Search

Objective: To evaluate the association of nociplastic (NoP) and neuropathic pain (NP) components with residual symptoms in patients with radiographic axial spondyloarthritis (r-axSpA) receiving biological disease-modifying antirheumatic drugs (bDMARDs)., Methods: 78 patients with r-axSpA from the GErman SPondyloarthritis Inception Cohort receiving a bDMARD for at least 3 months were included in this analysis. The Widespread Pain Index (WPI) and the PainDETECT (PD) questionnaire were used to quantify the NoP and the NP components, respectively. Axial Spondyloarthritis Disease Activity Score (ASDAS) and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) were used as measures of residual symptoms. C reactive protein (CRP) was used as a measure of systemic inflammatory activity. Univariable and multivariable regression analyses of disease activity were performed. The regions of the WPI score and items of the PD score were used for cluster analyses., Results: Linear multivariable regression analysis showed that WPI and PD were independently associated with ASDAS (b=0.1, 95% CI 0.04 to 0.17, and b=0.05, 95% CI 0.02 to 0.08, respectively) and BASDAI (b=0.24, 95% CI 0.08 to 0.39, and b=0.17, 95% CI 0.1 to 0.25, respectively) in r-axSpA patients receiving stable treatment with bDMARDs. Furthermore, WPI and PD were found to be significantly associated with the presence of relevant residual symptoms as defined by BASDAI ≥4 (OR 1.93, 95% CI 1.09 to 4.15, and OR 1.32, 95% CI 1.04 to 1.85, respectively). The effects were present also in patients with normal level of CRP. Cluster analysis revealed three distinct pain distribution profiles and four specific sensory symptom constellations allowing differentiation of different pain subtypes., Conclusion: Both NoP and NP components seem to be associated with residual symptoms in patients with r-axSpA receiving treatment with bDMARDs., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Upadacitinib, a Janus kinase inhibitor, has demonstrated efficacy and an acceptable safety profile in patients with ankylosing spondylitis (AS) in the phase III SELECT-AXIS programs. We report the 1-year efficacy and safety in patients with AS and an inadequate response to biologic disease-modifying antirheumatic drugs (bDMARD-IR) from the SELECT-AXIS 2 study., Methods: Patients ≥ 18 years with active AS who met the modified New York criteria for AS and were bDMARD-IR received double-blind upadacitinib 15 mg once daily (QD) or placebo for 14 weeks. Patients who completed 14 weeks could enter an open-label extension and receive upadacitinib 15 mg QD for up to 2 years. Efficacy endpoints included the percentage of patients achieving ≥ 40% improvement in Assessment of SpondyloArthritis international Society response (ASAS40), Ankylosing Spondylitis Disease Activity Score (ASDAS) low disease activity (LDA), and ASDAS inactive disease (ID); and change from baseline in total and nocturnal back pain, and Bath Ankylosing Spondylitis Functional Index (BASFI). Subgroup analyses (bDMARD lack of efficacy versus intolerance, and prior tumor necrosis factor inhibitor [TNFi] versus interleukin-17 inhibitor [IL-17i] exposure) were conducted. Binary and continuous efficacy endpoints were assessed using non-responder imputation with multiple imputation (NRI-MI) and as observed (AO) analyses; and mixed-effects model repeated measures (MMRM) and AO, respectively. Safety was assessed based on adverse events. Data through week 52 are reported., Results: Of 420 randomized patients, 366 (continuous upadacitinib: n = 181; placebo to upadacitinib: n = 185) completed 52 weeks of treatment. At week 52, in the continuous upadacitinib and placebo to upadacitinib groups, ASAS40, ASDAS LDA, and ASDAS ID were achieved by 66% and 65%, 57% and 55%, and 26% and 25% (all NRI-MI); and change from baseline in total back pain, nocturnal back pain, and BASFI was -4.5 and -4.3, -4.6 and -4.4, and -3.6 and -3.5 (all MMRM), respectively. No new safety risks were identified. Subgroup analyses were consistent with the overall study population., Conclusions: Upadacitinib 15 mg QD demonstrated sustained improvement up to 52 weeks in bDMARD-IR patients with AS. Efficacy was generally similar in patients with lack of efficacy versus intolerance to bDMARDs and prior TNFi versus IL-17i exposure., Trial Registration: NCT02049138., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objectives: To evaluate the efficacy and safety of upadacitinib, a Janus kinase inhibitor, in patients with active ankylosing spondylitis (AS) with an inadequate response (IR) to biological disease-modifying antirheumatic drugs (bDMARDs)., Methods: Adults with active AS who met modified New York criteria and had an IR to one or two bDMARDs (tumour necrosis factor or interleukin-17 inhibitors) were randomised 1:1 to oral upadacitinib 15 mg once daily or placebo. The primary endpoint was Assessment of SpondyloArthritis international Society 40 (ASAS40) response at week 14. Sequentially tested secondary endpoints included Ankylosing Spondylitis Disease Activity score, Spondyloarthritis Research Consortium of Canada MRI spine inflammation score, total back pain, nocturnal back pain, Bath Ankylosing Spondylitis Functional Index, Bath Ankylosing Spondylitis Metrology Index and Maastricht Ankylosing Spondylitis Enthesitis Score. Results are reported from the 14-week double-blind treatment period., Results: A total of 420 patients with active AS were randomised (upadacitinib 15 mg, n=211; placebo, n=209). Significantly more patients achieved the primary endpoint of ASAS40 at week 14 with upadacitinib vs placebo (45% vs 18%; p<0.0001). Statistically significant improvements were observed with upadacitinib vs placebo for all multiplicity-controlled secondary endpoints (p<0.0001). Adverse events were reported for 41% of upadacitinib-treated and 37% of placebo-treated patients through week 14. No events of malignancy, major adverse cardiovascular events, venous thromboembolism or deaths were reported with upadacitinib., Conclusion: Upadacitinib 15 mg was significantly more effective than placebo over 14 weeks of treatment in bDMARD-IR patients with active AS. No new safety risks were identified with upadacitinib., Trial Registration Number: NCT04169373., Competing Interests: Competing interests: DvdH has received consulting fees from AbbVie, Bayer, BMS, Cyxone, Eisai, Galapagos, Gilead, GSK, Janssen, Lilly, Novartis, Pfizer, and UCB Pharma; is the director of Imaging Rheumatology BV; is an Associate Editor of the Annals of Rheumatic Diseases; is an editorial board member of the Journal of Rheumatology; and is an advisor for the Assessment in SpondyloArthritis international Society. XB has received grant/research support from AbbVie and Novartis; consulting fees from AbbVie, BMS, Chugai, MSD, Novartis, Pfizer, and UCB; speakers’ bureau fees from AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, and UCB; and is an editorial board member of the Annals of Rheumatic Diseases. JS has received grant/research support from AbbVie, Merck, and UCB; has been a consultant for AbbVie, Merck, Novartis, and UCB; and has served on the speakers’ bureau for AbbVie, Merck, and Novartis. AD has received grant/research support from AbbVie, BMS, Celgene, GSK, Lilly, Novartis, Pfizer, and UCB; and honoraria or consultation fees from AbbVie, Amgen, Aurinia, BMS, Celgene, GSK, Janssen, Lilly, MoonLake, Novartis, Pfizer, and UCB. RDI has received grant/research support from AbbVie, Amgen, Janssen, and Novartis; and has been a consultant for AbbVie, Amgen, Janssen, Lilly, Novartis, Pfizer, and Sandoz. HK has received grant/research support from AbbVie, Asahi-Kasei, Boehringer Ingelheim, Chugai, Eisai, and Mitsubishi-Tanabe; consulting fees from AbbVie, Janssen, Lilly, Novartis, Sanofi, and UCB; and received speakers’ bureau fees from AbbVie, Asahi-Kasei, BMS, Chugai, Eisai, Janssen, Lilly, Mitsubishi-Tanabe, Novartis, and Pfizer. XZ has none declared. YS, XB, PW and I-HS are employees of AbbVie and may own stock or options. ALP is a former employee of AbbVie and may own stock or options., (© 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.)

