Objective: To update the evidence on efficacy and safety of biological disease-modifying antirheumatic drugs (bDMARDs) in patients with axial spondyloarthritis (axSpA) to inform the 2022 update of... Show moreObjective: To update the evidence on efficacy and safety of biological disease-modifying antirheumatic drugs (bDMARDs) in patients with axial spondyloarthritis (axSpA) to inform the 2022 update of the Assessment of SpondyloArthritis international Society/European Alliance of Associations for Rheumatology (ASAS-EULAR) recommendations for the management of axSpA. Methods: Systematic literature review (2016-2021) on efficacy and safety of bDMARDs in axSpA (radiographic axSpA (r-axSpA)/non-radiographic axSpA (nr-axSpA)). Eligible study designs included randomised controlled trials (RCTs), strategy trials and observational studies (the latter only for safety and extra-musculoskeletal manifestations). All relevant efficacy/safety outcomes were included. Results: In total, 148 publications were included. Efficacy of golimumab and certolizumab was confirmed. Tumour necrosis factor inhibitor (TNFi) biosimilar-originator equivalence was demonstrated. RCT (n=15) data on efficacy of interleukin-17 inhibitors (IL-17i) demonstrated clinically relevant effects (risk ratio vs placebo to achieve ASAS40 response 1.3-15.3 (r-axSpA, n=9), 1.4-2.1 (nr-axSpA, n=2)). Efficacy of secukinumab/ixekizumab was demonstrated in TNFi-naive and TNFi-inadequate responders. IL-23 and IL-12/23 inhibitors (risankizumab/ustekinumab) failed to show relevant benefits. Tapering of TNFi by spacing was non-inferior to standard-dose treatment. The first axSpA treat-to-target trial did not meet its primary endpoint, but showed improvements in secondary outcomes. No new risks were identified with TNFi use in observational studies (data lacking for IL-17i). Secukinumab (n=1) and etanercept (n=2) were associated with increased risk of uveitis in observational studies compared to monoclonal TNFi. Conclusions: New evidence supports the efficacy and safety of TNFi (originators/biosimilars) and IL-17i in r-axSpA and nr-axSpA, while IL-23i failed to show relevant effects. Observational studies are needed to confirm long-term IL-17i safety. PROSPERO registration number CRD42021257588 Show less
Objective: To update the evidence of non-biological treatments for axial spondyloarthritis (axSpA), as a basis for the 2022 Assessment of SpondyloArthritis international Society-European Alliance... Show moreObjective: To update the evidence of non-biological treatments for axial spondyloarthritis (axSpA), as a basis for the 2022 Assessment of SpondyloArthritis international Society-European Alliance of Associations for Rheumatology (ASAS-EULAR) recommendations for the management of axSpA. Methods: A systematic literature review (2016-2021) on efficacy and safety of non-pharmacological and non-biological pharmacological treatments was performed, up to 1 January 2022. The research question was formulated according to the PICO format: Population: adult patients with r-axSpA and nr-axSpA; Intervention: non-pharmacological and non-biological pharmacological treatments; Comparator: active comparator or placebo; Outcomes: all relevant efficacy and safety outcomes. Type of studies included were: randomised controlled trials (RCTs), observational studies (for efficacy of non-pharmacological treatments, and safety), qualitative studies. Cohen's effect size (ES) was calculated for non-pharmacological and risk ratio (RR) for pharmacological treatments. Results: Of 107 publications included, 63 addressed non-pharmacological interventions, including education (n=8) and exercise (n=20). The ES for education on disease activity, function, mobility was small to moderate (eg. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), ES: 0.06-0.59). Exercise had moderate to high ES on these outcomes (eg. BASDAI, ES: 0.14-1.43). Six RCTs on targeted synthetic disease-modifying antirheumatic drugs (DMARDs) showed efficacy of tofacitinib, upadacitinib and filgotinib (phase 2 only) in r-axSpA (range RR vs placebo for ASAS20: 1.91-3.10), while apremilast and nilotinib were not efficacious. Studies on conventional synthetic DMARDs (n=3), non-steroidal anti-inflammatory drugs (NSAIDs, n=8) and other drugs (n=12) did not provide new evidence on efficacy/safety (efficacy of NSAIDs confirmed; limited efficacy of short-term glucocorticoids in one RCT). Conclusions Education, exercise and NSAIDs confirmed to be efficacious in axSpA. JAKi were proved efficacious in r-axSpA. Show less
Capelusnik, D.; Benavent, D.; Heijde, D. van der; Landewe, R.; Poddubnyy, D.; Tubergen, A. van; ... ; Ramiro, S. 2022
