Myopathies: Skeletal Muscle Complications and Beyond

#### **Chapter 2**

## Musculoskeletal Manifestations in Sjogren's Syndrome

*Ridvan İşik and Ferhat Ege*

#### **Abstract**

Sjögren's syndrome (SS) is a chronic, autoimmune, inflammatory disease characterized by lymphocytic infiltration, destruction and dysfunction of the exocrine glands. Sjögren's syndrome can be described as primary or secondary, depending on whether it occurs alone or in association with other systemic autoimmune diseases. Systemic manifestations of SS involve the musculoskeletal system. SS can be seen in association with both joint and muscle manifestations, including arthralgia and arthritis, as well as myopathy, which is usually asymptomatic. Besides, it may include bone metabolic disorders, fatigue and fibromyalgia. The diagnosis of Sjögren's syndrome is based on characteristic clinical signs and symptoms. The etiology and pathogenesis of SS is elusive and has not yet been clarified. There is no curative treatment for SS, thus the aim in the treatment of SS is to alleviate the symptoms.

**Keywords:** musculoskeletal, joints, fibromyalgia, fatigue, bones

#### **1. Introduction**

Sjögren's syndrome (SS) is a chronic, autoimmune, systemic, inflammatory disease that develops as a result of lymphocytic infiltration, destruction and dysfunction of the exocrine glands, and the lacrimal and salivary glands in particular. In 1933, Swedish ophthalmologist Henrik Sjögren described the clinical and histological findings associated with SS in 19 patients with rheumatoid arthritis, 13 of whom had dry mouth and dry eye symptoms [1]. SS predominantly affects middle-aged women who are within the fourth to sixth decade of their lives. The male/female ratio in patients with SS is approximately 6:1 to 9:1. SS is usually diagnosed in the fifth decade of life, but the first symptoms may appear years before diagnosis [2]. The incidence and prevalence rates of SS were estimated approximately as 6.92 cases per 100.000 persons/year and as 60.82 cases per 100.000 persons, respectively [3]. Geographical location and ethnicity have a strong influence on the biological and clinical phenotype of the disease. The onset of diagnosis of Sjogren syndrome and the gender preference may be affected by racial variation: the diagnosis can be accomplished up to 7 years earlier in patients of black/African American origins compared to Caucasians. Furthermore, the female to male ratio might reach 27:1 in patients of Asian descent [4]. There are two types of SS; first type, that is the primary SS, is the type without any concomitant connective tissue disorder, whereas the second type, that is the secondary SS, is the type observed together with other autoimmune diseases such as systemic lupus erythematosus (SLE),

rheumatoid arthritis (RA) or systemic sclerosis (SSc). SS is characterized by a wide spectrum of signs and symptoms, ranging from glandular involvement, structural symptoms, extraglandular manifestations and systemic autoimmune features. SS can be seen in association with both joint and muscle manifestations, including arthralgia and arthritis, as well as myopathy, which is usually asymptomatic. SS mostly involves the bone, the synovium and the cartilage tissue [5].

#### **2. Pathogenesis**

The etiology and pathogenesis of SS has not been clarified, as is the case with other autoimmune diseases [6]. Until now, it has been widely accepted that environmental factors play a role in the pathogenesis of SS [7]. Nevertheless, a thorough review of the recently published studies available in the literature revealed that the complex interaction between epithelial cells and targets of the autoimmune response and genetic and epigenetic changes also play a role in the pathogenesis of SS, in addition to the activated innate and adaptive immune system [8, 9].

The genetic component of SS are yet to shed light on. However, recent studies have begun to elucidate the familial links of the disease, identify specific risk alleles, and even classify patients according to their global gene expression levels. In these studies, many risk alleles for SS have been highlighted. Identification of these risk alleles helps in early diagnosis and choice of treatment options. Patients with extra-glandular manifestations (EGM) were found to have higher expression of genes involved in innate (apoptosis, TLR and interferon signaling) and adaptive (T and B cell activation) immune responses that play a key role in SS. On the other hand, patients with glandular features (GF) and diffuse pain (WP) were found to have the highest differential gene expression related to sensory perception and pain [10]. In complex diseases such as SS, the on and off signals of gene expression related to inflammatory pathways are managed by epigenetic mechanisms. Several epigenetic mechanisms, i.e., DNA methylation, miRNAs, and lncRNAs, contribute to turning on and off the expression of genes involved in inflammatory pathways and may target amelioration of SS therapy [11].

Considerable efforts have been made to elucidate the role of the innate immune system in the pathogenesis of SS. Plasmacytoid dendritic cells (pDC) are the predominant type I interferon (IFN) producing cells. The transcriptional profile of SS plasmacytoid dendritic cells (pDCs) has been investigated and interestingly, it was found to be associated with enhanced cytokine production of pDCs. TLR7 dominant innate immunity may be associated with the development of sialadenitis in SS. Additionally, the few evidence supporting the role of TLR7-dominant innate immunity in the development of sialadenitis in SS [12].

The role of B and T cell subsets, particularly, of T follicular helper cells (Tfh) and of their regular counterparts, that is the T follicular regulatory cells (Tfr) cells, has been extensively investigated. The recent data on the subject revealed an increase in the proportion of Tfr and Tfh cells in SS patients as compared to the healthy control subjects, and an imbalance between proinflammatory and immune regulatory pathways in SS. Tertiary or ectopic lymphoid structures (TLS) are lymphoid clusters of T and B cells that form in non-lymphoid organs in response to chronic inflammation. TLS form in the target organ of autoimmune diseases, including SS, and is generally associated with worse disease progression. New insights into TLS formation and care are paving the way for new therapeutic approaches to SS [13].

#### **3. Articular involvement**

Most SS patients exhibit musculoskeletal symptoms such as arthralgia, myalgia, and morning stiffness. SS directly affects the peripheral joints, causing arthralgia in approximately 90% of the patients. Up to 17% arthritis incidence has been reported in SS patients [14, 15]. Arthritis is often symmetrical, intermittent, non-erosive and does not leave deformity. SS mainly affects the metacarpophalangeal joints located in the upper extremity, particularly the metacarpophalangeal joints with non-erosive synovitis, but also affects the wrists, knees, shoulders, and metatarsophalangeal joints [16]. Clinical symptoms of SS are similar to those of rheumatoid arthritis (RA), with the exception of bone erosion, which is very rare in SS [17]. Joint symptoms associated with primary Sjögren's syndrome (pSS) were reported as synovitis, which can mimic rheumatoid arthritis but were distinguished based on the absence of structural damage [18]. Joint involvement may precede the onset of SS in 10–20% of patients, but in a large amount of SS patients (40–50% of the cases) its onset is concurrent with the onset of sicca symptoms [19]. Ultrasonographic US imaging has proven to be of great value in identification of inflammatory synovitis and detection of erosions. Patients with SS were evaluated by ultrasonography(US), the prevalences of synovitis and erosion were found as 21.7% and 34.8%, respectively [20]. The incidence of synovitis in the metacarpophalangeal joints was found as 41.6% [21]. Additionally, a significant correlation was found between the ESSDAI scores of the SS patients whose disease activities were determined according to European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) and the frequency of synovitis and tenosynovitis detected by US. Based on these findings, it has been suggested that US is a useful method in the evaluation of joint involvement in SS [22]. SS is a complex and heterogeneous disease and has pleomorphic symptoms that can manifest in many different ways [23]. Joint involvement was present in 31.4% of the diagnosed patients, and was manifested as the first symptom in 17% of the patients [24]. Joint involvement is also associated with the presence of many serological markers such as cryoglobulins characterized by extraglandular manifestations, hypergammaglobulinemia, rheumatoid factor (RF) and anti-Sjögren's-syndromerelated antigen A (anti-SSA/Ro) or anti-Sjögren's-syndrome-related antigen B (anti-SSB/La) antibodies [25]. Apart from RA, the highest percetange of RF positivity is seen in SS patients. Approximately 40% of the SS patients, and even a higher percentage if only the SS patients with joint involvement were considered, were found to have RF positivity [25]. Another serological marker associated with arthritic manifestations is anti-citrullinated protein antibodies (ACPAs). ACPAs were found in 5–10% of the SS patients. SS patients with ACPAs were found to have a higher incidence of arthritis than those without ACPAs (43.7% vs. 12.2%). In addition, during a follow-up period of 5–10 years, 43.8% of the SS patients with ACPAs were found to have developed RA [26]. SS patients with ACPAs had a higher tendency to have arthritis and were at a higher risk of developing RA [27]. Joint involvement such as arthralgia and arthritis negatively affects the quality of life in patients with SS [28], creating the need for pharmacological treatment or surgical intervention [29]. It has been emphasized that SS causes higher disease activity scores, which are expressed using scoring systems such as ESSDAI, due to joint involvement, and that joint involvements an important clinical feature in predicting long-term disease outcome in SS [30]. Arthritic manifestations of the SS are mild, but course of SS in association with other diseases varies greatly. However, it is still unclear whether this variation is due to any change directly associated with SS or the combined effect of the disorders

accompanying SS. Findings that prove the association of SS with other autoimmune diseases have been demonstrated by epidemiological and genetic studies. SS was accompanied by RA and SLE in 19.5% and 13.6% of the patients, respectively [31]. There are also studies that revealed an epigenetic relationship linking such diseases. In one of these studies, a gene-expression meta-analysis study in respect of RA, SLE and SS, a common gene-expression was identified for these diseases [32]. It is a common concern that such disease combinations will worsen joint problems and adversely affect the course of the disease. The frequency of RA and SS association and the effects of this association on the course of the disease and comorbid conditions, it was found that 31.2% of the RA patients were also diagnosed with SS, and that the coexistence of these two diseases led to higher disease burden, higher disease activity, higher number og comorbidities (hypertension, cardiovascular diseases, malignancy and infections) and a higher degree of erosive changes [33]. Therefore, type of SS, whether it is primary or secondary SS, should be carefully considered and it should be kept in mind that other autoimmune diseases, including RA, can accompany SS during the course of the disease. Thus, the attending clinician should be able to also characterize these other patient populations.

