Search

ObjectivesA European League Against Rheumatism taskforce was convened to review the literature and develop recommendations on lifestyle behaviours for rheumatic and musculoskeletal diseases (RMDs).MethodsSix lifestyle exposures (exercise, diet, weight, alcohol, smoking, work participation) and seven RMDs (osteoarthritis, rheumatoid arthritis, axial spondyloarthritis, psoriatic arthritis, systemic lupus erythematosus, systemic sclerosis, gout) were considered. The taskforce included health professionals in rheumatology, geriatricians, epidemiologists, public health experts, people with RMDs and exposure domain experts. Systematic reviews were conducted to gather available evidence, from which recommendations were developed.ResultsFive overarching principles and 18 specific recommendations were defined based on available evidence. The overarching principles define the importance of a healthy lifestyle, how lifestyle modifications should be implemented, and their role in relation to medical treatments. Exercise recommendations highlight the safety and benefits of exercise on pain and disability, particularly among people with osteoarthritis and axial spondyloarthritis. The diet recommendations emphasise the importance of a healthy, balanced diet for people with RMDs. People with RMDs and health professionals should work together to achieve and maintain a healthy weight. Small amounts of alcohol are unlikely to negatively affect the outcomes of people with RMDs, although people with rheumatoid arthritis and gout may be at risk of flares after moderate alcohol consumption. Smokers should be supported to quit. Work participation may have benefits on RMD outcomes and should be discussed in consultations.ConclusionsThese recommendations cover a range of lifestyle behaviours and can guide shared decision making between people with RMDs and health professionals when developing and monitoring treatment plans.

Objective To describe the development of an Environmental contextual factors (EF) Item Set (EFIS) accompanying the disease specific Assessment of SpondyloArthritis international Society Health Index (ASAS HI). Method First, a candidate item pool was developed by linking items from existing questionnaires to 13 EF previously selected for the International Classification of Functioning, Disability and Health (ICF) /ASAS Core Set. Second, using data from two international surveys, which contained the EF item pool as well as the items from the ASAS HI, the number of EF items was reduced based on the correlation between the item and the ASAS HI sum score combined with expert opinion. Third, the final English EFIS was translated into 15 languages and cross-culturally validated. Results The initial item pool contained 53 EF addressing four ICF EF chapters: products and technology (e1), support and relationship (e3), attitudes (e4) and health services (e5). Based on 1754 responses of axial spondyloarthritis patients in an international survey, 44 of 53 initial items were removed based on low correlations to the ASAS HI or redundancy combined with expert opinion. Nine items of the initial item pool (range correlation 0.21–0.49) form the final EFIS. The EFIS was translated into 15 languages and field tested in 24 countries. Conclusions An EFIS is available complementing the ASAS HI and helps to interpret the ASAS HI results by gaining an understanding of the interaction between a health condition and contextual factors. The EFIS emphasizes the importance of support and relationships, as well as attitudes of the patient and health services in relation to self-reported health.

Objectives To evaluate the extent to which internationally agreed treat-to-target recommendations were applied in clinical practice in patients with axial spondyloarthritis. Methods Data were used from a web-based patient registry for monitoring SpA in daily practice in the Netherlands. The extent to which treat-to-target was applied was evaluated through four indicators: the proportion of patients (i) with ≥1 Ankylosing Spondylitis Disease Activity Score (ASDAS) assessed during a 1-year period, (ii) having inactive disease/low disease activity (i.e. ASDAS Results In 185 out of 219 patients (84%), disease activity was monitored with ≥1 ASDAS during a 1-year period, of whom 71 (38%) patients had a score below the target (ASDAS Conclusions Treat-to-target was applied to a limited extent in clinical practice in patients with axial spondyloarthritis. Available disease activity scores seemed not to be used for determining the frequency of re-evaluation nor treatment adaptation.

To investigate, in daily clinical practice, TNF-α inhibitor serum trough levels in patients experiencing an increase in axial spondyloarthritis (ax-SpA) related symptoms. Secondly, to explore if these serum trough levels are associated with disease activity (DA) and/or change in DA.Patients from the GLAS cohort treated with TNF-α inhibitors who had a serum trough level measurement during follow-up because of an increase in ax-SpA related symptoms between June 2015 and June 2018 were included. Serum trough levels were stratified in a therapeutic and below therapeutic range, based on published reference values of Sanquin in 2019. DA was assessed by ASDAS and BASDAI and change in DA (i.e. ΔASDAS or BASDAI compared to the visit before increasing symptoms).31 patients had a serum trough level measurement because of increasing symptoms. These patients had a median treatment duration of 4.8 years (IQR 0.9-8.6). 22 (71%) had active disease according to ASDAS (score ≥2.1) and 15 (47%) had therapeutic drug levels. The increase in DA was significantly larger in patients with below therapeutic drug levels compared to patients with therapeutic levels (ΔASDAS: 0.94±0.81 vs. -0.07±1.26, p0.05; ΔBASDAI: 1.72±1.73 vs. -0.53±1.8, p0.005). No significant differences were found in absolute DA scores between patients with or without therapeutic drug levels.In this observational study in daily clinical practice, approximately half of ax-SpA patients who experienced an increase in symptoms had below therapeutic TNF-α inhibitor serum trough levels. Change in DA and not absolute DA scores was significantly associated with drug levels.

ObjectiveTo investigate concurrent validity and discrimination of the Disease Activity Index for Psoriatic Arthritis (DAPSA) score, Psoriatic Arthritis Disease Activity Score (PASDAS), and Ankylosing Spondylitis Disease Activity Score (ASDAS) in peripheral spondyloarthritis (pSpA) in clinical practice.MethodsData from a Dutch registry for SpA (SpA-Net) were used. Predefined hypotheses on concurrent validity of the composite measures with 15 other outcome measures of disease activity, physical function, and health-related quality of life were tested. Concurrent validity was considered acceptable if ≥ 75% of the hypotheses were confirmed. Discrimination was assessed by stratifying patients in DAPSA, PASDAS, and ASDAS predefined disease activity states and studying mean differences in health outcomes by 1-way ANOVA. Further, the concordance in disease activity states was determined. All analyses were repeated in subgroups with and without psoriasis (PsO).ResultsDAPSA, PASDAS, and ASDAS scores were available for 191, 139, and 279 patients with pSpA, respectively. The concurrent validity and discrimination of all composite measures were acceptable, as the strength of correlations were as hypothesized in ≥ 75% of the studied correlations. With increasing disease activity states, scores in nearly all outcome measures worsened significantly. The DAPSA, PASDAS, and ASDAS classified 22%, 56%, and 48% of the patients, respectively, in the 2 highest disease activity states. Stratified analyses for concomitant PsO revealed no relevant subgroup differences.ConclusionThe performance of DAPSA, PASDAS, and ASDAS in pSpA was acceptable, and independent of concomitant PsO. Due to discrepancy in classification, the validity of existing thresholds for disease activity states warrants further study in pSpA.

IntroductionThere is an unmet need for biomarkers to identify patients with axial spondyloarthritis (axSpA). Increasing evidence suggest the presence of autoantibodies in a subset of axSpA patients. The aim of this study was to identify novel IgA antibodies in early axSpA patients and to determine their diagnostic potential in combination with previously determined IgG antibodies against UH (Hasselt University)-axSpA-IgG antigens. MethodsAn axSpA cDNA phage display library constructed from axSpA hip synovium, was used to screen for novel IgA antibodies in plasma from early axSpA patients. The presence of these antibodies against novel UH-axSpA-IgA antigens was determined in two independent axSpA cohorts, in healthy controls and in patients with chronic low back pain. ResultsWe identified antibodies to 7 novel UH-axSpA-IgA antigens, of which 6 correspond to non-physiological peptides and 1 to the human histone deacetylase 3 (HDAC3) protein. IgA antibodies against 2 of these 7 novel UH-axSpA-IgA antigens and IgG antibodies against 2 of the previously identified antigens were significantly more present in early axSpA patients from the UH cohort (18/70, 25.7%) and the (Bio)SPAR cohort (26/164, 15.9%), compared to controls with chronic low back pain (2/66, 3%). Antibodies to this panel of 4 antigens were present in 21.1% (30/142) of patients with early axSpA from the UH and (Bio)SPAR cohorts. The positive likelihood ratio for confirming early axSpA using antibodies to these 4 UH-axSpA antigens was 7.0. So far, no clinical correlation between the novel identified IgA antibodies and inflammatory bowel disease could be identified. DiscussionIn conclusion, screening an axSpA cDNA phage display library for IgA reactivity resulted in the identification of 7 novel UH-axSpA-IgA antigens, of which 2 show promising biomarker potential for the diagnosis of a subset of axSpA patients, in combination with previously identified UH-axSpA-IgG antigens. This study was supported by a grant from the Agency for Innovation by Science and Technology We thank the University Biobank Limburg and the Biobank of University Hospitals Leuven for providing the tissue samples, plasma/serum samples, and clinical characteristics of axial SpA patients and controls; Igna Rutten and Josianne Bleus (UHasselt, Biomedical Research Institute, Department of Immunology and Infection) for their excellent technical support.