Introduction: Long-term safety and efficacy of upadacitinib in patients with active ankylosing spondylitis (AS) has not been previously reported., Methods: In SELECT-AXIS 1, patients receiving placebo were switched to upadacitinib 15 mg once daily at week 14 while patients initially randomised to upadacitinib continued their regimen through week 104. Efficacy was assessed using as-observed (AO) and non-responder imputation (NRI)., Results: Of 187 patients randomised, 144 patients (77%) completed week 104. Among patients receiving continuous upadacitinib, 85.9% (AO) and 65.6% (NRI) achieved Assessment of SpondyloArthritis international Society 40 response (ASAS40) at week 104. Similar magnitude of ASAS40 responses were observed among patients who switched from placebo to upadacitinib (88.7% and 63.8%, respectively). The mean change from baseline to week 104 in Spondyloarthritis Research Consortium of Canada MRI spine and sacroiliac joint inflammation scores were -7.3 and -5.3, respectively, in the continuous upadacitinib group and -7.9 and -4.9 in the placebo-to-upadacitinib switch group. The mean (95% CI) change from baseline to week 104 in the modified Stoke Ankylosing Spondylitis Spine Score was 0.7 (0.3, 1.1) in the total group. Adverse event rate was 242.7/100 patient-years. No serious infections, adjudicated major adverse cardiovascular events, lymphoma, non-melanoma skin cancer, or gastrointestinal perforations were observed., Conclusions: Upadacitinib 15 mg once daily showed sustained and consistent efficacy over 2 years for ASAS40 and other clinically relevant endpoints. A low rate of radiographic progression was observed and no new safety findings were observed., Competing Interests: Competing interests: DvdH has received consultancy fees from AbbVie, Bayer, BMS, Cyxone, Eisai, Galapagos, Gilead, Glaxo-Smith-Kline, Janssen, Lilly, Novartis, Pfizer, and UCB Pharma and is a Director of Imaging Rheumatology BV. AD has received research grants, consultancy fees, speaker fees, and other support (medical writing support) from Novartis and Pfizer; research grants, consultancy fees, and other support (medical writing support) from AbbVie, Eli Lilly, and UCB Pharma; research grants and consultancy fees from GlaxoSmithKline; consultancy fees and other support (medical writing support) from Janssen; consultancy fees from Aurinia, Boehringer Ingelheim, Celgene, and MoonLake; and other support (medical writing support) from Amgen. WPM has received research grants and consultancy fees from AbbVie, Novartis, and Pfizer; and consultancy fees from Boehringer Ingelheim, Celgene, Galapagos, Gilead, Janssen, Lilly and UCB Pharma and is Chief Medical Officer of CARE Arthritis. JS has received consultancy and speaker fees from AbbVie, Janssen, Lilly, Merck, Novartis, and UCB. FVdB has received consultancy fees and/or speaker fees from AbbVie, Celgene, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, and UCB Pharma. T-HK has received speaker fees from AbbVie, Celltrion, Kirin, Lilly, and Novartis. MK has received consulting fees and/or speaker fees from AbbVie, Amgen, Asahi-Kasei Pharma, Astellas, Ayumi Pharma, BMS, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Janssen, Kyowa Kirin, Novartis, Ono Pharma, Pfizer, Tanabe-Mitsubishi, and UCB Pharma. AJO has served as a consultant and/or on advisory boards for AbbVie, BMS, Roche, Janssen, Lilly, Novartis, Pfizer, UCB, Gilead, and Paradigm. BC has received research grants, consultancy and speaker fees from and served as a board member for AbbVie and Lilly; received consultancy fees from and served as a board member for Gilead, Galapagos, and Janssen; received consultancy fees from Celltrion; and received speaker fees from BMS, Celltrion, Merck, Novartis, Pfizer, and Roche-Chugai. YS, YD and PKW are full-time, salaried employees of AbbVie Inc. and own AbbVie stock or stock options. I-HS is a full-time, salaried employee of AbbVie, owns AbbVie stock or stock options, and is an inventor on a patent application., (© 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 report the efficacy and safety of upadacitinib through 1 year in patients with ankylosing spondylitis (AS)., Methods: In the SELECT-AXIS 1 study, adults with active AS and an inadequate response to nonsteroidal antiinflammatory drugs were randomized to receive upadacitinib 15 mg once daily or placebo. At week 14, patients who had been randomized to receive placebo were switched to upadacitinib, and all patients continued in the open-label extension and received upadacitinib up to week 104; interim data up to week 64 are reported herein., Results: Of 187 patients, 178 completed week 14 on study drug and entered the open-label extension. Similar proportions of patients in either group (continuous upadacitinib or placebo-to-upadacitinib) achieved Assessment of SpondyloArthritis international Society 40% response (ASAS40) or Ankylosing Spondylitis Disease Activity Score (ASDAS) showing low disease activity at week 64: ≥70% of patients achieved these end points based on nonresponder imputation (NRI) and ≥81% based on as-observed analyses. Furthermore, ≥34% (NRI) and ≥39% (as-observed analysis) achieved ASDAS showing inactive disease or ASAS showing partial remission at week 64. Mean changes from baseline (week 0) to week 64 in pain, function, and inflammation showed consistent improvement or sustained maintenance through the study. Among 182 patients receiving upadacitinib (237.6 patient-years), 618 adverse events (260.1 per 100 patient-years) were reported. No serious infections, major adverse cardiovascular events, venous thromboembolic events, gastrointestinal perforation, or deaths were reported., Conclusion: Upadacitinib 15 mg once daily showed sustained and consistent efficacy over 1 year. Patients who switched from placebo to upadacitinib at week 14 showed similar efficacy versus those who received continuous upadacitinib., (© 2021 AbbVie Inc. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Purpose of Review: We have now about 20 years of experience with the treatment of axial spondyloarthritis with biologics, which raises the question what we can learn from past experience, and which open questions should be addressed in future investigations., Recent Findings: Many studies have shown that axSpA patients - both patients in their nonradiological and radiological stage - respond similarly well to biologic treatment and these patients should be seen as having the same disease at different stages. AxSpA respond best to TNF-blocker - and probably also to other biologics - if the disease duration is short and if objective parameters of inflammation, such as C-reactive protein or MRI are positive. Primary aim of treatment is to reach and maintain clinical remission. Once remission is achieved, it can be maintained by continuing treatment, and in a proportion of yet not well defined patients the drug dose can be reduced without inducing a flare. The recent demonstration of a good efficacy, in addition to TNF blockers, also of IL-17 inhibitors and JAK-inhibitors in axSpA patients raises the question how to select the best patients for the best treatment. Radiographic progression can best be stopped by effectively suppressing inflammation, whether different drugs have here a different effect has still to be defined. More sensitive measurements of radiographic progression are urgently needed., Summary: Reaching and maintaining clinical remission and preventing structural bony damage is the primary treatment target in patients with axSpA. How to reach this aim best has to be further explored in the future., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: To 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)., Methods: Adults 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., Results: In 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., Conclusion: The 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 Number: NCT02696785/NCT02696798., Competing Interests: Competing interests: MD has served as a consultant and received research grants from AbbVie, Eli Lilly and Company, Pfizer and UCB Pharma. JC-CW has served as a consultant and/or speaker and/or has received research grants from Abbott, Bristol-Myers Squibb, Celgene, Chugai, Eisai, Eli Lilly and Company, Janssen, Novartis, Pfizer, Sanofi-Aventis, TSH Taiwan and UCB Pharma. RL has served as a consultant and/or advisor and/or has received research grants from AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Janssen, Galapagos, Merck, Novartis, Pfizer and UCB Pharma. RL is the director of Rheumatology Consultancy BV, a company that was indirectly contracted by Eli Lilly and Company to perform read services for the COAST program. JS has served as a consultant and/or speaker for AbbVie, Boehringer Ingelheim, Eli Lilly and Company, Janssen, Merck, Novartis, Pfizer, Roche and UCB Pharma. XB has served as a consultant and/or has received research grants from AbbVie, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Pfizer, Roche and UCB Pharma. FVdB has served as a consultant and/or speaker and/or has received research grants from AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Janssen, Merck, Novartis, Pfizer, Sanofi and UCB Pharma. WPM has served as a consultant and/or received honoraria and/or research/educational grants from AbbVie, Boehringer Ingelheim, Celgene, Eli Lilly and Company, Galapagos, Janssen, Novartis, Pfizer and UCB Pharma, and is Chief Medical Officer of CARE Arthritis Limited. JE has served as a consultant and/or received research grants from AbbVie, Boehringer Ingelheim, Eli Lilly and Company, Janssen, Novartis, Pfizer, Takeda and UCB Pharma. JAW has been a consultant and/or received research grants from AbbVie, Amgen, Celgene, Eli Lilly and Company, Novartis, Pfizer and UCB Pharma. AD has been a consultant and/or received research support from AbbVie, Bristol-Myers Squibb, Eli Lilly and Company, Glaxo Smith & Klein, Janssen, Novartis, Pfizer and UCB Pharma. DvdH has been a consultant for AbbVie, Amgen, Astellas, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi, Eli Lilly and Company, Galapagos, Gilead, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda and UCB Pharma and is a Director of Imaging Rheumatology BV. TT has been a consultant and speaker for AbbVie, Astellas, Bristol-Myers Squibb, Eisai, Eli Lilly and Company, Janssen, Mitsubishi Tanabe, Novartis, Pfizer and Takeda. XL, FZ, CCB, GG and HC are current employees and shareholders of Eli Lilly and Company. LSG has been a consultant and/or received research grants/support from AbbVie, Amgen, Eli Lilly and Company, Galapagos, Janssen, Novartis, Pfizer and UCB Pharma., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The cytokines IL-23 and IL-17 have an important role in the pathogenesis of, and as a therapeutic target in, both animal models of chronic inflammation and some human chronic inflammatory diseases. The traditional view is that a main source of IL-17 is T cells and that IL-17 production is under the control of IL-23. IL-17 inhibition has shown good efficacy in clinical trials for ankylosing spondylitis (AS), a subtype of axial spondyloarthritis (axSpA) characterized by radiographic evidence of sacroiliitis. On the basis of data from animal models, genetic studies and the investigation of tissue and blood samples from patients with AS, IL-23 had also been predicted to be important in the pathogenesis of this disease and was therefore considered a potential therapeutic target for axSpA. However, two placebo-controlled, double-blind clinical trials in axSpA of monoclonal antibodies directed against either the p40 protein or the p19 protein of the IL-23 molecule had clear negative results. These findings indicate that IL-23 and IL-17 are at least partly uncoupled in axSpA. Reasons as to why, when and how such an uncoupling might occur are discussed in this Review, with special reference to the unique microenvironment of the subchondral bone marrow in axSpA.

Purpose of Review: There was a substantial progress in the field of spondyloarthritis (SpA) in terms of understanding disease mechanisms, early diagnosis, and improved treatment. Nonetheless, several unresolved questions and unmet needs do remain., Recent Findings: Although the diagnostic delay in axial SpA is decreasing, it remains one of the longest in rheumatology. Application of referral strategies, as well as correct application and interpretation of imaging finding in the clinical context, is the main key to early diagnosis of axial SpA. Tumor necrosis factor (TNF) alpha and interleukin (IL)-17 represent currently two major treatment targets in SpA, while other promising targets such as IL-23 or IL-6 failed in clinical trials. There is an unmet need for strategy trials to optimize and to individualize treatment in SpA. The role of Janus kinases and their blockade in SpA is still to be explored. TNF blockade showed efficacy in peripheral SpA, and other targets (IL-17 and IL-23) should be investigated in clinical trials. Early, effective, and long-term suppression of inflammation is currently the best method to prevent structural damage progression in the spine in axial SpA, while specific effects of IL-17 blockade and of nonsteroidal anti-inflammatory drugs on new bone formation are still being investigated. This review summarizes the recent advances in diagnosis and treatment of SpA and discusses the current unmet needs in the field.

