Treatment Of Spondyloarthritis Research Articles

Emerging story of gut dysbiosis in spondyloarthropathy: From gastrointestinal inflammation to spondyloarthritis.

As a set of inflammatory disorders, spondyloarthritis (SpA) exhibits distinct pathophysiological, clinical, radiological, and genetic characteristics. Due to the extra-articular features of this disorder, early recognition is crucial to limiting disability and improving outcomes. Gut dysbiosis has been linked to SpA development as evidence grows. A pathogenic SpA process is likely to occur when a mucosal immune system interacts with abnormal local microbiota, with subsequent joint involvement. It is largely unknown, however, how microbiota alterations predate the onset of SpA within the “gut-joint axis”. New microbiome therapies, such as probiotics, are used as an adjuvant therapy in the treatment of SpA, suggesting that the modulation of intestinal microbiota and/or intestinal barrier function may contribute to the prevention of SpA. In this review, we highlight the mechanisms of SpA by which the gut microbiota impacts gut inflammation and triggers the activation of immune responses. Additionally, we analyze the regulatory role of therapeutic SpA medication in the gut microbiota and the potential application of probiotics as adjunctive therapy for SpA.

Metabolomics: An Emerging Approach to Understand Pathogenesis and to Assess Diagnosis and Response to Treatment in Spondyloarthritis.

Spondyloarthritis (SpA) is a group of rheumatic diseases whose pathogenesis relies on a complex interplay between genetic and environmental factors. Over the last several years, the importance of the alteration of the gut microbiota, known as dysbiosis, and the interaction of bacterial products with host immunity have been highlighted as intriguing key players in SpA development. The recent advent of the so called “-omics” sciences, that include metabolomics, opened the way to a new approach to SpA through a deeper characterisation of the pathogenetic mechanisms behind the disease. In addition, metabolomics can reveal potential new biomarkers to diagnose and monitor SpA patients. The aim of this review is to highlight the most recent advances concerning the application of metabolomics to SpA, in particular focusing attention on Ankylosing Spondylitis and Psoriatic Arthritis.

A glance into the future of diagnosis and treatment of spondyloarthritis.

The last two decades have seen major developments in the field of spondyloarthritis (SpA), but there are still important unmet needs to address. In the future, we envisage important advances in the diagnosis and treatment of SpA. In the diagnosis of SpA, the use of online and social media tools will increase awareness of the disease and facilitate the referral of patients to rheumatology clinics. In addition, more specific diagnostic tests will be available, especially advanced imaging methods and new biomarkers. This will allow most patients to be diagnosed at an early stage of the disease. In the treatment of SpA, an increasing number of novel treatment targets can be expected, most of which will be directed against intracellular enzymes. We hope to see more strategy trials shaping treatment pathways in SpA and accommodating principals of precision medicine. Approved treatment options will be available for both axial and peripheral SpA. We also hope to intervene not only at the inflammation level but also at the level of underlying immunological processes that might be associated with a higher probability of long-standing remission if not a cure. Finally, artificial intelligence techniques will allow for the analysis of large-scale data to answer relevant research questions for the diagnosis and management of patients with SpA.