Objective: To assess the benefits and harms associated with biopsychosocial rehabilitation in patients with inflammatory arthritis and osteoarthritis (OA). Methods: We performed a systematic review and meta-analysis. Data were collected through electronic searches of Cochrane CENTRAL, MEDLINE, Embase, PsycInfo, and CINAHL databases up to March 2019. Trials examining the effect of biopsychosocial rehabilitation in adults with inflammatory arthritis and/or OA were considered eligible, excluding rehabilitation adjunct to surgery. The primary outcome for benefit was pain and total withdrawals for harm. Results: Of the 27 trials meeting the eligibility criteria, 22 trials (3,750 participants) reported sufficient data to be included in the quantitative synthesis. For patient-reported outcome measures, biopsychosocial rehabilitation was slightly superior to control for pain relief (standardized mean difference [SMD] −0.19 [95% confidence interval (95% CI) −0.31, –0.07]), had a small effect on patient global assessment score (SMD –0.13 [95% CI –0.26, –0.00]), with no apparent effect on health-related quality of life, fatigue, self-reported disability/physical function, mental well-being, and reduction in pain intensity ≥30%. Clinician-measured outcomes displayed a small effect on observed disability/physical function (SMD −0.34 [95% CI −0.57, −0.10]), a large effect on physician global assessment score (SMD −0.72 [95% CI −1.18, −0.26]), and no effect on inflammation. No difference in harms existed in terms of the number of withdrawals, adverse events, or serious adverse events. Conclusion: Biopsychosocial rehabilitation produces a significant but clinically small beneficial effect on patient-reported pain among patients with inflammatory arthritis and OA, with no difference in harm. Methodologic weaknesses were observed in the included trials, suggesting low-to-moderate confidence in the estimates of effect.

Objective: To assess the benefits and harms associated with biopsychosocial rehabilitation in patients with inflammatory arthritis and osteoarthritis (OA). Methods: We performed a systematic review and meta-analysis. Data were collected through electronic searches of Cochrane CENTRAL, MEDLINE, Embase, PsycInfo, and CINAHL databases up to March 2019. Trials examining the effect of biopsychosocial rehabilitation in adults with inflammatory arthritis and/or OA were considered eligible, excluding rehabilitation adjunct to surgery. The primary outcome for benefit was pain and total withdrawals for harm. Results: Of the 27 trials meeting the eligibility criteria, 22 trials (3,750 participants) reported sufficient data to be included in the quantitative synthesis. For patient-reported outcome measures, biopsychosocial rehabilitation was slightly superior to control for pain relief (standardized mean difference [SMD] −0.19 [95% confidence interval (95% CI) −0.31, –0.07]), had a small effect on patient global assessment score (SMD –0.13 [95% CI –0.26, –0.00]), with no apparent effect on health-related quality of life, fatigue, self-reported disability/physical function, mental well-being, and reduction in pain intensity ≥30%. Clinician-measured outcomes displayed a small effect on observed disability/physical function (SMD −0.34 [95% CI −0.57, −0.10]), a large effect on physician global assessment score (SMD −0.72 [95% CI −1.18, −0.26]), and no effect on inflammation. No difference in harms existed in terms of the number of withdrawals, adverse events, or serious adverse events. Conclusion: Biopsychosocial rehabilitation produces a significant but clinically small beneficial effect on patient-reported pain among patients with inflammatory arthritis and OA, with no difference in harm. Methodologic weaknesses were observed in the included trials, suggesting low-to-moderate confidence in the estimates of effect.

© 2022 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.Aim: Nail involvement is common in psoriatic arthritis. This study assesses clinical characteristics, nail psoriasis prevalence, and impact of nail psoriasis on disease activity in patients with psoriatic arthritis (PsA). Method: This cross-sectional multicenter study was conducted by the Turkish League Against Rheumatism using PsA patients recruited from 25 centers. Demographic and clinical characteristics of PsA patients, such as disease activity measures, quality of life, and nail involvement findings were assessed during routine follow-up examinations. Patients were divided into two groups according to the presence or absence of nail psoriasis and compared using the χ2 test or Fisher exact test for categorical variables and the t-test or Mann-Whitney U test for continuous variables. Results: In 1122 individuals with PsA, 645 (57.5%) displayed nail psoriasis. The most frequent features of fingernails were ridges (38%), followed by pitting (21%) and onycholysis (19%). More females were present in both groups (with and without nail psoriasis; 64% vs 67%, P < 0.282). Patients with nail psoriasis were older, indicated more pain and fatigue, experienced greater swelling, tender joint counts, and skin disease severity, and had a higher disease activity score compared with those without nail psoriasis (all P < 0.05). Conclusion: We demonstrate an increased prevalence of nail psoriasis observed in patients with psoriatic arthritis. Patients with nail involvement experience increased disease activity, lower quality of life, and diminished mental and physical status compared with those without nail involvement.

ObjectiveAdvances in the field of axial spondyloarthritis (axSpA) and the methodology to develop core sets have led the Assessment of SpondyloArthritis international Society (ASAS) group to update the ASAS–Outcomes in Rheumatology (OMERACT) core set. An important aspect was to ensure it would be applicable to the entire spectrum of axSpA. The first step was to define the most relevant disease domains.MethodsA 3-round Delphi survey was conducted to gather opinions of 188 patients and 188 axSpA experts to define the most relevant disease domains to be included in the core set. The Delphi survey evaluated 2 separate research settings: (1) studies assessing symptom-modifying therapies; and (2) studies evaluating disease-modifying therapies. Importance of the domains was rated on a 1–9 Likert scale. A domain was considered for inclusion if, for both stakeholder groups, ≥ 70% of participants scored the domain as critical (7–9) and ≤ 15% scored it as not important (1–3) after 3 rounds.ResultsA total of 132 (70%) patients and 135 (72%) experts completed at least 1 round. After 3 rounds, 7 domains (pain, physical function, stiffness, disease activity, mobility, overall functioning and health, peripheral manifestations) were selected for the symptom-modifying therapies setting. For the disease-modifying therapies setting, 6 domains (physical function, disease activity, mobility, structural damage, extramusculoskeletal manifestations, peripheral manifestations) were selected. All domains selected by experts were also selected by patients. Patients selected all offered domains except emotional function.ConclusionThis study provides the domains selected by patients and axSpA experts that should be considered for the core set for axSpA.

BACKGROUND: The current core outcome set for ankylosing spondylitis (AS) has had only minor adaptations since its development 20 years ago. Considering the significant advances in this field during the preceding decades, an update of this core set is necessary.OBJECTIVE: To update the ASAS-OMERACT core outcome set for AS into the ASAS-OMERACT core outcome set for axial spondyloarthritis (axSpA).METHODS: Following OMERACT and COMET guidelines, an international working group representing key stakeholders (patients, rheumatologists, health professionals, pharmaceutical industry and drug regulatory agency representatives) defined the core domain set for axSpA. The development process consisted of: i) Identifying candidate domains using a systematic literature review and qualitative studies; ii) Selection of the most relevant domains for different stakeholders through a 3-round Delphi survey involving axSpA patients and axSpA experts; iii) Consensus and voting by ASAS; iv) Endorsement by OMERACT. Two scenarios are considered based on the type of therapy investigated in the trial: symptom modifying therapies and disease modifying therapies.RESULTS: The updated core outcome set for axSpA includes 7 mandatory domains for all trials (disease activity, pain, morning stiffness, fatigue, physical function, overall functioning and health, and adverse events including death). There are 3 additional domains (extra-musculoskeletal manifestations, peripheral manifestations and structural damage) that are mandatory for disease modifying therapies and important but optional for symptom modifying therapies. Finally, 3 other domains (spinal mobility, sleep, and work and employment) are defined as important but optional domains for all trials.CONCLUSION: The ASAS-OMERACT core domain set for AS has been updated into the ASAS-OMERACT core domain set for axSpA. The next step is the selection of instruments for each domain.

Objectives To compare the benefits of a tight-control/treat-to-target strategy (TC/T2T) in axial spondyloarthritis (axSpA) with those of usual care (UC).Methods Pragmatic, prospective, cluster-randomised, controlled, open, 1-year trial (NCT03043846). 18 centres were randomised (1:1). Patients met Axial Spondylo Arthritis International Society (ASAS) criteria for axSpA, had an Ankylosing Spondylitis Disease Activity Score (ASDAS) >= 2.1, received non-optimal treatment by non-steroidal anti-inflammatory drugs and were biologic-naive.Interventions (1) TC/T2T: visits every 4 weeks and prespecified strategy based on treatment intensification until achieving target (ie, ASDAS = 30% improvement on the ASAS-Health Index (ASAS-HI). Other efficacy outcomes and adverse events were recorded. A health economic evaluation was performed.Statistical analysis Two-level mixed models were used to estimate efficacy outcomes. Cost-effectiveness was assessed by the incremental cost per quality-adjusted life-year (QALY) gained for TC/T2T versus UC.Results 160 patients were included (80/group). Mean (SD) age was 37.9 (11.0) years and disease duration was 3.7 (6.2) years; 51.2% were men. ASDAS at inclusion was 3.0 (0.7), and ASAS-HI was 8.6 (3.7). ASAS-HI improved by >= 30% in 47.3% of the TC/T2T arm and in 36.1% of those receiving UC (non-significant). All secondary efficacy outcomes were more frequent in the TC/T2T arm, although not all statistically significant. Safety was similar in both arms. From a societal perspective, TC/T2T resulted in an additional 0.04 QALY, and saved euro472 compared with UC.Conclusion TC/T2T was not significantly superior to UC for the primary outcome, while many secondary efficacy outcomes favoured it, had a similar safety profile and was favourable from a societal health economic perspective.

