Preface

Research in the last decades has provided new data improving the knowledge of the clinical findings, pathogenesis, and treatment of ankylosing spondylitis (AS). Magnetic resonance imaging (MRI) has helped to define two subsets of axial spondylarthritis (ax SpA) that may be considered different presentations of the same disease: non-radiographic ax SpA, which does not fulfill the radiographic criteria of the modified New York criteria, and radiographic ax SpA, which does fulfill the radiographic criteria of the modified New York criteria. Another important finding was reported in 2010, which showed that although most patients with AS have elevated levels of the inflammatory markers erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), some patients may have active disease with normal levels of these markers. These findings are clearly important for treatment decisions.

This book presents updated data on the diagnosis, pathogenesis, and treatment of AS. Section 1, "History, Classification Criteria and Imaging in AS", includes three chapters that describe how AS patients are characterized using metrology, functional indexes, diagnostic criteria, and imaging.

Chapter 1, "Introductory Chapter: AS Times Go by – An Axial Chronicle", is dedicated to the history of the first descriptions of AS by Bernard Connor, followed by those of Strumpell, Von Bechterew, and Pierre Marie. The chapter chronicles the evolution of the diagnostic criteria over time, starting with the Rome criteria in 1961, which used objective clinical methods to measure spinal mobility. The New York criteria introduced sacroiliitis, which is considered the hallmark of AS. These criteria were modified by van der Linden in 1984, expanding the diagnostic criteria to non-axial spondyloarthropathies. The Amor and the European Spondylarthritis Study Group (ESSG) criteria were developed in 1990, followed by the Assessment of Spondylarthritis International Society (ASAS) criteria, which defined the two subsets of ax SpA.

This chapter also examines metrology and self-administered questionnaires, including the test by Schoeber (1937), the Health Assessment Questionnaire (HAQ score), and the Bath indexes (BASDAI, BASFI, and BASMI) developed by Andrei Calin et al. at the Royal National Hospital for Rheumatic Diseases, Bath, UK, all of which are important contributions to AS characterization and research. The chapter also examines the mechanisms involved in AS pathogenesis, including major histocompatibility complex (MHC) alleles, non-MHC genetic associations, and new treatments targeting some of these genes.

Chapter 2, "Diagnostic/Classification Criteria", deals with the diagnostic and classification criteria of AS, emphasizing that they have different goals. While diagnostic criteria should be used to diagnose AS, classification criteria are intended to be used in already diagnosed patients, mainly for research purposes. As we know, the modified diagnostic criteria may fail to detect early AS, and MRI that helps to visualize early bone marrow

oedema led to the development of the ASAS classification criteria. According to the authors, the ASAS criteria have a specificity of 84.4% and a sensitivity of 82.9% and represent a major step forward for ax SpA. In clinical practice, most rheumatologists use the ASAS criteria for diagnostic purposes because it may ease the diagnostic process since they represent the most frequently encountered characteristics of the disease. Overdiagnosis may be a negative consequence of using classification criteria for diagnostic purposes.

Chapter 3, "Imaging Ankylosing Spondylitis", discusses imaging in AS. Conventional radiography remains an important tool for the diagnosis of structural changes in the sacroiliac joints (SIJs) and spine. According to the New York criteria, the SIJs findings have a high specificity but low sensitivity for ax SpA, especially in early disease. Syndesmophytes and ankylosis of the spine are almost pathognomonic of AS, and syndesmophytes are the best predictors of radiographic progression. Scoring systems include the Modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) and the Bath Ankylosing Spondylitis Radiology Index (BASRI). The first is derived from the sum of scores for the lumbar and cervical spine. The second may be subdivided into BASRI-s for the spine only, BASRI-h for the hips, and BASRI-T for the summation of both. For the lumbar spine is a composite of lateral and anteroposterior views, for the cervical spine only the spine lateral view is scored. mSASSS is the preferred scoring method to evaluate the radiographic progression of AS.

Computed tomography (CT) shows chronic changes more clearly than conventional radiography and permits imaging of structural changes without superposition of overlying structures. The main value of CT is to document erosions of bone at any joint or enthesis and documenting fractures, but unlike MRI it does not reveal bone marrow oedema.

MRI can detect both active inflammatory and structural changes like bone marrow oedema and osteitis and is particularly useful for the early diagnosis of AS and for classifying patients with SpA. The SPARCC method is the most used to score the MRI and is based on the evaluation of the stir sequences of six consecutive semicoronal slices focusing on the synovial part of the SIJ.

Ultrasonography is a noninvasive, low-cost, and highly operator-dependent technique that is very useful in the diagnosis of peripheral involvement of the disease. It is also used as a guide for intra-articular treatment in peripheral joints as well as SIJs. Bone scintigraphy has a limited value in clinical practice, but quality and specificity may be increased using single-photon emission CT (SPECT).

