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Objective: To characterise the population fulfilling the Assessment of SpondyloArthritis international Society (ASAS) consensus definition of early axial spondyloarthritis (axSpA) and to determine the effectiveness of a first tumour necrosis factor inhibitor (TNFi) in early versus established axSpA in a large observational registry., Methods: A total of 3064 patients with axSpA in the Swiss Clinical Quality Management registry with data on duration of axial symptoms were included (≤2 years=early axSpA, N=658; >2 years=established axSpA, N=2406). Drug retention was analysed in patients starting a first TNFi in early axSpA (N=250) versus established axSpA (N=874) with multiple-adjusted Cox proportional hazards models. Adjusted logistic regression analyses were used to determine the achievement of the ASAS criteria for 40% improvement (ASAS40) at 1 year., Results: Sex distribution, disease activity, impairments of function and health-related quality of life were comparable between patients with early and established axSpA. Patients with established disease were older, had more prevalent axial radiographical damage and had a higher impairment of mobility. A comparable TNFi retention was found in early versus established disease after adjustment for age, sex, human leucocyte antigen-B27 status, education, body mass index, smoking, elevated C reactive protein and sacroiliac inflammation on MRI (HR 1.05, 95% CI 0.78 to 1.42). The adjusted ASAS40 response was similar in the two groups (OR 1.09, 95% CI 0.67 to 1.78). Results were confirmed in the population fulfilling the ASAS classification criteria., Conclusion: Considering the recent ASAS definition of early axSpA, TNFi effectiveness seems comparable in early versus established disease., Competing Interests: Competing interests: The SCQM Foundation is supported by the Swiss Society of Rheumatology and by AbbVie, AstraZeneca, Eli Lilly, iQone Healthcare, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, Samsung Bioepis and Sandoz. AC received honoraria for lectures from AbbVie and Novartis. AR-R received consulting fees from AbbVie, Janssen and Pfizer; honoraria for lectures from AbbVie, Janssen, Novartis and Pfizer; as well as support for attending meetings from Janssen and Pfizer. AS received consulting fees from Pfizer and support for attending meetings from Gilead. BM received speaking fees from AbbVie, Janssen, Novartis and Pfizer, as well as support for attending meetings from Janssen. DK received a research grant from AbbVie, honoraria for presentations from AbbVie and Eli Lilly, support for attending meetings from Janssen and Eli Lilly, as well as payments for participation in advisory boards from AbbVie, Eli Lilly, Janssen, Novartis, Pfizer and Roche. MJN received consulting and/or speaking fees from AbbVie, Eli Lilly, Janssen, Novartis and Pfizer, as well as a research grant from Novartis. OD received consulting fees from AbbVie. PE received financial support from UCB to attend a meeting. RM received honoraria for lectures or presentations from AbbVie, Eli Lilly, Janssen, Gilead and Pfizer. TH received royalties from Curmed, payments for lectures and presentations from Pfizer, Fresenius Kabi, AbbVie, Merck Sharp & Dohme, Galapagos, Eli Lilly and Novartis. He participated in advisory boards for DETECTRA and holds stock or stock options of Atreon SA and Vtuls. AG, KB, MA and RB declare they have no conflicts of interest., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: As anaemia represents a biomarker for increased radiographic damage in rheumatoid arthritis, we aimed to investigate whether it independently predicts spinal radiographic progression in axial spondyloarthritis (axSpA)., Methods: AxSpA patients with available haemoglobin levels from the prospective Swiss Clinical Quality Management Registry were included for comparison of patients with and without anaemia. Spinal radiographic progression was assessed according to the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) in patients with ankylosing spondylitis (AS) if ≥ 2 sets of spinal radiographs were available every 2 years. The relationship between anaemia and progression (defined as an increase ≥ 2 mSASSS units in 2 years) was analysed with generalized estimating equation models after adjustment for the Ankylosing Spondylitis Disease Activity Score (ASDAS) and potential confounding, as well as after multiple imputations of missing values., Results: A total of 212/2522 axSpA patients presented with anaemia (9%). Anaemic patients had higher clinical disease activity, higher acute phase reactants and more severe impairments in physical function, mobility and quality of life. In the subgroup of patients with AS (N = 433), a comparable mSASSS progression was found in anaemic and non-anaemic patients (OR 0.69, 95% CI 0.25 to 1.96, p = 0.49). Age, male sex, baseline radiographic damage and ASDAS were associated with enhanced progression. The results were confirmed in complete case analyses and with progression defined as the formation of ≥ 1 syndesmophyte in 2 years., Conclusion: Although anaemia was associated with higher disease activity in axSpA, it did not additionally contribute to the prediction of spinal radiographic progression. Key Points • Anaemia is associated with higher disease activity and more severely impaired physical function, mobility and quality of life in axSpA. • Anaemia does not provide an additional value to ASDAS for prediction of spinal radiographic progression., (© 2023. The Author(s).)