Background: This analysis assessed baseline predictors of remission in patients with non-radiographic axial spondyloarthritis (nr-axSpA) who received open-label adalimumab therapy., Methods: ABILITY-3 enrolled 673 adult patients with nr-axSpA who had objective evidence of inflammation by MRI or elevated high-sensitivity C reactive protein at screening, active disease and an inadequate response to two or more non-steroidal anti-inflammatory drugs. Patients received adalimumab 40 mg every other week during a 28-week open-label lead-in period. Clinical remission was defined as Ankylosing Spondylitis Disease Activity Score inactive disease (ASDAS ID; score <1.3) and Assessment of SpondyloArthritis international Society partial remission (ASAS PR; score <2/10 in each of the four ASAS domains). Stepwise logistic regression was used to identify baseline predictors of remission at week 12 and at final visit (last postbaseline visit up to week 28). Only patients without missing data were included., Results: Overall, 593 patients were included in the ASDAS ID and 596 in the ASAS PR analysis at week 12. Younger age (≤45 years), male sex, positive human leucocyte antigen (HLA)-B27 and higher Spondyloarthritis Research Consortium of Canada (SPARCC) MRI sacroiliac joint score were consistent predictors of remission by both ASAS ID and ASDAS PR at week 12. Results were generally similar in the final visit analysis. Other variables did not consistently predict remission., Conclusions: In ABILITY-3, consistent and strong baseline predictors of remission included younger age, male sex, HLA-B27 positivity and higher SPARCC MRI sacroiliac joint score among patients with active nr-axSpA receiving adalimumab therapy, similar to previous findings in ankylosing spondylitis., Competing Interests: Competing interests: JS has received consulting fees from AbbVie, Boehringer Ingelheim, Janssen, Lilly, Merck, Novartis, Pfizer, Sun Pharma, and UCB; and speaker fees from AbbVie, Janssen, Lilly, Merck, Novartis, Pfizer and UCB. RL has received consulting or advisory board fees from Abbott/AbbVie, Ablynx, Amgen, AstraZeneca, Bristol Myers Squibb, Celgene, Janssen, Galapagos, GlaxoSmithKline, Novartis, Novo Nordisk, Merck, Pfizer, Roche, Schering-Plough, TiGenix, UCB and Wyeth; research grants from Abbott, Amgen, Centocor, Novartis, Pfizer, Roche, Schering-Plough, UCB and Wyeth; speaker fees from Abbott/AbbVie, Amgen, Bristol Myers Squibb, Janssen, Merck, Pfizer, Roche, Schering-Plough, UCB and Wyeth; and is director of Rheumatology Consultancy BV, a registered Dutch company. MM has received research grants from Amgen, AbbVie and UCB Pharma and consulting fees from Novartis and Eli Lilly. SZ, XW, AL and JKA are full-time employees of AbbVie and may own AbbVie stock and/or stock options.

Objective: To evaluate the efficacy and safety of ustekinumab in 3 randomized, placebo-controlled studies in patients with axial spondyloarthritis (SpA). Studies 1 and 2 included patients with radiographic axial SpA (anti-tumor necrosis factor [anti-TNF]-naive patients and patients with inadequate response or intolerance to anti-TNF, respectively); study 3 patients had nonradiographic axial SpA., Methods: In all 3 studies, patients were randomly assigned (1:1:1) to receive subcutaneous ustekinumab at 45 mg or 90 mg or placebo up to 24 weeks, after which placebo-treated patients were rerandomized to receive ustekinumab at 45 mg or 90 mg. The primary end point in studies 1 and 2 was the proportion of patients who met the Assessment of SpondyloArthritis international Society criteria for 40% improvement in disease activity (achieved an ASAS40 response). The primary end point in study 3 was the proportion of patients who achieved an ASAS20 response. Other disease activity and safety measures were also evaluated. A week 24 analysis of study 1 was preplanned to determine continuation of studies 2 and 3., Results: For study 1, the primary and major secondary end points were not met, and the study was discontinued. As a result, studies 2 and 3 were prematurely discontinued before they were fully enrolled. For all 3 studies, neither ustekinumab dose group demonstrated clinically meaningful improvement over placebo on key efficacy end points. The proportion of patients experiencing adverse events in the ustekinumab groups was consistent with that in previous studies., Conclusion: In these 3 placebo-controlled trials, efficacy of ustekinumab in the treatment of axial SpA was not demonstrated. The safety profile was consistent with that of studies in other indications., (© 2018, American College of Rheumatology.)

Objectives: To evaluate the efficacy and safety of risankizumab, a humanised monoclonal antibody targeting the p19 subunit of interleukin-23 (IL-23), in patients with active ankylosing spondylitis (AS)., Methods: A total of 159 patients with biological-naïve AS, with active disease (Bath Ankylosing Spondylitis Disease Activity Index score of ≥4), were randomised (1:1:1:1) to risankizumab (18 mg single dose, 90 mg or 180 mg at day 1 and weeks 8, 16 and 24) or placebo over a 24-week blinded period. The primary outcome was a 40% improvement in Assessment in Spondylo Arthritis International Society (ASAS40) at week 12. Safety was assessed in patients who received at least one dose of study drug., Results: At week 12, ASAS40 response rates were 25.5%, 20.5% and 15.0% in the 18 mg, 90 mg and 180 mg risankizumab groups, respectively, compared with 17.5% in the placebo group. The estimated difference in proportion between the 180 mg risankizumab and placebo groups (primary endpoint) was -2.5% (95% CI -21.8 to 17.0; p=0.42). Rates of adverse events were similar in all treatment groups., Conclusions: Treatment with risankizumab did not meet the study primary endpoint and showed no evidence of clinically meaningful improvements compared with placebo in patients with active AS, suggesting that IL-23 may not be a relevant driver of disease pathogenesis and symptoms in AS., Trial Registration Number: NCT02047110; Pre-results., Competing Interests: Competing interests: DB reports grants from AbbVie, Pfizer, UCB, MSD, Novartis and Eli Lilly and part-time employment at UCB. MØ reports grants, personal fees and non-financial support from AbbVie, BMS, Merck, UCB and Novartis; grants and personal fees from Celgene; personal fees and non-financial support from Janssen, Pfizer and Roche; and personal fees from Boehringer Ingelheim, Eli Lilly, Sanofi, Regeneron, Orion and Hospira. JS reports personal fees from Boehringer Ingelheim, AbbVie, Janssen, Lilly, Merck, Novartis, Pfizer and UCB. PJ reports grants from AbbVie, Daiichi Sankyo, Boehringer Ingelheim, Lilly, Novartis, Roche and UCB and grants and personal fees from BMS and Pfizer. YD, CP, SV, DBH, SA, PS and SJP report being employees of Boehringer Ingelheim., (© 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.)

Peripheral spondyloarthritis refers to spondyloarthritis with predominant peripheral (arthritis, enthesitis or dactylitis) involvement. Diagnosis can be challenging, particularly in the absence of SpA extra-articular manifestations such as uveitis, psoriasis or inflammatory bowel disease. Evaluation of disease activity should always include assessment of objective signs of inflammation, particularly in the presence of enthesitis as the sole peripheral manifestation, mainly due to the potential misdiagnosis with fibromyalgia tender points. Several recommendations for management/treatment of psoriatic arthritis have been published by EULAR and GRAPPA but none for peripheral SpA in general. NSAIDs and glucocorticoids are recommended as the first step of treatment in all peripheral manifestations, while conventional synthetic (cs) DMARDs seem only efficacious in arthritis. Several biologics and targeted synthetic (ts) DMARDs (TNFi, anti-IL17 and JAK-inhibitors) have been proven to be efficacious in peripheral involvement in PsA (arthritis and enthesitis), but studies on peripheral SpA are lacking., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

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.

Objective: To evaluate the long-term clinical and imaging efficacy of etanercept in patients with early, active nonradiographic axial spondyloarthritis (SpA)., Methods: Adult patients who satisfied the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axial SpA (but not the modified New York radiographic criteria), with symptom duration >3 months to <5 years, and who were unresponsive to ≥2 nonsteroidal antirheumatic drugs (NSAIDs) received double-blind etanercept 50 mg/week or placebo for 12 weeks, followed by open-label etanercept 50 mg/week to week 104. Clinical, magnetic resonance imaging (MRI; Spondyloarthritis Research Consortium of Canada [SPARCC] scores), and safety outcomes at 104 weeks were analyzed., Results: Of 215 randomized patients (etanercept: n = 106; placebo: n = 109), 205 entered the study (etanercept/etanercept: n = 100; placebo/etanercept: n = 105) and 169 completed the open-label period (etanercept/etanercept: n = 83; placebo/etanercept: n = 86). At week 104, 61 of 81 (75%), 49 of 81 (61%), 48 of 80 (60%), and 57 of 81 (70%) patients who received etanercept throughout the trial achieved ASAS20, ASAS40, Ankylosing Spondylitis Disease Activity Score (ASDAS) inactive disease, and Bath Ankylosing Spondylitis Disease Activity Index criteria for 50% improvement (BASDAI 50) scores, respectively (observed). From baseline to week 104, continued improvements in clinical outcomes (ASDAS-C-reactive protein: -1.5 and -1.7; BASDAI: -3.3 and -3.8 [last observation carried forward]), and SPARCC MRI scores (sacroiliac joint: -6.0 and -3.4; spinal: -2.1 and -0.8 [observed]) were seen in patients receiving etanercept/etanercept and placebo/etanercept. During the study, 8% in the etanercept/etanercept group and 7% in the placebo/etanercept group had serious adverse events; no new safety signals were seen., Conclusion: Patients with early, active nonradiographic axial SpA and an inadequate response to at least 2 NSAIDs demonstrated improvement in clinical and imaging outcomes that were sustained through 104 weeks of etanercept treatment., (© 2017, American College of Rheumatology.)