O10 Multi-disciplinary working in SpA diagnosis: case study

Case report - IntroductionHigh-intensity exercise is effective in treating Axial Spondyloarthritis (SpA). A reduction in morbidity therefore should be gained from accurate diagnosis early in the disease history. In 2021 the National Axial Spondylarthritis Society (NASS) released a statement to reduce time to diagnosis (TTD) of Axial SpA from 8 years to 1, to reduce morbidity and long-term complications of chronic inflammation.This case study aims to provide an example of how a multidisciplinary team working in close clinical proximity (CCP MDT) can be utilised to reduce the TTD and optimise treatment and biomechanics of acute and chronic SpA.Case report - Case descriptionCases 1 and 2 compare patients presenting to a musculoskeletal clinic with lower back pain, stiffness, and reduced range of movement. Case 1. Subacute presentation: 25-year-old male with a 3-month history of lower back pain and stiffness. This progressed to a month of not being able to walk, disturbed sleep and morning stiffness of > 1hr. Clinical examination showed no extra musculoskeletal manifestations, and no other joint pain. Tests showed HLA B27 positive status with florid bilateral sacroiliitis on MRI.Case 2. Chronic presentation: 34-year-old male with 20-year history of insidious onset lower back pain previously diagnosed as “non-specific” back pain by a series of health care professionals (HCPs). HLA B27 negative, MRI showed acute on chronic SIJ arthropathy with juxtarticular sclerosis.Patients were seen by a HCP who referred to a rheumatologist. In both, clinical and radiological signs indicated Axial SpA which was treated with 120mg of IM Depo-Medorone and 8-weeks of strength-based active intervention from a physiotherapist and strength and conditioning coach. BASDAI, 5-rep max single leg press scores were recorded pre- and post-intervention (Table 1.). Case 1Pre-interventionPost-interventionBASDAI5.10.9Single leg press 5RM55kg75kgCase 2Pre-interventionPost-interventionBASDAI 6.14.2Single leg press 5RM65kg115kgCase report - DiscussionConventional therapies for SpA back pain are effective even in chronic cases; this is reflected in the improvements made across both cases. Using a similar approach of high-intensity exercise and mobility both were able to significantly improve BASDAI scores and lower limb strength.We can hypothesise that attempts to innovate the biomechanics of the treatments is missing the fundamental issue surrounding SpA back pain highlighted by NASS; TTD takes too long for too many. There is a feasible argument therefore that it is the structures of how we operate as HCPs that is reducing the efficacy of said treatments. This is evidenced by case 2 (Table 1), whose multiple presentations to different HCPs over 20 years led to potentially preventable prolonged morbidity as well as increased the risk of future complications due to chronic inflammation. This is a story that is sadly reflective of the disease histories of many SpA patients.Much like any primary care provider, patients at this clinic will first present to a HCP. The difference is that all HCPs are trained to recognise features of SpA back pain and encouraged to flag concerns to a doctor.HCPs work in adjacent spaces allowing for better sharing of ideas and concerns that is often reduced by physical separation. This creates the concept of a CCP MDT. HCPs are encouraged to share concerns face to face without reproach or the formality or delay of a written request. This structure has proven to be effective in diagnosis in both of these cases but has proven to be as useful in many more instances to rule out a differential or allay a concern.These cases argue that the low lying fruit of improving clinical outcomes in this cohort is addressing how we as HCPs interact and cooperate. Case report - Key learning pointsBiomechanics of the treatments of SpA are effective in the majority of cases when applied by sufficiently skilled practitioners. It is the TTD that we should address to aid the reduction in morbidity in this patient group through the following recommendations: Foster education of SpA in allied health professionals. This allows us to be aware of the boundaries of our own knowledge and at what point a different clinical perspective should be sought.Diversify clinical environments and encourage MDT working. The use of CCP MDT structures allows more nuanced access to different opinions in a safe supportive manner, allowing for sharing of ideas and concerns – allowing for supporting diverse expertise and insight. If we are to reduce TTD to the 1-year NASS hopes for, we should first look at how we work, not what we do. Ongoing research and auditing of patients is being carried out to better assess how educational practices can be optimised to help meet the NASS targets. For more information or to collaborate contact matthew.virden@puresportsmed.com

O03 Continuation of golimumab (anti-TNF) in a patient with SpA and low-risk prostate cancer, what is the right decision?