Objective: To investigate sex differences in spinal radiographic progression in axial spondyloarthritis (axSpA)., Methods: AxSpA patients in the Swiss Clinical Quality Management cohort with available spinal radiographs every 2 years were included. Paired radiographs were scored by two readers according to the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). Progression was defined as an increase of ≥2 mSASSS units in 2 years. The relationship between sex and progression was investigated with binomial generalised estimating equation models, considering baseline spinal damage as an intermediate covariate. Additional analyses included adjustments for explanatory variables and multiple imputations for missingness., Results: In a total of 505 axSpA patients (317 men and 188 women), mean±SD radiographic progression over 2 years was 1.0±2.8 years in men and 0.3±1.1 years in women (p<0.001). Male sex was associated with enhanced progression in a small model not including baseline damage (OR 3.41, 95% CI 1.87 to 6.21). Both a direct effect of male sex on spinal progression, and an indirect effect, via enhancement of baseline spinal damage were significant (OR 2.06, 95% CI 1.15 to 3.67 and OR 1.04, 95% CI 1.01 to 1.07, respectively). A significant impact of male sex on spinal radiographic progression was still demonstrated after multiple adjustments for covariates known to potentially affect spinal radiographic progression (OR 1.97, 95% CI 1.04 to 3.71)., Conclusions: Spinal radiographic progression in axSpA is more severe in men than in women, with three times higher odds of progression in male patients and an effect that is mediated in part through an increase in baseline radiographic damage., Competing Interests: Competing interests: The SCQM foundation is supported by the Swiss Society of Rheumatology and by Abbvie, Astra Zeneca, Eli Lilly, iQone Healthcare, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, Samsung Bioepis, and Sandoz. AC received honoraria for lectures from AbbVie, and Novartis. AS received consulting fees from Pfizer and support for attending meetings from Gilead. BM received speaking fees from Jansen, Novartis and Pfizer, support for attending meetings from Janssen and Pfizer, and a research grant from Celgene. MdH received grants from FWRO/FRSR and honoraria from UCB for participation in an advisory board. MJN received consulting and/or speaking fees from Abbvie, Amgen, Eli Lilly, Janssen, Novartis and Pfizer and a research grant from Novartis. He also received support from attending meetings from Janssen and UCB and participated in advisory boards for Eli Lilly, Janssen, Novartis and Pfizer. PE received financial support from UCB for attending a meeting. RM received honoraria for lectures or presentations from Abbvie, Eli Lilly, Janssen, Gilead and Pfizer. XB received consulting fees from Abbvie, BMS, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Pfizer, Roche, Sandoz, Sanofi, and UCB. He received payment or honoraria for lectures or presentations from Abbvie, BMS, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Pfizer, Roche, Sandoz, Sanofi, and UCB. He participated on advisory boards for Abbvie, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Pfizer and UCB. He is president of the Assessment of Spondyloarthritis international Society (ASAS) and EULAR president-elect. AG, CE, KB, MA, OD, RB and SK declare they have no conflicts of interest., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Within the spectrum of spondyloarthritides, axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) present with overlapping features. Axial involvement in PsA (axial PsA) is treated according to recommendations for axSpA, as specific studies in axial PsA are scarce. We compared characteristics of patients with axSpA (particularly of patients with axSpA and concomitant psoriasis (pso)) with those of patients with axial PsA., Methods: Patients with axSpA and PsA in the Swiss Clinical Quality Management (SCQM) registry were included if information on pso and axial involvement was available. Patients with AxSpA were stratified by axSpA with and without pso (axSpA±pso) and patients with PsA were stratified to axial PsA or strictly peripheral PsA., Results: Previous or current psoriasis was observed in 479/4489 patients with axSpA (10.7%). Of 2631 patients with PsA, 1153 (43.8%) presented with axial involvement (opinion of the treating rheumatologist). Compared with patients with axSpA+pso, patients with axial PsA were older at symptom onset and at inclusion in SCQM, were less frequently HLA-B27 positive, had back pain less frequently and a higher prevalence of dactylitis and peripheral arthritis. A positive family history of pso or PsA was more frequent in axial PsA, while a positive family history of axSpA was more frequent in patients with axSpA+pso. Disease activity, function and mobility were comparable in axSpA+pso versus axial PsA., Conclusion: Patients with axial PsA differ from patients with axSpA+pso in important demographic and clinical characteristics, and genetically, but present with a comparable disease burden. Treatment studies specifically dedicated to axial PsA seem warranted., Competing Interests: Competing interests: The SCQM foundation is supported by the Swiss Society of Rheumatology and by Abbvie, AstraZeneca, Biogen, iQone, Janssen, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Samsung Bioepis, Sandoz. AC received honoraria for lectures or presentations from AbbVie, Merck Sharp & Dohme and Novartis. AG and SK are employees of SCQM and part of their salary in relation to statistical work performed for this study was financed through a research grant from Eli Lilly to SCQM (see funding). AS received consulting fees from Pfizer and support for attending meetings from Gilead. BM received speaking fees from Janssen, Eli Lilly, Novartis and Pfizer, support for attending meetings from Janssen and Pfizer and a research grant from Celgene. MSN received consulting and/or speaking fees from Abbvie, Eli Lilly, Janssen, Novartis and Pfizer, a research grant from Novartis. PE received financial support from UCB for attending a meeting. RM received honoraria for lectures or presentations from Abbvie, Eli Lilly, Janssen, Gilead and Pfizer. AB and KB declare they have no conflicts of interest., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To explore the impact of the human leucocyte antigen (HLA)-B27 on the effectiveness of tumor necrosis factor inhibitors (TNFi) in patients with axial spondyloarthritis (axSpA)., Methods: A total of 1109 patients with available HLA-B27 status (831 B27+ patients and 278 B27- patients) fulfilling the Assessment of Spondyloarthritis international Society classification criteria for axSpA from the prospective Swiss Clinical Quality Management Registry initiating a first TNFi were included. Drug retention was investigated with multiple adjusted Cox proportional hazard models with imputation of missing values. Multiple-adjusted logistic regression analyses were used to assess the proportion of patients reaching 50% reduction in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI50) at 1 year., Results: B27+ and B27- patients differed with regard to age, sex, BASDAI, C-reactive protein (CRP), body mass index, enthesitis, uveitis, and classification status. After adjustment for potential confounders for the relationship between HLA-B27 and drug effectiveness (sex and family history of spondyloarthritis), a higher risk of drug discontinuation was found in B27- patients (HR 1.53, 95% CI 1.27-1.83). This difference decreased after additional adjustment for parameters which may act as mediators (HR 1.30, 95% CI 1.30-1.55). Male sex and elevated C-reactive protein (CRP) levels were consistently associated with longer retention. Comparable results were obtained for BASDAI50 responses., Conclusion: The HLA-B27 genotype is an important predictor of treatment effectiveness. Male sex and CRP seem, however, to better describe variability of response in individual patients. This data may help avoiding potential discrimination of B27- individuals with regard to TNFi initiation. Key Points • HLA-B27 is a predictor of effectiveness of TNF inhibitors in axial spondyloarthritis. • Variability of response in individual patients is better defined by sex and objective markers of disease activity, such as C-reactive protein., (© 2022. The Author(s).)