Section 2, "Pathogenesis and Treatment of Ankylosing Spondylitis", includes two chapters that update our knowledge about the role of genetics, immunological factors, and infections and the enteric microbiome on AS pathogenesis.

Chapter 4, "Ankylosing Spondylitis Pathogenesis and Pathophysiology", examines the role of genetic factors in AS. HLA-B27 has 223 subtypes and is the most common recognizable susceptibility genetic factor for AS; however, it accounts for only around 20% of AS development, suggesting that other factors are also responsible. Other HLA genes have been recognized as being AS-associated, and many other non-HLA genes have been identified, namely, ERAP1, ERAP2, NPEPPS, IL23R, and KIRLR

**V**

genes. Genetic variants and expression levels of TLR4 implicate innate immunity in the pathogenesis of AS and support the concept that AS has autoinflammatory components in its physiopathology. Immune pathways such as autophagy and ubiquitination and inflammasome are involved in both innate and adaptative response, and innate and innate-like immune cells can be found at sites of disease, likely representing the major source of IL-17 production in AS. Both autoimmune (the production of specific autoantibodies is very well-known in AS) and autoinflammatory factors are probably

Finally, Chapter 5, "Treatment Modalities of Ankylosing Spondylitis", discusses the treatment modalities for controlling AS. It describes the treatment of AS across the years, focusing on the use of biologic drugs that block inflammatory cytokines, halt disease progression, and improve patient quality of life. The chapter first discusses nonpharmacological treatment, including individual home-based or supervised exercise programs, including Yoga, which are internationally accepted as a good strategy for AS treatment. The chapter next discusses pharmacological treatments, including nonsteroidal anti-inflammatory drugs (NSAIDs) and different types of disease-modifying antirheumatic drugs (DMARDs) as second-line treatment for patients with AS. A substantial part of the chapter is dedicated to cytokine therapy, which is classified into three groups: TNF inhibitors (infliximab, etanercept, adalimumab, golimumab, and certolizumab), IL inhibitors (secukinumab and ixekizumab,) and JAK1 and 3 inhibitors (tofacitinib and upadacitinib) A last point is dedicated to therapies under study, including ustekinumab, a humanized IgG1k mAB that binds

**Jácome Bruges Armas MD, Ph.D.**

Terceira Island, The Azores, Portugal

Nova Medical School, University of Lisbon, Lisbon, Portugal

Epidemiology and Molecular Biology Service (SEEBMO),

Hospital de Santo Espirito de Angra do Heroísmo,

Comprehensive Health Research Centre (CHRC),

to p40-subunit shared by IL-12 and IL23, and stem cell therapy.

involved in AS pathogenesis.

genes. Genetic variants and expression levels of TLR4 implicate innate immunity in the pathogenesis of AS and support the concept that AS has autoinflammatory components in its physiopathology. Immune pathways such as autophagy and ubiquitination and inflammasome are involved in both innate and adaptative response, and innate and innate-like immune cells can be found at sites of disease, likely representing the major source of IL-17 production in AS. Both autoimmune (the production of specific autoantibodies is very well-known in AS) and autoinflammatory factors are probably involved in AS pathogenesis.

Finally, Chapter 5, "Treatment Modalities of Ankylosing Spondylitis", discusses the treatment modalities for controlling AS. It describes the treatment of AS across the years, focusing on the use of biologic drugs that block inflammatory cytokines, halt disease progression, and improve patient quality of life. The chapter first discusses nonpharmacological treatment, including individual home-based or supervised exercise programs, including Yoga, which are internationally accepted as a good strategy for AS treatment. The chapter next discusses pharmacological treatments, including nonsteroidal anti-inflammatory drugs (NSAIDs) and different types of disease-modifying antirheumatic drugs (DMARDs) as second-line treatment for patients with AS. A substantial part of the chapter is dedicated to cytokine therapy, which is classified into three groups: TNF inhibitors (infliximab, etanercept, adalimumab, golimumab, and certolizumab), IL inhibitors (secukinumab and ixekizumab,) and JAK1 and 3 inhibitors (tofacitinib and upadacitinib) A last point is dedicated to therapies under study, including ustekinumab, a humanized IgG1k mAB that binds to p40-subunit shared by IL-12 and IL23, and stem cell therapy.

## **Jácome Bruges Armas MD, Ph.D.**

Epidemiology and Molecular Biology Service (SEEBMO), Hospital de Santo Espirito de Angra do Heroísmo, Terceira Island, The Azores, Portugal

> Comprehensive Health Research Centre (CHRC), Nova Medical School, University of Lisbon, Lisbon, Portugal

**1**

Section 1

History, Classification Criteria

and Imaging in AS

Section 1
