Whang et al, 2009). Furthermore, where an interval occurs between trauma and the onset of neurologic signs or worsening of the neurologic picture the formation of an epidural hematoma should be suspected and excluded by means of an MRI scan (Thumbicat et al., 2007). Diagnosis can be difficult due to pre-existing spinal alterations (distortion of the normal spinal anatomy by ectopic bone formation, erosions, sclerosis, disk ossification, vertebral wedging). The standard radiographs are inadequate to fully evaluate shearing fractures due to osteoporosis, and the position of the shoulders (which are usually are located at a higher position). Thus, these fractures can be missed in the first examination and in the later stages, are characterized by vertebral corrosion, collapse and deformity. A misdiagnosed fracture can possibly lead to

The low grade of clinical suspicion makes the diagnosis difficult. The low imaging quality due to osteoporosis and the position of the shoulders (which usually are located in higher position) raise the difficulty level. Shearing fractures are possible to be missed in the first examination. All the available radiological tools should be used in order to validate the diagnosis, particularly when the injury concerns the occipital-cervical, the cervical-thoracic,

Plain radiographs (face, profile and oblique views) of the injured region may not reveal the fracture, giving only indirect information, such as widening of the disk space and discontinuity of the ossified paraspinal ligaments (Hanson and Mirza, 2000) which unfortunately are not able to set the diagnosis. In later stages these fractures are characterized by vertebral corrosion, collapse and deformity. A misdiagnosed fracture

The neurological disorders may be established at the time of injury but it is not unusual to be established progressively with several days delay. It is not an exaggeration to say, that new back pain in patients with ankylosing spondylitis should be assumed to be caused by a fracture until proven otherwise (Einsiedel et al., 2006; Hanson and Mirza, 2000; Trent et al., 1988). Thus, thorough clinical and radiological assessment should be performed in these patients and should be repeated for the first few weeks, especially if the patient complains for indefinable pain or if neurological disorders are noted. The clinical doctor should always have in mind that the simple radiological evaluation of these injuries may not be able to reveal the fractures from the very first time. CT and MRI are valuable tools in order to reveal

neurological injury (Gelman and Umber, 1978; Rasker et al., 1996).

**2. Diagnostic approach and clinical / radiological findings** 

the thoracolumbar or the lumbar-sacral junctions (Figures 1, 2, 3).

pseudarthrosis or Andersson lesion.

possibly leads to pseudarthrosis.

these fractures.

Fig. 1. Anteroposterior radiograph showing Chance type fracture due to a hyperextension injury at T12-L1 level.

Fig. 2. Lateral MRI of the same case with a Chance type of fracture at T12-L1 level.

Surgical Treatment After Spinal Trauma in Patients with Ankylosing Spondylitis 59

1993; Kanter et al., 2008). Under these circumstances a potential neurological deficit is often and that necessitate early and aggressive surgical management with posterior and/or anterior fixation techniques to enable neural decompression, spinal stability, and optimal

A surgical intervention is necessary in cases of traumatic instability, significant deformity, and persistent degenerative radiculopathy with axial pain. In addition, selection of the patients that require surgical treatment is based on the degree of deformity, the level of pain

It is well documented that a crucial step in airway management and prior to any surgical intervention, is a smooth and successful intubation (Hoh et al., 2008; Sciubba et al., 2008). The risks during obtaining airway access are significantly increased in patients with AS. The presence of large anterior cervical osteophytes may prohibit successful visualization of the larynx and may prevent endotracheal intubation due to significant mass obstruction. In addition, intubation may be impossible in cases in which the patient cannot extend his neck. Therefore, relatively minor flexion or extension forces during head positioning for intubation could lead to the creation of iatrogenic fractures or neurological injury by the intubation professional (Palmer, 1993). With modern anesthesia techniques, however, awake intubation allows for constant neurological monitoring during induction and insertion of an endotracheal tube. Fiberoptic visualization facilitates inserting a nasotracheal tube to secure

With endotracheal intubation, airway access is secured throughout the duration of the procedure. With a secured airway, the procedure can be performed in the prone position, facilitating placement of instrumentation, particularly at the upper thoracic levels, and reduces the risk of air embolism. General anesthesia also ensures patient comfort throughout the procedure. General anesthesia, however, impairs the ability to monitor neurological function, particularly immediately. While a wake-up test definitively demonstrates the patient's neurological function, expert anesthesia is required to perform a safe and timely evaluation. In a recent study, have been considered that as a special consideration for patients with AS, informed consent should include obtaining a consent for tracheotomy in the event that an obstructive cervical osteophyte or severe cervical flexion