#### **4. Muscles**

Muscle pain has been reported in approximately 45–50% of the patients with SS [34]. A thorough literature review reveals that a mild inflammatory myopathy with subclinical or insidious onset has been observed in SS. Generally, this condition manifests itself as muscle pain and proximal muscle weakness. Histopathological examination was performed in SS patients with muscle pain, inflammation was found in 72% of the patients, and signs of degeneration/regeneration (i.e., histological findings of myositis) were found in 47% of the patients along with inflammation [35]. In that regard, it has been shown that although rare, inflammatory muscle diseases (particularly, inclusion body myositis and polymyositis) may be associated with SS. Accordingly, patients with more insidious onset muscle weakness and low muscle enzyme elevations in particular should be suspected of inflammatory muscle diseases. There are case reports, which argued that inflammatory muscle diseases and SS can progress together in patients with SS, and that the possible cause of the co-existence of these diseases is a common autoimmune pathway [36, 37]. Additionally, it was reported that cytosolic 5′-nucleotidase 1A, which is a specific marker for inclusion body myositis, can be detected in approximately 30% of the patients with SS [38]. Given this finding, SS patients with muscle weakness should also be screened for inflammatory muscle diseases.

#### **5. Fibromyalgia and fatigue**

Fibromyalgia (FM) is a common disease characterized by widespread chronic body pain, sleep disturbance, weakness, and mood disorders. One of the hypotheses put forward in respect of the formation of FM disease is chronic inflammation. It was reported in many studies that pro-inflammatory cytokines and mediators are higher in patients with FM than in general population [39]. Frequency of FM is high in rheumatic diseases such as ankylosing spondylitis and rheumatoid arthritis. One-third of FM patients (about 33%) with sicca syndrome and/or xerostomia tested

#### *Musculoskeletal Manifestations in Sjogren's Syndrome DOI: http://dx.doi.org/10.5772/intechopen.101369*

positive for Sjögren's syndrome biomarkers [40]. In parallel, association of FM with these autoimmune diseases is common. To give an example, in a recent study, in which the frequency of FM was investigated in patients with inflammatory arthritis (IA), it was found that frequency of FM in IA patients was found to be 15–20% more than the frequency of FM in general population [41]. When it comes to FM and SS, it is seen that these two diseases share common symptoms such as muscle aches, fatigue, and dry mouth and eyes, and there are many studies available in the literature that investigated the relationship between the two. In one of these studies, in which SS-related auto-antibodies in FM patients presented with dry mouth and/or dry eye complaints were investigated, SS biomarkers were found to be positive in 32% of the FM patients. It was suggested by the authors of the study that SS may play a role in the pathophysiology of FM [40]. The comorbidities and clinical symptoms of the two diseases largely overlap. To give a few examples; in a cross-sectional study conducted by Choi et al., which investigated the frequency and clinical effect of FM onpatients with SS, as well as FM frequency, disease activity scales such as Eular Sjogren's Syndrome Patient Reported Index (ESSPRI) and Eular Sjogren Syndrome Disease Activity Index (ESSDAI), and depression in patients with pSS, FM was detected in 31% of the SS patients, and both ESSPRI and ESSDAI scores and depression scores were found to be higher in patients who have both SS with FM, as compared to patients without FM [42]; and in a very recent population-based retrospective-cohort study conducted with 149.706 participants, in which the future risk of developing SS in patients with FM was investigated, patients with FM were found to have a higher risk of developing SS as compared to the control subjects without FM [43]. Given the results of these studies, which suggest that the relationship between SS and FM affects the disease activity and diagnosis, clinicians should consider the two-way relationship between SS and FM in the management of SS or FM. Fatigue is one of the most common symptoms of both SS and FM. The pathophysiology in SS is not fully understood. Patients with SS suffer from sleep disorders as they feel the urge to drink excess water due to dry mouth resulting in sleep disruptions. Fatigue in patients with SS has been associated with the coexistence of sleep disorders and FM. The pathophysiology in SS is not fully understood. Patients with SS suffer from sleep disorders, since they feel the urge to drink excess water due to dry mouth. Fatigue in patients with SS has been associated in the literature with the coexistence of sleep disorders and FM. To give an example; ina large cohort study conducted with 437 patients with pSS, it was found that patients with both FM and pSS manifested significantly more structural, fatigue, and arthralgia symptoms than patients with only pSS [44]. The presence of such symptoms substantially impairs the quality of life in patients with SS. As a matter of fact, it was concluded as a result of a cross-sectional study conducted using questionnaires to measure quality of life of patients with SS that the main determinants of the poor quality of life in patients with SS were pain and fatigue, and that disease activity scores were higher in patients with a high incidence of the said symptoms [45]. For this reason, sleep quality of SS patients should be improved against the symptom of fatigue, which is very common in patients with SS. In addition, in the event that SS accompanied by FM, disease management should be adjusted accordingly.

#### **6. Bones**

SS impairs the bone metabolism not just because it is a systemic autoimmune disease, but also because of some other factors associated with SS such as interstitial nephritis, renal tubular acidosis, steroid use, coexistence with other autoimmune diseases, and low vitamin D levels. As is the case with other autoimmune diseases, SS also causes osteoporosis (OP) and osteomalacia (OM). SS plays a role in metabolic bone diseasesby causing variations in the signaling pathways of the Wingless-type (Wnt) and Nf-κB receptor activating factor (RANK), its ligand (RANKL) and osteoprotegerin (OPG) [46]. It has been reported in the pathophysiological studies conducted on the aforementioned signaling pathways that autoimmune diseases such as SS inhibits bone formation, since it reduces the levels of DKK1 (Dickkopf-related protein 1), a protein which is involved in the Wnt pathway and plays a role in bone formation. In addition, it has been shown that the RANKL/RANK/OPG signaling pathway, which features the main osteogenic factors and plays an important role in bone homeostasis, is activated in many autoimmune diseases, and it has been suggested that this leads to bone destruction [47, 48]. Furthermore, the Wnt/b-catenin signaling pathway plays a key role also in the development and regulation of the immune system, in addition to organogenesis and morphogenesis of the exocrine gland. In that regard, it was found in a study by Fernandez-Torres et al. on the genetic polymorphisms of the Wnt/b-catenin signaling pathway in SS patients that some genes associated with the Wnt/b-catenin signaling pathway, such as LRP5 (lowdensity lipoprotein receptor-related protein 5), FRZB (frizzled related protein), and ADIPOQ (adiponectin), significantly increase the risk of developing SS [49]. In another study, in which impaired bone metabolism in SS was investigated, osteoporosis/osteopenia was detected in ⅔ (two-thirds) of the SS patients. In the same study, it has been shown that DKK1, one of the Wnt signal mediators, was low in SS patients and that this low level is associated with a decrease in bone mineral density, suggesting that Wnt signaling mediators are potentially involved in the pathogenesis of SS [50]. In a case-control study conducted by Pasoto et al. with 71 SS patients and 71 healthy control subjects of matching age, sex, and race, study participants were screened for bone mineral density (BMD), vertebral fracture (VF), and bone microarchitecture (by means of high-resolution peripheral quantitative computer tomography (HR-pQCT)). Consequentially, as compared to the healthy control subjects, it was found that patients with SS had lower mean BMD values in both hip and lumbar vertebrae, and less cortical bone thickness, and that a higher frequency of SS patients (approximately 20% of the SS patients) had VF and significantly impaired bone microarchitecture [51]. Additionally, in the same study, HR-pQCT revealed significant cortical deterioration in SS patients. However, the final assessment on the primary causative factor for osteoporosis (OP) could not be made, due to the fact that all SS patients were on corticosteroid therapy at the time of the study. There is a significant relationship between corticosteroid use and the development of OP. In a recent large-scale cross-sectional study, in which the frequency of OP, risk factors and fragility fractures were investigated in relation to SS, a significant correlation was found between the development of OP and factors such as age, duration of disease, corticosteroid use, presence of anti-La antibodies and ESSDAI scores in patients with SS. Up to 8.5% of the patients with SS were found to have fragility fractures, and a significant correlation was observed between the SS disease duration and age, ESSDAI scores and fragility fracture [52]. Osteomalacia (OM) is a disease characterized by impaired bone mineralization. The development of OM in SS patients has been associated with tubulointerstitial nephritis (TIN) or distal renal tubular acidosis (dRTA). There areseveral studies available in the literature to that effect thathighlight the effect of TIN and dRTA in patients with SS and its contribution to the development of osteomalacia [53, 54]. Patients with OM are susceptible to pseudo-fractures.

*Musculoskeletal Manifestations in Sjogren's Syndrome DOI: http://dx.doi.org/10.5772/intechopen.101369*

Therefore, diagnosis of OM in patients with SS is very important. It is not yet known whether these findings can be directly attributed to the relationship between SS, OP and OM, pathophysiologically. Nevertheless, the direct clinical relevance between these conditions should not be overlooked. The exact mechanism of the effect of SS on bone metabolism has not been determined, but it is obvious that there is a relationship, albeit an indirect one. The part which is not yet clear is whether it is the SS itself or the drugs used for the treatment of SS or the target organs affected in relation thereto are the main factors creating the said effect.