Objective: The aim was to assess the long-term safety and efficacy of certolizumab pegol over 4 years of continuous treatment in patients with axial spondyloarthritis (axSpA), including both AS and non-radiographic (nr-) axSpA., Methods: RAPID-axSpA was a phase 3 randomized trial, double blind and placebo controlled to week 24, dose blind to week 48 and open label to week 204. Patients had a clinical diagnosis of axSpA, meeting Assessment of SpondyloArthritis international Society (ASAS) criteria, and had active disease. The assessed outcomes included ASAS20, ASAS40, AS DAS (ASDAS), BASDAI, BASFI and BASMI scores, along with selected measures of remission. Further patient-reported outcomes, peripheral arthritis, enthesitis, uveitis and quality-of-life measures are also reported., Results: Two hundred and eighteen of 325 patients randomized (AS: 121; nr-axSpA: 97) received certolizumab pegol from week 0. Of these, 65% remained in the study at week 204 (AS: 67%; nr-axSpA: 63%). Across all outcomes, for AS and nr-axSpA, sustained improvements were observed to week 204 [week 204 overall axSpA: ASAS20: 54.1% (non-responder imputation); 83.7% (observed case, OC); ASAS40: 44.0% (non-responder imputation); 68.1% (OC); ASDAS inactive disease: 32.1% (last observation carried forward); 31.4% (OC)]. In the safety set (n = 315), there were 292.8 adverse events and 10.4 serious adverse events per 100 patient-years. No deaths were reported., Conclusion: In the first study to evaluate the efficacy of an anti-TNF across both axSpA subpopulations, improvements in clinical and patient-reported outcomes at 24 and 96 weeks were sustained through 4 years of treatment, with no new safety signals., Trial Registration: ClinicalTrials.gov, http://clinicaltrials.gov, NCT01087762., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: To evaluate the effect of secukinumab, an interleukin-17A inhibitor, on clinical signs and symptoms and radiographic changes through 2 years in patients with ankylosing spondylitis (AS)., Methods: In the phase III MEASURE 1 study, patients were randomised to receive intravenous secukinumab 10 mg/kg (at baseline, week 2 and week 4) followed by subcutaneous secukinumab 150 mg (intravenous 150 mg; n=125) or 75 mg (intravenous 75 mg; n=124) every four weeks, or matched placebo (n=122). Placebo-treated patients were re-randomised to subcutaneous secukinumab 150 or 75 mg from week 16. Clinical efficacy assessments included Assessment of SpondyloArthritis international Society 20 (ASAS20) response rates through week 104. Radiographic changes at week 104 were assessed using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS)., Results: 97 (77.6%) and 103 (83.1%) patients in the intravenous 150 mg and intravenous 75 mg groups, respectively, completed week 104. In the full analysis set (intent-to-treat), ASAS20 response rates at week 104 were 73.7% and 68.0% in the intravenous 150 mg and intravenous 75 mg groups, respectively. Among patients with evaluable X-rays who were originally randomised to secukinumab (n=168), mean change in mSASSS from baseline to week 104 was 0.30±2.53. Serious adverse events were reported in 12.2% and 13.4% of patients in the 150 mg and 75 mg groups, respectively., Conclusions: Secukinumab improved AS signs and symptoms through 2 years of therapy, with no unexpected safety findings. Data from this study suggest a low mean progression of spinal radiographic changes, which will need to be confirmed in longer-term controlled studies., Trial Registration Number: NCT01358175., Competing Interests: Competing interests: JB has received honoraria for talks, advisory boards, paid consultancies and grants for studies from Abbott/AbbVie, Amgen, BMS, Boehringer Ingelheim, Celgene, Celltrion, Centocor, Chugai, EBEWE Pharma, Janssen, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis and UCB. XB has served as a consultant or paid speaker for or participated in clinical trials sponsored by AbbVie, Boehringer Ingelheim, Celgene, Centocor, Chugai, MSD, Novartis, Pfizer and UCB. AD has received research grants and honorarium for serving on the advisory boards of AbbVie, Amgen, Boehringer Ingelheim, Janssen, Novartis, Pfizer and UCB. DB has served as a consultant or paid speaker for or participated in clinical trials sponsored by AbbVie, BMS, Boehringer Ingelheim, Glenmark, Janssen, Eli Lilly, MSD, Novartis, Novo Nordisk, Pfizer, Roche and UCB. JS has served as a consultant or paid speaker for or participated in clinical trials sponsored by AbbVie, Janssen, Eli Lilly, Merck, Novartis, Pfizer and UCB. PE has participated in clinical trials for and provided expert advice to AbbVie, BMS, Eli Lilly, MSD, Novartis, Pfizer, Roche, Samsung, Takeda and UCB. AR, RM and HBR are employees of Novartis. AR and HBR own Novartis stock., (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 validity of enthesitis indices in patients with peripheral spondyloarthritis (pSpA)., Methods: The ABILITY-2 study evaluated the efficacy of adalimumab (ADA) versus placebo (PBO) in patients with active pSpA over 12 weeks. Patients received open-label ADA for an additional 144 weeks. Twenty-nine enthesitis sites used in 3 enthesitis scoring systems [Leeds Enthesitis Index (LEI), Spondyloarthritis Research Consortium of Canada (SPARCC) Enthesitis Index, Maastricht Ankylosing Spondylitis Enthesitis Score (MASES)] were assessed; discriminatory capacity and treatment response at Week 12 were calculated by standardized mean difference (SMD) and Guyatt's effect size (ES). Sites showing resolution or new-onset enthesitis from baseline to Week 12 were analyzed., Results: Overall, 165 patients (ADA, n = 84; PBO, n = 81) were randomized; 143 had ≥ 1 enthesitis site at baseline. The LEI (SMD -0.73, ES -1.07) and SPARCC (SMD -0.56, ES -0.99) enthesitis indices showed higher discriminatory ability and treatment response than MASES (SMD -0.32, ES -0.81). At Week 12, among sites that were positive at baseline, significantly more (p < 0.05) showed resolution among patients treated with ADA versus PBO in the Achilles tendon (60.4% and 36.5%, respectively), medial epicondyle (73.2%, 48.7%), lateral epicondyle (80.6%, 52.8%), and iliac crest (73.5%, 47.2%). Among negative sites at baseline, significantly less (p < 0.05) new-onset enthesitis was observed with ADA versus PBO for Achilles tendon (3.6% and 10.9%, respectively), greater trochanter (3.4%, 14.4%), lateral epicondyle humerus (4.7%, 15.1%), medial femoral condyle (1.6%, 9.2%), and quadriceps insertion superior patella (1.5%, 7.0%)., Conclusion: The LEI and SPARCC enthesitis indices showed better discriminatory capacity and treatment response in patients with pSpA versus MASES, likely because these indices contain more peripheral sites., Trial Registration Number: ClinicalTrials.gov NCT01064856.