Objectives: To analyse whether time-varying treatment with tumour necrosis factor inhibitors (TNFi) in radiographic axial spondyloarthritis (r-axSpA) has a differential impact on structural damage progression on different spinal segments (cervical versus lumbar spine)., Methods: Patients with r-axSpA in the Swiss Clinical Quality Management cohort were included if cervical and lumbar radiographs were available at intervals of 2 years for a maximum of 10 years. Paired radiographs were scored by two calibrated readers according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). The relationship between TNFi use and progression in the cervical and the lumbar spine was analysed using generalised estimating equation models and adjustment for potential confounding. Radiographic progression per spinal segment was defined as an increase of ≥ 1 mSASSS unit or by the formation of ≥ 1 new syndesmophyte over 2 years., Results: Mean ± SD symptom duration was 13.8 ± 9.8 years. Mean ± SD mSASSS progression per radiographic interval was 0.41 ± 1.69 units in the cervical spine and 0.45 ± 1.45 units in the lumbar spine (p = 0.66). Prior use of TNFi significantly reduced the odds of progression in the cervical spine by 68% (OR 0.32, 95% CI 0.14-0.72), but not in the lumbar spine (OR 0.99, 95% CI 0.52-1.88). A more restricted inhibition of progression in the lumbar spine was confirmed after multiple imputation of missing covariate data (OR 0.43, 95% CI 0.24-0.77 and 0.85, 95% CI 0.51-1.41, for the cervical and lumbar spine, respectively). It was also confirmed with progression defined as formation of ≥ 1 syndesmophyte (OR 0.31, 95% CI 0.12-0.80 versus OR 0.56, 95% CI 0.26-1.24 for the cervical and lumbar spine, respectively)., Conclusion: Disease modification by treatment with TNFi seems to more profoundly affect the cervical spine in this r-axSpA population with longstanding disease. Site-specific analysis of spinal progression might, therefore, improve detection of disease modification in clinical trials in axSpA., (© 2023. The Author(s).)

Objectives: To analyse the effect of tumour necrosis factor inhibitors (TNFi) on sacroiliac joint (SIJ) radiographic progression in axial spondyloarthritis (axSpA)., Methods: Patients with axSpA in the Swiss Clinical Quality Management cohort with up to 12 years of follow-up and radiographic assessments every 2 years were included. SIJs were scored by two readers according to the modified New York criteria blinded to chronology. The relationship between TNFi use before or during a 2-year radiographic interval and SIJ progression was investigated using generalised estimating equation models with adjustment for potential confounding. Progression was defined as worsening of ≥1 grade in ≥1 SIJ and ignoring a change from 0 to 1 over 2 years, if both readers agreed. A third reading of radiographs was integrated in sensitivity analyses., Results: A total of 515 patients with axSpA contributed to data for 894 radiographic intervals (24 progression events). In patients with complete covariate data, prior use of TNFi reduced the odds of progression (OR 0.21, 95% CI 0.07 to 0.65). A comparable effect was found for use of TNFi for ≥1 year within a 2-year radiographic interval (OR 0.21, 95% CI 0.08 to 0.55). The inhibitory impact of TNFi was confirmed if progression was demonstrated in 2/3 readings: OR 0.50, 95% CI 0.28 to 0.89 and OR 0.46, 95% CI 0.27 to 0.78 for TNFi treatment before and for ≥1 year within the interval, respectively., Conclusion: TNFi are associated with deceleration of SIJ radiographic progression in patients with axSpA if treatment is continued for ≥1 year., Competing Interests: Competing interests: AC received honoraria for lectures or presentations from AbbVie, Merck Sharp & Dohme and Novartis. AS received consulting fees from Pfizer and support for attending meetings from Gilead. BM received speaking fees from Jansen, Novartis and Pfizer and support for attending meetings from Janssen and Pfizer. MJN received consulting and/or speaking fees from Abbvie, Eli Lilly, Janssen, Novartis and Pfizer and a research grant from Novartis. OD received consulting fees from Abbvie. PE received financial support from UCB for attending a meeting. RM received honoraria for lectures or presentations from Abbvie, Eli Lilly, Janssen, Gilead and Pfizer. KB, MA, RB, and SK declare they have no conflicts of interest., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To compare disease characteristics and outcomes between patients with axial spondyloarthritis with non-radiographic disease (nr-axSpA), bilateral grade 2 sacroiliitis (r22axSpA) and unilateral/bilateral grade 3-4 sacroiliitis (r3+axSpA) according to the modified New York criteria., Methods: We included patients with axial spondyloarthritis with available pelvic radiographs from the Swiss Clinical Quality Management Cohort. Retention of a first tumour necrosis factor inhibitor (TNFi) was investigated with multiple adjusted Cox proportional hazards models. The proportion of patients reaching 50% reduction in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI50) at 1 year was assessed with multiple adjusted logistic regression analyses. Spinal radiographic progression, defined as an increase in ≥2 mSASSS units in 2 years, was assessed in generalised estimating equation models., Results: From 2080 patients, those with nr-axSpA (n=485) and r22axSpA (n=443) presented with lower C reactive protein levels and less severe clinical spinal involvement compared with patients with r3+axSpA (n=1152). While TNFi retention was similar in r22axSpA and nr-axSpA, the risk of discontinuation was significantly lower in r3+axSpA (HR 0.60, 95% CI 0.44 to 0.82 vs nr-axSpA). BASDAI50 responses at 1 year were comparable in r22axSpA and nr-axSpA, with a better response associated with r3+axSpA (OR 2.05, 95% CI 1.09 to 3.91 vs nr-axSpA). Spinal radiographic progression was similar in r22axSpA and nr-axSpA and significantly higher