Proper positioning of a patient with AS in the operating room or the ICU is imperative not only for the patient with an unstable fracture, but in all AS patients because of their increased risk of iatrogenic injury. During head positioning, the surgeon must take into account the sagittal alignment of the cervical spine, which may often be significantly kyphotic. When fractures already exist in these patients, inadequate assessment of the mass of the head and the extent of cervical kyphosis can have disastrous effects such as complete spinal cord damage and possible death (Hunter and Dubo, 1978; Sciubba et al., 2008).

In surgical procedures, preoperative halo placement and traction have shown success in improving stability during positioning (Chin and Ahn, 2007; Simmons et al., 2006;

functionality (Broom and Raycroft, 1988; Deutsch and Haid, 2008).

**3.1 Anesthesia options** 

**3.1.1 Patient positioning** 

and disability, and the medical status of the patient (Mundwiler et al., 2008).

airway access in patients with fixed cervical flexion (Hoh et al., 2008).

deformity prevent successful intubation (Cesur et al., 2005).

Fig. 3. Lateral 3D reconstruction image of the same case.

Preoperative evaluation of the cervical spine is essential when manipulating the neck during intubation and patient positioning. Physicians also must be aware that, because the atlantooccipital joint is last to fuse, atlantoaxial instability may occur. Instability is usually demonstrated on lateral flexion-extension views of the neck, where the atlantodens and posterior atlantodens intervals are measured. An atlantodens interval >3.5 mm is indicative of instability. A difference of 7 mm indicates disruption of the alar ligaments, and a difference >9 to 10 mm or a posterior atlantodens interval >14 mm is associated with an increased risk of neurologic injury and usually requires surgical intervention (Kubiak et al, 2005). However, there are no guidelines for the management of atlantoaxial subluxation in patients with AS. Such management is similar to that performed in patients with rheumatoid arthritis (Ramos-Remus et al., 2006).

#### **3. Surgical treatment**

The majority of the cervical spine fractures occur at the level of the intervertebral disc and result in anatomic displacement and instability (Graham and Van Peteghem, 1987; Fox et al., 1993; Kanter et al., 2008). Under these circumstances a potential neurological deficit is often and that necessitate early and aggressive surgical management with posterior and/or anterior fixation techniques to enable neural decompression, spinal stability, and optimal functionality (Broom and Raycroft, 1988; Deutsch and Haid, 2008).

A surgical intervention is necessary in cases of traumatic instability, significant deformity, and persistent degenerative radiculopathy with axial pain. In addition, selection of the patients that require surgical treatment is based on the degree of deformity, the level of pain and disability, and the medical status of the patient (Mundwiler et al., 2008).

#### **3.1 Anesthesia options**

58 Clinical and Molecular Advances in Ankylosing Spondylitis

Preoperative evaluation of the cervical spine is essential when manipulating the neck during intubation and patient positioning. Physicians also must be aware that, because the atlantooccipital joint is last to fuse, atlantoaxial instability may occur. Instability is usually demonstrated on lateral flexion-extension views of the neck, where the atlantodens and posterior atlantodens intervals are measured. An atlantodens interval >3.5 mm is indicative of instability. A difference of 7 mm indicates disruption of the alar ligaments, and a difference >9 to 10 mm or a posterior atlantodens interval >14 mm is associated with an increased risk of neurologic injury and usually requires surgical intervention (Kubiak et al, 2005). However, there are no guidelines for the management of atlantoaxial subluxation in patients with AS. Such management is similar to that performed in patients with

The majority of the cervical spine fractures occur at the level of the intervertebral disc and result in anatomic displacement and instability (Graham and Van Peteghem, 1987; Fox et al.,

Fig. 3. Lateral 3D reconstruction image of the same case.

rheumatoid arthritis (Ramos-Remus et al., 2006).