#### **7. Available therapeutic options with possible benefit in musculoskeletal disease**

There is no curative treatment for SS, thus the aim in the treatment of SS is to alleviate the symptoms of exocrinopathy and also to get the extraglandular manifestations of the disease under control. Management of SS patients requires a multidisciplinary approach involving collaboration with specialist doctors from different specializations, such as clinical immunologists, rheumatologists, ophthalmologists, otolaryngologists and/or dentists. Centers such as The Sjögren's Foundation, The British Society for Rheumatology, and EULAR publish guidelines for the management of SS [55–57]. Nevertheless, no specific therapeutic goal other than symptomatic relief has been put forward in these guidelines. Fatigue, one of the major symptoms targeted to be relieved by the treatment modalities used for the treatment of SS, is a symptom that significantly impairs quality of life in patients with SS. However, the effectiveness of the current medical treatments used to contain this symptom is still not up to the level. Available guidelines suggest regular physical activity as the best approach to improve fatigue [56, 57]. Hydroxychloroquine (HCQ ) is usually recommended as the first-line treatment for musculoskeletal pain relief. On the other hand, methotrexate (MTX) is recommended to be used as a stand-alone medication or in combination with HCQ in patients who do not respond to HCQ, and particularly in those with severe inflammatory arthritis [56]. In cases where the combination of HCQ and MTX has proven ineffective in the treatment of inflammatory musculoskeletal symptoms, alternative options such as use of corticosteroids, leflunomide, sulfasalazine, azathioprine, cyclosporine, or biologic drugs may be considered [55, 57].

### **Author details**

Ridvan İşik\* and Ferhat Ege Hatay Training and Research Hospital, Hatay, Turkey

\*Address all correspondence to: dr.ridvanisik@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

[1] Henrik S. Zur Kenntnis der keratoconjunctivitis sicca. Keratitis filiformis bei Hypofunktion der Tränendrüsen [On knowledge of keratoconjunctivitis sicca. Keratitis filiformis due to lacrimal gland hypofunction]. Acta Ophthalmologica. 1933;**2**:1-151

[2] Brito-Zeron P, Theander E, Baldini C, et al. Early diagnosis of primary Sjogren's syndrome: EULAR-SS task force clinical recommendations. Expert Review of Clinical Immunology. 2016;**12**(2): 137-156

[3] Qin B, Wang J, Yang Z, Yang M, Ma N, Huang F, et al. Epidemiology of primary Sjögren's syndrome: A systematic review and meta-analysis. Annals of the Rheumatic Diseases. 2015;**74**(11):1983

[4] Brito-Zeron P, Acar-Denizli N, Zeher M, et al. Influence of geolocation and ethnicity on the phenotypic expression of primary Sjogren's syndrome at diagnosis in 8310 patients: A cross-sectional study from the big data Sjogren project consortium. Annals of the Rheumatic Diseases. 2017;**76**(6): 1042-1050

[5] Saraux A, Pers JO, Devauchelle-Pensec V. Treatment of primary Sjogren syndrome. Nature Reviews Rheumatology. 2016;**12**:456-471

[6] Shimizu T, Nakamura H, Kawakami A. Role of the innate immunity signaling pathway in the pathogenesis of Sjögren's syndrome. International Journal of Molecular Sciences. 2021;**22**(6):3090

[7] Brito-Zeron P, Baldini C, Bootsma H, et al. Sjogren syndrome. Nature Reviews. Disease Primers. 2016;**2**:16047

[8] Bombardieri M, Argyropoulou OD, Ferro F, et al. One year in review 2020: Pathogenesis of primary Sjogren's syndrome. Clinical and Experimental Rheumatology. 2020;**126**(4):3-9

[9] Chivasso C, Sarrand J, Perret J, Delporte C, Soyfoo MS. The involvement of innate and adaptive immunity in the initiation and perpetuation of Sjogren's syndrome. International Journal of Molecular Sciences. 2021;**22**(2):658

[10] Vıtalı C, Dolcıno M, Del Papa N, et al. Gene expression profiles in primary Sjögren's syndrome with and without systemic manifestations. ACR Open Rheumatology. 2019;**1**:603-613

[11] Imgenberg-kreuz J, AlmlÖF JC, Leonard D, et al. Shared and unique patterns of DNA methylation in systemic lupus erythematosus and primary Sögren's syndrome. Frontiers in Immunology. 2019;**10**:1686

[12] Davıes R, Sarkar I, Hammenfors D, et al. Single cell based phosphorylation profiling identifies alterations in toll-like receptor 7 and 9 signaling in patients with primary Sjögren's syndrome. Frontiers in Immunology. 2019;**10**:281

[13] Luo S, Zhu R, Yu T, et al. Chronic inflammation: A common promoter in tertiary lymphoid organ neogenesis. Frontiers in Immunology. 2019;**10**:2938

[14] Baldini C, Pepe P, Quartuccio L, et al. Primary Sjogren's syndrome as a multiorgan disease: Impact of the serological profile on the clinical presentation of the disease in a large cohort of Italian patients. Rheumatology (Oxford, England). 2014;**53**(5):839-844

[15] Ramos-Casals M, Brito-Zerón P, Solans R, et al. Systemic involvement in *Musculoskeletal Manifestations in Sjogren's Syndrome DOI: http://dx.doi.org/10.5772/intechopen.101369*

primary Sjogren's syndrome evaluated by the EULAR-SS disease activity index: Analysis of 921 Spanish patients (GEAS-SS Registry). Rheumatology (Oxford, England). 2014;**53**(2):321-331

[16] Amezcua-Guerra LM, Hofmann F, Vargas A, et al. Joint involvement in primary Sjögren's syndrome: An ultrasound "target area approach to arthritis". BioMed Research International. 2013;**2013**:640265

[17] Jacques T, Sudoł-Szopińska I, Larkman N, O'Connor P, Cotten A. Musculoskeletal manifestations of non-RA connective tissue diseases: Scleroderma, systemic lupus erythematosus, Still's disease, dermatomyositis/polymyositis, sjögren's syndrome, and mixed connective tissue disease. Seminars in Musculoskeletal Radiology. 2018;**22**(2):166-179

[18] Mirouse A, Seror R, Vicaut E, et al. Arthritis in primary Sjögren's syndrome: Characteristics, outcome and treatment from French multicenter retrospective study. Autoimmunity Reviews. 2019; **18**(1):9-14

[19] Vitali C, Del Papa N. Pain in primary Sjögren's syndrome. Best Practice & Research. Clinical Rheumatology. 2015;**29**(1):63-70

[20] Lei L, Morgan S, Ntatsaki E, Ciurtin C. Comparative assessment of hand joint ultrasound findings in symptomatic patients with systemic lupus erythematosus and Sjögren's syndrome: A pilot study. Ultrasound in Medicine & Biology. 2019;**45**(2):452-460

[21] Riente L, Scirè CA, Delle Sedie A, et al. Ultrasound imaging for the rheumatologist. XXIII. Sonographic evaluation of hand joint involvement in primary Sjögren's syndrome. Clinical and Experimental Rheumatology. 2009;**27**(5):747-750

[22] Guedes LKN, Leon EP, Bocate TS, Bonfigliolli KR, Lourenço SV, Bonfa E, et al. Characterizing hand and wrist ultrasound pattern in primary Sjögren's syndrome: A case-control study. Clinical Rheumatology. 2020;**39**(6):1907-1918

[23] Leone MC, Alunno A, Cafaro G, et al. The clinical spectrum of primary Sjögren's syndrome: Beyond exocrine glands. Reumatismo. 2017;**69**(3):93-100

[24] Fauchais AL, Ouattara B, Gondran G, et al. Articular manifestations in primary Sjögren's syndrome: Clinical significance and prognosis of 188 patients. Rheumatology (Oxford, England). 2010;**49**(6): 1164-1172

[25] García-Carrasco M, Ramos-Casals M, Rosas J, et al. Primary Sjögren syndrome: Clinical and immunologic disease patterns in a cohort of 400 patients. Medicine (Baltimore). 2002;**81**(4): 270-280

[26] Payet J, Belkhir R, Gottenberg JE, et al. ACPA-positive primary Sjögren's syndrome: True primary or rheumatoid arthritis-associated Sjögren's syndrome? RMD Open. 2015;**1**(1):26-44

[27] Molano-González N, Olivares-Martínez E, Anaya JM, Hernández-Molina G. Anti-citrullinated protein antibodies and arthritis in Sjögren's syndrome: A systematic review and meta-analysis. Scandinavian Journal of Rheumatology. 2019;**48**(2):157-163

[28] Cornec D, Devauchelle-Pensec V, Mariette X, et al. Severe health-related quality of life impairment in active primary Sjögren's syndrome and patientreported outcomes: Data from a large therapeutic trial. Arthritis Care & Research. 2017;**69**(4):528-535

[29] Chu LL, Cui K, Pope JE. Metaanalysis of treatment for primary

Sjögren's syndrome. Arthritis Care & Research. 2020;**72**(7):1011-1021

[30] Quartuccio L, Gandolfo S, Zabotti A, Zandonella Callegher S, Fabro C, De Vita S. Articular and peripheral nervous system involvement are linked to the long-term outcome in primary Sjögren's syndrome: The relevance of single organ manifestations rather than a composite score as predictors. Frontiers in Immunology. 2019;**10**:1527

[31] Alani H, Henty JR, Thompson NL, Jury E, Ciurtin C. Systematic review and meta-analysis of the epidemiology of polyautoimmunity in Sjögren's syndrome (secondary Sjögren's syndrome) focusing on autoimmune rheumatic diseases. Scandinavian Journal of Rheumatology. 2018;**47**(2):141-154

[32] Toro-Domínguez D, Carmona-Sáez P, Alarcón-Riquelme ME. Shared signatures between rheumatoid arthritis, systemic lupus erythematosus and Sjögren's syndrome uncovered through gene expression meta-analysis. Arthritis Research & Therapy. 2014;**16**(6):489

[33] Harrold LR, Shan Y, Rebello S, et al. Prevalence of Sjögren's syndrome associated with rheumatoid arthritis in the USA: An observational study from the Corrona registry. Clinical Rheumatology. 2020;**39**(6):1899-1905

[34] Tishler M, Barak Y, Paran D, Yaron M. Sleep disturbances, fibromyalgia and primary Sjögren's syndrome. Clinical and Experimental Rheumatology. 1997;**15**:71-74