Aim: To evaluate efficacy and safety of secukinumab in Asian patients with active ankylosing spondylitis (AS) via a pooled subgroup analysis from two phase 3 studies, MEASURE 1 (NCT01358175) and MEASURE 2 (NCT01649375)., Methods: In MEASURE 1, patients were randomized to intravenous secukinumab 10 mg/kg or placebo at baseline, Weeks 2 and 4, followed by subcutaneous (s.c.) secukinumab 150 mg, 75 mg or placebo every 4 weeks (q4w) at Week 8. In MEASURE 2, patients were randomized to s.c. secukinumab 150 mg, 75 mg or placebo at baseline, Weeks 1, 2 and 3, and q4w starting at Week 4. Efficacy outcomes were SpondyloArthritis International Society (ASAS) 20/40, high-sensitivity C-reactive protein (hsCRP), ASAS5/6, Bath Ankylosing Spondylitis Disease Activity Index, Short Form-36 physical component summary, AS quality of life (QoL), ASAS partial remission, and Ankylosing Spondylitis Disease Activity Score - CRP at Weeks 16 and 52. Due to lack of efficacy, the secukinumab 75 mg dose in MEASURE 2 was excluded from this pooled Asian subgroup analysis. Safety analysis included patients who received ≥ 1 dose of study treatment., Results: Of 517 patients enrolled into the MEASURE studies, 69 (13.3%) were Asians: 46 in pooled secukinumab and 23 in placebo. At Week 16, ASAS20/40 responses in Asian patients were 69.6%/43.5% with pooled secukinumab versus 26.1%/17.4% with placebo, which were comparable with rates reported in the overall study population. Secukinumab improved predefined efficacy endpoints at Week 16, with responses sustained through Week 52. Secukinumab was well tolerated in Asian patients, with a safety profile consistent with that reported in the overall study population., Conclusion: Secukinumab improved signs and symptoms, physical function, and disease-specific QoL in Asian patients with active AS., (© 2017 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Background: There is significant unmet need in patients with ankylosing spondylitis (AS) who have inadequate response or intolerance to anti-tumour necrosis factor (TNF) treatment. Secukinumab, an anti-interleukin-17A monoclonal antibody, significantly improved signs and symptoms of AS in the MEASURE 2 study (NCT01649375)., Methods: Subjects with active AS (N=219) received secukinumab (150 or 75 mg) or placebo at baseline, weeks 1, 2, 3 and 4, and every 4 weeks thereafter. Randomisation was stratified by prior anti-TNF use: anti-TNF-naive or inadequate response/intolerance to one anti-TNF (anti-TNF-IR). The primary endpoint was Assessment of SpondyloArthritis International Society criteria (ASAS) 20 at week 16., Results: At week 16, 68.2% of anti-TNF-naive subjects treated with secukinumab 150 mg achieved ASAS20 compared with 31.1% treated with placebo (p<0.001). In the anti-TNF-IR group, 50.0% of subjects treated with secukinumab 150 mg achieved an ASAS20 response compared with 24.1% treated with placebo (p<0.05). Numerically greater improvements were observed with secukinumab than with placebo for most secondary endpoints. Clinical responses were sustained through week 52., Conclusions: Secukinumab 150 mg provided sustained improvements in signs and symptoms of AS in anti-TNF-naive and anti-TNF-IR subjects through 52 weeks of therapy., Trial Registration Number: NCT01649375., (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: The aim of the study was to investigate the effect of radiographic spinal progression and disease activity on function and spinal mobility in patients with ankylosing spondylitis (AS) treated with tumor necrosis factor-α (TNF-α) inhibitors for up to 10 years., Methods: Patients with AS who participated in 2 longterm open-label extensions of clinical trials with TNF-α inhibitors (43 receiving infliximab and 17 receiving etanercept) were included in this analysis based on the availability of spinal radiographs performed at baseline and at a later timepoint (yr 2, 4, 6, 8, and 10) during followup. Spinal radiographs were scored according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Function was assessed by the Bath Ankylosing Spondylitis Functional Index (BASFI), spinal mobility by the Bath Ankylosing Spondylitis Metrology Index (BASMI), and disease activity by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)., Results: After the initial improvement, BASFI and BASMI remained remarkably stable at low levels over up to 10 years despite radiographic spinal progression. In the generalized mixed effects model analysis, no association between the mSASSS and the BASFI change (β = 0.0, 95% CI -0.03 to 0.03) was found, while there was some effect of mSASSS changes on BASMI changes over time (β = 0.05, 95% CI 0.01-0.09). BASDAI showed a strong association with function (β = 0.64, 95% CI 0.54-0.73) and to a lesser extent, with spinal mobility (β = 0.14, 95% CI 0.01-0.26)., Conclusion: Functional status and spinal mobility of patients with established AS remained stable during longterm anti-TNF-α therapy despite radiographic progression. This indicates that reduction and continuous control of inflammation might be able to outweigh the functional effect of structural damage progression in AS.

Axial spondyloarthritis (axSpA) patients can be divided into those with structural damage in the SI joint visible on X-rays, termed radiographic axSpA or AS, and those in an earlier phase of the disease, without structural damage in the SI joint, termed non-radiographic axSpA. TNF-blockers have been shown to be highly effective in the treatment of active axSpA. Interestingly, conventional DMARDs and also non-TNF-blocker biologics targeting IL-1, IL-6 and T cells (abatacept) are not effective. Recent interest has focused on the cytokines IL-23 and IL-17 as potential treatment targets in axSpA. An open-label trial with ustekinumab showed a good efficacy in AS patients. Two placebo-controlled phase 3 trials with a mAb blocking IL-17, secukinumab, showed a good reduction in disease activity, similar to that shown for TNF blockers. Probably triggered by inflammation, new bone formation is another hallmark in AS and a potentially important treatment target. However, a previously reported inhibitory effect of NSAID treatment could not be confirmed in a recent NSAID trial., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: To investigate the course of active inflammatory and fatty lesions seen on magnetic resonance imaging (MRI) in patients with early axial spondyloarthritis (SpA) treated with the tumor necrosis factor (TNF) inhibitor infliximab added to naproxen as compared to those treated with naproxen alone., Methods: A total of 158 patients with active axial SpA were randomized (2:1) to receive 28 weeks of treatment with either infliximab 5 mg/kg plus naproxen 1,000 mg/day or placebo plus naproxen 1,000 mg/day. MRI of the sacroiliac (SI) joints and of the spine was performed at baseline and week 28. Images were scored for active inflammation and for fatty lesions., Results: After 28 weeks, there was a significant reduction of inflammation in the spine and in the SI joints in both treatment groups, which was, however, more prominent in the infliximab plus naproxen group (mean ± SD spine osteitis change score -2.9 ± 5.1, versus -2.0 ± 4.2 in the placebo plus naproxen group [P < 0.001]; SI joint osteitis change score -4.3 ± 5.2 in the infliximab plus naproxen group versus -3.9 ± 3.7 in the placebo plus naproxen group [P = 0.003]). Similarly, there was a significant increase in the fatty lesion score after 28 weeks in both groups; this change did not, however, differ significantly between groups (spine fatty lesion change score 0.8 ± 1.7 in the infliximab plus naproxen group versus 1.0 ± 1.8 in the placebo plus naproxen group [P = 0.72]; SI joint fatty lesion change score 1.7 ± 2.7 in the infliximab plus naproxen group versus 1.4 ± 2.6 in the placebo plus naproxen group [P = 0.86])., Conclusion: These findings indicate that effective antiinflammatory treatment of axial SpA is associated with an increase in fatty lesion scores, independent of concomitant treatment with or without anti-TNF., (© 2016, American College of Rheumatology.)

Objective: To evaluate the efficacy and safety of etanercept (ETN) after 48 weeks in patients with early active non-radiographic axial spondyloarthritis (nr-axSpA)., Methods: Patients meeting Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axSpA, but not modified New York radiographic criteria, received double-blind ETN 50 mg/week or placebo (PBO) for 12 weeks, then open-label ETN (ETN/ETN or PBO/ETN). Clinical, health, productivity, MRI and safety outcomes were assessed and the 48-week data are presented here., Results: 208/225 patients (92%) entered the open-label phase at week 12 (ETN, n=102; PBO, n=106). The percentage of patients achieving ASAS40 increased from 33% to 52% between weeks 12 and 48 for ETN/ETN and from 15% to 53% for PBO/ETN (within-group p value <0.001 for both). For ETN/ETN and PBO/ETN, the EuroQol 5 Dimensions utility score improved by 0.14 and 0.08, respectively, between baseline and week 12 and by 0.23 and 0.22 between baseline and week 48. Between weeks 12 and 48, MRI Spondyloarthritis Research Consortium of Canada sacroiliac joint (SIJ) scores decreased by -1.1 for ETN/ETN and by -3.0 for PBO/ETN, p<0.001 for both. Decreases in MRI SIJ inflammation and C-reactive protein correlated with several clinical outcomes at weeks 12 and 48., Conclusions: Patients with early active nr-axSpA demonstrated improvement from week 12 in clinical, health, productivity and MRI outcomes that was sustained to 48 weeks., Trial Registration Number: NCT01258738., (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/)

Non-steroidal anti-inflammatory drugs (NSAIDs) are the first-line treatment for patients with symptomatic axial spondyloarthritis (SpA), who seem to respond best if treated early in the course of disease. The effect of NSAIDs on radiographic disease progression is less clear. Conventional disease-modifying antirheumatic drugs (DMARDs) are not recommended in the treatment of axial SpA, either alone or in combination with TNF blockers. Patients with nonradiographic axial SpA (nr-axSpA) seem to respond as well to TNF blockers as do patients with radiographic axial SpA (ankylosing spondylitis (AS)). However, patients with nr-axSpA should, in addition to a high severity of symptoms, also have objective signs of inflammation, detectable by MRI or by C-reactive protein testing, to be treated with TNF blockers. Whether early TNF-blocker treatment can retard new bone formation needs clarification. In clinical trials, anti-IL-17 agents and TNF blockers showed similar efficacy in patients with AS. The potential of IL-23 blockade for treatment of axial SpA needs to be further investigated. Treatment options for peripheral SpA have been much less thoroughly investigated than those for axial SpA. However, some data indicate that TNF blockers are effective for treating peripheral arthritis, enthesitis and dactylitis, the typical manifestations of peripheral SpA.

Objective: To compare clinical examination versus whole-body magnetic resonance imaging (WB-MRI) of enthesitis in patients with early axial spondyloarthritis during 3 years of continuous etanercept (ETN) treatment., Methods: Forty-one patients underwent clinical and WB-MRI examinations for enthesitis at baseline and after 2 and 3 years of treatment. Twenty-one sites were assessed in 4 anatomic regions - anterior chest wall, pelvis, knee, and foot., Results: Clinical examination at baseline detected enthesitis in 57% of the patients (85 lesions, mean 2.1 lesions, SD 2.9), most of them in the pelvis (42 lesions in 17 patients) and anterior chest wall (19 lesions in 10 patients). The proportion of patients with clinically detected enthesitis decreased to 19% at Year 2 (mean 0.5, SD 1.5) and 14% at Year 3 (mean 0.7, SD 1.8). WB-MRI detected enthesitis at baseline in 21% of patients (22 lesions, mean 0.5 lesions, SD 1.1), also most frequently in the pelvis (12 lesions) and anterior chest wall (7 lesions). MRI-positive enthesitis decreased to 13% at Year 2 (mean 0.2 lesions, SD 0.5) and 14% at Year 3 (mean 0.2 lesions, SD 0.5). There was positive correlation of clinical and MRI findings at baseline at the anterior chest wall (p = 0.001) and the pelvis (p = 0.0001). No correlation was found at the knee and foot at baseline and for all regions at followup., Conclusion: Both clinical examination and WB-MRI show a decrease in enthesitis after 2 and 3 years of ETN treatment, but correlation was limited to the pelvis and anterior chest wall at baseline.