**3. Surgical treatment** 

It is well documented that a crucial step in airway management and prior to any surgical intervention, is a smooth and successful intubation (Hoh et al., 2008; Sciubba et al., 2008). The risks during obtaining airway access are significantly increased in patients with AS. The presence of large anterior cervical osteophytes may prohibit successful visualization of the larynx and may prevent endotracheal intubation due to significant mass obstruction. In addition, intubation may be impossible in cases in which the patient cannot extend his neck. Therefore, relatively minor flexion or extension forces during head positioning for intubation could lead to the creation of iatrogenic fractures or neurological injury by the intubation professional (Palmer, 1993). With modern anesthesia techniques, however, awake intubation allows for constant neurological monitoring during induction and insertion of an endotracheal tube. Fiberoptic visualization facilitates inserting a nasotracheal tube to secure airway access in patients with fixed cervical flexion (Hoh et al., 2008).

With endotracheal intubation, airway access is secured throughout the duration of the procedure. With a secured airway, the procedure can be performed in the prone position, facilitating placement of instrumentation, particularly at the upper thoracic levels, and reduces the risk of air embolism. General anesthesia also ensures patient comfort throughout the procedure. General anesthesia, however, impairs the ability to monitor neurological function, particularly immediately. While a wake-up test definitively demonstrates the patient's neurological function, expert anesthesia is required to perform a safe and timely evaluation. In a recent study, have been considered that as a special consideration for patients with AS, informed consent should include obtaining a consent for tracheotomy in the event that an obstructive cervical osteophyte or severe cervical flexion deformity prevent successful intubation (Cesur et al., 2005).

#### **3.1.1 Patient positioning**

Proper positioning of a patient with AS in the operating room or the ICU is imperative not only for the patient with an unstable fracture, but in all AS patients because of their increased risk of iatrogenic injury. During head positioning, the surgeon must take into account the sagittal alignment of the cervical spine, which may often be significantly kyphotic. When fractures already exist in these patients, inadequate assessment of the mass of the head and the extent of cervical kyphosis can have disastrous effects such as complete spinal cord damage and possible death (Hunter and Dubo, 1978; Sciubba et al., 2008).

In surgical procedures, preoperative halo placement and traction have shown success in improving stability during positioning (Chin and Ahn, 2007; Simmons et al., 2006;

Surgical Treatment After Spinal Trauma in Patients with Ankylosing Spondylitis 61

Because there may exist discrepancies in sensitivity among the various monitoring techniques, it is now recommended that multiple and continuous neurological monitoring methods be used in addition to wake-up tests so that any false negatives provided by the electrophysiological recording are eliminated (Chin and Ahn, 2007; Tamaki and Yamane,

Conservative treatment either by prolonged bed rest in traction or in a cervical collar, or by early realignment and immobilization in a halo vest has been advocated because of supposed higher mortality after surgery (Graham and Van Peteghem, 1987). However, maintaining reduction is a major concern for conservative treatment: distraction, halo vest application, and transfer to a stretcher have led to secondary dislocation and neurological deterioration. Furthermore, immobilization in a halo has been associated with serious complications. Poor bone quality, vulnerable skin, and difficulty in achieving good alignment are additional arguments against the use of a halo (Schroder et al., 2003). Surgical treatment is more commonly used, especially in patients with neurologic compromise, obscured visual fields, pseudarthrosis, or recurrent fracture. When traction or internal fixation is used to manage these injuries, the neck should be aligned to prefracture position, not necessarily to a normal position. Minor findings in patients with AS may be associated with substantial instability in the cervical spine, secondary to the altered biomechanics of the fused spine in addition to osteopenia and the concentration of forces at the cervico-occipital and cervico-thoracic junctions. The choice of the stabilization method is depending on the patient's personality, the type of the injury and the surgeon's experience. Currently, surgical stabilization with a rigid fixation is the choice of treatment that many

1975).

**3.2 Management of a fracture** 

surgeons perform (Figures 4, 5, 6).

Fig. 4. CT image showing a fracture of the axis at the Cervical Spine.

Upadhyay et al., 1991). To allow a certain degree of freedom for patients with AS in the operating room or ICU, a number of adaptations to patient beds have been developed to accommodate prolonged immobilization. Such advances have particular relevance for the AS population because they allow the patient to maintain a more comfortable kyphotic condition with cervical traction.

#### **3.1.2 Neurological monitoring**

The ability to monitor the neurological status of any patient during positioning or surgical manipulation is extremely important in any spine surgery (Sciubba et al., 2008). In 1974 Scoliosis Research Society found that aggressive surgeries to correct deformities were associated with severe postoperative neurological deficits, and thus the society advised the universal use of intraoperative monitoring. In patients with AS, this statement is especially relevant. The surgeon must first decide whether the patient should receive general anesthesia at all. Because of the potentially hazardous nature of osteotomy procedures, a local anesthetic can be administered for frequent neurological assessments during deformity correction.