Objectives: In patients with axial spondyloarthritis (axSpA) initiating their first tumor necrosis factor alpha-inhibitor (TNFi), we aimed to identify common baseline predictors of Ankylosing Spondylitis Disease Activity Score (ASDAS-CRP) inactive disease (primary objective) and clinically important improvement (CII) at 6 months, and drug retention at 12-months across 15 European registries. Methods: Baseline demographic and clinical characteristics were collected. Outcomes were investigated per registry and in pooled data using logistic regression analyses on multiply imputed data. Results: The consistency of baseline predictors in individual registries justified pooling the data. In the pooled dataset (n = 21,196), the 6-month rates for ASDAS inactive disease and ASDAS CII were 26% and 51%, and the 12-month drug retention rate 65% in patients with available data (n = 9,845, n = 6,948 and n = 21,196, respectively). Nine common baseline predictors of ASDAS inactive disease, ASDAS CII and 12-month drug retention were identified, and the odds ratios (95%-confidence interval) for ASDAS inactive disease were: age, per year: 0.97 (0.97–0.98), men vs. women: 1.88 (1.60–2.22), current vs. non-smoking: 0.76 (0.63–0.91), HLA-B27 positive vs. negative: 1.51 (1.20–1.91), TNF start year 2015–2018 vs. 2009–2014: 1.24 (1.06–1.45), CRP>10 vs. ≤10 mg/l: 1.49 (1.25–1.77), one unit increase in health assessment questionnaire (HAQ): 0.77 (0.58–1.03), one-millimeter (mm) increase in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) fatigue and spinal pain: 0.99 (0.99–1.00) and 0.99 (0.99–1.99), respectively Conclusion: Common baseline predictors of treatment response and adherence to TNFi could be identified across data from 15 European registries, indicating that they may be universal across different axSpA populations.

ObjectivesThe objective of COAST-Y was to evaluate the effect of continuing versus withdrawing ixekizumab (IXE) in patients with axial spondyloarthritis (axSpA) who had achieved remission.MethodsCOAST-Y is an ongoing, phase III, long-term extension study that included a double-blind, placebo (PBO)-controlled, randomised withdrawal-retreatment period (RWRP). Patients who completed the originating 52-week COAST-V, COAST-W or COAST-X studies entered a 24-week lead-in period and continued either 80 mg IXE every 2 (Q2W) or 4 weeks (Q4W). Patients who achieved remission (an Ankylosing Spondylitis Disease Activity Score (ASDAS)3.5 at any visit) after the 40-week RWRP, with time-to-flare as a major secondary endpoint.ResultsOf 773 enrolled patients, 741 completed the 24-week lead-in period and 155 entered the RWRP. Forty weeks after randomised withdrawal, 83.3% of patients in the combined IXE (85/102, pConclusionsPatients with axSpA who continued treatment with IXE were significantly less likely to flare and had significantly delayed time-to-flare compared with patients who withdrew to PBO.

Objectives: To investigate growth differentiation factor-15 (GDF-15) levels and the thickness of epicardial adipose tissue (EAT) in patients with axial spondyloarthritis (axSpA) and to evaluate their relationship with functional status, disease activity, disease duration, and the type of medical treatment received by the patients.Methods: This cross-sectional study was carried out at Kirsehir Ahievran University School of Medicine between February and June 2020. Twenty-nine healthy controls and 44 patients with axSpA were included in the study. Gender, age, erythrocyte sedimentation rate, GDF-15, body mass index, complete blood count, ejection fraction, the EAT thickness, and C-reactive protein of all participants were recorded. Ankylosing Spondylitis Quality of Life Index, Bath Ankylosing Spondylitis Functional Index, the disease duration, Bath Ankylosing Spondylitis Metrology Index, and Bath Ankylosing Spondylitis Disease Activity Index scores of patients with axSpA were noted.Results: Epicardial adipose tissue thickness values (0.35 +/- 0.09 cm) in the AxSpA group were higher compared to the control group (0.26 +/- 0.06 cm) (p

Objectives: This study aims to investigate the effects of fluoroscopy-guided sacroiliac joint steroid injection in patients with acute bilateral sacroiliitis diagnosed with axial spondyloarthritis (axSpA) and how those injections affect the current need for nonsteroidal anti-inflammatory drug (NSAID) usage. Patients and methods: We retrospectively evaluated 43 patients (28 males, 15 females; mean age, 31.7 +/- 6.3 years; range, 18 to 44 years) fulfilling the Assessment of SpondyloArthritis international Society 2009 criteria for axSpA between June 2015 and May 2016. One group included 22 patients (injection group) treated with sacroiliac joint steroid injection (triamcinolone acetonide) and the other group included 21 patients (non-injection group) not receiving the injection. All 43 patients in both groups were treated with indomethacin peroral. Pre-treatment, first week and first, third and sixth month follow-up examinations were evaluated. Results: A >= 50% reduction in the numeric rating scale score compared with the baseline was considered as significant pain relief. The mean pain relief rates in patients receiving injections were higher at all inspections. This difference was statistically significant at first week (p0.05). There was no statistically significant difference between the two groups when indomethacin dose was evaluated cumulatively for six months (p>0.05). Conclusion: Fluoroscopy-guided sacroiliac joint steroid injections can be recommended in patients with active sacroiliitis, particularly in those with severe axial pain, for rapid analgesia in the initial term. It was concluded that steroid injections applied to the sacroiliac joint did not affect disease activity. It is noteworthy that there is a trend to reduce the use of NSAIDs in patients receiving these injections, although it does not make a statistically significant difference in the long term.

The objectives of this review were to collect and summarise evidence on therapeutic drug monitoring (TDM) of biopharmaceuticals in inflammatory rheumatic and musculoskeletal diseases and to inform the EULAR Task Force for the formulation of evidence-based points to consider. A systematic literature review (SLR) was performed, covering technical aspects and (clinical) utility of TDM, to answer 13 research questions. MEDLINE, Embase and Cochrane were searched until July 2020. American College of Rheumatology and EULAR abstracts were also considered for inclusion. Data were extracted in evidence tables and risk of bias assessment was performed. For the search on technical aspects, 678 records were identified, of which 22 papers were selected. For the clinical utility search, 3846 records were identified, of which 108 papers were included. Patient-related factors associated with biopharmaceutical blood concentrations included body weight, methotrexate comedication and disease activity. The identification of a target range was hampered by study variability, mainly disease activity measures and study type. Evidence was inconsistent for multiple clinical situations in which TDM is currently applied. However, for some particular scenarios, including prediction of future treatment response, non-response to treatment, tapering and hypersensitivity reactions, robust evidence was found. There is currently no evidence for routine use of proactive TDM, in part because published cost-effectiveness analyses do not incorporate the current landscape of biopharmaceutical costs and usage. This SLR yields evidence in favour of TDM of biopharmaceuticals in some clinical scenarios, but evidence is insufficient to support implementation of routine use of TDM.

The objectives of this review were to collect and summarise evidence on therapeutic drug monitoring (TDM) of biopharmaceuticals in inflammatory rheumatic and musculoskeletal diseases and to inform the EULAR Task Force for the formulation of evidence-based points to consider. A systematic literature review (SLR) was performed, covering technical aspects and (clinical) utility of TDM, to answer 13 research questions. MEDLINE, Embase and Cochrane were searched until July 2020. American College of Rheumatology and EULAR abstracts were also considered for inclusion. Data were extracted in evidence tables and risk of bias assessment was performed. For the search on technical aspects, 678 records were identified, of which 22 papers were selected. For the clinical utility search, 3846 records were identified, of which 108 papers were included. Patient-related factors associated with biopharmaceutical blood concentrations included body weight, methotrexate comedication and disease activity. The identification of a target range was hampered by study variability, mainly disease activity measures and study type. Evidence was inconsistent for multiple clinical situations in which TDM is currently applied. However, for some particular scenarios, including prediction of future treatment response, non-response to treatment, tapering and hypersensitivity reactions, robust evidence was found. There is currently no evidence for routine use of proactive TDM, in part because published cost-effectiveness analyses do not incorporate the current landscape of biopharmaceutical costs and usage. This SLR yields evidence in favour of TDM of biopharmaceuticals in some clinical scenarios, but evidence is insufficient to support implementation of routine use of TDM.