Case report - IntroductionGolimumab is an anti-TNF alpha drug used in the treatment of inflammatory arthritis including spondyloarthritis (SpA). The introduction of this drug class has revolutionised the treatment of SpA over the last 20 years with significantly improved patient outcomes.Despite their treatment benefits multiple adverse effects of TNF-alpha inhibition have been reported through clinical trials including a possible increased risk of malignancy.We describe a case of a patient with known ankylosing spondylitis (AS) on golimumab who was diagnosed with low-grade prostate carcinoma and discuss the factors taken into consideration in guiding our decision-making process regarding ongoing treatment. Case report - Case descriptionA 57-year-old gentleman with known AS presented to the rheumatology clinic for routine review. His AS was well controlled, and he had been taking golimumab for the past 3 years. Upon review he was in clinical remission with a CRP <1 and ESR 5. Prior to the initiation of anti-TNF therapy his disease had been poorly controlled. However, following commencement his symptoms had significantly improved and he was able to work as a professional sports coach whilst bringing up a young family.On review he had recently been diagnosed with low-risk cancer of the prostate by his urologist. A prostate biopsy found Gleason 3 + 3 adenocarcinoma involving 2 out of 22 cores on each side, with a prostate specific antigen (PSA) of 3.95ng/ml. An MRI had shown chronic prostatitis. He was in the lowest risk category of grade group 1 prostate cancer and no treatment for his prostate cancer was indicated. The plan from his urology team was active surveillance with PSA monitoring.Whilst being investigated for possible malignancy his golimumab had been held for six months and during this period he had a significant flare in symptoms. He experienced severe back pain that forced him to stop working. Following his prostate cancer diagnosis, golimumab was restarted by his urologist with a subsequent improvement in his AS symptoms.To guide ongoing treatment his case was reviewed in the local biologics multi-disciplinary team meeting, alongside close communication with his urologist. The patient was informed of the risks of continuing golimumab in relation to his malignancy. Despite this he was reluctant to stop anti-TNF therapy or switch to another treatment, citing concerns about the impact it might have on his symptoms and ability to work.Case report - Discussion This case highlights the complexities involved in the management of a patient on anti-TNF therapy, who receives a diagnosis of malignancy, particularly when the diagnosis is classed as low risk. Traditionally anti-TNF therapy was contraindicated for patients with a history of a solid organ tumour within the previous five years. The British Society of Rheumatology (BSR) guidelines recommends that patients should be advised that there is no conclusive evidence for an increased risk of solid organ tumours but that on-going vigilance is required.A holistic patient-centred approach needs to be taken in these contexts, and consideration of cases on an individual basis is needed. Inter-disciplinary and multi-speciality team input, with the effective use of a biologics MDT, is crucial. The patient was understandably reluctant to stop his treatment due to the significant impact this may have on his quality of life.On liaison with his urologist his prostate cancer was in the lowest risk category with 99% 5-year survival rates with low risk of disease progression or spread.Evidence in this field to date has been conflicting and studies have predominantly focused on the safety of anti-TNFs in rheumatoid arthritis patients. Recent large national registry data has been reassuring. Few studies have looked at the AS and psoriatic arthritis anti-TNF treated population; however, a meta-analysis of RCTs found no evidence of increased incidence of malignancy.Taking into account his low-risk cancer, the patient’s wishes and clinical evidence in this field we have made to decision to continue anti-TNF treatment for now but with ongoing surveillance for any tumour progression. The patient will undergo urology follow up alongside regular PSA monitoring, and there will be a low threshold to stop or switch treatment in the futureCase report - Key learning pointsTreatment with anti-TNF therapy in patients with concomitant inflammatory arthritis and malignancy pose a specific challenge that require close co-ordination of care between rheumatologists, oncologists, other relevant teams and may benefit from the use of local biologics MDT to guide ongoing drug therapy.It is important to take a patient centred approach and consider cases on an individual basis taking into account their cancer diagnosis, extent of disease, histology findings and their response to TNF treatment.Patients must always be counselled on the risk of continuing anti-TNF and be involved in the decision-making process.Further research is required to look at the safety of anti-TNF particularly in SpA and if there is an increased risk of malignancy.

The importance of non-pharmacological treatment in spondyloarthritis

Spondyloarthritis (SpA) is a related group of inflammatory joint diseases comprising axial SpA (axSpA), psoriatic arthritis (PsA), arthritis associated with inflammatory bowel disease, reactive arthritis and undifferentiated SpA [1]. These entities share clinical features like asymmetrical oligoarticular arthritis, sacroiliitis and/or spondylitis, enthesitis, dactylitis and/or uveitis.

Clinical Trials Supporting the Role of the IL-17/IL-23 Axis in Axial Spondyloarthritis.