Objectives: Knowledge on the long-term effects of anti-TNF therapy in patients with ankylosing spondylitis (AS) is still limited. Our objective was to study the long-term efficacy and safety of anti-TNF therapy in AS., Methods: After having completed the first part of the EASIC trial a total of 71 patients were enrolled into this 96-week extension study. Patients were treated with the same dosages and dosing intervals of infliximab as in the EASIC core study. Efficacy was assessed by using standardised assessment tools such as BASDAI, BASFI, BASMI, patient global assessment, CRP levels and the proportion of patients without any sign of enthesitis or arthritis. Long-term safety was assessed by documenting adverse events (AE), serious adverse events (SAE) and reasons for dropping out., Results: Of the 71 patients included, 64 (90.1%) completed the trial , and 7 discontinued: one was lost to follow-up, 3 withdrew informed consent and in 3 patients therapy was stopped for different reasons: secondary loss of response, recurrent infections and basal cell carcinoma of the skin. The completers showed rather stable low scores of BASDAI (mean 2.4, median 2.52), BASFI (mean 3.1, median 2.76) and BASMI (mean 3.2, median 3) as well as patients global assessment and CRP. The vast majority of patients did not have enthesitis or arthritis. A total of 476 AE were observed, 13 of which were SAE. The majority of these were infections and most of them affected the respiratory tract. Two malignancies occurred: one basal cell carcinoma and one malignant melanoma. These were the only SAE judged to be possibly related to the study drug., Conclusions: Anti-TNF treatment with infliximab is efficacious over long periods of time in patients with AS. The observation of two skin related malignancies, including one melanoma, during the whole study period of 7 years is in line with reports from previous large AS data sets.

Objective: To investigate changes in magnetic resonance imaging (MRI)-assessed inflammation and structural lesions in the sacroiliac (SI) joints during treatment with adalimumab versus placebo., Methods: In a 48-week double-blind, placebo-controlled trial, 52 patients with spondyloarthritis were randomized to receive subcutaneous injections of either adalimumab 40 mg (n = 25) or placebo (n = 27) every other week for 12 weeks. Patients in the adalimumab group continued to receive and patients in the placebo group were switched to adalimumab 40 mg every other week for an additional 12 weeks. MRI of the SI joints was performed at weeks 0, 12, 24, and 48, and the images were assessed independently in a blinded manner using the modified Berlin and the Spondyloarthritis Research Consortium of Canada (SPARCC) MRI scores for inflammation and structural lesions of the SI joints., Results: At baseline, 56% of the adalimumab group and ∼72% of the placebo group had an MRI-assessed inflammation score of ≥1. Among the patients with inflammation at baseline, the mean percent reductions in MRI scores for inflammation from week 0 to 12 were greater in the adalimumab group compared with the placebo group (Berlin method, -62% versus -5%; SPARCC method, -58% versus -12% [both P < 0.04]). Furthermore, the mean SPARCC erosion score decreased (-0.6) and the SPARCC backfill score increased (+0.8) in the adalimumab group from week 0 to week 12. From week 12 to week 24, larger absolute reductions in the Berlin/SPARCC inflammation scores and the SPARCC erosion score and larger increases in the Berlin/SPARCC fatty lesion scores were seen in the placebo group compared with the adalimumab group. In univariate regression analyses (analysis of covariance) and multivariate stepwise regression analyses, treatment with adalimumab was independently associated with regression of the SPARCC erosion score from week 0 to 12 but not with changes in the other types of MRI lesions., Conclusion: Significant changes in the Berlin and SPARCC MRI-assessed inflammation scores and in the SPARCC MRI-assessed erosion scores occurred within 12 weeks after initiation of adalimumab. Tumor necrosis factor inhibitor treatment was associated with resolution of erosions and the development of backfill., (© 2016, American College of Rheumatology.)

Objective: Chronic pain and progressive loss of physical function with AS may adversely affect health-related quality of life (HRQoL). The objective of this study was to assess the 5-year data regarding spinal mobility, physical function and HRQoL in patients with AS who participated in the Adalimumab Trial Evaluating Long-term Efficacy and Safety for AS (ATLAS) study., Methods: Patients received blinded adalimumab 40 mg or placebo every other week for 24 weeks, then open-label adalimumab for up to 5 years. Spinal mobility was evaluated using linear BASMI (BASMIlin). BASDAI, total back pain, CRP, BASFI, Short Form-36 and AS quality of life (ASQoL) were also assessed. Correlations between BASMIlin and clinical, functional and ASQoL outcomes after 12 weeks and after 5years of adalimumab exposure were evaluated using Spearman's rank correlation. Associations were further analysed using multivariate regression., Results: Three hundred and eleven patients received ≥1 dose of adalimumab; 125 of the 208 patients originally randomized to adalimumab received treatment for 5 years. Improvements in BASMIlin were sustained through 5 years, with a mean change of -0.6 from baseline in the population who completed 5 years of treatment with adalimumab. Improvements in disease activity, physical function and ASQoL were also sustained through 5 years. BASMIlin was significantly correlated with all evaluated clinical outcomes (P < 0.001). The highest correlation was with BASFI at 12 weeks (r = 0.52) and at 5 years (r = 0.65). Multivariate regression analysis confirmed this association (P < 0.001)., Conclusion: Treatment with adalimumab for up to 5 years demonstrated sustained benefits in spinal mobility, disease activity, physical function and HRQoL in patients with active AS. Spinal mobility was significantly associated with short- and long-term physical function in these patients., Trial Registration: Clinicaltrials.gov; https://clinicaltrials.gov/NCT00085644., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: This meta-analysis investigates the efficacy of tumour necrosis factor α (TNFα) blockers versus placebo for the treatment of ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA)., Methods: A systematic literature search was conducted independently by two reviewers. Double-blind randomised controlled trials (RCTs) investigating the efficacy of adalimumab, certolizumab, etanercept, golimumab or infliximab in approved dosages in comparison with placebo were included. The use of concomitant non-steroidal antirheumatic drugs was allowed. The outcome parameters were improvement in disease activity and function measured by the Bath AS disease activity index (BASDAI), Bath AS functional index (BASFI) and ASAS40 response. The effect sizes of the changes in BASDAI/BASFI between TNFα blocker and placebo comparator groups were calculated. Mixed effect models were applied separately for RCTs with AS and nr-axSpA patients and differences between those groups were evaluated in a joint model., Results: 20 studies with data from 3096 patients were included in the analysis: 15 studies with AS patients, four with nr-axSpA patients and one with both. For AS patients, TNFα blockers showed better efficacy than placebo for BASDAI (effect size 1.00), BASFI (effect size 0.67) and ASAS40 response (OR 4.7). For nr-axSpA patients, the differences were smaller (effect sizes 0.73, 0.57; OR 3.6). However, after adjustment for the year of publication as a proxy for disease severity, no differences in the effect sizes between the AS and nr-axSpA trials were observed., Conclusions: Compared with placebo, TNFα blockers improve disease activity and functional capacity clinically meaningful for both AS and nr-axSpA patients., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objectives: The ALIGN study (NCT01061723) evaluated the efficacy and safety of sarilumab, the first fully human monoclonal antibody against interleukin-6 receptor-α (IL-6Rα), in patients with ankylosing spondylitis (AS)., Methods: Patients with active AS despite conventional treatment were randomised to placebo, or one of five subcutaneous dose regimens of sarilumab (100, 150 or 200 mg every other week, or 100 or 150 mg every week), for 12 weeks. The primary efficacy end point was the percentage of patients achieving the Axial SpondyloArthritis international Society (ASAS) 20 response criteria at week 12. Secondary endpoints included ASAS40 response, ASAS partial remission, AS Disease Activity Score, high-sensitivity C-reactive protein (hs-CRP) value, and safety., Results: Baseline demographic and disease characteristics of the 301 patients enrolled were similar across treatment groups. At week 12, there was no statistically significant difference in ASAS20 response rate between placebo (ASAS20 = 24.0%) and any sarilumab dose group. A significantly greater reduction in hs-CRP value was achieved with the higher sarilumab doses versus placebo. No other statistically significant differences were evident for secondary efficacy endpoints. The most common treatment-emergent adverse events reported for sarilumab included infections (non-serious), neutropenia, and increase in alanine aminotransferase. No cases of tuberculosis, opportunistic, or fungal infections, or bowel perforations were reported. Seven patients experienced a treatment-emergent serious adverse event (all in sarilumab treatment groups). No deaths occurred., Conclusions: The ALIGN study shows that IL-6Rα blockade with sarilumab was not an effective treatment for AS. Sarilumab was generally well tolerated with a manageable safety profile., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: To evaluate the efficacy and safety of adalimumab in patients with active nonpsoriatic peripheral spondyloarthritis (SpA)., Methods: ABILITY-2 is an ongoing phase III, multicenter study of adalimumab treatment. Eligible patients age ≥18 years fulfilled the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for peripheral SpA, did not have a prior diagnosis of psoriasis, psoriatic arthritis (PsA), or ankylosing spondylitis (AS), and had an inadequate response or intolerance to nonsteroidal antiinflammatory drugs (NSAIDs). Patients were randomized 1:1 to receive adalimumab 40 mg every other week or matching placebo for 12 weeks, followed by a 144-week open-label period. The primary end point was the proportion of patients achieving 40% improvement in disease activity according to the Peripheral SpA Response Criteria (PSpARC40) at week 12. This was defined as ≥40% improvement from baseline (≥20-mm absolute improvement on a visual analog scale) in patient's global assessments of disease activity and pain, and ≥40% improvement in at least one of the following features: swollen joint and tender joint counts, total enthesitis count, or dactylitis count. Adverse events were recorded throughout the study., Results: In total, 165 patients were randomized to a treatment group, of whom 81 were randomized to receive placebo and 84 to receive adalimumab. Baseline demographics and disease characteristics were generally similar between the 2 groups. At week 12, a greater proportion of patients receiving adalimumab achieved a PSpARC40 response compared to patients receiving placebo (39% versus 20%; P = 0.006). Overall, improvement in other outcomes was greater in the adalimumab group compared to the placebo group. The rates of adverse events were similar in both treatment groups., Conclusion: Treatment with adalimumab ameliorated the signs and symptoms of disease and improved physical function in patients with active nonpsoriatic peripheral SpA who exhibited an inadequate response or intolerance to NSAIDs, with a safety profile consistent with that observed in patients with AS, PsA, or other immune-mediated diseases., (© 2015 AbbVie, Inc. Arthritis & Rheumatology is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.)