Objective To summarize evidence on the relationship between early treatment (definition based on symptom/disease duration or radiographic damage) and treatment clinical response in patients with... Show moreObjective To summarize evidence on the relationship between early treatment (definition based on symptom/disease duration or radiographic damage) and treatment clinical response in patients with SpA. Methods A systematic literature review was conducted in studies on SpA patients treated with NSAIDs or biological/targeted synthetic DMARDs addressing the impact of symptom/disease duration or presence of radiographic damage on treatment response assessed by any disease activity outcome. For categorical outcomes, relative risk, relative risk ratio and number needed to treat were calculated, and for continuous outcomes, differences in differences, to compare groups stratified based on symptom/disease duration or the presence of radiographic damage. Results From the 8769 articles retrieved, 25 were included and 2 added by hand-search, all in axial SpA (axSpA), most of them with low risk of bias. Twenty-one studies compared groups based on symptom duration (n = 6) or disease duration (n = 15) and seven studies based on absence/presence of radiographic damage (two studies used two comparisons). When early axSpA was defined by symptom duration (<5 years) in randomized controlled trials, early treatment was associated with better outcomes in patients with non-radiographic axSpA [n = 2, ASAS40 relative risk ratio 5.24 (95% CI 1.12, 24.41) and 1.52 (0.60, 3.87)] but not in radiographic axSpA (n = 1) [ASAS20 0.96 (0.53-1.73)]. When early axSpA was defined based on disease duration or radiographic damage, no differences were found between groups. Conclusion Evidence towards better outcomes in early axSpA is very limited and restricted to non-radiographic axSpA and <5 years symptom duration. When early axSpA is defined based on disease duration or radiographic damage, no differences in response to treatment are found. Show less
Benavent, D.; Capelusnik, D.; Heijde, D. van der; Landewe, R.; Poddubnyy, D.; Tubergen, A. van; ... ; Navarro-Compan, V. 2022
Aim: To identify all possible definitions of "early SpA" employed in the literature, including "early axial SpA (axSpA)" and "early peripheral SpA (pSpA)".Methods: A systematic literature review... Show moreAim: To identify all possible definitions of "early SpA" employed in the literature, including "early axial SpA (axSpA)" and "early peripheral SpA (pSpA)".Methods: A systematic literature review was conducted in Medline, EMBASE and the Cochrane Library for studies that included any mention of "early SpA" or its subtypes. The proportion of studies including a definition was calculated, and the different definitions were assessed.Results: Out of 9651 titles identified, 336 publications reporting data from 183 studies were included. Over time, an increasing number of publications were identified. In total, 114 (62%) studies reported a specific definition: 33% of them based it on symptom duration, 31% on radiographic damage, 28% on disease duration, 5% on both symptom/disease duration and radiographic damage, and 3% on other aspects. Overall, 61 (33%) studies included the term "early axSpA", whereas 60 (33%) included "early ankylosing spondylitis (AS)". Regarding the studies that referred to "early axSpA", the most used definition was symptom/disease duration <5 years, whereas for "early AS" was symptom/disease duration <10 years. After 2010, the definition of "early axSpA" based on the absence of radiographic sacroiliitis was less used compared to before 2010 (17% vs 38%).Conclusion: Over time, the term "early SpA" and its subtypes is increasingly used. More than one third of the studies did not include a definition of the term and the studies reporting one showed a large heterogeneity. These results emphasize the need for a standardised definition of early SpA. Show less
Onna, M. van; Ramiro, S.; Haines, C.; Holland-Fischer, M.; Silva, J.A.P. da; Dudler, J.; ... ; Working Grp Dev EULAR Portfolio Rh 2021
ObjectiveAbout half of the rheumatology trainees do not use a portfolio. This project was established to reach consensus about the content of a EULAR portfolio for Rheumatology training and... Show moreObjectiveAbout half of the rheumatology trainees do not use a portfolio. This project was established to reach consensus about the content of a EULAR portfolio for Rheumatology training and subsequently develop portfolio assessment forms.MethodsAfter establishing a portfolio working group (WG), including nine rheumatologists and one educationalist, a systematic literature review (SLR) on the content and structure of portfolios for postgraduate learning was conducted (November 2018). This was followed by a survey among WG members and members of the EMerging EUlar NETwork, inquiring about the content and structure of existing national portfolios. The portfolio WG selected the key components of the portfolio, taking previous experience and feasibility into account. Assessment forms (eg, case-based discussion) were developed and pilot-tested.Results13/2034 articles were included in the SLR (12 high/1 moderate risk of bias). Information on procedural skills, personal reflections, learning goals and