The term spondyloarthritis (SpA) encompasses a heterogeneous group of inflammatory musculoskeletal diseases with several common genetic background and clinical features, including the possible involvement of the axial skeleton with peripheral mono- or oligo- arthritis and frequently coexisting skin, eye and intestinal manifestations. When the sacroiliac joints or other parts of the spine or thoracic wall are predominantly affected at magnetic resonance or X-ray imaging with inflammatory back pain, the disease is classified as axial SpA and the therapeutic choices are significantly different compared to cases of peripheral arthritis. Moving from the narrow effectiveness and safety profiles of non-steroidal anti-inflammatory drugs, there has been a significant research effort aimed at identifying new treatments based on our better understanding of the pathogenesis of SpA. Indeed, in parallel with the solid data demonstrating that IL-17 and IL-23 are key cytokines in the development of enthesitis and spondylitis, monoclonal antibodies interfering with this pathway have been developed for the treatment of axial SpA. Furthermore, the IL-17/IL-23 axis is key to extra-articular manifestations such as inflammatory bowel disease, uveitis, and psoriasis which are frequent comorbidities of SpA. Currently available drugs act through these mechanisms recognizing IL-23 and targeting IL-17, such as secukinumab and ixekizumab. These therapeutic approaches are now envisioned in the international treatment recommendations for psoriatic arthritis with an axial phenotype as well as for ankylosing spondylitis (AS). We will provide herein a concise comprehensive overview of the clinical evidence supporting the use of these and other drugs acting on IL-23 and IL-17 in axial SpA.

Similarities and Differences Between Juvenile and Adult Spondyloarthropathies.

Spondyloarthritis (SpA) encompasses a broad spectrum of conditions occurring from childhood to middle age. Key features of SpA include axial and peripheral arthritis, enthesitis, extra-articular manifestations, and a strong association with HLA-B27. These features are common across the ages but there are important differences between juvenile and adult onset disease. Juvenile SpA predominantly affects the peripheral joints and the incidence of axial arthritis increases with age. Enthesitis is important in early disease. This review article highlights the similarities and differences between juvenile and adult SpA including classification, pathogenesis, clinical features, imaging, therapeutic strategies, and disease outcomes. In addition, the impact of the biological transition from childhood to adulthood is explored including the importance of musculoskeletal and immunological maturation. We discuss how the changes associated with adolescence may be important in explaining age-related differences in the clinical phenotype between juvenile and adult SpA and their implications for the treatment of juvenile SpA.

Janus kinase-signal transducers and activators of transcription cell signaling in Spondyloarthritis: rationale and evidence for JAK inhibition.

The Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling proteins represent a group of intracellular kinase molecules that play a central role in the signaling pathways induced by cytokines, chemokines, and certain growth factors associated with systemic and local inflammation of autoimmune diseases including in Spondyloarthritis (SpA). Here, we will discuss (i) the functional significance of the JAK-STAT kinase cascades in the inflammatory-proliferative processes of SpA and its cellular/molecular mechanisms (ii) progress in the development of oral synthetic JAK inhibitors (JAKi) and their therapeutic efficacies in SpA. Development JAKi is a fast-moving field in the medical science. Several new-generation JAKi are being identified for psoriatic arthritis and ankylosing spondylitis. It is expected these JAKi likely to have higher potency and less adverse effects. Here, we are providing an updated review on the significance of JAK-STAT signaling proteins in SpA with an emphasis on new-generation of JAK-STAT inhibitors for the treatment of SpA.

Takayasu's arteritis occurring under TNF blockers in a patient with spondyloarthritis: is it an association or a paradoxical effect?

Coexistence of spondyloarthritis (SpA) and Takayasu’s arteritis is not a common finding, but such cases have been discussed, particularly in the context of choice of therapy. Inhibition of inflammation by tumor necrosis factor inhibitors (TNFi) is a key aspect of the treatment of SpA and also positive effects of such treatment in concomitant large vessel vasculitis have been reported. However, TNFi is also associated with the possibility of initiating vasculitis.The present article based on a case study and the available literature is an attempt to discuss coexistence of these two diseases and the impact of treatment with biological drugs from the anti-TNF group in the course of SpA with Takayasu’s arteritis.