in r3 +axSpA., Conclusion: Patients with r22axSpA are comparable to nr-axSpA patients but differ from patients with more severe sacroiliac damage with regard to treatment effectiveness and spinal radiographic progression. Therefore, current differentiation between nr-axSpA and radiographic disease seems of limited use for outcome prediction., Competing Interests: Competing interests: AC received consulting and/or speaking fees from AbbVie, Eli Lilly, Merck Sharp & Dohme, Novartis and Pfizer. AS received consulting fees from Pfizer and support for attending meetings from Gilead. BM received speaking fees from Jansen and Novartis and support for attending meetings from Pfizer (payments to institution). DK received consulting and/or speaking fees from Abbvie, Gilead, Eli Lilly, Novartis and Pfizer. MJN received consulting and/or speaking fees from Abbvie, Celgene, Eli Lilly, Novartis and Pfizer. OD received consulting and/or speaking fees from Abbvie, Amgen, Eli Lilly and Pfizer. RM received consulting and/or speaking fees from Abbvie, Eli Lilly, Gilead and Pfizer., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Sex differences with regard to clinical manifestations and response to tumor necrosis factor inhibitors (TNFi) have been delineated for the radiographic form of axial spondyloarthritis (axSpA). More limited evidence for a differential effectiveness of treatment in genders exists for the nonradiographic disease state (nr-axSpA). The aim of the study was to compare demographics, clinical parameters, and response to TNFi in women versus men with nr-axSpA., Methods: We compared disease characteristics of 264 women and 231 men with nr-axSpA at inclusion in the prospective Swiss Clinical Quality Management Cohort. Response to a first TNFi was assessed in 85 women and 78 men without diagnosed co-morbid fibromyalgia. The primary outcome was the proportion of patients achieving the 40% improvement in the Assessment of SpondyloArthritis international Society criteria (ASAS40) at 1 year. Additional response outcomes were evaluated as secondary outcomes. Patients having discontinued TNFi were considered non-responders. Logistic regression analyses were adjusted for baseline differences, which might potentially mediate the effect of sex on treatment response., Results: Compared to men, women had a longer diagnostic delay, a higher level of perceived disease activity, and more enthesitis and were in a lower percentage HLA-B27 positive. An ASAS40 response was achieved by 17% of women and 38% of men (OR 0.34; 95% CI 0.12, 0.93; p = 0.02). A significantly lower response rate in women was confirmed in the adjusted analysis (OR 0.19; 95% CI 0.05, 0.62; p = 0.009) as well as for the other outcomes assessed., Conclusion: Despite only few sex differences in patient characteristics in nr-axSpA, response rates to TNFi are significantly lower in women than in men.

Objective: To compare effectiveness of treatment with secukinumab (SEC) with that of alternative tumour necrosis factor inhibitors (TNFis) in patients with axial spondyloarthritis (axSpA) after withdrawal from one or more TNFis., Methods: Patients diagnosed as having axSpA in the Swiss Clinical Quality Management cohort were included if they had initiated SEC (n=106) or an alternative TNFi (n=284) after experiencing TNFi failure. Drug retention was investigated with matching weights propensity score (PS) analyses and multiple adjusted Cox proportional hazards models. Matching weights PS-based analyses and multiple-adjusted logistic regression analyses were used to assess the proportion of patients reaching 50% reduction in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI50) at 1 year., Results: SEC was more often used as third-line or later-line biological drug (76% vs 40% for TNFi). Patients starting SEC had higher BASDAI, Bath Ankylosing Spondylitis Functional Index, Bath Ankylosing Spondylitis Metrology Index and C reactive protein levels. A comparable risk of drug discontinuation was found for SEC versus TNFi (HR 1.14, 95% CI 0.78 to 1.68 in the PS-based analysis and HR 1.16, 95% CI 0.79 to 1.71 in the multiple-adjusted analysis). No significant difference in BASDAI50 responses at 1 year was demonstrated between the two modes of biological drug action, with CI of estimates being, however, wide (OR for SEC vs TNFi 0.76, 95% CI 0.26 to 2.18 and 0.78, 95% CI 0.24 to 2.48 in the PS-based and the covariate-adjusted model, respectively)., Conclusion: Our data suggest a comparable effectiveness of SEC versus an alternative TNFi after prior TNFi exposure., Competing Interests: Competing interests: AC has received consulting and/or speaking fees from AbbVie, Celgene, Eli Lilly, Janssen-Cilag, Merck Sharp & Dohme, Novartis, Pfizer and UCB. MJN has received consulting and/or speaking fees from Abbvie, Celgene, Eli Lilly, Novartis and Pfizer., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

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., Competing Interests: The authors have read the journal’s policy and the authors of this manuscript have the following competing interests: A.C. has received consulting and/or speaking fees from AbbVie, Celgene, Eli Lilly, Janssen-Cilag, Merck Sharp & Dohme, Novartis, Pfizer and UCB. M.J.N. has received consulting and/or speaking fees from Abbvie, Eli Lilly, Novartis and Pfizer. D.v.d.H. has received consulting fees from Abbvie, Amgen, Astellas, AstraZeneca, Bristol-Myers Squibb, Boeringer Ingelheim, Celgene, Daiichi, Eli-Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, UCB Pharma, and is the director of Imaging Rheumatology BV. M.H., A.S., X.B. and M.d.H. have received salaries from the Swiss Clinical Quality Management (SCQM) Foundation for specific roles in this study as detailed in the “financial disclosure” section, which were funded by the Stiftung für Rheumaforschung, Zurich, Switzerland, as well as by Merck Sharp & Dohme Corp. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.