Urist (1958) was one of the first to report success with cervical osteotomy with the patient in the sitting position and with local anesthesia. Such operations carry a high risk of neurological complications due to the potential for iatrogenic cervical subluxation and spinal cord compromise, and thus continual feedback on neurological status provided by the awake patient is especially important (Belanger et al., 2005; Chin and Ahn, 2007). Nevertheless, performing these complex corrective spinal procedures on awake patients is a challenging task and is done on a rare basis.

Many complex spine surgeries however, require patients to be in the prone position for prolonged periods with extensive soft tissue exposure, making awake surgeries uncomfortable or completely infeasible for the patient. Hence, the wake-up test, which introduced by Vazuelle et al. in 1973, has been used to monitor the neurological status of patients undergoing prolonged spine deformity surgeries in the prone position.

Nowadays, placement of the patient in the prone position under general anesthesia is the preferred method for most spine surgeries, including those in patients with AS because it allows the surgeon easier access and manipulations of the spine, and the patient can tolerate a longer procedure (Bridwell et al., 2003, 2004; Hitchon et al., 2002, 2006; Langeloo et al., 2006).

Some surgeons feel that the cervical spine region is at a particularly high risk for neurovascular complications compared with the lumbar or thoracic area due to the higher level of the associated spine cord and accompanying vertebral arteries (Simmons et al., 2006). Therefore, if the decision has been made to proceed using general anesthesia, with or without the use of wake-up tests, many authors have stated that neurolophysiological monitoring is absolutely required (Chin and Ahn, 2007; Langeloo et al., 2006; Law, 1959). Common techniques include spinal cord evoked potentials introduced by Tamaki and Yamane, (1975), somatosensory cortical evoked potentials introduced by Nash and Brown, (1979), spinal somatosensory evoked potentials introduced by Shimoji et al. (1971), and muscle MEPs introduced by Merton and Morton, (1980). Unfortunately, such studies may not be sensitive enough to reliably predict neurological damage (Tamaki and Kubota, 2007).

Because there may exist discrepancies in sensitivity among the various monitoring techniques, it is now recommended that multiple and continuous neurological monitoring methods be used in addition to wake-up tests so that any false negatives provided by the electrophysiological recording are eliminated (Chin and Ahn, 2007; Tamaki and Yamane, 1975).

#### **3.2 Management of a fracture**

60 Clinical and Molecular Advances in Ankylosing Spondylitis

Upadhyay et al., 1991). To allow a certain degree of freedom for patients with AS in the operating room or ICU, a number of adaptations to patient beds have been developed to accommodate prolonged immobilization. Such advances have particular relevance for the AS population because they allow the patient to maintain a more comfortable kyphotic

The ability to monitor the neurological status of any patient during positioning or surgical manipulation is extremely important in any spine surgery (Sciubba et al., 2008). In 1974 Scoliosis Research Society found that aggressive surgeries to correct deformities were associated with severe postoperative neurological deficits, and thus the society advised the universal use of intraoperative monitoring. In patients with AS, this statement is especially relevant. The surgeon must first decide whether the patient should receive general anesthesia at all. Because of the potentially hazardous nature of osteotomy procedures, a local anesthetic can be administered for frequent neurological assessments during deformity

Urist (1958) was one of the first to report success with cervical osteotomy with the patient in the sitting position and with local anesthesia. Such operations carry a high risk of neurological complications due to the potential for iatrogenic cervical subluxation and spinal cord compromise, and thus continual feedback on neurological status provided by the awake patient is especially important (Belanger et al., 2005; Chin and Ahn, 2007). Nevertheless, performing these complex corrective spinal procedures on awake patients is a

Many complex spine surgeries however, require patients to be in the prone position for prolonged periods with extensive soft tissue exposure, making awake surgeries uncomfortable or completely infeasible for the patient. Hence, the wake-up test, which introduced by Vazuelle et al. in 1973, has been used to monitor the neurological status of

Nowadays, placement of the patient in the prone position under general anesthesia is the preferred method for most spine surgeries, including those in patients with AS because it allows the surgeon easier access and manipulations of the spine, and the patient can tolerate a longer procedure (Bridwell et al., 2003, 2004; Hitchon et al., 2002, 2006; Langeloo et al.,