A Systematic Review of Models Used in Cost-Effectiveness of Treatments in Spondyloarthritis

This review was aimed to evaluate health economic models used in evaluations of different treatment strategies in spondyloarthritis (SpA). Model-based health economic evaluation studies are increasing and complex models with short-term and long-term horizon are applied to investigate the cost-effectiveness of SpA treatments. The objective of this study was to carry out a systematic review of the evolution of health economic models used in the treatment of SpA. Electronic searches within MEDLINE and EMBASE were carried out using a predefined search strategy. Inclusion and exclusion criteria were used to select relevant studies. Data on country, intervention, evaluation perspective, type of model, time horizon, types of costs and effectiveness measurement were extracted. Eighteen models were described in 22 publications, of which 81.8% were European. Study perspectives included the societal (n=6), healthcare system and payer (n=14), or patient and government (n=1). Time horizon ranged from 52 weeks to lifetime. Markov model was the most frequently used model, only one individual patient simulation models accounting for uncertainty in multiple parameters was reported. Most studies compared different biologics (including different TNFi/biosimilar and IL-17A antibody) with conventional care (NSAIDs) because of the high prize. Only half of studies took indirect costs into account. Modeling is of importance in health economic evaluations of SpA treatment. Long-term costs especially indirect costs should be considered when comparing different treatment alternatives in order to provide more information for policy makers and clinicians.

Secukinumab treatment in spondyloarthritis: Retention rate and effectiveness data at 12 months – data from the Romanian Registry of Rheumatic Diseases

Secukinumab treatment in spondyloarthritis: Retention rate and effectiveness data at 12 months – data from the Romanian Registry of Rheumatic Diseases

Comorbid infections in spondyloarthritis: a modern view of the problem

The review considers the problem of comorbid infections (CIs) in ankylosing spondylitis and psoriatic arthritis (PsA) as the main nosological entities of spondyloarthritis (SpA). It analyzes the frequency of CIs during therapy with biological agents and targeted synthetic disease-modifying anti-rheumatic drugs. It is concluded that the problem of CI in SpA deserves the closest attention. The review also shows the importance of preventive measures for CI in the treatment of SpA. It is in particular noted that in accordance with the updated guidelines of the European League Against Rheumatism and other rheumatology research associations, all patients with immunemediated inflammatory rheumatic diseases (including SpA) on immunosuppressive therapy are recommended to get influenza and pneumococcal vaccines due to the high risk of death from respiratory tract infections. Moreover, vaccination is indicated even for patients with an expected suboptimal response. The review gives the main points of the recommendations of the Medical Board of the National Psoriasis (Ps) Foundation on the use of recombinant Herpes zoster vaccine in patients with Ps/PsA. There is a need for further investigations of the frequency and pattern of CIs and the impact of new therapy options on the prevalence of CIs in patients with SpA. Determination of the effectiveness and safety of vaccination in this patient population should become an important area for future investigations.

The Role of the IL-23/IL-17 Pathway in the Pathogenesis of Spondyloarthritis.

Spondyloarthritis (SpA) is a subset of seronegative rheumatic-related autoimmune diseases that consist of ankylosing spondylitis (AS), psoriatic spondylitis (PsA), reactive spondylitis (re-SpA), inflammatory bowel disease (IBD)-associated spondylitis, and unclassifiable spondylitis. These subsets share clinical phenotypes such as joint inflammation and extra-articular manifestations (uveitis, IBD, and psoriasis [Ps]). Inflammation at the enthesis, where ligaments and tendons attach to bones, characterizes and distinguishes SpA from other types of arthritis. Over the past several years, genetic, experimental, and clinical studies have accumulated evidence showing that the IL-23/IL-17 axis plays a critical role in the pathogenesis of SpA. These discoveries include genetic association and the identification of IL-23- and IL-17-producing cells in the tissue of mouse models and human patients. In this review, we summarize the current knowledge of the pathomechanism by focusing on the IL-23/IL-17 pathway and examine the recent clinical studies of biological agents targeting IL-23 and IL-17 in the treatment of SpA.

The usefulness and validity of English-language videos on YouTube as an educational resource for spondyloarthritis.