Objectives: To compare drug survival in patients with axial spondyloarthritis treated with different TNF inhibitors in standard dosage., Methods: Patients fulfilling the Assessment in SpondyloArthritis international Society classification criteria for axial spondyloarthritis in the Swiss Clinical Quality Management cohort were included in this study if a first TNF inhibitor on standard dosage was started after recruitment and if a baseline visit was available. Drug maintenance up to drug discontinuation or dose escalation was compared between TNF inhibitors with multiple adjusted Cox proportional hazards models and multiple imputation for missing baseline covariate data., Results: A total of 966 patients were included (adalimumab 344, etanercept 237, golimumab 214, infliximab 171). Patients on certolizumab (n = 18) were excluded. Patients starting golimumab had lower disease activity as well as better physical function and quality of life in comparison to patients starting another drug. A higher proportion of patients starting infliximab had a history of extra-articular manifestations. Drug dosage was more often escalated during follow-up in patients treated with infliximab than with subcutaneously administered agents. However, no significant differences in time up to drug discontinuation or dose escalation were observed in multiple adjusted analyses if treatment was initiated after 2009, when all 4 TNF inhibitors were available: hazard ratio for infliximab versus etanercept 1.16 (95% confidence interval 0.80; 1.67), p = 0.44, for golimumab versus etanercept 0.80 (0.58; 1.10), p = 0.17 and for adalimumab versus etanercept 0.93 (0.69; 1.26), p = 0.66., Conclusion: In axial spondyloarthritis, drug survival with standard doses of different TNF inhibitors is comparable., Competing Interests: The authors of this manuscript have read the journal's policy and have the following competing interests: A.C. has received consulting and/or speaking fees from AbbVie, Celgene, Eli Lilly, Janssen-Cilag, Merck Sharp & Dohme, Novartis, Pfizer and UCB. M.J.N has received consulting and/or speaking fees from Abbvie, Novartis and Pfizer. Additional commercial support came the SCQM Foundation which is supported by the Swiss Society of Rheumatology and by AbbVie, Celgene, iQone, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sandoz, Sanofi Genzyme, UCB. It has also been supported by Bristol-Myers-Squibb and Janssen-Cilag, and has received project-based financial supports from the Arco Foundation, Switzerland; as well as from the Swiss Balgrist Society, Switzerland. Additionally, this study was supported by Pfizer through an investigator-initiated research grant to SCQM. There are no patents, products in development or marketed products associated with this research to declare. A.S., B.M., G.T., M.H., P.M., P. Z. and R.M declare that they have no conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objective: To investigate sex differences in connection with the effectiveness of tumor necrosis factor inhibitors (TNFi) in patients with ankylosing spondylitis (AS)., Methods: A total of 440 patients with AS (294 men; 146 women) initiating a first TNFi in the prospective Swiss Clinical Quality Management Cohort were included. We evaluated the proportion of patients achieving the 20% and 40% improvement in the Assessment of Spondyloarthritis international Society criteria (ASAS20 and ASAS40) as well as Ankylosing Spondylitis Disease Activity Score (ASDAS) improvement and status scores at 1 year. Patients having discontinued TNFi were considered nonresponders. Logistic regression analyses were performed to adjust for important predictors of response., Results: Compared to men, female patients had lower mean C-reactive protein levels, better spinal mobility, and more peripheral disease at the start. There was no sex disparity with regard to the ASDAS, the Bath Ankylosing Spondylitis Disease Activity and Functional indices, and the quality of life. At 1 year, 52% of women and 63% of men achieved an ASAS20 response (OR 0.63, 95% CI 0.37-1.07, p = 0.09). An inactive disease status (ASDAS < 1.3) was reached by 18% of women and 26% of men (OR 0.65, 95% CI 0.32-1.27, p = 0.22). These sex differences in response to TNFi were more pronounced in adjusted analyses (OR 0.34, 95% CI 0.16-0.71, p = 0.005 for ASAS20 and OR 0.10, 95% CI 0.03-0.31, p < 0.001 for ASDAS < 1.3) and confirmed for all the other outcomes assessed., Conclusion: In AS, fewer women respond to TNFi and women show a reduced response in comparison to men.