multisource feedback was most often included a portfolio. Twenty-five respondents completed the survey (response approximate to 50%). Feedback from assessors, reflective writing and formulation of learning goals were considered important dimensions to be covered in a portfolio. Six key components of the portfolio were established: curriculum vitae, personal development plan, clinical work, professional behaviours, education and research activities. Suggested minimal content for each component was formulated. Four assessment forms were successfully pilot-tested by 11 rheumatologists and their trainees.ConclusionA EULAR portfolio for Rheumatology training and assessment forms were developed. Portfolio implementation, particularly in countries without an existing portfolio, may promote a higher standard of rheumatology training across Europe. Show less
Kerschbaumer, A.; Smolen, J.S.; Nash, P.; Doerner, T.; Dougados, M.; Fleischmann, R.; ... ; Heijde, D. van der 2020
Objectives Review of efficacy and safety of Janus kinase (JAK) inhibition in immune-mediated inflammatory diseases (IMIDs). Methods A systematic literature research (SLR) of all publications on JAK... Show moreObjectives Review of efficacy and safety of Janus kinase (JAK) inhibition in immune-mediated inflammatory diseases (IMIDs). Methods A systematic literature research (SLR) of all publications on JAK inhibitors (JAKi) treatment published until March 2019 using MEDLINE, EMBASE and the Cochrane Library. Efficacy and safety were assessed in randomised controlled trials (RCTs), integrating long-term extension periods additionally for safety evaluation. Results 3454 abstracts were screened with 85 included in the final analysis (efficacy and RCT safety: n=72; safety only: n=13). Efficacy of RCTs investigating tofacitinib (TOFA, n=27), baricitinib (BARI, n=9), upadacitinib (UPA, n=14), filgotinib (FILGO, n=7), decernotinib (DEC, n=3) and peficitinib (PEF, n=7) was evaluated. Six head-to-head trials comparing JAKi with tumour necrosis factor inhibitors (TNFi) were included. Efficacy of JAKi was shown in rheumatoid arthritis (RA) for all agents, psoriatic arthritis (TOFA, FILGO), ankylosing spondylitis (TOFA, FILGO), systemic lupus erythematosus (BARI), chronic plaque psoriasis (TOFA, BARI, PEF), ulcerative colitis (TOFA, UPA), Crohn's disease (UPA, FILGO) and atopic dermatitis (TOFA, BARI, UPA). Safety analysis of 72 RCTs, one cohort study and 12 articles on long-term extension studies showed increased risks for infections, especially herpes zoster, serious infections and numerically higher rates of venous thromboembolic events. No increased malignancy rates or major adverse cardiac events were observed. Conclusion JAKi provide good efficacy compared to placebo (and to TNFi in RA and Pso) across various IMIDs with an acceptable safety profile. This SLR informed the task force on points to consider for the treatment of IMIDs with JAKi with the available evidence. Show less
Sepriano, A.; Kerschbaumer, A.; Smolen, J.S.; Heijde, D. van der; Dougados, M.; Vollenhoven, R. van; ... ; Landewe, R. 2020
Objectives To perform a systematic literature review (SLR) concerning the safety of synthetic (s) and biological (b) disease-modifying anti rheumatic dugs (DMARDs) to inform the 2019 update of the... Show moreObjectives To perform a systematic literature review (SLR) concerning the safety of synthetic (s) and biological (b) disease-modifying anti rheumatic dugs (DMARDs) to inform the 2019 update of the EULAR recommendations for the management of rheumatoid arthritis (RA).Methods An SLR of observational studies comparing safety outcomes of any DMARD with another intervention for the management of RA. A comparator group was required for inclusion. For treatments still without registry data (eg, sarilumab and the Janus kinase (JAK) inhibitors baricitinib, upadacitinib), randomised controlled trials (RCTs) and long-term extensions (LTEs) were used. Risk of bias (RoB) was assessed according to standard procedures.Results Forty-two observational studies fulfilled the inclusion criteria, addressing safety outcomes with bDMARDs and sDMARDs. Nine studies showed no difference in the risk of serious infections across bDMARDs and two studies (high RoB) showed an increased risk with bDMARDs compared with conventional synthetic (cs) DMARDs (adjusted incidence rate ratio 3.1-3.9). The risk of Herpes zoster infection was similar across bDMARDs, but one study showed an increased risk with tofacitinib compared with abatacept (adjusted HR (aHR) 2.0). Five studies showed no increased risk of cancer for bDMARDs compared with csDMARDs. An increased risk of lower intestinal perforation was found for tocilizumab compared with csDMARDs (aHR 4.5) and tumour necrosis factor inhibitor (TNFi) (aHR 2.6-4.0). Sixty manuscripts reported safety data from RCTs/LTEs. Overall, no unexpected safety outcomes were found, except for the possibly increased risk of venous thromboembolism (VTE) with JAK inhibitors.Conclusion Data obtained by this SLR confirm the known safety profile of bDMARDs. The risk of VTE in RA, especially in patients on JAK inhibitors, needs further evaluation. Show less