[35] Lindvall B, Bengtsson A, Ernerudh J, Eriksson P. Subclinical myositis is common in primary Sjögren's syndrome and is not related to muscle pain. The Journal of Rheumatology. 2002;**29**(4):717-725

[36] Kanellopoulos P, Baltoyiannis C, Tzioufas AG. Primary Sjögren's syndrome associated with inclusion body myositis. Rheumatology (Oxford, England). 2002;**41**(4):440-444

[37] Migkos MP, Sarmas I, Somarakis GA, Voulgari PV, Tsamis KI, Drosos AA. Sjögren syndrome associated with inflammatory muscle diseases. Mediterranean Journal of Rheumatology. 2018;**29**(2):92-96

[38] Rietveld A, van den Hoogen LL, Bizzaro N, et al. Autoantibodies to cytosolic 5'-nucleotidase 1A in primary Sjögren's syndrome and systemic lupus erythematosus. Frontiers in Immunology. 2018;**9**:1200

[39] Mendieta D, De la Cruz-Aguilera DL, Barrera-Villalpando MI, et al. IL-8 and IL-6 primarily mediate the inflammatory response in fibromyalgia patients. Journal of Neuroimmunology. 2016;**290**:22-25

[40] Applbaum E, Lichtbroun A. Novel Sjögren's autoantibodies found in fibromyalgia patients with sicca and/or xerostomia. Autoimmunity Reviews. 2019;**18**(2):199-202

[41] Zhao SS, Duffield SJ, Goodson NJ. The prevalence and impact of comorbid fibromyalgia in inflammatory arthritis. Best Practice & Research. Clinical Rheumatology. 2019;**33**(3):101423

[42] Choi BY, Oh HJ, Lee YJ, Song YW. Prevalence and clinical impact of fibromyalgia in patients with primary Sjögren's syndrome. Clinical and Experimental Rheumatology. 2016;**34** (2 Suppl 96):S9-S13. Epub 2015 Aug 27

[43] Gau SY, Leong PY, Lin CL, Tsou HK, Wei JC. Higher risk for Sjögren's syndrome in patients with fibromyalgia: A nationwide population-based Cohort study. Frontiers in Immunology. 2021;**12**:640618

*Musculoskeletal Manifestations in Sjogren's Syndrome DOI: http://dx.doi.org/10.5772/intechopen.101369*

[44] Torrente-Segarra V, Corominas H, Sánchez-Piedra C, et al. Fibromyalgia prevalence and associated factors in primary Sjögren's syndrome patients in a large cohort from the Spanish Society of Rheumatology registry (SJOGRENSER). Clinical and Experimental Rheumatology. 2017;**35**

[45] Dias LH, Miyamoto ST, Giovelli RA, de Magalhães CIM, Valim V. Pain and fatigue are predictors of quality of life in primary Sjögren's syndrome. Advances in Rheumatology. 2021;**61**(1):28

[46] Skarlis C, Palli E, Nezos A, Koutsilieris M, Mavragani CP. Study of the incidence of osteoporosis in patients with Sjögren's syndrome (pSS) and investigation of activation of the RANKL/RANK and osteoprotegerin (OPG) system. Mediterranean Journal of Rheumatology. 2018;**29**(4):224-227

[47] Baron R, Kneissel M. WNT signaling in bone homeostasis and disease: From human mutations to treatments. Nature Medicine. 2013;**19**(2):179-192

[48] Leibbrandt A, Penninger JM. RANK/RANKL: Regulators of immune responses and bone physiology. Annals of the New York Academy of Sciences. 2008;**1143**:123-150

[49] Fernández-Torres J, Pérez-Hernández N, Hernández-Molina G, et al. Risk of Wnt/β-catenin signalling pathway gene polymorphisms in primary Sjögren's syndrome. Rheumatology (Oxford, England). 2020;**59**(2): 418-425

[50] Gravani F, Papadaki I, Antypa E, et al. Subclinical atherosclerosis and impaired bone health in patients with primary Sjogren's syndrome: Prevalence, clinical and laboratory associations. Arthritis Research & Therapy. 2015; **17**(1):99

[51] Pasoto SG, Augusto KL, Alvarenga JC, Takayama L, Oliveira RM, Bonfa E, et al. Cortical bone density and thickness alterations by high-resolution peripheral quantitative computed tomography: Association with vertebral fractures in primary Sjögren's syndrome. Rheumatology (Oxford, England). 2016;**55**(12):2200-2211

[52] Salman-Monte TC, Sanchez-Piedra C, Fernandez Castro M, et al. Prevalence and factors associated with osteoporosis and fragility fractures in patients with primary Sjögren syndrome. Rheumatology International. 2020;**40**(8): 1259-1265

[53] Geng Y, Zhao Y, Zhang Z. Tubulointerstitial nephritis-induced hypophosphatemic osteomalacia in Sjögren's syndrome: A case report and review of the literature. Clinical Rheumatology. 2018;**37**(1):257-263

[54] Nagae H, Noguchi Y, Ogata S, et al. Osteomalacia secondary to renal tubular acidosis due to Sjögren's syndrome: A case report and review of the literature. CEN Case Reports. 2012;**1**(2):123-127

[55] Vivino FB, Carsons SE, Foulks G, et al. New treatment guidelines for Sjogren's disease. Rheumatic Diseases Clinics of North America. 2016;**42**(3): 531-551

[56] Price EJ, Rauz S, Tappuni AR, et al. The British Society for Rheumatology guideline for the management of adults with primary Sjögren's syndrome. Rheumatology. 2017;**56**(10):1643-1647

[57] Ramos-Casals M, Brito-Zeron P, Bombardieri S, et al. EULAR recommendations for the management of Sjogren's syndrome with topical and systemic therapies. Annals of the Rheumatic Diseases. 2020;**79**(1):3-18

#### **Chapter 3**

## Musculoskeletal Abnormalities Caused by Cystic Fibrosis

*Mark Lambrechts*

#### **Abstract**

Cystic Fibrosis (CF) can affect all organs of the human body including the musculoskeletal system. Although the musculoskeletal aspects of CF are less commonly studied, fractures (predominantly spinal), muscle injuries, and joint pain are more commonly seen in the CF population compared to the general public due to their lower bone mineral density, dysfunctional skeletal muscle, and elevated levels of pro-inflammatory cytokines. Additionally, due to elevated levels of inflammation in the CF population diagnosis of musculoskeletal injuries can be difficult to pinpoint. As treatment for CF evolves, an increased understanding of how CF affects the musculoskeletal system is imperative. We will discuss the orthopedic aspects of CF and provide potential insights into the future direction of orthopedic care in the CF population.

**Keywords:** cystic fibrosis, musculoskeletal, spine, arthropathy, fracture, bisphosphonates, allele specific drugs, cytokines, bone mineral density

#### **1. Introduction**

Cystic Fibrosis (CF) is an autosomal recessive disorder causing loss of function of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The most common gene alteration present in CF patients is a deletion of phenylalanine at position 508 (ΔF508). Fortunately, researchers and pharmaceutical companies have produced allele-specific drugs targeting CF genetic mutations. These work through multiple potential mechanisms, but allele potentiation (ivacaftor) and allele correction (tezacaftor) are some of the more promising therapeutics to date [1, 2].

Historically, patients with any combination of CFTR gene mutations could invariably expect a progressive course of worsening respiratory and endocrine function, resulting in irreversible and severe lung and pancreas damage. However, the introduction of allele-specific drugs has had a profound impact on improving both the length and quality of life in CF patients [3]. Given the improved life expectancy, orthopedic providers can expect to see a resultant increase in the proportion of patients with CF.

Throughout this chapter, we will discuss the three most likely scenarios for orthopedic consultation in the CF population: bone health/fracture, muscle and soft tissue dysfunction, and joint pain and arthralgia. In order to understand each of these topics appropriately, each subtopic will be prefaced by an in-depth introduction to the basic science causing the musculoskeletal pathology with subsequent detailed management of the disease.

#### **1.1 Cystic fibrosis- related bone disease (CFBD): understanding the abnormal molecular pathway**

Healthy bone undergoes continuous remodeling – bone resorption is mediated by osteoclasts through the RANK-RANKL (receptor activator of nuclear factor kappa-β ligand) pathway. Meanwhile, bone deposition occurs through activation of osteoblasts, which signal through the WNT-β-catenin pathway [4]. Osteoblasts also secrete osteoprotegrin, which binds to RANKL thus limiting activation of osteoclasts. In this manner, osteoblasts and osteoclasts are in delicate balance, and their goal is to optimize bone mineral density (BMD) while minimizing unnecessary storage of essential nutrients via reorganization of the boney trabecular microarchitecture. Bones under continual heavy loads (stress) or tension (strain) will adapt to the increase in forces imparted to the bone, while bones undergoing less frequent loading, will have a resultant leach of essential nutrients, thus allowing each bone to maximize its function (Wolff's Law) [5].

Mounting research is focused on improving our understanding of osteoblast and osteoclast function in CF patients. Emerging evidence indicates CF patients with pulmonary exacerbations caused by underlying indolent lung infections, have elevated cytokine levels [6]. The systemic increase in pro-inflammatory cytokines during these CF "flare-ups" leads to formation and activation of osteoclasts, resulting in bone resorption [7]. Additionally, the ΔF508 phenotype is known to promote RANKL production, which is normalized with the allele specific drug ivacaftor [8–10] and the drug miglustat [11].

Cystic Fibrosis not only increases osteoclast activity, but it also detrimentally affects osteoblast function and uncouples osteoblast–osteoclast homeostatsis leading to severe trabecular and cortical bone osteopenia through net bone mineral resorption [12]. Diminished ΔF508 osteoblast activity is thought to contribute to poor COX-2, PGE2, and osteoprotegrin expression [13]. One potential therapeutic to mitigate poor bone quality and inhibited fracture healing is ivacaftor, which works through allele potentiation of the ΔF508-CFTR channel and channel optimization returns osteoblast function to 85% of normal [14]. This effectively increases systemic levels of cyclooxygenase-2 (COX-2) and PGE2, which are integral for effective bone maturation and fracture healing [13].