OBJECTIVES: Assess baseline characteristics and treatment response to ixekizumab (IXE) categorised by sex in patients with radiographic axial spondyloarthritis (r-axSpA) and non-radiographic axSpA (nr-axSpA) up to 52 weeks. METHODS: Data were analysed from three randomised controlled trials of IXE through 52 weeks. Patients fulfilled ASAS classification criteria for r-axSpA or nr-axSpA and were randomised to receive 80 mg subcutaneous administration of IXE every 2 weeks (Q2W) or 4 weeks (Q4W), or placebo (16 weeks COAST-V/W; 52 weeks COAST-X). Baseline characteristics and treatment outcomes were assessed. Patients were categorised by sex; methods included non-responder imputation for categorical variables, and modified baseline observation carried forward for continuous efficacy variables. RESULTS: At presentation, female patients had higher disease burden as reflected by significantly higher spinal pain at night, fatigue scores and pain/swelling in joints other than the neck, back or hip. ASAS40 response rate with the approved label dose, IXEQ4W, was achieved in 39% of male patients with r-axSpA by week 16, and 44% by week 52. For female patients, 16.7% and 33.3% achieved ASAS40 at week 16 and 52, respectively. In nr-axSpA, 46% of male patients achieved ASAS40 at week 16 and 30% at week 52. In total, 23.9% of female patients achieved ASAS40 at week 16, and 30.4% at week 52. CONCLUSIONS: This analysis demonstrates that for the axSpA disease spectrum, female patients present with higher disease burden. Following treatment with IXE, there is a higher proportion of male responders up to 16 weeks, while female patients show less robust responses for the first 16 weeks but larger responses from weeks 16 through 52. TRIAL REGISTRATION NUMBERS: NCT02696785, NCT02696798 and NCT02757352. ispartof: ADVANCES IN THERAPY vol:39 issue:6 pages:2806-2819 ispartof: location:United States status: published

Background: The long-term use of anti-TNF-α agents can lead to adverse effects, such as infections and immune-mediated cutaneous reactions. Whether de-escalation by dose reduction or interval lengthening reduces these adverse effects is uncertain. This systematic review aims to compare the incidence of infections and skin manifestations after anti-TNF-α dose de-escalation with standard dosing. Methods: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from inception to 14 January 2022. Randomized controlled trials (RCTs) and observational studies comparing anti-TNF-α de-escalation strategies with standard dosing among patients with inflammatory conditions, that report on infections, skin manifestations, or both, were included. The risk of bias was assessed with the revised Cochrane risk-of bias tool (RCTs) or the Newcastle–Ottawa scale (non-RCTs). Results: Fourteen RCTs and six observational studies (or 2706 patients) were included. Eight RCTs had low risk of bias or some concerns. Four non-RCTs were of good methodological quality. The studies described patients with axial spondyloarthritis (8 studies, 780 patients), rheumatoid arthritis (7 studies, 1458 patients), psoriasis (3 studies, 332 patients), or inflammatory bowel disease (2 studies, 136 patients). De-escalation strategies included interval lengthening (12 studies, 1317 patients), dose reduction (6 studies, 1130 patients), or both (2 studies, 259 patients). Overall, the occurrence of infections and skin manifestations did not differ between standard treatment and de-escalation. The disappearance of infections or skin manifestations after de-escalation was only reported in two studies. The majority of studies focused on etanercept and adalimumab. Heterogeneity in reporting of infections and skin manifestations precluded meta-analysis. Conclusion: We found that anti-TNF-α de-escalation does not reduce infections or skin reactions. A de-escalation strategy should not be recommended for the sole purpose of reducing drug-related adverse effects. The meticulous documentation of adverse effects is recommended to further address this question. Registration: PROSPERO CRD42021252977.

Background: The long-term use of anti-TNF-alpha agents can lead to adverse effects, such as infections and immune-mediated cutaneous reactions. Whether de-escalation by dose reduction or interval lengthening reduces these adverse effects is uncertain. This systematic review aims to compare the incidence of infections and skin manifestations after anti-TNF-alpha dose de-escalation with standard dosing. Methods: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from inception to January 14, 2022. Randomized controlled trials (RCTs) and observational studies comparing anti-TNF-alpha-de-escalation strategies with standard dosing among patients with inflammatory conditions, that report on infections, skin manifestations, or both, were included. The risk of bias was assessed with the revised Cochrane risk-of bias tool (RCTs) or the Newcastle-Ottawa scale (non-RCTs). Results: Fourteen RCTs and six observational studies (or 2706 patients) were included. Eight RCTs had low risk of bias or some concerns. Four non-RCTs were of good methodological quality. The studies described patients with axial spondyloarthritis (8 studies, 780 patients), rheumatoid arthritis (7 studies, 1458 patients), psoriasis (3 studies, 332 patients), or inflammatory bowel disease (2 studies, 136 patients). De-escalation strategies included interval lengthening (12 studies, 1317 patients), dose reduction (6 studies, 1130 patients), or both (2 studies, 259 patients). Overall, the occurrence of infections and skin manifestations did not differ between standard treatment and de-escalation. The disappearance of infections or skin manifestations after de-escalation was only reported in two studies. The majority of studies focused on etanercept and adalimumab. Heterogeneity in reporting of infections and skin manifestations precluded metaanalysis. Conclusion: We found that anti-TNF-alpha de-escalation does not reduce infections or skin reactions. A de-escalation strategy should not be recommended for the sole purpose of reducing drug-related adverse effects. The meticulous documentation of adverse effects is recommended to further address this question.

OBJECTIVE: This study was undertaken to identify novel autoantibodies in axial spondyloarthritis (SpA) and determine their diagnostic potential in patients with early axial SpA and controls from 2 independent cohorts. METHODS: An axial SpA complementary DNA phage display library was used to screen for novel IgG antibodies in plasma from patients with early axial SpA. The presence of these antibodies against novel peptides (i.e., peptides identified in an early axial SpA cohort from Hasselt University, designated UH-axSpA) was determined by enzyme-linked immunosorbent assay in 76 patients with early axial SpA, 75 controls with nonspecific chronic low back pain, 60 patients with rheumatoid arthritis, and 94 healthy controls from the UH cohort. Antibody reactivity to these novel peptides was further validated in 174 patients with axial SpA (of whom 79 had early axial SpA) from the University Hospitals Leuven (Bio)SPAR (Spondyloarthritis [Biologics]) cohort. RESULTS: We identified antibodies to 9 novel UH-axSpA peptides, corresponding to randomly formed peptides and to a novel axial SpA autoantigen, double homeobox protein 4. Antibodies to 3 UH-axSpA peptides with the highest positive likelihood ratio (LR) for a diagnosis of axial SpA were present in significantly more patients with early axial SpA from the UH and (Bio)SPAR cohorts (14.2% [22/155]) compared to controls with chronic low back pain (5% [4/75]), resulting in 95% specificity. The positive LR for confirming axial SpA using antibodies to these 3 UH-axSpA peptides was 2.7, which is higher than the LR obtained with the currently used laboratory marker C-reactive protein. Testing for antibodies to these 3 UH-axSpA peptides in patients with chronic low back pain increased the posttest probability of a diagnosis of axial SpA from 79% to 91%. CONCLUSION: Antibodies to 3 UH-axSpA peptides could provide a novel tool in the diagnosis of a subset of axial SpA patients. ispartof: ARTHRITIS & RHEUMATOLOGY vol:72 issue:12 pages:2094-2105 ispartof: location:United States status: published

The most prevalent health concerns in patients with axial spondyloarthritis (axSpA) include spinal stiffness, spinal pain, mobility limitations, fatigue, and disturbed sleep. Many patients experience impairments related to extraspinal disease, extra-articular disease, or drug side effects. To capture overall life impact, self-reported measurement instruments assessing health-related quality of life (HRQoL) have been developed. This article summarizes the literature on relevant concepts and frameworks when measuring overall health or HRQoL, available measures assessing this outcome in axSpA, the hierarchical relations between overall health/ HRQoL and specific axSpA impairments, and the role of context when interpreting interventions for overall health or HRQoL outcomes.

Objectives To systematically review the impact of tapering targeted therapies (bDMARDs or JAKis) on the risk of serious infections and severe adverse events (SAEs) in patients with rheumatoid arthritis (RA) or axial spondyloarthritis (axSpA) in remission or low disease activity (LDA) state. Materials and methods A meta-analysis based on a systematic review of PubMed, Embase, Cochrane, until August 2019, as well as relevant databases of international conferences, was used to evaluate the risk difference (RD) at 95% confidence interval (95% CI) of incidence density of serious infections, SAEs, malignancies, cardiovascular adverse events (CV AEs), or deaths after tapering (dose reduction or spacing) compared to continuation of targeted therapies. Results Of the 1957 studies initially identified, 13 controlled trials (9 RA and 4 SpA trials) were included in the meta-analysis. 1174 patient-years were studied in the tapering group (TG) versus 1086 in the usual care group (UC). There were 1.7/100 patient-year (p-y) serious infections in TG versus 2.6/100 p-y in UC (RD (95% CI) 0.01 (0.00 to 0.02), p = 0.13) and 7.4/100 p-y SAEs in TG versus 6.7/100 p-y in UC (RD 0.00 (− 0.02 to 0.02), p = 0.82). The risk of malignancies, CV AEs, or deaths did not differ between the tapering and the usual care groups. Subgroup analysis (RA and SpA) detected no significant differences between the two groups. Conclusion We could not show significant impact of tapering bDMARD or JAKi over continuation concerning the risk of serious infections, SAEs, malignancies, CV AEs, or deaths in RA and SpA patients in remission or LDA state.