Some surgeons feel that the cervical spine region is at a particularly high risk for neurovascular complications compared with the lumbar or thoracic area due to the higher level of the associated spine cord and accompanying vertebral arteries (Simmons et al., 2006). Therefore, if the decision has been made to proceed using general anesthesia, with or without the use of wake-up tests, many authors have stated that neurolophysiological monitoring is absolutely required (Chin and Ahn, 2007; Langeloo et al., 2006; Law, 1959). Common techniques include spinal cord evoked potentials introduced by Tamaki and Yamane, (1975), somatosensory cortical evoked potentials introduced by Nash and Brown, (1979), spinal somatosensory evoked potentials introduced by Shimoji et al. (1971), and muscle MEPs introduced by Merton and Morton, (1980). Unfortunately, such studies may not be sensitive enough to reliably predict neurological damage (Tamaki and Kubota, 2007).

patients undergoing prolonged spine deformity surgeries in the prone position.

condition with cervical traction.

**3.1.2 Neurological monitoring** 

challenging task and is done on a rare basis.

correction.

2006).

Conservative treatment either by prolonged bed rest in traction or in a cervical collar, or by early realignment and immobilization in a halo vest has been advocated because of supposed higher mortality after surgery (Graham and Van Peteghem, 1987). However, maintaining reduction is a major concern for conservative treatment: distraction, halo vest application, and transfer to a stretcher have led to secondary dislocation and neurological deterioration. Furthermore, immobilization in a halo has been associated with serious complications. Poor bone quality, vulnerable skin, and difficulty in achieving good alignment are additional arguments against the use of a halo (Schroder et al., 2003).

Surgical treatment is more commonly used, especially in patients with neurologic compromise, obscured visual fields, pseudarthrosis, or recurrent fracture. When traction or internal fixation is used to manage these injuries, the neck should be aligned to prefracture position, not necessarily to a normal position. Minor findings in patients with AS may be associated with substantial instability in the cervical spine, secondary to the altered biomechanics of the fused spine in addition to osteopenia and the concentration of forces at the cervico-occipital and cervico-thoracic junctions. The choice of the stabilization method is depending on the patient's personality, the type of the injury and the surgeon's experience. Currently, surgical stabilization with a rigid fixation is the choice of treatment that many surgeons perform (Figures 4, 5, 6).

Fig. 4. CT image showing a fracture of the axis at the Cervical Spine.

Surgical Treatment After Spinal Trauma in Patients with Ankylosing Spondylitis 63

1. Patients with an ankylosed spine have an increased fracture risk even after minor

2. Delayed diagnosis of fractures in patients with ankylosing spinal disorders often occur

3. Fractures of the ankylosed spine tend to be unstable, because ossified ligaments and

4. An intrinsic unstable fracture configuration may lead to primary and secondary

5. The clinical outcome of patients fracturing their ankylosed spine is worse compared to

6. Surgical treatment may be favorable for patients with an ankylosed spine and spinal fracture, as this treatment option may be associated with lower complication and

7. The presence of ankylosed spine segments should alert the treating physician for

8. In trauma registries ankylotic conditions of the spine should be registered separately, in order to acquire more knowledge on the patterns and prognosis of these injuries. In a retrospective review of 12 patients with AS and 18 patients with diffuse idiopathic skeletal hyperostosis (DISH), authors mentioned that the treatment algorithm for managing spinal trauma is similar for both of these disorders, and the specific approach that is selected may be influenced by the type of injury, degree of spinal instability, and neurologic status of the individual (Wang et al., 2009). On the basis of these criteria, most of the injuries in those series were addressed with surgical intervention to more reliably stabilize the spine and prevent further neurologic decline. Although the operative rate observed for the AS group was higher than that of the DISH patients (83.3% vs. 66.7%, respectively), which may reflect the relatively greater neurologic impairment that was displayed by the subjects with AS, this difference was not found to be statistically significant. Even if it may not be feasible to formulate a definitive treatment protocol from the results of the above case series, it is clear that there are several important technical considerations that merit further discussion. As both of these diseases are associated with the development of kyphotic deformities, it is essential that the preinjury alignment of the spine be restored to achieve an adequate and hopefully stable reduction of the fracture. The authors recommended against any attempts to improve upon the preinjury sagittal alignment of these patients in the acute setting because aggressive manipulation may result in an unstable spinal construct that may subject the spinal cord or nerve roots to further harm; consequently, osteotomies and other corrective procedures should be delayed until the original injury has resolved so that they may be performed in a more controlled fashion. Although low-weight traction may be employed for selected cervical lesions to facilitate angular correction and postural positioning with wedge inserts may be useful for addressing any sagittal plane abnormalities associated with thoracolumbar injuries, the application of any type of distraction force is strictly contraindicated in these clinical scenarios because of the increased risk of precipitating a secondary neurologic insult at the level of an unstable spinal