YouTube is a popular online platform where patients often visit for information. However, the validity of the content on spondyloarthritis (SpA) on YouTube is not known. To evaluate the content, reliability, and quality of the most viewed English-language YouTube videos on SpA. Keywords "spondyloarthritis," "spondyloarthropathy," and "ankylosing spondylitis" were searched on YouTube on October 7, 2019. The top 270 videos were screened. Videos were excluded if they were irrelevant, in non-English language, or if they had no audio. Total number of views, duration on YouTube (days), video length, upload date, and number of likes, dislikes, subscribers, and comments were recorded for videos. A modified 5-point DISCERN tool and the 5-point Global Quality Scale (GQS) score were used to assess the reliability and quality of the videos. Two hundred videos were included in the final analysis (62% from healthcare professionals, 37% from patients, and 2% from news channels). Useful information, useful patient opinion, misleading patient opinion, and misleading information comprised o60%, 26%, 11%, and 3% of videos respectively. Majority of misleading videos were uploaded by patients (82%). Misleading videos commonly included wrong clinical features and unproven alternative treatments of SpA. Videos by healthcare professionals had more useful information, higher reliability, and GQS scores. Majority of YouTube videos have useful information on SpA and are important educational sources to patients. However, rheumatologists should be aware that misleading patient opinions on alternative therapies can contain inaccurate information and should hence actively correct these misinformation during their clinic consults Key Points • The majority of videos on Spondyloarthritis found on YouTube are deemed useful and are uploaded by healthcare professionals. • The majority of misleading videos were uploaded by patients and the main theme of misinformation was on clinical features and treatment of spondyloarthritis.

Sex differences in disease activity and efficacy of treatment in spondyloarthritis: is body composition the cause?

The body composition and fat distribution is different between men and women, with different levels of circulating adipokines. These differences become more evident when suffering from an inflammatory disease, such as spondyloarthritris. In this review, we will explore the influence of obesity, body composition and adipokines on the differences in disease activity, progression and response to treatment, between men and women with spondyloarthritis. Obesity, mainly determined by the body fat content, which is higher in women, is related to worse disease activity scores. Men with higher disease activity lose more muscle mass than women. Leptin, which is usually found at higher levels in overweight women, seems to be associated with greater spinal radiographic progression when it rises during the course of the disease. Being a woman and obesity, mainly because of the body fat content, are related to a worse response to TNF-α blockers. Overlooking biological sex variation in body composition, circulating adipokines and hormonal levels, and the subsequent differences in clinical presentation, may ultimately hamper clinical treatment.

TYK2 inhibition reduces type 3 immunity and modifies disease progression in murine spondyloarthritis.

Spondyloarthritis (SpA) represents a family of inflammatory diseases of the spine and peripheral joints. Ankylosing spondylitis (AS) is the prototypic form of SpA in which progressive disease can lead to fusion of the spine. Therapeutically, knowledge of type 3 immunity has translated into the development of IL-23– and IL-17A–blocking antibodies for the treatment of SpA. Despite being able to provide symptomatic control, the current biologics do not prevent the fusion of joints in AS patients. Thus, there is an unmet need for disease-modifying drugs. Genetic studies have linked the Janus kinase TYK2 to AS. TYK2 is a mediator of type 3 immunity through intracellular signaling of IL-23. Here, we describe and characterize a potentially novel small-molecule inhibitor of TYK2 that blocked IL-23 signaling in vitro and inhibited disease progression in animal models of SpA. The effect of the inhibitor appears to be TYK2 specific, using TYK2-inactive mice, which further revealed a duality in the induction of IL-17A and IL-22 by IL-23. Specifically, IL-22 production was TYK2/JAK2/STAT3 dependent, while IL-17A was mostly JAK2 dependent. Finally, we examined the effects of AS-associated TYK2 SNPs on TYK2 expression and function and correlated them with AS disease progression. This work provides evidence that TYK2 inhibitors have great potential as an orally delivered therapeutic for SpA.

Introduction: Evolution of inflammatory arthritis from innate to adaptive immune mechanisms.

Introduction: Evolution of inflammatory arthritis from innate to adaptive immune mechanisms.

Evaluation of a special concept of physical therapy in spondyloarthritis: German multimodal rheumatologic complex treatment for spondyloarthritis.