Objective To evaluate the effect of ixekizumab on self-reported functioning and health in patients with active nonradiographic axial spondyloarthritis (SpA). Methods COAST-X was a randomized, controlled trial conducted in patients with nonradiographic axial SpA over 52 weeks. Participants were randomized at a ratio of 1:1:1 to receive 80 mg of ixekizumab subcutaneously every 4 weeks or 2 weeks or placebo for 52 weeks. Self-reported functioning and health end points included the Medical Outcomes Study Short Form 36 (SF-36) health survey, Assessment of Spondyloarthritis International Society (ASAS) health index, and European Quality of Life-5 Dimensions-5 Level (EQ-5D-5L) health-utility descriptive system. Results Compared to placebo, ixekizumab treatment resulted in improvement of SF-36 physical component summary scores from baseline, with a score of 4.7 improving to 8.9 with ixekizumab therapy every 4 weeks (P < 0.05) and a score of 9.3 with ixekizumab therapy every 2 weeks (P < 0.01); the greatest improvements were observed in the domains of physical functioning, role-physical, and bodily pain at weeks 16 and 52. A higher proportion of patients receiving ixekizumab therapy every 2 weeks reported >= 3 improvements based on the ASAS health index from baseline to weeks 16 and 52 (P < 0.05). Significantly more patients receiving ixekizumab every 4 weeks reported improvements in "good health status" on the ASAS health index (ASAS score of

Human expansion in the course of the Neolithic transition in western Eurasia has been one of the major topics in ancient DNA research in the last 10 years. Multiple studies have shown that the spread of agriculture and animal husbandry from the Near East across Europe was accompanied by large-scale human expansions. Moreover, changes in subsistence and migration associated with the Neolithic transition have been hypothesized to involve genetic adaptation. Here, we present high quality genome-wide data from the Linear Pottery Culture site Derenburg-Meerenstieg II (DER) (N = 32 individuals) in Central Germany. Population genetic analyses show that the DER individuals carried predominantly Anatolian Neolithic-like ancestry and a very limited degree of local hunter-gatherer admixture, similar to other early European farmers. Increasing the Linear Pottery culture cohort size to ∼100 individuals allowed us to perform various frequency- and haplotype-based analyses to investigate signatures of selection associated with changes following the adoption of the Neolithic lifestyle. In addition, we developed a new method called Admixture-informed Maximum-likelihood Estimation for Selection Scans that allowed us test for selection signatures in an admixture-aware fashion. Focusing on the intersection of results from these selection scans, we identified various loci associated with immune function (JAK1, HLA-DQB1) and metabolism (LMF1, LEPR, SORBS1), as well as skin color (SLC24A5, CD82) and folate synthesis (MTHFR, NBPF3). Our findings shed light on the evolutionary pressures, such as infectious disease and changing diet, that were faced by the early farmers of Western Eurasia. Introduction New Approaches Results and discussion - Data generation and authentication. - Genome-wide data analysis. - Uniparentally inherited markers. - Biological Relatedness. - LBK inter-site comparisons. - Phenotypic analysis. - HLA class-I and II allele analysis. - Selection Scans Conclusions Material and methods - Archaeological background/site description. - Sample preparation. - Genotyping. - F-statistics - Biological Relatedness and ROH Analyses. - Mitochondrial and Y haplotype analysis. - Shotgun data. - HLA typing. - Selection scans. - AIMLESS Admixture-Informed Maximum-Likelihood Estimation for Selection Scans. - Haplotype-based scan.

Spondyloarthritis is a group of chronic inflammatory diseases that primarily affects axial or peripheral joints and is frequently associated with inflammation at non-articular sites. The disease is multifactorial, involving genetics, immunity and environmental factors, including the gut microbiota. In vivo, microbiome contributions are difficult to assess due to the multifactorial disease complexity. In a proof-of-concept approach, we therefore used a triple coculture model of immune-like, goblet and epithelial cells to investigate whether we could detect a differential impact from spondyloarthritis- vs. healthy-derived gut microbiota on host cell response. Despite their phylogenetic resemblance, flow cytometry-based phenotypic clustering revealed human-derived gut microbiota from healthy origin to cluster together and apart from spondyloarthritis donors. At host level, mucus production was higher upon exposure to healthy microbiota. Pro-inflammatory cytokine responses displayed more inter-individual variability in spondyloarthritis than in healthy donors. Interestingly, the high dominance in the initial sample of one patient of Prevotella, a genus previously linked to spondyloarthritis, resulted in the most differential host response upon 16 h host-microbe coincubation. While future research should further focus on inter-individual variability by using gut microbiota from a large cohort of patients, this study underscores the importance of the gut microbiota during the SpA disease course.

Objectives Factors associated with disease activity of axial spondyloarthritis (axSpA) and switching of biologic diseasemodifying anti-rheumatic drugs have not been clearly defned. We aimed to evaluate clinical characteristics of patients with axSpA, factors related to remission in treat to target era and predictive factors for biologic disease-modifying anti-rheumatic drug switching. Method A multicenter, observational cross-sectional study was performed between February 2019 and August 2019. We included all consecutive patients≥18 years with axSpA. Demographic and clinical variables were prospectively recorded. Clinical tools included Ankylosing Spondylitis Disease Activity Score with C-reactive protein (ASDAS-CRP), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Metrology Index (BASMI), and Maastricht Ankylosing Spondylitis Enthesitis Score (MASES). Results There were 969 patients with a mean age of 43.4±10.8 years. There were 143 patients (14.8%) with remission and 223 (23.1%) patients with low disease activity. Male sex (p=0.021), positive family history (p=0.036), and human leukocyte antigen-B27 (p=0.011) were predictors of remission by ASDAS-CRP. There were 654 patients (67.5%) who did not switch to another drug. The highest BASMI and MASES scores were calculated in patients with very high disease activity (p

Objective: To investigate the associations between complement C3d and inflammatory and structural changes by magnetic resonance imaging (MRI) at the sacroiliac joints (SIJ) suggestive of axial spondyloarthritis, according to the Assessment of SpondyloArthritis international Society (ASAS) criteria, in patients with low back pain.Method: This was a cross-sectional study of patients referred to the Spine Centre of Southern Denmark owing to unspecified low back pain (Spines of Southern Denmark cohort). The patients were divided into three groups: group 1: patients fulfilling the ASAS criteria for axial spondyloarthritis (axSpA, n = 96); group 2: patients with either a positive MRI of the SIJ and no spondyloarthritis features, or a negative MRI of the SIJ but positive human leucocyte antigen-B27 and one spondyloarthritis feature (non-axSpA, n = 38); group 3: patients with unspecified low back pain for > 3 months (control group, n = 82). Complement C3d was measured with double-decker rocket immunoelectrophoresis and evaluated in relation to the group division and baseline findings by SIJ MRI.Results: In total, 184 C3d analyses were performed. The mean ± sd level of C3d was 33.8 ± 8.1 AU/mL. There were no differences in C3d levels between the three patient groups, mean values being: axSpA = 34.3 ± 7.9 AU/mL, non-axSpA = 33.5 ± 6.9 AU/mL, and controls = 33.4 ± 9.2 AU/mL. The level of C3d was not related to MRI findings.Conclusions: In these patients, complement C3d was not associated with active or structural SIJ changes on MRI suggestive of axial spondyloarthritis.

Funder: AbbVie; FundRef: https://doi.org/10.13039/100006483, Funder: Galapagos Conservancy; FundRef: https://doi.org/10.13039/100012525, Funder: Janssen Pharmaceuticals; FundRef: https://doi.org/10.13039/100008897, Funder: Novartis; FundRef: https://doi.org/10.13039/100004336, Funder: Pfizer; FundRef: https://doi.org/10.13039/100004319, Funder: UCB; FundRef: https://doi.org/10.13039/100011110, Funder: Eli Lilly and Company; FundRef: https://doi.org/10.13039/100004312, Background:: Involvement of the axial skeleton (sacroiliac joints and spine) is a relatively frequent manifestation associated with psoriatic skin disease, mostly along with involvement of peripheral musculoskeletal structures (peripheral arthritis, enthesitis, dactylitis), which are referred to as psoriatic arthritis (PsA). Data suggest that up to 30% of patients with psoriasis have PsA. Depending on the definition used, the prevalence of axial involvement varies from 25% to 70% of patients with PsA. However, there are currently no widely accepted criteria for axial involvement in PsA.Objective: The overarching aim of the Axial Involvement in Psoriatic Arthritis (AXIS) study is to systematically evaluate clinical and imaging manifestations indicative of axial involvement in patients with PsA and to develop classification criteria and a unified nomenclature for axial involvement in PsA that would allow defining a homogeneous subgroup of patients for research. Design:: Prospective, multicenter, multinational, cross-sectional study. Methods and analyses:: In this multicenter, multinational, cross-sectional study, eligible patients [adult patients diagnosed with PsA and fulfilling Classification Criteria for Psoriatic Arthritis (CASPAR) with musculoskeletal symptom duration of ���10 years not treated with biological or targeted synthetic disease-modifying anti-rheumatic drugs] will be recruited prospectively. They will undergo study-related clinical and imaging examinations. Imaging will include radiography and magnetic resonance imaging examinations of sacroiliac joints and spine. Local investigators will evaluate for the presence of axial involvement based on clinical and imaging information which will represent the primary outcome of the study. In addition, imaging will undergo evaluation by central review. Finally, the central clinical committee will determine the presence of axial involvement based on all available information. Ethics:: The study will be performed according to the ethical principles of the Declaration of Helsinki and International Council for Harmonisation Good Clinical Practice guidelines. The study protocol will be approved by the individual Independent Ethics Committee / Institutional Review Board of participating centers. Written informed consent will be obtained from all included patients.Registration: ClinicalTrials.gov ID: NCT04434885.