Objectives: To analyse the impact of tumour necrosis factor inhibitors (TNFis) on spinal radiographic progression in ankylosing spondylitis (AS)., Methods: Patients with AS in the Swiss Clinical Quality Management cohort with up to 10 years of follow-up and radiographic assessments every 2 years were included. Radiographs were scored by two readers according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) with known chronology. The relationship between TNFi use before a 2-year radiographic interval and progression within the interval was investigated using binomial generalised estimating equation models with adjustment for potential confounding and multiple imputation of missing values. Ankylosing Spondylitis Disease Activity Score (ASDAS) was regarded as mediating the effect of TNFi on progression and added to the model in a sensitivity analysis., Results: A total of 432 patients with AS contributed to data for 616 radiographic intervals. Radiographic progression was defined as an increase in ≥2 mSASSS units in 2 years. Mean (SD) mSASSS increase was 0.9 (2.6) units in 2 years. Prior use of TNFi reduced the odds of progression by 50% (OR 0.50, 95% CI 0.28 to 0.88) in the multivariable analysis. While no direct effect of TNFi on progression was present in an analysis including time-varying ASDAS (OR 0.61, 95% CI 0.34 to 1.08), the indirect effect, via a reduction in ASDAS, was statistically significant (OR 0.75, 95% CI 0.59 to 0.97)., Conclusion: TNFis are associated with a reduction of spinal radiographic progression in patients with AS. This effect seems mediated through the inhibiting effect of TNFi on disease activity., Competing Interests: Competing interests: JB has received consulting fees from Merck Sharp & Dohme, Pfizer and Roche. AC has received consulting and/or speaking fees from AbbVie, Celgene, Eli Lilly, Janssen-Cilag, Merck Sharp & Dohme, Novartis, Pfizer and UCB. MJN has received consulting and/or speaking fees from Abbvie, Novartis and Pfizer. DvdH has received consulting fees from Abbvie, Amgen, Astellas, AstraZeneca, BMS, Boeringer Ingelheim, Celgene, Daiichi, Eli-Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi and UCB and is director of Imaging Rheumatology BV. UW has received speaking fees from AbbVie. AS, GT, LMW, MC, MdH, PE, PZ, RBML, RK, RM and XBdeclare no conflict of interest. No non-financial conflicts of interest exist for any of the authors., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Few studies have investigated the impact of obesity on the response to tumor necrosis factor inhibitors (TNFi) in patients with axial spondyloarthritis (axSpA). The aim of our study was to investigate the impact of different body mass index (BMI) categories on TNFi response in a large cohort of patients with axSpA., Methods: Patients with axSpA within the Swiss Clinical Quality Management (SCQM) program were included in the current study if they fulfilled the Assessment in Spondyloarthritis International Society (ASAS) criteria for axSpA, started a first TNFi after recruitment, and had available BMI data as well as a baseline and follow-up visit at 1 year (±6 months). Patients were categorized according to BMI: normal (BMI 18.5 to <25), overweight (BMI 25-30), and obese (BMI >30). We evaluated the proportion of patients achieving the 40% improvement in ASAS criteria (ASAS40), as well as Ankylosing Spondylitis Disease Activity Score (ASDAS) improvement and status scores at 1 year. Patients having discontinued the TNFi were considered nonresponders. We controlled for age, sex, HLA-B27, axSpA type, BASDAI, BASMI, elevated C-reactive protein (CRP), current smoking, enthesitis, physical exercise, and co-medication with disease-modifying antirheumatic drugs, as well as with nonsteroidal anti-inflammatory drugs in multiple adjusted logistic regression analyses., Results: A total of 624 axSpA patients starting a first TNFi were considered in the current study (332 patients of normal weight, 204 patients with overweight, and 88 obese patients). Obese individuals were older, had higher BASDAI levels, and had a more important impairment of physical function in comparison to patients of normal weight, while ASDAS and CRP levels were comparable between the three BMI groups. An ASAS40 response was reached by 44%, 34%, and 29% of patients of normal weight, overweight, and obesity, respectively (overall p = 0.02). Significantly lower odds ratios (ORs) for achieving ASAS40 response were found in adjusted analyses in obese patients versus patients with normal BMI (OR 0.27, 95% confidence interval (CI) 0.09-0.70). The respective adjusted ASAS40 OR in overweight versus normal weight patients was 0.62 (95% CI 0.24-1.14). Comparable results were found for the other outcomes assessed., Conclusions: Obesity is associated with significantly lower response rates to TNFi in patients with axSpA.

Objective: To explore the effect of comedication with conventional synthetic disease-modifying antirheumatic drugs (DMARDs) on drug retention and clinical effectiveness of tumor necrosis factor inhibitors (TNFi) in patients with axial spondyloarthritis (SpA)., Methods: The study included all patients starting treatment with a TNFi in a large prospective cohort of axial SpA patients (Swiss Clinical Quality Management in axial SpA). Crude drug retention was analyzed using the Kaplan-Meier method, and in adjusted analyses, Cox proportional hazards regression was used to model TNFi discontinuation. We evaluated multiple disease activity measures and validated clinical response criteria over time., Results: A total of 2,765 TNFi treatment courses were included from 1,914 patients with axial SpA, 20.4% in combination with a conventional synthetic DMARD. In unadjusted analyses, the monotherapy group had significantly shorter median TNFi retention time (32.7 months) compared to the cotherapy group (39.1 months) (P = 0.04). In multivariate adjusted analyses, the monotherapy group had significantly lower TNFi retention, with a hazard ratio (HR) of 1.17 (95% confidence interval [95% CI] 1.01-1.35). This effect was even larger when only infliximab-treated patients were considered, with an HR for monotherapy of 1.36 (95% CI 1.06-1.74). Clinical response rates were almost identical at 1 year, with a change in the Bath Ankylosing Spondylitis Disease Activity Index of -2.02 and -2.00 (P = 0.83) and a change in the Ankylosing Spondylitis Disease Activity Score using C-reactive protein of -1.14 and -1.12 (P = 0.45) in the monotherapy and cotherapy groups, respectively., Conclusion: We demonstrate an association between the combination of a TNFi with conventional synthetic DMARDs and improved drug retention in patients with axial SpA, particularly in the subgroup of patients with infliximab., (© 2016, American College of Rheumatology.)