Kerschbaumer, A.; Smolen, J.S.; Dougados, M.; Wit, M. de; Primdahl, J.; McInnes, I.; ... ; Gossec, L. 2020
Objective To perform an update of a review of the efficacy and safety of disease-modifying antirheumatic drugs (DMARDs) in psoriatic arthritis (PsA).Methods This is a systematic literature research... Show moreObjective To perform an update of a review of the efficacy and safety of disease-modifying antirheumatic drugs (DMARDs) in psoriatic arthritis (PsA).Methods This is a systematic literature research of 2015-2018 publications on all DMARDs in patients with PsA, searching Medline, Embase and the Cochrane Library. Efficacy was assessed in randomised controlled trials. For safety, cohort studies, case-control studies and long-term extensions (LTEs) were analysed.Results 56 publications (efficacy: n=33; safety n=23) were analysed. The articles were on tumour necrosis factor (TNF) inhibitors (n=6; golimumab, etanercept and biosimilars), interleukin (IL)-17A inhibitors (n=10; ixekizumab, secukinumab), IL-23-p19 inhibitors (n=2; guselkumab, risankizumab), clazakizumab (IL-6 inhibitor), abatacept (CD80/86 inhibitor) and ABT-122 (anti-TNF/IL-17A), respectively. One study compared ustekinumab (IL-12/23i) with TNF inhibitor therapy in patients with entheseal disease. Three articles investigated DMARD tapering. Trials on targeted synthetic DMARDs investigated apremilast (phosphodiesterase-4 inhibitor) and Janus kinase inhibitors (JAKi; tofacitinib, filgotinib). Biosimilar comparison with bio-originator showed non-inferiority. Safety was evaluated in 13 LTEs, 9 cohort studies and 1 case-control study investigating malignancies, infections, infusion reactions, multiple sclerosis and major cardiovascular events, as well as efficacy and safety of vaccination. No new safety signals were identified; however, warnings on the risk of venous thromboembolic events including pulmonary embolism when using JAKi were issued by regulators based on other studies.Conclusion Many drugs in PsA are available and have demonstrated efficacy against placebo. Efficacy varies across PsA manifestations. Safety must also be taken into account. This review informed the development of the European League Against Rheumatism 2019 updated PsA management recommendations. Show less
Kerschbaumer, A.; Sepriano, A.; Smolen, J.S.; Heijde, D. van der; Dougados, M.; Vollenhoven, R. van; ... ; Landewe, R. 2020
Objectives To inform the 2019 update of the European League against Rheumatism (EULAR) recommendations for the management of rheumatoid arthritis (RA).Methods A systematic literature research (SLR)... Show moreObjectives To inform the 2019 update of the European League against Rheumatism (EULAR) recommendations for the management of rheumatoid arthritis (RA).Methods A systematic literature research (SLR) to investigate the efficacy of any disease-modifying antirheumatic drug (DMARD) (conventional synthetic (cs)DMARD, biological (b) and biosimilar DMARD, targeted synthetic (ts)DMARD) or glucocorticoid (GC) therapy in patients with RA was done by searching MEDLINE, Embase and the Cochrane Library for articles published between 2016 and 8 March 2019.Results 234 abstracts were selected for detailed assessment, with 136 finally included. They comprised the efficacy of bDMARDs versus placebo or other bDMARDs, efficacy of Janus kinase (JAK) inhibitors (JAKi) across different patient populations and head-to-head of different bDMARDs versus JAKi or other bDMARDs. Switching of bDMARDs to other bDMARDs or tsDMARDs, strategic trials and tapering studies of bDMARDs, csDMARDs and JAKi were assessed. The drugs evaluated included abatacept, adalimumab, ABT-122, baricitinib, certolizumab pegol, SBI-087, CNTO6785, decernotinib, etanercept, filgotinib, golimumab, GCs, GS-9876, guselkumab, hydroxychloroquine, infliximab, leflunomide, mavrilimumab, methotrexate, olokizumab, otilimab, peficitinib, rituximab, sarilumab, salazopyrine, secukinumab, sirukumab, tacrolimus, tocilizumab, tofacitinib, tregalizumab, upadacitinib, ustekinumab and vobarilizumab. The efficacy of many bDMARDs and tsDMARDs was shown. Switching to another tumour necrosis factor inhibitor (TNFi) or non-TNFi bDMARDs after TNFi treatment failure is efficacious. Tapering of DMARDs is possible in patients achieving long-standing stringent clinical remission; in patients with residual disease activity (including patients in LDA) the risk of flares is increased during the tapering. Biosimilars are non-inferior to their reference products.Conclusion This SLR informed the task force regarding the evidence base of various therapeutic regimen for the development of the update of EULAR's RA management recommendation. Show less
Ramiro, S.; Sepriano, A.; Chatzidionysiou, K.; Nam, J.L.; Smolen, J.S.; Heijde, D. van der; ... ; Landewe, R.B.M. 2017