Objective: The aim of this study was to assess the degree of fluctuation of osteitis on MRI during long-term treatment with etanercept (ETN) in patients with early axial SpA (axSpA) with active inflammation (osteitis) on whole-body MRI in the spine and/or the SI joints at baseline., Methods: We analysed MRI data from 328 SI joint quadrants and 943 spine vertebral units (VUs) in terms of osteitis in the pooled data set of 41 patients who were treated with ETN for 3 consecutive years. Scoring was performed by two blinded radiologists at baseline, year 2 and year 3., Results: Through years 2 and 3, osteitis on MRI resolved completely in 56 of 144 (38.9%) SI joint quadrants and in 20 of 40 (50%) VUs affected at baseline, while persistent osteitis was found in 24 of 144 (16.7%) SI joint quadrants and in 8 of 40 (20.0%) spine VUs. The development of new osteitis in sites that were free of osteitis at baseline only occurred in 2 of 131 (1.5%) SI joint quadrants and in 3 of 862 (0.4%) spine VUs in both year 2 and year 3., Conclusion: There was a consistently small amount of osteitis on MRI in patients with early axSpA compared with baseline values, and only a very low rate of new-onset osteitis was found during 3 years of continuous treatment with ETN., Trial Registration: www.clinicaltrials.gov, NCT00844142., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: In patients with early active axial spondyloarthritis (axSpA) with a disease duration of < 5 years, the longterm efficacy of 3 years of continuous etanercept (ETN) treatment was assessed., Methods: In a previously reported ESTHER trial, patients with axSpA were randomized to treatment with ETN (n = 40) versus sulfasalazine (SSZ; n = 36) in the first year. We analyzed the clinical, laboratory, and magnetic resonance imaging (MRI) response in the pooled dataset of patients (study population; n = 61), including patients with ankylosing spondylitis (AS, n = 31) and nonradiographic axSpA (nr-axSpA, n = 30) who were continuously treated with ETN for 3 consecutive years. Data were analyzed using the last observation carried forward and completer analysis., Results: In the entire group of patients in the study population (n = 61), the mean Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) decreased from 5.7 (± 1.3) at baseline to 2.6 (± 2.4) at Year 3. The Ankylosing Spondylitis Disease Activity Score (ASDAS) decreased from 3.4 (± 0.8) to 1.5 (± 1.0). Also, mean values for MRI spine and sacroiliac joint scores showed a significant decrease. Response rates in the nr-axSpA group were similar and at least as good compared to the AS group for all outcome measures. When comparing remission stages, we found that ASDAS inactive disease correlated better with C-reactive protein and MRI remission than with Assessment of SpondyloArthritis international Society partial remission., Conclusion: There was a consistent and sustained clinical response in patients with early axSpA treated with ETN over 3 years. ClinicalTrials.gov registration number NCT00844142.

Objective: Compare the radiographic progression of ankylosing spondylitis (AS) patients treated with infliximab (INF) versus historical controls (Herne cohort, HC) never treated with tumour necrosis factor (TNF)-blockers over 8 years., Methods: Patients were selected based on the availability of lateral cervical and lumbar radiographs at baseline (BL) and after 8 years. Radiographs were scored by two blinded readers using modified Stokes AS spinal score (mSASSS). Mixed linear models were applied to compare radiographic progression between cohorts after adjustment for baseline status., Results: Patients in INF (n=22) and HC (n=34) did not differ in the mSASSS status: 13.2 ± 17.6 in INF versus 14.2 ± 13.8 in HC (p=0.254). Both showed progression at 8 years: mean mSASSS 20.2 ± 21.4 in INF and 25.9 ± 17.8 in HC. After adjustment for baseline damage the mean mSASSS (SEM) at 8 years was 21.0 (1.4) in INF and 25.5 (1.1) HC (p=0.047). The mean mSASSS difference was similar in the groups between baseline and 4 years but was more pronounced in HC between 4 and 8 years (p=0.03 between groups). The mean number of syndesmophytes, although similar at baseline, differed significantly at 8 years: 1.0 ± 0.6 new syndesmophytes/patient in INF versus 2.7 ± 0.8 in HC (p=0.007). Adjustment for age, symptom duration, HLA-B27, Bath AS disease activity index and Bath AS function index at baseline had no influence., Conclusions: Despite limitations of patient numbers and retrospective study design, these data show increase in new bone formation in both patients treated with anti-TNF and those who did not. However, since there was even less bone formation in the INF treated group after 8 years, these data argue against a major role for the TNF-brake hypothesis.

Objective: To evaluate the efficacy and safety of secukinumab, a fully human, anti-interleukin (IL)-17A monoclonal antibody, in patients with psoriatic arthritis (PsA)., Methods: 42 patients with active PsA fulfilling ClASsification for Psoriatic ARthritis (CASPAR) criteria were randomly assigned (2:1) to receive two intravenous secukinumab doses (10 mg/kg; n=28) or placebo (n=14) 3 weeks apart. The primary endpoint was the proportion of American College of Rheumatology (ACR) 20 responses at week 6 for secukinumab versus placebo (one-sided p<0.1)., Results: Primary endpoint: ACR20 responses at week 6 were 39% (9/23) for secukinumab versus 23% (3/13) for placebo (p=0.27). ACR20 responses were greater with secukinumab versus placebo at week 12 (39% (9/23) vs 15% (2/13), p=0.13) and week 24 (43% (10/23) vs 18% (2/11), p= 0.14). At week 6, 'good' European League Against Rheumatism response was seen in 21.7% (5/23) secukinumab versus 9.1% (1/11) placebo patients. Compared with placebo at week 6, significant reductions were observed among secukinumab recipients for C reactive protein (p=0.039), erythrocyte sedimentation rate (p=0.038), Health Assessment Questionnaire Disability Index (p=0.002) and Short Form Health Survey (SF-36; p=0.030) scores. The overall adverse event (AE) frequency was comparable between secukinumab (26 (93%)) and placebo (11 (79%)) recipients. Six serious AEs (SAEs) were reported in four secukinumab patients and one SAE in one placebo patient., Conclusions: Although the primary endpoint was not met, clinical responses, acute-phase reactant and quality of life improvements were greater with secukinumab versus placebo, suggesting some clinical benefit. Secukinumab exhibited satisfactory safety. Larger clinical trials of secukinumab in PsA are warranted.

Introduction: The aim of this study was to investigate the influence of symptom duration on treatment response and on the correlation between improvements in patient reported outcomes (PRO) and objective inflammation in patients with axial spondylarthritis (SpA) treated with etanercept (ETA) or adalimumab (ADA)., Methods: Data from 112 patients with axial SpA originally enrolled in two randomized controlled clinical trials were pooled and analyzed after one year of treatment with ETA (n = 66) or ADA (n = 46). Patients with <4 years and ≥4 years of disease were compared for improvement in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Ankylosing Spondylitis Disease Activity Score (ASDAS), C-reactive protein (CRP) and magnetic resonance imaging (MRI) score for sacroiliac joints (SIJ)., Results: Patients with <4 years of disease showed a significantly better improvement than longer diseased patients in BASDAI (3.2 (95% confidence interval (CI): 2.7 to 3.7) vs. 1.7 (1.1 to 2.2)), BASFI, BASMI and ASDAS (1.6 (1.4 to 1.8) vs. 0.9 (0.7 to 1.1)). The change in BASDAI showed a significant correlation with the change in SIJ score (Spearman's rank correlation coefficient (rho) = 0.37, P = 0.01) and the change in CRP (rho = 0.45, P = 0.001) in patients with <4 years of disease. For long diseased patients this correlation was poor and did not achieve statistical significance (rho = 0.13, P = 0.46; rho = 0.22, P = 0.13 respectively)., Conclusion: The low correlation between change of PROs and change of objective signs of inflammation seen in axial SpA patients with longer symptom duration treated with tumor necrosis factor-blocker seems to indicate that inflammation is not the only cause of the patients' symptoms, while inflammation seems to be the major cause in short diseased patients., Trial Registration: Clinical Trials.gov NCT00844142 (Trial 1); NCT00235105 (Trial 2).

Objectives: BUILDER-1 and BUILDER-2 aimed to assess the efficacy and safety of tocilizumab (TCZ) in patients with ankylosing spondylitis (AS)., Methods: BUILDER-1 was a two part, phase II-III parallel-group trial in patients with AS naive to antitumour necrosis factor (aTNF) treatment. Patients in part 1 received TCZ 8 mg/kg or placebo for 12 weeks. In part 2 (beginning after part 1 enrolment ended), newly enrolled patients received TCZ 4 or 8 mg/kg or placebo for 24 weeks. The same treatment arms were used in BUILDER-2, a phase III study in aTNF-inadequate responders. The primary endpoint for both studies was the proportion of patients achieving 20% improvement in the Assessments in Axial SpondyloArthritis international Society (ASAS). Secondary and exploratory endpoints included ASAS40 response rates, Bath Ankylosing Spondylitis Disease Activity Index improvement, changes in joint counts, enthesitis score and C reactive protein (CRP)., Results: 102 patients were randomised in BUILDER-1 part 1; 99 (48 TCZ, 51 placebo) completed 12 weeks. Week 12 ASAS20 response rates were 37.3% and 27.5% in the TCZ and placebo arms, respectively (p=0.2823). Secondary and exploratory endpoints did not differ between treatment arms. CRP levels declined with TCZ treatment, suggesting adequate IL-6 receptor blockade. As a result, BUILDER-1 part 2 and BUILDER-2 were terminated. TCZ safety results were consistent with previous observations in rheumatoid arthritis, except for a cluster of anaphylactic and hypersensitivity events at Bulgarian study sites. No apparent explanation for this clustering could be found., Conclusions: BUILDER-1 failed to demonstrate TCZ efficacy in treating aTNF-naive patients with AS.