Translational research performed in mouse models indicates that Cftr−/− mice have 50% less cortical bone width, thinner and less plentiful trabeculae and greater trabecular separation compared to normal mice [15]. Trabecular bone formation was also decreased by 92% in Cftr−/− mice likely due to the density of osteoclasts near the cortical surface [15]. Skeletal growth also appears to be hindered by 40% in Cftr−/− mice, due to a reduction in the hypertrophic zone of the growth plate [15]. The combination of these findings results in smaller bones that have decreased thickness and strength compared to normal bones [16]. This results in CF bones being able to tolerate less load to failure, which increases fracture risk [17]. It is believed that issues with poor BMD and increased fracture risk manifest prior to age six with no further significant worsening of BMD until after adolescence [18]. However, exercise programs in pre-adolescent children may increase BMD by 7% and these programs should be routinely implemented in all children with CF [19].

Aside from the poor bone quality imparted from phenotypic alterations by the CFTR gene, additional causes of lower BMD in CF patients include female sex, cystic fibrosis related diabetes (CFRD), vitamin D malabsorption, malnutrition, pancreatic insufficiency, exogenous corticosteroid use, chronic inflammation/chronic

 **Figure 1.**

 *Risk factors for decreased bone mineral density (BMD) in patients with cystic fibrosis. \* bold ovals indicate high quality evidence for risk factor contribution to decreased BMD in cystic fibrosis patients, while non-bolded ovals indicate poor quality evidence of contribution to diminished BMD.* 

pulmonary infections, and decreased activity levels ( **Figure 1** ). It should be noted that there is a paucity of well-designed studies demonstrating female sex [ 15 , 20 , 21 ], pancreatic [ 21 , 22 ], CFRD [ 22 , 23 ], and chronic inflammation/pulmonary infections [ 18 , 24 ] have a significant effect on BMD. However, sufficient evidence does appear to suggest decreased activity levels, malnutrition, exogenous corticosteroid use, and vitamin D deficiency or malabsorption are potentially controllable risk factors that lead to a significant reduction in BMD [ 18 , 21 , 22 , 25 ].

 The net bone resorption in CF patients can be evaluated through serum or urinary analysis of type I collagen N-telopeptides, free deoxypyridinoline, and alkaline phosphatase. Increased levels of each of these molecular markers is common in CF patients, which may be further elevated by increased serum parathyroid hormone (PTH) levels and diminished serum 25-hydoxyvitamin D levels in these patients [ 26 ]. PTH and 25-hydoxyvitamin D create a positive feedback loop signaling the body to continue to resorb bone and increase serum calcium levels [ 27 ]. The combination of elevated osteoclast function and diminished osteoblast function results in early osteopenia or osteoporosis, which are diagnosed in 23.5% and 38% of the adult CF population, respectively [ 28 ].

#### **1.2 Is there a role for bisphosphonates to improve bone health for CF patients?**

 Vitamin D deficiency affects up to 90% of patients with CF [ 29 ]. This is predominantly caused by poor systemic vitamin D absorption since CF patients absorb less than 50% of the dietary vitamin D absorbed by normal patients and 20% of CF patients have no measurable vitamin D absorption [ 30 ]. For this reason, the Cystic Fibrosis Foundation recommends each CF patient be given a daily prescription of vitamin D 3 to maintain baseline 25-hyroxyvitamin D levels at a minimum of 30 ng/ml [ 31 ]. However, even with sufficient vitamin D levels, patients with CF should undergo a dual energy X-ray absorptiometry (DEXA) scan at the age of 18 [ 26 ]. Repeat DEXA scans should occur every five years if the BMD is normal but repeat testing should occur every 2–4 years if the DEXA scan is between the ranges of <−1 and > −2 ( osteopenia range) [ 26 ].

 Current recommendations for initiation of bisphosphonate administration can be seen in **Table 1** [ 32 ]. In patients who are started on an oral or intravenous (IV) course of bisphosphonates, an approximate 3–6% increase in BMD can be expected at


#### **Table 1.**

*Indications for initiation of oral or IV bisphosphonates in the adult or pediatric cystic fibrosis population.*

1-year in the lumbar spine and femoral neck [33–35]. However, IV bisphosphonates are associated with severe bone pain and flu-like symptoms that should be discussed with patients prior to initiation [33, 36]. Additionally, atypical femur fractures and jaw osteonecrosis are risk factors for long-term treatment with bisphosphonates [37]. Clinicians should also keep in mind that BMD increases after bisphosphonate administration, but there is currently no evidence to support bisphosphonates ability to reduce the likelihood of sustaining a lower extremity or spine fracture [36].

Historically, there has been concern about fracture healing during bisphosphonate use. While there does appear to be a delay in fracture callus reorganization (immature woven bone is not replaced as quickly with mature lamellar bone), bisphosphonates do not inhibit fracture callus formation [38]. This type of fracture healing is referred to as secondary bone healing or endochondral ossification (examples of this type of healing include patients placed in a cast, surgery which involves an intramedullary nail/rod, or a bridge plate where the bone is not compressed together). While this type of fracture healing appears to be less affected by bisphosphonates, animal models suggest primary fracture healing (e.g. compression plating) is affected by bisphosphonates and causes lower BMD at the fracture site, decreases load to failure, and increases the presence of cartilaginous tissue at the fracture site [38]. However, clinical studies have not found any evidence to support a significant difference in fracture healing based on the administration of bisphosphonates, so at this time CF patients should be allowed to continue taking bisphosphonates even in the presence of a fracture [39, 40].

#### **1.3 Predisposition to appendicular skeletal fractures: fracture management**

Cystic Fibrosis predisposes patients to fracture even with minimal or no traumatic etiology due to their low BMD. Appendicular skeleton fractures occur at a rate of approximately 20% [28]. Notably, one case report described a femur fracture in an adolescent male baseball player who was running and had no associated trauma. In this instance, the femur fracture healed after treatment with an intramedullary nail; however, the patient then had an atraumatic contralateral femur fracture months later that was treated in the same manner [41]. There have also been reports of a unilateral femoral neck fracture in a 25-year-old male without associated trauma and bilateral femoral neck fractures in a 34-year-old male after a grand mal seizure [42, 43]. The 25-year-old patient had severe osteoporosis and was treated with internal fixation,

while the 34-year-old was treated with bilateral bipolar hemiarthroplasties [42, 43]. It should be noted that in non-CF patients, the femoral neck fractures would have been treated with fracture fixation instead of hip replacement. Since CF patients are now frequently treated with allele-specific drugs, there is no evidence to indicate CF patients should have fractures managed any different from patients without a diagnosis of Cystic Fibrosis. In instances of delayed fracture healing, subcutaneous teriparatide may be another effective tool to promote fracture healing, although there is poor quality evidence to support this management [44].

#### **1.4 Spinal fractures and CF-related spine disease**

Up to 94% of CF patients have back pain with potential etiologies often multifactorial, but they include muscle weakness, rib fracture, scoliosis, spinous process bursitis, and vertebral fracture [45–47]. A significantly higher rate of vertebral fractures are identified in CF patients with an incidence of approximately 14%, but interestingly BMD and the risk of vertebral fracture is not correlated [28, 48]. Vertebral fractures often result in vertebral wedging, which progresses to structural kyphosis if wedging is greater than 15% [45]. Since vertebral wedging is typically minimal, only 8% of pediatric patients develop structural kyphosis, with the rate nearly doubling in adult patients [45, 49]. This may be due to the increased rates of muscle weakness and osteopenia/osteoporosis as patients age [50].

Additional considerations for spinal pain include spinal process bursitis, which may be caused by improperly fitting high frequency chest wall oscillation devices (vest) [46]. In these instances, the bursitis should be managed expectantly as it will resolve without surgical intervention after appropriate vest adjustment [46]. Another consideration of spinal pain is idiopathic scoliosis, which is more prevalent in the CF population and typically manifests as a short mid thoracic curve [51]. Idiopathic scoliosis in CF patients is often treated non-surgically with bracing [47]. However, in skeletally immature patients with curve progression to 50 degrees the scoliosis should be managed with surgical correction [52].

#### **1.5 Muscular/soft tissue dysfunction: is there a molecular basis for muscular dysfunction?**

Diminished muscle mass and force is a common affliction of CF patients and lower extremity muscles are frequently affected to a greater degree than the upper extremity [53]. Theories abound as to the potential causes of muscle weakness and include elevated cytokine (IL-6) levels, low vitamin D levels, corticosteroids, presence of the ΔF508 phenotype, altered CFTR function in the sarcoplasmic reticulum, muscle disuse, and poor pulmonary function (**Figure 2**) [54–57]. The reality is the cumulative effect of each of these mechanisms contributes to decreased muscle mass since each theory is intertwined.

One of the more prominent theories for muscle dysfunction in CF patients includes abnormal function of the CFTR chloride channels in the sarcoplasmic reticulum, which results in inappropriate regulation of calcium homeostasis [57]. Since calcium is essential for muscle depolarization, dysregulation of these channels may lead to muscle mass loss, early fatigue, and generalized weakness. This mechanism was further evaluated in human and mice diaphragms, where intracellular calcium was significantly elevated after muscle depolarization in the presence of an inflammatory environment [54]. In the presence of *Pseudomonas aeruginosa*,

#### **Figure 2.**

*Potential contributors to muscle dysfunction and muscle weakness in cystic fibrosis patients. \* CFTR = cystic fibrosis transmembrane conductance regulator; SR = sarcoplasmic reticulum.*

elevated pro-inflammatory cytokines were overexpressed and E3 ubiquitin ligases were upregulated (these are often identified in muscle atrophy) resulting in a significant decrease in muscle force generation [54]. Separate research has also identified elevated IL-6 levels and ΔF508 are correlated with diminished muscle mass [56].