Objective To identify clusters of peripheral involvement according to the specific location of peripheral manifestations (ie, arthritis, enthesitis and dactylitis) in patients with spondyloarthritis (SpA) including psoriatic arthritis (PsA), and to evaluate whether these clusters correspond with the clinical diagnosis of a rheumatologist. Methods Cross-sectional study with 24 participating countries. Consecutive patients diagnosed by their rheumatologist as PsA, axial SpA or peripheral SpA were enrolled. Four different cluster analyses were conducted: one using information on the specific location from all the peripheral manifestations, and a cluster analysis for each peripheral manifestation, separately. Multiple correspondence analyses and k-means clustering methods were used. Distribution of peripheral manifestations and clinical characteristics were compared across the different clusters. Results The different cluster analyses performed in the 4465 patients clearly distinguished a predominantly axial phenotype (cluster 1) and a predominantly peripheral phenotype (cluster 2). In the predominantly axial phenotype, hip involvement and lower limb large joint arthritis, heel enthesitis and lack of dactylitis were more prevalent. In the predominantly peripheral phenotype, different subgroups were distinguished based on the type and location of peripheral involvement: a predominantly involvement of upper versus lower limbs joints, a predominantly axial enthesitis versus peripheral enthesitis, and predominantly finger versus toe involvement in dactylitis. A poor agreement between the clusters and the rheumatologist's diagnosis as well as with the classification criteria was found. Conclusion These results suggest the presence of two main phenotypes (predominantly axial and predominantly peripheral) based on the presence and location of the peripheral manifestations.

Objectives To compare the benefits of a tight-control/treat-to-target strategy (TC/T2T) in axial spondyloarthritis (axSpA) with those of usual care (UC). Methods Pragmatic, prospective, cluster-randomised, controlled, open, 1-year trial (NCT03043846). 18 centres were randomised (1:1). Patients met Axial Spondylo Arthritis International Society (ASAS) criteria for axSpA, had an Ankylosing Spondylitis Disease Activity Score (ASDAS) ≥2.1, received non-optimal treatment by non-steroidal anti-inflammatory drugs and were biologic-naive. Interventions (1) TC/T2T: visits every 4 weeks and prespecified strategy based on treatment intensification until achieving target (ie, ASDAS

Objective: To examine whether associations between socioeconomic factors and work outcomes in spondyloarthritis (SpA) differ across axial (axSpA), peripheral SpA (pSpA) and psoriatic arthritis (PsA), and whether associations for individual-level socioeconomic factors are modified by country-level factors. Methods: Patients with a physician diagnosis of SpA within working age (18-65 years) were included. Associations between individual-(age, gender, education, marital status) and country-level factors (Human Development Index, Health Care Expenditure (HCE), Gross Domestic Product, percentage unemployed) with work outcomes (employment status, absenteeism, presenteeism) were assessed using multivariable mixed-effects models. Associations between individual factors and outcomes were compared according to SpA phenotypes and country-level factors using interaction terms. Results: A total of 3835 patients (mean age 42 years, 61% males) from 23 countries worldwide were included (66% axSpA, 10% pSpA, 23% PsA). Being employed was associated with gender (male vs. female OR 2.5; 95%CI 1.9-3.2), education (university vs. primary OR 3.7; 2.9-4.7), marital status (married vs. single OR 1.3; 1.04-1.6), and age in a non-linear manner. University (vs primary) education was associated with lower odds of absenteeism (OR 0.7; 0.5-0.96) and presenteeism (OR 0.5; 0.3-0.7). Associations were similar across SpA phenotypes. Higher HCE was associated with more favourable work outcomes, e.g., higher odds of employment (OR 2.5; 1.5-4.1). Gender discrepancy in odds of employment was greater in countries with lower socioeconomic development. Conclusion: Higher educational attainment and higher HCE were associated with more favourable work outcomes, independently of SpA phenotype. The disadvantageous effect of female gender on employment is particularly strong in countries with lower socioeconomic development. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

Purpose of Review: To explore how imaging may assist diagnosing axial spondyloarthritis in rheumatology practice. Recent Findings: A diagnosis of axial spondyloarthritis is based on pattern recognition by synthesizing clinical, laboratory, and imaging findings. In health care settings providing low threshold access to advanced imaging, sacroiliac joint MRI is the preferred imaging modality in clinically suspected axial spondyloarthritis. In daily routine, the optimum protocol to assess suspected inflammatory back pain combines sacroiliac joint and spine MRI fitting a 30-min slot. Contextual assessment of concomitant structural and active MRI lesions is key to enhance diagnostic utility. In women with postpartum back pain suggestive of axial spondyloarthritis, recent reports advocate waiting 6–12 months after delivery before acquiring sacroiliac joint MRI. Major unmet needs are consistent MRI protocols, standardized training modules on how to evaluate axial MRI, and timely dissemination of imaging advances into mainstream practice both in rheumatology and in radiology. Summary: In rheumatology practice, MRI has become indispensable to help diagnose early axial spondyloarthritis. However, major gaps in training and knowledge transfer to daily care need to be closed.

ObjectivesTo investigate the occurrence of sick leave (SL) and the impact of clinical and socioeconomic factors on SL in early axial spondyloarthritis (axSpA).MethodsPatients with a clinical diagnosis of axSpA from the DEvenir des Spondyloarthrites Indifférenciées Récentes (DESIR) cohort with work-related data and up to 5-year follow-up were studied. Incidence, time to first SL and potential role of baseline and time-varying clinical and socioeconomic factors (age, gender, ethnicity, education, job type, marital and parental status) were analysed. Univariable analyses, followed by collinearity and interaction tests, guided subsequent multivariable time-varying Cox survival model building.ResultsIn total, 704 axSpA patients were included (mean (SD) age 33.8 (8.6); 46% men). At baseline, 80% of patients were employed; of these, 5.7% reported being on SL. The incidence of SL among those at risk during the study period (n=620, 88%) was 0.05 (95% CI 0.03 to 0.06) per 1000 days of follow-up. Mean (SD) time to first SL was 806 (595) days (range: 175–2021 days). In multivariable models, male gender (HR 0.41 (95% CI 0.20 to 0.86)) and higher education (HR 0.48 (95% CI 0.24 to 0.95)) were associated with lower hazard of SL, while higher disease activity (HR 1.49 (95% CI 1.04 to 2.13)), older age, smoking and use of tumour necrosis factor inhibitors were associated with higher hazard of SL.ConclusionsIn this early axSpA cohort of young, working-age individuals, male gender and higher education were independently associated with a lower hazard of SL, whereas older age and higher disease activity were associated with higher hazard of SL. The findings suggest a role of socioeconomic factors in adverse work outcomes, alongside active disease.

B-cells have received little attention in axial spondyloarthritis (axSpA) and for this reason their role in pathogenesis remains unclear. However, there are indications that B-cells may be involved in the disease process. Our objective was to obtain insights into the composition of the peripheral B-cell compartment of axSpA patients compared to healthy donors (HD) and patients with primary Sjögren’s syndrome (pSS), a typical B-cell-associated autoimmune disease. Special emphasis was given to CD27-negative B-cells expressing low levels of CD21 (CD21low B-cells), since this subset is implicated in autoimmune diseases with strong involvement of B-cells. Transitional B-cells (CD38hi) were excluded from the analysis of the CD27-CD21low B-cell compartment. This study included 45 axSpA patients, 20 pSS patients and 30 HDs. Intriguingly, compared to HDs the frequency of CD27-CD38lowCD21low B-cells was significantly elevated in both axSpA and pSS patients (P-CD38lowCD21low B-cells expressing the activation-induced immune markers T-bet and CD11c was decreased in axSpA patients compared to HDs. A higher proportion of CD27-CD38lowCD21low B-cells expressed the chemokine receptor CXCR3 in axSpA compared to HDs, suggestive for active involvement of these cells in an inflammatory process. The frequency of CD27-CD38lowCD21low B-cells in axSpA patients correlated positively with age and erythrocyte sedimentation rate. Furthermore, axSpA patients with extra-skeletal manifestations (ESM) showed increased frequencies of CD27-CD38lowCD21low B-cells compared to patients without ESM. In conclusion, our findings are suggestive of active B-cell involvement in the pathogenesis of axSpA, against prevailing dogma.