Background: With regard to switching tumor necrosis factor inhibitors (TNFi) in axial spondyloarthritis (axSpA), conflicting results have been reported as to whether the effectiveness of a second TNFi depends on the reason for discontinuation of the first TNFi., Methods: Patients with a clinical diagnosis of axSpA starting a second TNFi in the Swiss Clinical Quality Management cohort were included. Effectiveness of treatment at 1 year, as well as drug survival, was compared between subgroups having discontinued the first TNFi because of lack of response, adverse events (AEs), or other reasons. Lack of response was further divided into primary or secondary lack of response (PLR or SLR, respectively), depending on whether the first TNFi was stopped before or after 6 months of treatment., Results: Among 632 patients with axSpA, median survival of a second TNFi was 1.1 years after PLR and 3.8 years after SLR (p = 0.003). At least moderate disease activity as defined by an Ankylosing Spondylitis Disease Activity Score using the erythrocyte sedimentation rate (ASDAS-ESR) <2.1 was achieved after 12 months by 11 %, 39 %, 26 %, and 39 % of patients who discontinued their first TNFi because of PLR, SLR, AEs, and other reasons, respectively (p = 0.01). Only 4 % of patients achieved an ASDAS-ESR inactive disease state after PLR, in comparison to 22 % of those after SLR. Similar results were demonstrated in patients fulfilling the Assessment of SpondyloArthritis international Society classification criteria for axSpA (n = 488): ASDAS-ESR <2.1 was achieved after 12 months by 9 %, 41 %, 29 %, and 39 % of patients who discontinued their first TNFi because of PLR, SLR, AEs, and other reasons, respectively (p = 0.01)., Conclusions: The effectiveness of a second TNFi is significantly impaired in patients with axSpA after PLR to a first TNFi compared with SLR.

Objectives: To investigate the impact of smoking on the response to treatment with a first tumour necrosis factor inhibitor (TNFi) in patients with axial spondyloarthritis (axSpA) in a real-life cohort., Methods: Patients fulfilling the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axSpA in the Swiss Clinical Quality Management Cohort were included in this study. The potential association between smoking status and differential response to TNFi in terms of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Ankylosing Spondylitis Disease Activity Score (ASDAS) was analysed using multiple adjusted longitudinal mixed effect models. Binary response rates at 1 year were assessed with multiple adjusted logistic analyses., Results: A first TNFi was initiated in 698 patients with axSpA with available smoking status and a baseline or follow-up BASDAI assessment, of which 490 (70%) had complete covariate data. In comparison to non-smokers, current smokers demonstrated significantly smaller reductions in BASDAI and ASDAS scores upon treatment with TNFi (0.75 BASDAI units and 0.69 ASDAS units less, p=0.005 and 0.001, respectively) for patients with elevated baseline C-reactive protein (CRP) level. This effect was numerically smaller in patients with normal CRP. The odds for reaching a 50% improvement in BASDAI response or the ASAS criteria for 40% improvement after 1 year were significantly lower in current smokers than in non-smokers (0.54, 95% CI 0.31 to 0.95, p=0.03 and 0.43, 95% CI 0.24 to 0.76, p=0.004, respectively)., Conclusions: Current smoking is associated with an impaired response to TNFi in axSpA., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Objective: To evaluate the initiation of and response to tumor necrosis factor (TNF) inhibitors for axial spondyloarthritis (axSpA) in private rheumatology practices versus academic centers., Methods: We compared newly initiated TNF inhibition for axSpA in 363 patients enrolled in private practices with 100 patients recruited in 6 university hospitals within the Swiss Clinical Quality Management (SCQM) cohort., Results: All patients had been treated with ≥ 1 nonsteroidal antiinflammatory drug and > 70% of patients had a baseline Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥ 4 before anti-TNF agent initiation. The proportion of patients with nonradiographic axSpA (nr-axSpA) treated with TNF inhibitors was higher in hospitals versus private practices (30.4% vs 18.7%, p = 0.02). The burden of disease as assessed by patient-reported outcomes at baseline was slightly higher in the hospital setting. Mean levels (± SD) of the Ankylosing Spondylitis Disease Activity Score were, however, virtually identical in private practices and academic centers (3.4 ± 1.0 vs 3.4 ± 0.9, p = 0.68). An Assessment of SpondyloArthritis international Society (ASAS40) response at 1 year was reached for ankylosing spondylitis in 51.7% in private practices and 52.9% in university hospitals (p = 1.0) and for nr-axSpA in 27.5% versus 25.0%, respectively (p = 1.0)., Conclusion: With the exception of a lower proportion of patients with nr-axSpA newly treated with anti-TNF agents in private practices in comparison to academic centers, adherence to ASAS treatment recommendations for TNF inhibition was equally high, and similar response rates to TNF blockers were achieved in both clinical settings.