The net loss of peripheral muscle strength has continuously been associated with poor pulmonary function [50, 58]. When decreased muscle strength is coupled with poor anaerobic capacity – evidenced by the decreased oxygenation of muscles due to the suboptimal VO 2 max – [59, 60] early lactic acid accumulation may occur [58]. This can result in muscle disuse through early muscle fatigue. Additional contributing factors include low vitamin D levels, which have been linked to poor peripheral muscle strength although the exact mechanistic role linking vitamin D and muscle weakness is incompletely understood [61]. Luckily, muscle atrophy may not be permanent. Ivacaftor appears to independently increase fat free mass by one kilogram and significantly increases lung function, which may lead to significant long-term improvements in CF patients' health, endurance, and muscle function [62, 63].

Muscle dysfunction may also be linked to low-energy muscle injuries. A single case report identified an adolescent CF patient with an atraumatic mid-substance muscle rupture caused by running during a basketball game. Management of these injuries are typically non-surgical with gradual return to sport [46]. Similar to bony injuries, muscle injuries in the CF population should be treated comparably to muscle injuries in the general population. Future research is necessary to improve our understanding of muscle dysfunction in CF patients and to identify if allele specific drugs are effective at reducing CF patient's predisposition to muscle atrophy and subsequent muscle rupture.

#### **1.6 Weight and aerobic training: improving quality of life**

Baseline muscle weakness is present in CF patients, which is linked to decreased quality of life [64]. Therefore, multiple studies have explored the effect of exercise on improvements in strength, endurance, and quality of life [65–67]. An eight-week

#### *Musculoskeletal Abnormalities Caused by Cystic Fibrosis DOI: http://dx.doi.org/10.5772/intechopen.104591*

resistance and aerobic training program demonstrated improved strength, pulmonary function, and % fat free mass [68]. Similar results were found comparing CF patients who participated versus those who did not in a six-month weight training program, which demonstrated effectiveness of the program at increasing muscle size, strength, and overall weight gain [66]. Further, a combined home exercise program including aerobic exercise and resistance training resulted in improved weight gain and quality of life [65]. Respiratory muscle endurance training has also been found to improve both respiratory endurance and exercise endurance [67]. Based on the overwhelming positive effects of exercise on lung and peripheral muscle endurance, consensus guidelines on aerobic activity and resistance training has been established [69]. These guidelines recommend that children and adolescents with CF should engage in at least moderate intensity exercise for 60 minutes per day, while adults should ideally participate in at least moderate intensity exercise for 300 minutes per week [69]. Adults should also participate in upper body, lower body, and trunk resistance training 3–5 times per week with 1–3 sets of 8–15 repetitions. The weight should be based on 70% of maximum weight. In fact, patients with severe CF may maximally benefit from resistance training since they may struggle to have the aerobic capacity for prolonged endurance training [69].

#### **1.7 Joint pain: cytokines effect on the musculoskeletal system**

Arthropathy is commonly identified in CF patients at a rate of ranging from 8.5 to 29% [70–72]. Two main forms of CF-related arthropathy exist: cystic fibrosis related arthropathy (CFA) and hypertrophic osteoarthropathy (HOA), although lesser forms of arthropathy have also been described including fluoroquinolone associated arthropathy and an elevated incidence of rheumatoid arthritis [72]. Although no definitive pathway has established the causality of arthropathy in the CF population, risk factors appear to include pulmonary exacerbations with *Pseudomonas* or *Aspergillus*, female gender, older age, serum levels of IgG, CFRD, pancreatic insufficiency, greater number of hospitalizations, and sinusitis (**Figure 3**) [71, 72]. One potential theory linking many of these risk factors with arthropathy is the associated increase in cytokines, especially IL-6, IL-8, and TNF-α [73]. A rapid increase in these cytokines is often associated with pulmonary exacerbations and joint pain is a common additional complaint during these CF "flare-ups" [72]. Further, these proinflammatory cytokines are also more prevalent in non-CF patients with radiographic evidence of osteoarthritis and are one potential mechanism that may potentiate joint degeneration [74]. Arthropathy can typically be managed with non-steroidal antiinflammatory drugs (NSAIDs), which are the first line of treatment, but if corticosteroids are administered due to the underlying pulmonary exacerbation, they may be effective at treating the associated arthropathy [75].

Patients with CF commonly have elevated levels of inflammatory markers including CRP and ESR [76, 77]. The combination of elevated inflammatory markers and a propensity to develop joint pain makes consults for potential septic arthritis more likely for orthopedists. Therefore, physicians need to carefully evaluate the patient's cause of joint pain. Although arthrocentesis may be necessary to rule out septic arthritis for disabling joint pain, inflammatory markers are typically significantly elevated with septic arthritis while they may only be marginally elevated in cases of CFA or HOA [78]. A meticulous physical exam aimed at identifying limited passive range of motion and an inability to ambulate on the affected joint may further distinguish septic arthritis from either CFA or HOA.

**Figure 3.** *Potential risk factors contributing to arthropathy episodes in cystic fibrosis patients.*

#### **1.8 Cystic fibrosis-related Arthropathy**

CFA is the more common form of joint related pain with typical age of onset of approximately 13 years [79]. Although the incidence of CFA ranges from 8.5 to 29%, as the CF population continues to have a longer life span, the expected number of patients with CFA is expected to grow tremendously [71]. As such, practitioners should be cognizant of the symptoms of CFA and should systematically differentiate it from HOA and a septic joint.

CFA has distinct symptoms including, but not limited to, short bursts of recurring episodes of joint pain, fevers, joint swelling, and a rash that resembles erythema nodosum. However, pain and swelling are the most commonly identified forms of CFA and they typically present in the small joints of the hands, although knees and shoulders are also commonly affected [72, 80]. The combination of joint pain, joint swelling, overlying joint reddening, and severe pain causing loss of function is only present in around 13% of patients, allowing CFA to typically be easily differentiated from septic arthritis [72]. Further, CFA is often seen in the setting of oligo- or polyarthritis, which is uncommonly seen in patients with septic arthritis [72]. The onset of CFA symptoms occurs in less than 24 hours but the pain is often limited to four days after initiation of NSAIDs. After symptom resolution, the patient typically has no pain, but the arthropathy typically returns at variable, seemingly random time points. Further, there is often no evidence of radiographic abnormalities if x-rays are taken of the involved joint [79]. Although less commonly associated with pulmonary exacerbations, elevated systemic cytokines may exacerbate CFA [80].

#### **1.9 Hypertrophic osteoarthropathy**

HOA is characterized by a combination of medical conditions including periostitis of long bones, digital clubbing, and severe joint arthropathy with or without synovial effusions. Radiographs can help differentiate HOA from CFA due to characteristic periosteal elevation on the distal aspect of the tubular bones [81]. HPOA is also more commonly seen after initiation of a pulmonary exacerbation [82]. CF patients presenting with HOA also typically present with polyarthralgia, which may allow physicians to differentiate it from septic arthritis.

#### *Musculoskeletal Abnormalities Caused by Cystic Fibrosis DOI: http://dx.doi.org/10.5772/intechopen.104591*

Two main pathways have been proposed for the underlying cause of HOA: humoral and vagal. The humoral pathway has two subtypes: (1) elevated cytokine levels and hypoxemia, which produces hypoxia-inducing factors including VEGF and PDGF or (2) lung arteriovenous [83]. VEGF and PDGF induce proliferation of the endothelial smooth muscle and vascular permeability resulting in angiogenesis. VEGF also stimulates osteoblast and osteoclast induction and the combination of these effects ultimately results in subperiosteal collagen deposition leading to periosteal elevation of the distal portion of the tubular bones [83]. The periosteal reaction seen in this condition results in the variable pain responses seen in these patients. From a mechanistic standpoint, this pathway has the most traction, especially amongst the CF population. The vagal pathway is not as well supported but includes stimulation of organs innervated by the vagal nerve resulting in peripheral vasodilation of the extremities [84]. However, to date, neither mechanism has been unequivocally supported with evidence.

#### **2. Conclusion**

Musculoskeletal manifestations are common in Cystic Fibrosis patients with most patients having arthropathy, muscular dysfunction or decreased bone quality at some point during their lifetime. The decrease in BMD in CF patients leads to an elevated risk of both appendicular and axial skeletal fractures, which can be mitigated with allele specific drugs due to their ability to return osteoblast function to near normal levels, while also significantly improving BMD. Vitamin D supplementation is also an important adjunct to maximize both bone health and muscular function. Although a combination of factors ultimately leads to skeletal and muscular dysfunction, targeted exercise and resistance programs have been shown to be effective at improving both BMD and muscular function (**Figure 4**).

As CF patients have improved life expectancies due to rapid improvements in pharmaceuticals and CF treatment protocols, the prevalence of arthropathy will continue to increase. Differentiating CFA and HOA from septic arthritis via non-invasive measures can help minimize unnecessary procedures including arthrocentesis, while optimizing outcomes. Additionally, both CFA and HOA can be treated with NSAIDs

#### **Figure 4.**

*Treatment algorithm for the varying presentations of the musculoskeletal manifestations of Cystic Fibrosis.*

with abrupt minimization of symptoms. Future research is necessary to document the role of allele specific drugs in improving the musculoskeletal manifestations of Cystic Fibrosis.

### **Conflict of interest**

The author declares no conflict of interest.