Multimodal rheumatologic complex treatment (MRCT) is a specific concept of German inpatient care focusing on physical therapy for patients with rheumatic diseases suffering from exacerbated pain and functional impairment. As physical therapy is a key concept in the treatment of spondyloarthritis (SpA), we conducted a monocentric retrospective analysis of the effects of MRCT on pain and functional status in patients with SpA including patients with axial spondyloarthritis (axSpA), non-radiographic axial spondyloarthritis (nr-axSpA) and psoriatic arthritis with axial involvement (axPsA). 134 treatment episodes provided to 100 patients with SpA between 2014 and 2017 were analysed. We evaluated changes in pain intensity, in functional status and in disease activity before and after a treatment episode. In addition, we assessed potential influences of various patient characteristics, the course of the disease and comorbidities. Overall, MRCT resulted in significant amelioration of pain (NRS: p < 0.001), significant improvement of functional capacity (FFbH: p = 0.03; HAQ: p = 0.02; BASFI: p < 0.001) and significant reduction of disease activity (BASDAI p < 0.001; DAS28: p = 0.009). In general, treatment effects on axSpA, nr-axSpA and axPsA were comparable. Different aspects of the disease and its previous course did not have a significant effect on the outcome parameters. Comorbidities (e.g. fibromyalgia) did not significantly influence treatment response. MRCT not only decreases pain and improves function but also reduces disease activity in patients with axSpA, nr-axSpA and axPsA irrespective of the course of disease and comorbidities (e.g. fibromyalgia), thus underlining the importance of non-pharmacological and physical treatment in the treatment of SpA.Key Points• Physical treatment is a key component in treating SpA.• Multimodal rheumatologic complex treatment (MRCT) is a specific concept of German inpatient care focusing on physical therapy for patients with rheumatic diseases suffering from exacerbated pain and functional impairment.• MRCT not only decreases pain and improves function but also reduces disease activity in patients with axSpA, nr-axSpA and axPsA irrespective of the course of disease and comorbidities (e.g. fibromyalgia).• MRCT could be a role model of treating SpA by means of physical therapy as its effects are not influenced by therapy, disease duration or comorbidities and as it has no side effects.

Cytokine-Induced and Stretch-Induced Sphingosine 1-Phosphate Production by Enthesis Cells Could Favor Abnormal Ossification in Spondyloarthritis.

Spondyloarthritis (SpA) is a common rheumatic disease characterized by enthesis inflammation (enthesitis) and ectopic ossification (enthesophytes). The current pathogenesis model suggests that inflammation and mechanical stress are both strongly involved in SpA pathophysiology. We have previously observed that the levels of sphingosine 1-phosphate (S1P), a bone anabolic molecule, were particularly high in SpA patients' serum compared to healthy donors. Therefore, we wondered how this deregulation was related to SpA molecular mechanisms. Mouse primary osteoblasts, chondrocytes, and tenocytes were used as cell culture models. The sphingosine kinase 1 (Sphk1) gene expression and S1P secretion were significantly enhanced by cyclic stretch in osteoblasts and chondrocytes. Further, TNF-α and IL-17, cytokines implicated in enthesitis, increased Sphk1 mRNA in chondrocytes in an additive manner when combined to stretch. The immunochemistry on mouse ankles showed that sphingosine kinase 1 (SK1) was localized in some chondrocytes; the addition of a pro-inflammatory cocktail augmented Sphk1 expression in cultured ankles. Subsequently, fingolimod was used to block S1P metabolism in cell cultures. It inhibited S1P receptors (S1PRs) signaling and SK1 and SK2 activity in both osteoblasts and chondrocytes. Fingolimod also reduced S1PR-induced activation by SpA patients' synovial fluid (SF), demonstrating that the stimulation of chondrocytes by SFs from SpA patients involves S1P. In addition, when the osteogenic culture medium was supplemented with fingolimod, alkaline phosphatase activity, matrix mineralization, and bone formation markers were significantly reduced in osteoblasts and hypertrophic chondrocytes. Osteogenic differentiation was accompanied by an increase in S1prs mRNA, especially S1P1/3 , but their contribution to S1P-impact on mineralization seemed limited. Our results suggest that S1P might be overproduced in SpA enthesis in response to cytokines and mechanical stress, most likely by chondrocytes. Moreover, S1P could locally favor the abnormal ossification of the enthesis; therefore, blocking the S1P metabolic pathway could be a potential therapeutic approach for the treatment of SpA. © 2019 American Society for Bone and Mineral Research.