BackgroundClinical studies with work participation (WP) as an outcome domain pose particular methodological challenges that hamper interpretation, comparison between studies and meta-analyses.ObjectivesTo develop Points to Consider (PtC) for design, analysis and reporting of studies of patients with inflammatory arthritis that include WP as a primary or secondary outcome domain.MethodsThe EULAR Standardised Operating Procedures were followed. A multidisciplinary taskforce with 22 experts including patients with rheumatic diseases, from 10 EULAR countries and Canada, identified methodologic areas of concern. Two systematic literature reviews (SLR) appraised the methodology across these areas. In parallel, two surveys among professional societies and experts outside the taskforce sought for additional methodological areas or existing conducting/reporting recommendations. The taskforce formulated the PtC after presentation of the SLRs and survey results, and discussion. Consensus was obtained through informal voting, with levels of agreement obtained anonymously.ResultsTwo overarching principles and nine PtC were formulated. The taskforce recommends to align the work-related study objective to the design, duration, and outcome domains/measurement instruments of the study (PtC: 1–3); to identify contextual factors upfront and account for them in analyses (PtC: 4); to account for interdependence of different work outcome domains and for changes in work status over time (PtC: 5–7); to present results as means as well as proportions of patients reaching predefined meaningful categories (PtC: 8) and to explicitly report volumes of productivity loss when costs are an outcome (PtC:9).ConclusionAdherence to these EULAR PtC will improve the methodological quality of studies evaluating WP.

Purpose: To investigate the association of CARD9 gene polymorphisms with Behcet's disease (BD) and acute anterior uveitis (AAU) in a Chinese Han population. Methods: We performed a case-control association study in 480 patients with BD, 1151 patients with AAU and 1440 healthy controls. Six single nucleotide polymorphisms (SNPs) of CARD9 were genotyped, including rs4077515, rs11145769, rs59902911, rs9411205, rs4073153 and rs1135314. Results: None of the individual SNPs in the CARD9 gene showed an association with either BD or AAU. Haplotype analysis revealed a significant decrease of the frequency of a CARD9 gene haplotype CGCCA (rs4077515, rs11145769, rs59902911, rs9411205, rs4073153) in BD when compared to healthy controls (Pc = 0.012, OR = 0.585, 95%CI = 0.409 similar to 0.837). Haplotype analysis did not show an association between CARD9 and AAU. Conclusions: This study shows that a five-SNP haplotype of the CARD9 gene (CGCCA) may be a protective factor for BD with ocular involvement, but not for AAU.

Spondyloarthritis (SpA) is a family of inflammatory arthritic diseases, which includes the prototypes of psoriatic arthritis and ankylosing spondylitis. SpA is commonly associated with systemic inflammatory diseases, such as psoriasis and inflammatory bowel disease. Immunological studies, murine models and the genetics of SpA all indicate a pathogenic role for the IL-23/IL-17 axis. Therapeutics targeting the IL-23/IL-17 pathway are successful at providing symptomatic relief, but may not provide complete protection against progression of arthritis. Thus there is still tremendous interest in the discovery of novel therapeutic targets for SpA. Tyrosine kinase 2 (TYK2) is a member of the Janus kinases, which mediate intracellular signaling of cytokines via signal transducer and activator of transcription (STAT) activation. TYK2 plays a crucial role in mediating IL-23 receptor signaling and STAT3 activation. A plethora of natural mutations in and around TYK2 have provided a wealth of data to associate this kinase with autoimmune/autoinflammatory diseases in humans. Induced and natural mutations in murine Tyk2 largely support human data; however, key inter-species differences exist, which means extrapolation of data from murine models to humans needs to be done with caution. Despite these reservations, novel selective TYK2 inhibitors are now proving successful in advanced clinical trials of inflammatory diseases. In this review, we will discuss TYK2 from basic biology to therapeutic targeting, with an emphasis on studies in SpA. Seminal studies uncovering the basic science of TYK2 have provided sound foundations for targeting it in SpA and related inflammatory diseases. TYK2 inhibitors may well be the next blockbuster therapeutic for SpA.

ObjectivesTo characterise peripheral musculoskeletal involvement in patients with spondyloarthritis (SpA) including psoriatic arthritis (PsA), across the world.MethodsCross-sectional study with 24 participating countries. Patients with a diagnosis of axial SpA (axSpA), peripheral SpA (pSpA) or PsA according to their rheumatologist were included. The investigators were asked which diagnosis out of a list of six (axSpA, PsA, pSpA, inflammatory bowel disease-associated SpA, reactive arthritis or juvenile SpA (Juv-SpA)) fitted the patient best. Peripheral manifestations (ie, peripheral joint disease, enthesitis, dactylitis and root joint disease), their localisation and treatments were evaluated.ResultsA total of 4465 patients were included (61% men, mean age 44.5 years) from four geographic areas: Latin America (n=538), Europe plus North America (n=1677), Asia (n=975) and the Middle East plus North Africa (n=1275). Of those, 78% had ever suffered from at least one peripheral musculoskeletal manifestation; 57% had peripheral joint disease, 44% had enthesitis and 15% had dactylitis. Latin American had far more often peripheral joint disease (80%) than patients from other areas. Patients with PsA had predominantly upper limb and small joint involvement (52%).Hip and shoulder involvement was found in 34% of patients. The prevalence of enthesitis ranged between 41% in patients with axSpA and 65% in patients with Juv-SpA. Dactylitis was most frequent among patients with PsA (37%).ConclusionThese results suggest that all peripheral features can be found in all subtypes of SpA, and that differences are quantitative rather than qualitative. In a high proportion of patients, axial and peripheral manifestations coincided. These findings reconfirm SpA clinical subtypes are descendants of the same underlying disease, called SpA.

Behcet's disease (BD) is a heterogeneous multi-organ disorder in search of a unified pathophysiological theory and classification. The disease frequently has overlapping features resembling other disease clusters, such as vasculitides, spondyloarthritides and thrombophilias with similar genetic risk variants, namelyHLA-B*51,ERAP1,IL-10,IL-23R. Many of the BD manifestations, such as unprovoked recurrent episodes of inflammation and increased expression of IL-1, IL-6 and TNF alpha, overlap with those of the hereditary monogenic autoinflammatory syndromes, positioning BD at the crossroads between autoimmune and autoinflammatory syndromes. BD-like disease associates with various inborn errors of immunity, including familial Mediterranean fever, conditions related to dysregulated NF-kappa B activation (egTNFAIP3,NFKB1,OTULIN,RELA,IKBKG) and either constitutional trisomy 8 or acquired trisomy 8 in myelodysplastic syndromes. We review here the recent advances in the immunopathology of BD, BD-like diseases and the NF-kappa B pathway suggesting new elements in the elusive BD etiopathogenesis.

Introduction Achievement of remission is a key treatment goal for patients with axial spondyloarthritis (axSpA). C-OPTIMISE assessed achievement of sustained clinical remission in patients with axSpA, including radiographic (r) and non-radiographic (nr) axSpA, during certolizumab pegol (CZP) treatment, and subsequent maintenance of remission following CZP dose continuation, dose reduction or withdrawal. Here, we report outcomes from the first 48 weeks (induction period) of C-OPTIMISE, during which patients received open-label CZP. Methods C-OPTIMISE (NCT02505542) was a two-part, multicenter, phase 3b study in adult patients with early axSpA (r-/nr-axSpA), including a 48-week open-label induction period followed by a 48-week maintenance period. Patients with active adult-onset axSpA

Autoimmune rheumatic diseases are systemic diseases frequently affecting the heart and vessels. The main cardiovascular complications are pericarditis, myocarditis, valvular disease, obstructive coronary artery disease and coronary microcirculatory dysfunction, cardiac failure and pulmonary hypertension. Echocardiography, including transthoracic two and three-dimensional echocardiography, Doppler imaging, myocardial deformation and transesophageal echo, is an established and widely available imaging technique for the identification of cardiovascular manifestations that are crucial for prognosis in rheumatic diseases. Echocardiography is also important for monitoring the impact of drug treatment on cardiac function, coronary microcirculatory function, valvular function and pulmonary artery pressures. In this article we summarize established and evolving knowledge on the role of echocardiography for diagnosis and prognosis of cardiovascular abnormalities in rheumatic diseases. ispartof: MEDICINA-LITHUANIA vol:56 issue:9 ispartof: location:Switzerland status: published

Objective To confirm validity of the Self-administered Comorbidity Questionnaire modified for patients with SpA (mSCQ), and assess whether validity improves when adding items on extra-articular manifestations (EAMs), i.e. uveitis, psoriasis, and IBD, and osteoporosis and fractures. Methods Data from the Assessment in SpondyloArthritis international Society COMOrbidities in SPondyloArthritis study were used. Criterion validity of presence of EAMs, osteoporosis and fractures was assessed as agreement (kappa) between patients’ self-reported and physician-confirmed disease. Construct validity of the mSCQ including EAMs, osteoporosis and/or fractures (SpA-SCQ) was assessed by testing hypotheses about correlations with demographics, physical function, work ability, health utility and disease activity, and was compared with construct validity of the rheumatic disease comorbidity index. Results In total, 3984 patients contributed to the analyses. Agreement between patient-reported and physician-reported EAMs was substantial to almost perfect (uveitis ĸ = 0.81, IBD ĸ = 0.73, psoriasis ĸ = 0.86). Agreement for osteoporosis (ĸ = 0.38) and fractures (ĸ = 0.39) was fair. As hypothesized, the mSCQ correlated moderately to weakly with age, physical function, work limitations and health utility, and very weakly with disease activity. In contrast to our hypothesis, adding EAMs, osteoporosis and/or fractures to the mSCQ decreased correlations with several external constructs, especially among patients with peripheral SpA. Correlations with the different constructs were stronger for the both mSCQ and SpA-SCQ (rBASFI = 0.34; rEQ-5D = −0.33) compared with the rheumatic disease comorbidity index (rBASFI = 0.24; rEQ-5D = −0.21). Conclusion The mSCQ is a valid self-report instrument to assess the influence of comorbidities on health outcomes in patients with SpA. Adding EAMs and/or osteoporosis or fractures does not improve validity of the mSCQ.