### **Author details**

Mark Lambrechts Rothman Orthopaedic Institute at Thomas Jefferson University, Philadelphia, PA, USA

\*Address all correspondence to: mark.lambrechts2016@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **References**

[1] Sala MA, Jain M. Tezacaftor for the treatment of cystic fibrosis. Expert Review of Respiratory Medicine. 2018;**12**(9):725-732

[2] Rowe SM, Heltshe SL, Gonska T, et al. Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis. American Journal of Respiratory and Critical Care Medicine. 2014;**190**(2):175-184

[3] Scotet V, L'Hostis C, Férec C. The changing epidemiology of cystic fibrosis: Incidence, survival and impact of the *CFTR* gene discovery. Genes (Basel). 2020;**11**(6):589

[4] Brunetti G, D'Amato G, Chiarito M, Tullo A, Colaianni G, Colucci S, et al. An update on the role of RANKL-RANK/ osteoprotegerin and WNT-ß-catenin signaling pathways in pediatric diseases. World Journal of Pediatrics. 2019;**15**(1):4-11

[5] Turner CH. On Wolff's law of trabecular architecture. Journal of Biomechanics. 1992;**25**(1):1-9

[6] Courtney JM, Ennis M, Elborn JS. Cytokines and inflammatory mediators in cystic fibrosis. Journal of Cystic Fibrosis. 2004;**3**(4):223-231

[7] Shead EF, Haworth CS, Barker H, Bilton D, Compston JE. Osteoclast function, bone turnover and inflammatory cytokines during infective exacerbations of cystic fibrosis. Journal of Cystic Fibrosis. 2010;**9**(2):93-98

[8] Sermet-Gaudelus I, Delion M, Durieu I, Jacquot J, Hubert D. Bone demineralization is improved by ivacaftor in patients with cystic

fibrosis carrying the p.Gly551Asp mutation. Journal of Cystic Fibrosis. 2016;**15**(6):e67-e69

[9] Delion M, Braux J, Jourdain ML, Guillaume C, Bour C, Gangloff S, et al. Overexpression of RANKL in osteoblasts: A possible mechanism of susceptibility to bone disease in cystic fibrosis. The Journal of Pathology. 2016;**240**(1):50-60

[10] Ambroszkiewicz J, Sands D, Gajewska J, Chelchowska M, Laskowska-Klita T. Bone turnover markers, osteoprotegerin and RANKL cytokines in children with cystic fibrosis. Advances in Medical Sciences. 2013;**58**:338-343

[11] Le Henaff C, Haÿ E, Velard F, et al. Enhanced F508del-CFTR channel activity ameliorates bone pathology in murine cystic fibrosis. The American Journal of Pathology. 2014;**184**(4):1132-1141

[12] Haworth CS, Webb AK, Egan JJ, et al. Bone histomorphometry in adult patients with cystic fibrosis. Chest. 2000;**118**(2):434-439

[13] Velard F, Delion M, Le Henaff C, et al. Cystic fibrosis and bone disease: Defective osteoblast maturation with the F508del mutation in cystic fibrosis transmembrane conductance regulator. American Journal of Respiratory and Critical Care Medicine. 2014;**189**(6):746-748

[14] Velard F, Delion M, Lemaire F, et al. Cystic fibrosis bone disease: Is the CFTR corrector C18 an option for therapy? The European Respiratory Journal. 2015;**45**(3):845-848

[15] Dif F, Marty C, Baudoin C, de Vernejoul MC, Levi G. Severe osteopenia in CFTR-null mice. Bone. 2004;**35**(3):595-603

[16] Brookes DS, Briody JN, Munns CF, Davies PS, Hill RJ. Cystic fibrosis-related bone disease in children: Examination of peripheral quantitative computed tomography (pQCT) data. Journal of Cystic Fibrosis. 2015;**14**(5):668-677

[17] Putman MS, Milliren CE, Derrico N, et al. Compromised bone microarchitecture and estimated bone strength in young adults with cystic fibrosis. The Journal of Clinical Endocrinology and Metabolism. 2014;**99**(9):3399-3407

[18] Sermet-Gaudelus I, Souberbielle JC, Ruiz JC, Vrielynck S, Heuillon B, Azhar I, et al. Low bone mineral density in young children with cystic fibrosis. American Journal of Respiratory and Critical Care Medicine. 2007;**175**:951-957

[19] Hind K, Truscott JG, Conway SP. Exercise during childhood and adolescence: A prophylaxis against cystic fibrosis-related low bone mineral density? Exercise for bone health in children with cystic fibrosis. Journal of Cystic Fibrosis. 2008;**7**(4):270-276. DOI: 10.1016/j.jcf.2008.02.001

[20] Pashuck TD, Franz SE, Altman MK, Wasserfall CH, Atkinson MA, Wronski TJ, et al. Murine model for cystic fibrosis bone disease demonstrates osteopenia and sex-related differences in bone formation. Pediatric Research. 2009;**65**(3):311-316

[21] King SJ, Topliss DJ, Kotsimbos T, Nyulasi IB, Bailey M, Ebeling PR, et al. Reduced bone density in cystic fibrosis: DeltaF508 mutation is an independent risk factor. The European Respiratory Journal. 2005;**25**(1):54-61

[22] Legroux-Gérot I, Leroy S, Prudhomme C, Perez T, Flipo RM, Wallaert B, et al. Bone loss in adults with cystic fibrosis: Prevalence, associated factors, and usefulness of biological markers. Joint, Bone, Spine. 2012;**79**(1):73-77

[23] Rana M, Munns CF, Selvadurai H, Briody J, Craig ME. The impact of dysglycaemia on bone mineral accrual in young people with cystic fibrosis. Clinical Endocrinology. 2013;**78**(1): 36-42

[24] Gronowitz E, Mellström D, Strandvik B. Normal annual increase of bone mineral density during two years in patients with cystic fibrosis. Pediatrics. 2004;**114**(2):435-442

[25] Hardin DS, Arumugam R, Seilheimer DK, LeBlanc A, Ellis KJ. Normal bone mineral density in cystic fibrosis. Archives of Disease in Childhood. 2001;**84**(4):363-368

[26] Aris RM, Merkel PA, Bachrach LK, et al. Guide to bone health and disease in cystic fibrosis. The Journal of Clinical Endocrinology and Metabolism. 2005;**90**(3):1888-1896

[27] Khundmiri SJ, Murray RD, Lederer E. PTH and vitamin D. Comprehensive Physiology. 2016;**6**(2):561-601

[28] Paccou J, Zeboulon N, Combescure C, Gossec L, Cortet B. The prevalence of osteoporosis, osteopenia, and fractures among adults with cystic fibrosis: A systematic literature review with meta-analysis. Calcified Tissue International. 2010;**86**(1):1-7

[29] McCauley LA, Thomas W, Laguna TA, Regelmann WE, Moran A, Polgreen LE. Vitamin D deficiency is associated with pulmonary exacerbations in children with cystic fibrosis. Annals of the American Thoracic Society. 2014;**11**(2):198-204

*Musculoskeletal Abnormalities Caused by Cystic Fibrosis DOI: http://dx.doi.org/10.5772/intechopen.104591*

[30] Lark RK, Lester GE, Ontjes DA, Blackwood AD, Hollis BW, Hensler MM, et al. Diminished and erratic absorption of ergocalciferol in adult cystic fibrosis patients. The American Journal of Clinical Nutrition. 2001;**73**(3):602-606

[31] Tangpricha V, Lukemire J, Chen Y, et al. Vitamin D for the immune system in cystic fibrosis (DISC): A doubleblind, multicenter, randomized, placebo-controlled clinical trial. The American Journal of Clinical Nutrition. 2019;**109**(3):544-553

[32] Sermet-Gaudelus I, Bianchi ML, Garabédian M, et al. European cystic fibrosis bone mineralisation guidelines. Journal of Cystic Fibrosis. 2011;**10** (Suppl 2):S16-S23

[33] Chapman I, Greville H, Ebeling PR, King SJ, Kotsimbos T, Nugent P, et al. Intravenous zoledronate improves bone density in adults with cystic fibrosis (CF). Clinical Endocrinology. 2009;**70**(6):838-846

[34] Haworth CS, Selby PL, Adams JE, Mawer EB, Horrocks AW, Webb AK. Effect of intravenous pamidronate on bone mineral density in adults with cystic fibrosis. Thorax. 2001;**56**(4):314-316

[35] Aris RM, Lester GE, Caminiti M, Blackwood AD, Hensler M, Lark RK, et al. Efficacy of alendronate in adults with cystic fibrosis with low bone density. American Journal of Respiratory and Critical Care Medicine. 2004;**169**(1):77-82

[36] Conwell LS, Chang AB. Bisphosphonates for osteoporosis in people with cystic fibrosis. Cochrane Database of Systematic Reviews. 2014;**2014**(3):CD002010. DOI: 10.1002/ 14651858.CD002010.pub4

[37] Compston JE, McClung MR, Leslie WD. Osteoporosis. Lancet. 2019;**393**(10169):364-376

[38] Kates SL, Ackert-Bicknell CL. How do bisphosphonates affect fracture healing? Injury. 2016;**47**(Suppl 1(0 1)): S65-S68

[39] Xue D, Li F, Chen G, Yan S, Pan Z. Do bisphosphonates affect bone healing? A meta-analysis of randomized controlled trials. Journal of Orthopaedic Surgery and Research. 2014;**5**(9):45

[40] Gao Y, Liu X, Gu Y, et al. The effect of bisphosphonates on fracture healing time and changes in bone mass density: A meta-analysis. Front Endocrinology (Lausanne). 2021;**12**:688269 Published 2021 Aug 30

[41] Ju DG, Mogayzel PJ Jr, Sponseller PD, Familiari F, McFarland EG. Bilateral midshaft femoral fractures in an adolescent baseball player. Journal of Cystic Fibrosis. 2016;**15**(4):e41-e43

[42] Lim AY, Isopescu S, Thickett KM, et al. Bilateral fractured neck of the femur in an adult patient with cystic fibrosis. European Journal of Internal Medicine. 2003;**14**(3):196-198

[43] Haworth CS, Freemont AJ, Webb AK, et al. Hip fracture and bone histomorphometry in a young adult with cystic fibrosis. The European Respiratory Journal. 1999;**14**(2):478-479

[44] Al-Azzani WA, Evans L, Speight L, et al. Hyperpharmacotherapy in ageing cystic fibrosis patients: The first report of an atypical hip fracture. Respiratory Medicine Case Reports. 2015;**16**:148-150