It is generally assumed that the stabilization of cervical fractures is better performed with anterior and posterior support of the spine. Sapkas et al., (2009) presented their surgical

mortality rates and may lead to neurological improvement more frequently,

In a review study by Westerveld et al., (2009) authors have recommended the follows:

due to both doctor and patient related factors,

unstable spine fractures in every trauma patient,

surrounding tissue also fracture,

the general spine trauma population,

segment, particularly in the cervical spine.

neurological deficit,

trauma,

Fig. 5. MRI of the same patient with a fracture of the axis.

Fig. 6. The patient was treated with occipitocervical fusion by using a screw-rod stabilizing system.

Fig. 6. The patient was treated with occipitocervical fusion by using a screw-rod stabilizing

Fig. 5. MRI of the same patient with a fracture of the axis.

system.

In a review study by Westerveld et al., (2009) authors have recommended the follows:


In a retrospective review of 12 patients with AS and 18 patients with diffuse idiopathic skeletal hyperostosis (DISH), authors mentioned that the treatment algorithm for managing spinal trauma is similar for both of these disorders, and the specific approach that is selected may be influenced by the type of injury, degree of spinal instability, and neurologic status of the individual (Wang et al., 2009). On the basis of these criteria, most of the injuries in those series were addressed with surgical intervention to more reliably stabilize the spine and prevent further neurologic decline. Although the operative rate observed for the AS group was higher than that of the DISH patients (83.3% vs. 66.7%, respectively), which may reflect the relatively greater neurologic impairment that was displayed by the subjects with AS, this difference was not found to be statistically significant. Even if it may not be feasible to formulate a definitive treatment protocol from the results of the above case series, it is clear that there are several important technical considerations that merit further discussion. As both of these diseases are associated with the development of kyphotic deformities, it is essential that the preinjury alignment of the spine be restored to achieve an adequate and hopefully stable reduction of the fracture. The authors recommended against any attempts to improve upon the preinjury sagittal alignment of these patients in the acute setting because aggressive manipulation may result in an unstable spinal construct that may subject the spinal cord or nerve roots to further harm; consequently, osteotomies and other corrective procedures should be delayed until the original injury has resolved so that they may be performed in a more controlled fashion. Although low-weight traction may be employed for selected cervical lesions to facilitate angular correction and postural positioning with wedge inserts may be useful for addressing any sagittal plane abnormalities associated with thoracolumbar injuries, the application of any type of distraction force is strictly contraindicated in these clinical scenarios because of the increased risk of precipitating a secondary neurologic insult at the level of an unstable spinal segment, particularly in the cervical spine.

It is generally assumed that the stabilization of cervical fractures is better performed with anterior and posterior support of the spine. Sapkas et al., (2009) presented their surgical

Surgical Treatment After Spinal Trauma in Patients with Ankylosing Spondylitis 65

Neurological status preoperatively

Treatment/Levels of Fusion

Posterior instrumentation/ Occipito-C4

Posterior instrumentation/ Occipito-C4

Anterior + Posterior instrumentation/ C4-T2

Anterior + Posterior instrumentation/ C4-T2

Posterior instrumentation/ C4-T2

Anterior + Posterior instrumentation/ C4-T2

Posterior instrumentation/ C4-T2

Posterior instrumentation/ T3-T8

Posterior instrumentation/ T6-T10

Posterior instrumentation/ T6-T11

Posterior instrumentation/ T6-T11

Posterior instrumentation/ T7-T11

Posterior instrumentation/ T8-L1

Posterior instrumentation/ T8-L1

Posterior instrumentation/ T8-L1

Posterior instrumentation/ T9-L2

Neurological status postoperatively

Frankel D

Frankel E

Frankel E

Frankel E

Frankel E

Frankel A

Frankel E

Frankel E

Frankel E

Frankel D

Frankel E

Frankel E

Frankel A

Frankel D

Frankel A

Frankel E

Level of fracture/Type

height C6 – C7/A.2.3.1 Frankel C