Background: Therapeutic targets have been defined for diseases like diabetes, hypertension or rheumatoid arthritis and adhering to them has improved outcomes. Such targets are just emerging for spondyloarthritis (SpA)., Objective: To define the treatment target for SpA including ankylosing spondylitis and psoriatic arthritis (PsA) and develop recommendations for achieving the target, including a treat-to-target management strategy., Methods: Based on results of a systematic literature review and expert opinion, a task force of expert physicians and patients developed recommendations which were broadly discussed and voted upon in a Delphi-like process. Level of evidence, grade and strength of the recommendations were derived by respective means. The commonalities between axial SpA, peripheral SpA and PsA were discussed in detail., Results: Although the literature review did not reveal trials comparing a treat-to-target approach with another or no strategy, it provided indirect evidence regarding an optimised approach to therapy that facilitated the development of recommendations. The group agreed on 5 overarching principles and 11 recommendations; 9 of these recommendations related commonly to the whole spectrum of SpA and PsA, and only 2 were designed separately for axial SpA, peripheral SpA and PsA. The main treatment target, which should be based on a shared decision with the patient, was defined as remission, with the alternative target of low disease activity. Follow-up examinations at regular intervals that depend on the patient's status should safeguard the evolution of disease activity towards the targeted goal. Additional recommendations relate to extra-articular and extramusculoskeletal aspects and other important factors, such as comorbidity. While the level of evidence was generally quite low, the mean strength of recommendation was 9-10 (10: maximum agreement) for all recommendations. A research agenda was formulated., Conclusions: The task force defined the treatment target as remission or, alternatively, low disease activity, being aware that the evidence base is not strong and needs to be expanded by future research. These recommendations can inform the various stakeholders about expert opinion that aims for reaching optimal outcomes of SpA.

Background: Ankylosing spondylitis is a chronic immune-mediated inflammatory disease characterised by spinal inflammation, progressive spinal rigidity, and peripheral arthritis. Interleukin 17 (IL-17) is thought to be a key inflammatory cytokine in the development of ankylosing spondylitis, the prototypical form of spondyloarthritis. We assessed the efficacy and safety of the anti-IL-17A monoclonal antibody secukinumab in treating patients with active ankylosing spondylitis., Methods: We did a randomised double-blind proof-of-concept study at eight centres in Europe (four in Germany, two in the Netherlands, and two in the UK). Patients aged 18-65 years were randomly assigned (in a 4:1 ratio) to either intravenous secukinumab (2×10 mg/kg) or placebo, given 3 weeks apart. Randomisation was done with a computer-generated block randomisation list without a stratification process. The primary efficacy endpoint was the percentage of patients with a 20% response according to the Assessment of SpondyloArthritis international Society criteria for improvement (ASAS20) at week 6 (Bayesian analysis). Safety was assessed up to week 28. This study is registered with ClinicalTrials.gov, number NCT00809159., Findings: 37 patients with moderate-to-severe ankylosing spondylitis were screened, and 30 were randomly assigned to receive either intravenous secukinumab (n=24) or placebo (n=6). The final efficacy analysis included 23 patients receiving secukinumab and six patients receiving placebo, and the safety analysis included all 30 patients. At week 6, ASAS20 response estimates were 59% on secukinumab versus 24% on placebo (99·8% probability that secukinumab is superior to placebo). One serious adverse event (subcutaneous abscess caused by Staphylococcus aureus) occurred in the secukinumab-treated group., Interpretation: Secukinumab rapidly reduced clinical or biological signs of active ankylosing spondylitis and was well tolerated. It is the first targeted therapy that we know of that is an alternative to tumour necrosis factor inhibition to reach its primary endpoint in a phase 2 trial., Funding: Novartis., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objective: Spinal inflammation and erosions have been described in magnetic resonance imaging (MRI) examinations of patients with ankylosing spondylitis (AS). MRI scoring systems have implemented these observations., Methods: MRI scans (T1 or short-tau inversion recovery) from tumor necrosis factor-α blocker (anti-TNF) trials with patients with active AS (n = 22) were analyzed at baseline and after 2 years based on vertebral units (VU). The analysis was based on the prevalence of spinal erosions in relation to inflammation (active erosions) or without it (inactive erosions) as an outcome measure on MRI and their course under anti-TNF therapy. The results of MRI scoring systems that include (ASspiMRI) or exclude (Berlin score) erosions were also compared., Results: At baseline, there were more VU with inflammation (33.7%) than with erosions irrespective of activity (10.6%). After 2 years, active erosions decreased to 3.7% while inflammation was seen in a total of 12% of VU - a reduction of 58.9% and 64.5%, respectively (both p < 0.02). The overall extent of erosions decreased from 10.6% at baseline to 5.6% at 2 years. At the patient level, 73% and 32% of patients showed active erosions (p = 0.002), while 100% and 64% of patients showed inflammation (p = 0.029) at baseline and 2 years, respectively. Both scoring systems showed similar improvement, independent of inclusion or exclusion of erosions., Conclusion: Inflammation with erosions was observed in the spine of most patients with AS but their contribution to changes observed upon anti-TNF therapy was small, indicating that erosions do not need to be included in quantitative scoring systems of inflammation. Spinal inflammation was still present after 2 years of anti-TNF therapy in two-thirds of patients.

Major progress has been made in recent years in the management of axial spondyloarthritis (axSpA), including ankylosing spondylitis (AS) and non-radiographic axSpA (nr-axSpA). Most predictors of response have been defined for TNF-blocker therapy, and new treatment strategies are being discussed about how to best reach remission and how to maintain remission. Other biologics besides TNF-blockers have been tested in AS but have so far failed. The IL-17/IL-23 cytokines currently seem to be the most interesting targets. Short-term TNF-blocker therapy does not inhibit radiographic progression but long-term might do so. NSAIDs have been proven to inhibit such progression, even after 2 years of treatment. The effect of a combined therapy of NSAIDs with TNF-blockers on the inhibition of new bone formation in AS patients is currently unknown.

Purpose: To evaluate the efficacy and safety of adalimumab in patients with non-radiographic axial spondyloarthritis (nr-axSpA)., Methods: Patients fulfilled Assessment of Spondyloarthritis international Society (ASAS) criteria for axial spondyloarthritis, had a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of ≥ 4, total back pain score of ≥ 4 (10 cm visual analogue scale) and inadequate response, intolerance or contraindication to non-steroidal anti-inflammatory drugs (NSAIDs); patients fulfilling modified New York criteria for ankylosing spondylitis were excluded. Patients were randomised to adalimumab (N=91) or placebo (N=94). The primary endpoint was the percentage of patients achieving ASAS40 at week 12. Efficacy assessments included BASDAI and Ankylosing Spondylitis Disease Activity Score (ASDAS). MRI was performed at baseline and week 12 and scored using the Spondyloarthritis Research Consortium of Canada (SPARCC) index., Results: Significantly more patients in the adalimumab group achieved ASAS40 at week 12 compared with patients in the placebo group (36% vs 15%, p<0.001). Significant clinical improvements based on other ASAS responses, ASDAS and BASDAI were also detected at week 12 with adalimumab treatment, as were improvements in quality of life measures. Inflammation in the spine and sacroiliac joints on MRI significantly decreased after 12 weeks of adalimumab treatment. Shorter disease duration, younger age, elevated baseline C-reactive protein or higher SPARCC MRI sacroiliac joint scores were associated with better week 12 responses to adalimumab. The safety profile was consistent with what is known for adalimumab in ankylosing spondylitis and other diseases., Conclusions: In patients with nr-axSpA, adalimumab treatment resulted in effective control of disease activity, decreased inflammation and improved quality of life compared with placebo. Results from ABILITY-1 suggest that adalimumab has a positive benefit-risk profile in active nr-axSpA patients with inadequate response to NSAIDs.

Objective: We assessed whether there is a difference to etanercept (ETA) treatment in patients with ankylosing spondylitis (AS) compared with non-radiographic axial SpA (nr-axSpA) patients with a disease duration <5 years., Method: AS (n=20) and nr-axSpA (n=20) patients who were treated with ETA for 1 year were compared for differences in baseline data and treatment effect. Clinical, laboratory and MRI of sacroiliac joints (SI-joints) and spine were analysed., Results: At baseline, there were no significant differences between the 20 AS and the 20 nr-axSpA patients regarding age, disease duration, gender, HLA-B27 and clinical disease activity in terms of Bath AS Disease Activity Index (BASDAI), C-reactive protein and MRI SI-joint and spine scores in the AS compared with the nr-axSpA group. After 1 year of treatment with ETA the treatment effect was similarly good in AS and nr-axSpA (reduction of BASDAI by 3.3 (95% CI 2.2 to 3.8) vs 3.6 (95% CI 2.8 to 4.4) and reduction of AS Disease Activity Score by 1.8 (95% CI 1.5 to 2.2) vs 1.8 (95% CI 1.5 to 2.1), respectively., Conclusions: The response rate to TNF-blockers does not differ between AS and nr-axSpA if the baseline data regarding symptom duration and disease activity are similar for the two groups.