[45] Ross J, Gamble J, Schultz A, Lewiston N. Back pain and spinal deformity in cystic fibrosis. American Journal of Diseases of Children. 1987;**141**(12):1313-1316

[46] Lambrechts MJ, Smith MJ, Choma TJ. Orthopedic manifestations of cystic fibrosis. Orthopedics. 2021;**44**(3):e440-e445. DOI: 10.3928/ 01477447-20210415-03

[47] Kumar N, Balachandran S, Millner PA, Littlewood JM, Conway SP, Dickson RA. Scoliosis in cystic fibrosis: Is it idiopathic? Spine. 2004;**29**(18):1990- 1995

[48] Tejero S, Cejudo P, Quintana-Gallego E, Sañudo B, Oliva-Pascual-Vaca A. The role of daily physical activity and nutritional status on bone turnover in cystic fibrosis: A crosssectional study. Brazilian Journal of Physical Therapy. 2016;**20**(3):206-212

[49] Aris RM, Renner JB, Winders AD, et al. Increased rate of fractures and severe kyphosis: Sequelae of living into adulthood with cystic fibrosis. Annals of Internal Medicine. 1998;**128**(3):186-193

[50] de Meer K, Gulmans VA, van Der Laag J. Peripheral muscle weakness and exercise capacity in children with cystic fibrosis. American Journal of Respiratory and Critical Care Medicine. 1999;**159**(3):748-754

[51] Hathorn C, Fall A, McGurk S, Tsirikos AI, Urquhart DS. G101(P) incidence of scoliosis in adolescent cystic fibrosis patients. Archives of Disease in Childhood. 2014;**99**(suppl 1):A43

[52] Weinstein SL, Ponseti IV. Curve progression in idiopathic scoliosis. The Journal of Bone and Joint Surgery. American Volume. 1983;**65**(4):447-455

[53] Troosters T, Langer D, Vrijsen B, et al. Skeletal muscle weakness, exercise tolerance and physical activity in adults with cystic fibrosis. The European Respiratory Journal. 2009;**33**(1):99-106

[54] Divangahi M, Balghi H, Danialou G, et al. Lack of CFTR in skeletal muscle

predisposes to muscle wasting and diaphragm muscle pump failure in cystic fibrosis mice. PLoS Genetics. 2009;**5**(7):e1000586

[55] Rosenthal M, Narang I, Edwards L, Bush A. Non-invasive assessment of exercise performance in children with cystic fibrosis (CF) and non-cystic fibrosis bronchiectasis: Is there a CF specific muscle defect? Pediatric Pulmonology. 2009;**44**(3):222-230

[56] King SJ, Nyulasi IB, Bailey M, Kotsimbos T, Wilson JW. Loss of fatfree mass over four years in adult cystic fibrosis is associated with high serum interleukin-6 levels but not tumour necrosis factor-alpha. Clinical Nutrition. 2014;**33**(1):150-155

[57] Lamhonwah AM, Bear CE, Huan LJ, Kim Chiaw P, Ackerley CA, Tein I. Cystic fibrosis transmembrane conductance regulator in human muscle: Dysfunction causes abnormal metabolic recovery in exercise. Annals of Neurology. 2010;**67**(6):802-808

[58] Gruet M, Decorte N, Mely L, Vallier JM, Camara B, Quetant S, et al. Skeletal muscle contractility and fatigability in adults with cystic fibrosis. Journal of Cystic Fibrosis. 2016;**15**(1):e1-e8

[59] Shah AR, Gozal D, Keens TG. Determinants of aerobic and anaerobic exercise performance in cystic fibrosis. American Journal of Respiratory and Critical Care Medicine. 1998;**157**(4 Pt 1): 1145-1150

[60] Boas SR, Joswiak ML, Nixon PA, Fulton JA, Orenstein DM. Factors limiting anaerobic performance in adolescent males with cystic fibrosis. Medicine and Science in Sports and Exercise. 1996;**28**(3):291-298

*Musculoskeletal Abnormalities Caused by Cystic Fibrosis DOI: http://dx.doi.org/10.5772/intechopen.104591*

[61] Gilsanz V, Kremer A, Mo AO, Wren TA, Kremer R. Vitamin D status and its relation to muscle mass and muscle fat in young women. The Journal of Clinical Endocrinology and Metabolism. 2010;**95**(4):1595-1601

[62] King SJ, Tierney AC, Edgeworth D, et al. Body composition and weight changes after ivacaftor treatment in adults with cystic fibrosis carrying the G551 D cystic fibrosis transmembrane conductance regulator mutation: A double-blind, placebo-controlled, randomized, crossover study with open-label extension. Nutrition. 2021;**85**:111124

[63] Stallings VA, Sainath N, Oberle M, Bertolaso C, Schall JI. Energy balance and mechanisms of weight gain with Ivacaftor treatment of cystic fibrosis gating mutations. The Journal of Pediatrics. 2018;**201**:229-237.e4

[64] Gruet M, Troosters T, Verges S. Peripheral muscle abnormalities in cystic fibrosis: Etiology, clinical implications and response to therapeutic interventions. Journal of Cystic Fibrosis. 2017;**16**(5):538-552

[65] Rovedder PM, Flores J, Ziegler B, Casarotto F, Jaques P, Barreto SS, et al. Exercise programme in patients with cystic fibrosis: A randomized controlled trial. Respiratory Medicine. 2014;**108**(8):1134-1140

[66] Strauss GD, Osher A, Wang CI, Goodrich E, Gold F, Colman W, et al. Variable weight training in cystic fibrosis. Chest. 1987;**92**(2):273-276

[67] Bieli C, Summermatter S, Boutellier U, Moeller A. Respiratory muscle training improves respiratory muscle endurance but not exercise tolerance in children with cystic fibrosis. Pediatric Pulmonology. 2017;**52**(3): 331-336. DOI: 10.1002/ppul.23647

[68] Santana-Sosa E, Gonzalez-Saiz L, Groeneveld IF, Villa-Asensi JR, Gómez B, de Aguero MI, et al. Benefits of combining inspiratory muscle with 'whole muscle' training in children with cystic fibrosis: A randomised controlled trial. British Journal of Sports Medicine. 2014;**48**(20):1513-1517

[69] Swisher AK, Hebestreit H, Mejia-Downs A, et al. Exercise and habitual physical activity for people with cystic fibrosis. Cardiopulmonary Physical Therapy Journal. 2015;**26**(4):85-98

[70] Botton E, Saraux A, Laselve H, Jousse S, Le Goff P. Musculoskeletal manifestations in cystic fibrosis. Joint, Bone, Spine. 2003;**70**(5):327-335

[71] Grehn C, Dittrich AM, Wosniok J, Holz F, Hafkemeyer S, Naehrlich L, et al. Registry working group of the German CF registry. Risk factors for cystic fibrosis arthropathy: Data from the German cystic fibrosis registry. Journal of Cystic Fibrosis. 2021;**20**(6):e87-e92

[72] Roehmel JF, Kallinich T, Staab D, Schwarz C. Clinical manifestations and risk factors of arthropathy in cystic fibrosis. Respiratory Medicine. 2019;**147**:66-71

[73] Nixon LS, Yung B, Bell SC, Elborn JS, Shale DJ. Circulating immunoreactive interleukin-6 in cystic fibrosis. American Journal of Respiratory and Critical Care Medicine. 1998;**157**(6 pt 1):1764-1769

[74] Stannus O, Jones G, Cicuttini F, et al. Circulating levels of IL-6 and TNF-alpha are associated with knee radiographic osteoarthritis and knee cartilage loss in older adults. Osteoarthritis and Cartilage. 2010;**18**(11):1441-1447

[75] Lands LC, Stanojevic S. Oral non-steroidal anti-inflammatory drug therapy for lung disease in cystic fibrosis. Cochrane Database of Systematic Reviews. 2019;**9**:CD001505

[76] Loh G, Ryaboy I, Skabelund A, French A. Procalcitonin, erythrocyte sedimentation rate and C-reactive protein in acute pulmonary exacerbations of cystic fibrosis. The Clinical Respiratory Journal. 2018;**12**(4):1545-1549

[77] Matouk E, Nguyen D, Benedetti A, Bernier J, Gruber J, Landry J, et al. C-reactive protein in stable cystic fibrosis: An additional indicator of clinical disease activity and risk of future pulmonary exacerbations. Journal of Pulmonary Respiratory Medicine. 2016;**6**(5):1000375

[78] Talebi-Taher M, Shirani F, Nikanjam N, Shekarabi M. Septic versus inflammatory arthritis: Discriminating the ability of serum inflammatory markers. Rheumatology International. 2013;**33**(2):319-324

[79] Turner MA, Baildam E, Patel L, David TJ. Joint disorders in cystic fibrosis. Journal of the Royal Society of Medicine. 1997;**90**(Suppl 31):13-20

[80] Johnson S, Knox AJ. Arthropathy in cystic fibrosis. Respiratory Medicine. 1994;**88**(8):567-570

[81] Prajapati BB, Filippi A, Sears EH. Chronic joint pain in a young adult with cystic fibrosis. Cureus. 2021;**13**(8):e17229 [Published 2021 Aug 16]

[82] Tekiteki A, Good WR, Diggins B, Anderson G, Wong CA. Recurrent hypertrophic pulmonary osteoarthropathy in an adult with bronchiectasis. Respirology Case Reports. 2020;**8**(6):e00602 [Published 2020 Jun 23]

[83] Yap FY, Skalski MR, Patel DB, Schein AJ, White EA, Tomasian A, et al. Hypertrophic Osteoarthropathy: Clinical and imaging features. Radiographics. 2017;**37**(1):157-195

[84] Treasure T. Hypertrophic pulmonary osteoarthropathy and the vagus nerve: An historical note. Journal of the Royal Society of Medicine. 2006;**99**(8):388-390

### Section 3