Objective: To evaluate the baseline characteristics of patients with radiographic axial spondyloarthritis (SpA; ankylosing spondylitis [AS]) and patients with nonradiographic axial SpA, to investigate determinants of anti-tumor necrosis factor (anti-TNF) agent prescription on the background of a nonrestrictive reimbursement policy, and to assess the response to TNF inhibition., Methods: We compared the characteristics of radiographic axial SpA and nonradiographic axial SpA in 1,070 patients from the Swiss Clinical Quality Management (SCQM) Cohort who fulfilled the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axial SpA. By taking advantage of the situation that patients who are eligible for anti-TNF treatment are preferentially enrolled in the SCQM Cohort for patients with AS/axial SpA, we explored parameters leading to the initiation of anti-TNF treatment in single and multiple regression models and assessed treatment responses., Results: We confirmed a similar burden of disease (as determined by self-reported disease activity, impaired function, and quality of life) in patients with nonradiographic axial SpA (n = 232) and those with radiographic axial SpA (n = 838). Patients with radiographic axial SpA had higher median levels of acute-phase reactants and higher median AS Disease Activity Scores (ASDAS; 3.2 versus 3.0). Anti-TNF treatment was initiated in 363 patients with radiographic axial SpA and 102 patients with nonradiographic axial SpA, preferentially in those with sacroiliitis on magnetic resonance imaging, peripheral arthritis, a higher C-reactive protein (CRP) level, a higher ASDAS, and a higher Bath Ankylosing Spondylitis Disease Activity Index level. The ASAS criteria for 40% improvement responses at 1 year were higher in patients with radiographic axial SpA compared with those with nonradiographic axial SpA (48.1% versus 29.6%; odds ratio [OR] 2.2, 95% confidence interval [95% CI] 1.12-4.46, P = 0.02). The difference was smaller in the subgroups of patients with elevated baseline CRP levels (51.6% in patients with radiographic axial SpA versus 38.5% in those with nonradiographic axial SpA; OR 1.7, 95% CI 0.68-4.48, P = 0.29)., Conclusion: The indications for treatment with anti-TNF agents were comparable for patients with radiographic axial SpA and those with nonradiographic axial SpA. With the exception of patients with elevated CRP levels at baseline, higher rates of response to TNF inhibition were achieved in the group of patients with radiographic axial SpA than in the group with nonradiographic axial SpA., (Copyright © 2013 by the American College of Rheumatology.)

Target of this paper is to focus on the current knowledge about viscosupplementation in the management of osteoarthritis. The molecular structure and the effects of hyaluronic acid derivates on mechanical, biochemical and cellular level are described. Since the exogenously introduced hyaluronic acid derivates stay on average only 10 to 20 hour in the synovial fluid and yet its effect continues over months, an additional effect is postulated: modulation of the activity of the different cells in the development and progression of the osteoarthritis (synoviocytes, chondrocytes, inflammatory cells), probably by direct effect on their specific receptors. These receptors play an important role in the migration, adhesion and activation of inflammatory cells, as well as maturation and differentiation of the chondrocytes for synthesizing the cartilage matrix. In experimental studies in vitro and in vivo an analgetic and anti-inflammatory effect of hyaluronic acid derivates was proven. These results were confirmed in clinical studies. An amelioration of symptoms was shown and a delay of disease progression seems possible. This therapy is well tolerated and complications are few. Further studies to determine the optimal dosage and product (low or high-molecular preparation), the possible combination with other therapies in ideal sequence and the effect in the different subtypes of population are needed.

The classical signs and symptoms of hypothyroidism were reevaluated in the light of the modern laboratory tests for thyroid function. We analyzed 332 female subjects: 50 overt hypothyroid patients, 93 with subclinical hypothyroidism (SCH), 67 hypothyroid patients treated with T4, and 189 euthyroid subjects. The clinical score was defined as the sum of the 2 best discriminating signs and symptoms. Beside TSH and thyroid hormones, we measured parameters known to reflect tissue manifestations of hypothyroidism, such as ankle reflex relaxation time and total cholesterol. Classical signs of hypothyroidism were present only in patients with severe overt hypothyroidism with low T3, but were rare or absent in patients with normal T3 but low free T4 or in patients with SCH (normal thyroid hormones but elevated basal TSH; mean scores, 7.8 +/- 2.7 vs. 4.4 +/- 2.2 vs. 3.4 +/- 2.0; P < 0.001). Assessment of euthyroid subjects and T4-treated patients revealed very similar results (mean score, 1.6 +/- 1.6 vs. 2.1 +/- 1.5). In overt hypothyroid patients, the new score showed an excellent correlation with ankle reflex relaxation time and total cholesterol (r = 0.76 and r = 0.60; P < 0.0001), but no correlation with TSH (r = 0.01). The correlation with free T4 was r = -0.52 (P < 0.0004), and that with T3 was r = -0.56 (P < 0.0001). In SCH, the best correlation was found between the new score and free T4 (r = -0.41; P < 0.0001) and TSH (r = 0.35; P < 0.0005). Evaluation of symptoms and signs of hypothyroidism with the new score in addition to thyroid function testing is very useful for the individual assessment of thyroid failure and the monitoring of treatment.

Unlabelled: We measured basal and TRH-stimulated TSH values with a 3rd generation assay in patients under suppressive thyroxine (T4) therapy for thyroid carcinoma or goiter and in patients with overt hyperthyroidism. All hyperthyroid patients had undetectable basal TSH levels (< 0.01 mU/l). In patients on suppressive T4 treatment basal TSH values were undetectable in 37.5% (= group A) and measurable in the intermediate range of 0.01-0.05 mU/l in 62.5% (= group B). After TRH administration there was no TSH increase in the hyperthyroid patients (< 0.01 mU/l in 100%). T4-treated patients of group A showed no relevant TSH stimulation in 58% (peak < or = 0.05 mU/l = total TSH suppression). An increase of > 0.05 mU/l could be measured in 42% of group A and 100% of group B (= subtotal TSH suppression). Many of these TSH values measured by a 3rd generation assay are in the undetectable range for most of the commercially available 2nd generation assays (< 0.10 mU/l)., Conclusion: TSH assay of the 3rd generation decisively improves the diagnosis of hyperthyroidism and probably also borderline hyperthyroidism. Against the background of increased risk of osteoporosis and cardiac function disorders as a result of suppressive T4 treatment, our results suggest the following practical therapeutic guidelines: total TSH suppression with the risk of iatrogenic hyperthyroidism should be confined to high risk patients (eg with metastatic thyroid cancer). Where the risk is low, however (thyroid cancer with favourable prognosis, goiter, goiter prophylaxis), only subtotal TSH suppression is indicated.