ObjectiveTo update the European League Against Rheumatism (EULAR) recommendations for the pharmacological treatment of psoriatic arthritis (PsA).MethodsAccording to the EULAR standardised operating procedures, a systematic literature review was followed by a consensus meeting to develop this update involving 28 international taskforce members in May 2019. Levels of evidence and strengths of recommendations were determined.ResultsThe updated recommendations comprise 6 overarching principles and 12 recommendations. The overarching principles address the nature of PsA and diversity of both musculoskeletal and non-musculoskeletal manifestations; the need for collaborative management and shared decision-making is highlighted. The recommendations provide a treatment strategy for pharmacological therapies. Non-steroidal anti-inflammatory drugs and local glucocorticoid injections are proposed as initial therapy; for patients with arthritis and poor prognostic factors, such as polyarthritis or monoarthritis/oligoarthritis accompanied by factors such as dactylitis or joint damage, rapid initiation of conventional synthetic disease-modifying antirheumatic drugs is recommended. If the treatment target is not achieved with this strategy, a biological disease-modifying antirheumatic drugs (bDMARDs) targeting tumour necrosis factor (TNF), interleukin (IL)-17A or IL-12/23 should be initiated, taking into account skin involvement if relevant. If axial disease predominates, a TNF inhibitor or IL-17A inhibitor should be started as first-line disease-modifying antirheumatic drug. Use of Janus kinase inhibitors is addressed primarily after bDMARD failure. Phosphodiesterase-4 inhibition is proposed for patients in whom these other drugs are inappropriate, generally in the context of mild disease. Drug switches and tapering in sustained remission are addressed.ConclusionThese recommendations provide stakeholders with an updated consensus on the pharmacological management of PsA, based on a combination of evidence and expert opinion.

ObjectiveMany individuals with axial spondyloarthritis (axSpA) do not engage in adequate exercise, despite its proven health benefits. This study aimed to identify the intervention components needed to optimize exercise behavior in people with axSpA.MethodsThe first three steps of the Intervention Mapping protocol were used: 1) needs assessment; 2) identification of axSpA-specific exercise barriers and facilitators (´determinants’); 3) selection of effective intervention components addressing potentially modifiable determinants. All three steps included scoping reviews and semi-structured interviews with patients (n = 2) and physical therapists (n = 2).ResultsThe scoping reviews included 28, 23 and 15 papers, respectively. Step 1 showed that only one third of axSpA patients exercise regularly, demonstrating especially a lack of strengthening and cardiorespiratory exercises. Based on eight determinants identified in Step 2, 10 intervention components were selected in Step 3: education, motivational interviewing, goal setting, action planning, monitoring, feedback, tailoring, guided practice, therapists’ training and group exercise encouragement.ConclusionUsing the Intervention Mapping method, 10 intervention components for optimizing exercise behavior in people with axSpA were identified and an intervention with behavior change guidance and a training for health professionals is proposed.Practice ImplicationsThis study provides a foundation for the development of an axSpA-specific exercise intervention.

Objective To investigate whether spinal radiographic progression relates to structural damage at the sacroiliac level in axial spondyloarthritis (axSpA). Methods Patients classified as nonradiographic (nr-) and radiographic (r-) axSpA in the Swiss Clinical Quality Management cohort with radiographs performed every 2 years, scored according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS), were included. The relationship between classification status and spinal progression during 2 years was investigated using binomial generalized estimating equations models with adjustment for sex, ankylosing spondylitis disease activity score (ASDAS) and tumour necrosis factor inhibitor treatment. Baseline spinal damage was considered an intermediate variable and included in sensitivity analyses. Results In total, 88 nr-axSpA and 418 r-axSpA patients contributed to data for 725 radiographic intervals. R-axSpA patients were more frequently male, had a longer disease duration and higher structural damage at baseline. Mean (SD) mSASSS change over 2 years was 0.16 (0.62) units in nr-axSpA and 0.92 (2.78) units in r-axSpA, p = 0.01. Nr-axSpA was associated with a significantly lower progression in 2 years (defined as an increase in ≥2 mSASSS units) in adjusted analyses (OR 0.33, 95%CI 0.13; 0.83), confirmed with progression defined as the formation of ≥1 syndesmophyte. Mediation analyses revealed that sacroiliitis exerted its effect on spinal progression indirectly by being associated with the appearance of a first syndesmophyte (OR 0.09, 95%CI 0.02; 0.36 for nr-axSpA vs r-axSpA). Baseline syndesmophytes were predictors of further progression. Conclusion Spinal structural damage is mainly restricted to patients with r-axSpA, leading to relevant prognostic and therapeutic implications.

ObjectivesTo investigate the efficacy and safety of ixekizumab for up to 52 weeks in two phase 3 studies of patients with active radiographic axial spondyloarthritis (r-axSpA) who were biological disease-modifying antirheumatic drug (bDMARD)-naive (COAST-V) or tumour necrosis factor inhibitor (TNFi)-experienced (COAST-W).MethodsAdults with active r-axSpA were randomised 1:1:1:1 (n=341) to 80 mg ixekizumab every 2 (IXE Q2W) or 4 weeks (IXE Q4W), placebo (PBO) or 40 mg adalimumab Q2W (ADA) in COAST-V and 1:1:1 (n=316) to IXE Q2W, IXE Q4W or PBO in COAST-W. At week 16, patients receiving ixekizumab continued their assigned treatment; patients receiving PBO or ADA were rerandomised 1:1 to IXE Q2W or IXE Q4W (PBO/IXE, ADA/IXE) through week 52.ResultsIn COAST-V, Assessment of SpondyloArthritis international Society 40 (ASAS40) responses rates (intent-to-treat population, non-responder imputation) at weeks 16 and 52 were 48% and 53% (IXE Q4W); 52% and 51% (IXE Q2W); 36% and 51% (ADA/IXE); 19% and 47% (PBO/IXE). Corresponding ASAS40 response rates in COAST-W were 25% and 34% (IXE Q4W); 31% and 31% (IXE Q2W); 14% and 39% (PBO/IXE). Both ixekizumab regimens sustained improvements in disease activity, physical function, objective markers of inflammation, QoL, health status and overall function up to 52 weeks. Safety through 52 weeks of ixekizumab was consistent with safety through 16 weeks.ConclusionThe significant efficacy demonstrated with ixekizumab at week 16 was sustained for up to 52 weeks in bDMARD-naive and TNFi-experienced patients. bDMARD-naive patients initially treated with ADA demonstrated further numerical improvements after switching to ixekizumab. Safety findings were consistent with the known safety profile of ixekizumab.Trial registration numberNCT02696785/NCT02696798.

Background S100A4 is a member of calcium binding S100 protein family well known for its role in cancer progression and metastasis. Nevertheless, S100A4 also serves as a negative regulator of bone formation. Dickkopf-1 (DKK-1), marker of bone remodelling, is also implicated in the process of syndesmophyte formation in ankylosing spondylitis. The aim of our study was to evaluate plasma levels of S100A4 in patients with axial spondyloarthritis and to determine the potential association of S100A4 with disease severity, clinical manifestations and with bone changes in a cross-sectional study. Methods Fifty-eight patients with axial spondyloarthritis and 40 healthy controls were studied. Biological samples were analysed for S100A4 and Dickkopf-1. Disease activity was assessed according to the Bath Ankylosing Spondylitis Disease Activity Index. C-reactive protein (CRP) was used as a marker of inflammation. Radiographic damage was assessed using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). Results The plasma levels of S100A4 were significantly higher in patients with axial spondyloarthritis compared to heathy controls (p p = 0.009). Furthermore, we found weak but significant inverse correlation of plasma S100A4 with the mSASSS (r = − 0.363, p = 0.030). Levels of S100A4 were negatively associated with disease duration (r = − 0.404, p = 0.002) and positively with Dickkopf-1 binding capacity (r = 0.312, p = 0.023). Conclusions This is the first study showing elevated circulating levels of S100A4 in patients with axial spondyloarthritis, particularly in early stages of the disease prior to spinal involvement, and its significantly lower levels in patients with syndesmophytes. The role of S100A4 in the pathogenesis of axial spondyloarthritis can be suggested.

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.