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Objectives: Rheumatoid arthritis (RA), psoriatic arthritis (PsA), and axial spondyloarthritis (axSpA) patients often experience secondary non-response to a first-line tumour necrosis factor alpha inhibitor (TNFαi). This pooled analysis of six observational studies in Europe (GO-BEYOND program) provides an estimate of second-line golimumab (GLM) effectiveness for these rheumatic diseases., Methods: The GO-BEYOND studies included common disease-specific endpoints allowing for a pooled analysis. Patients had discontinued one prior TNFαi (due to loss of efficacy, tolerability, or inconvenience) and were followed for 12 months after GLM initiation. Primary endpoints included the proportion of patients achieving low disease activity (LDA, DAS28-CRP<3.2) in RA, minimal disease activity (MDA, fulfilment of 5 of 7 outcome measures) in PsA, or low disease activity (ASDAS<2.1) in axSpA at 6 months. Disease activity at 3 and 12 months and quality of life (QoL; EQ-5D-3L) were also assessed. Adverse events were monitored. Protocol-specified analyses were based on observed data., Results: In 712 patients, (n=325, RA; 186, PsA; 201, axSpA), mean age was 54 years, 64% were female, and median disease duration was 5 years. Primary endpoints were achieved in 58.3% (RA), 45.5% (PsA), and 45.4% (axSpA) of patients; disease activity improvements were observed at 3 and 12 months and EQ-5D-3L results showed improved QoL over time. The treatment persistence rate at 12 months was 67.8% of patients. No new safety signals were observed., Conclusions: This pooled analysis of the GO-BEYOND studies showed that treatment with GLM was effective and represented a valid second-line option for RA, PsA, and axSpA patients.

Introduction: COMPACT, a non-interventional study, evaluated the persistence, effectiveness, safety and patient-reported outcomes (PROs) in patients with rheumatoid arthritis (RA), axial-spondyloarthritis (axSpA) or psoriatic arthritis (PsA) treated with SDZ ETN (etanercept [ETN] biosimilar) in Europe and Canada., Methods: Patients (aged ≥ 18 years) who have been treated with SDZ ETN were categorised on the basis of prior treatment status (groups A-D): patients in clinical remission or with low disease activity under treatment with reference ETN or biosimilar ETN and switched to SDZ ETN; patients who received non-ETN targeted therapies and switched to SDZ ETN; biologic-naïve patients who started SDZ ETN after conventional therapy failure; or disease-modifying anti-rheumatic drug (DMARD)-naïve patients with RA considered suitable for treatment initiation with a biologic and started on treatment with SDZ ETN. The primary endpoint was drug persistence, defined as time from study enrolment until discontinuation of SDZ ETN treatment., Results: Of the 1466 patients recruited, 844 (57.6%) had RA, 334 (22.8%) had axSpA and 288 (19.6%) had PsA. Patients had an ongoing SDZ ETN treatment at the time of enrolment for an observed average of 138 days (range 1-841); 22.7% of patients discontinued SDZ ETN through 12 months of study observation. Overall, all the patients receiving SDZ ETN showed good treatment persistence at 12 months with discontinuation rates of 15.2%, 25.7% and 27.8% in groups A, B and C, respectively. Across all patient groups, no major differences were observed in the disease activity and PRO scores between baseline and month 12. Injection-site reactions were low across the treatment groups., Conclusion: These results support the effectiveness and safety of SDZ ETN treatment in patients with RA, axSpA or PsA in real-life conditions. The treatment persistence rates observed were consistent with previously published reports of patients treated with reference or other biosimilar ETN. No new safety signals were identified., (© 2023. The Author(s).)

Background: The influence of sex on treatment outcomes during interleukin-12/23 therapy in patients with psoriatic arthritis (PsA) has not been explored., Objective: To conduct exploratory post hoc analyses of sex-stratified data from the MUST trial, an investigator-initiated, multicentre, phase 3b study in which patients with active PsA initiating treatment with open-label ustekinumab were randomised to treatment with placebo or methotrexate (MTX)., Methods: We evaluated baseline characteristics, key treatment outcomes and adverse events stratified by sex, with a focus on outcomes that did not include erythrocyte sedimentation rate (ESR) as a component due to the known elevation of ESR in females., Results: A total of 166 patients were treated with ustekinumab+MTX (37 female, 50 male) or ustekinumab+placebo (32 female, 47 male). At baseline, females had a significantly longer time since PsA diagnosis and greater impairment in physical function, but similar joint counts. At week 24, both females and males showed marked improvements to ustekinumab with or without MTX. Females generally had numerically reduced treatment responses compared with males, although differences did not achieve statistical significance. MTX did not show an overall effect on treatment outcomes, but was associated with faster enthesitis responses in males only. Adverse events were generally comparable, but females in the ustekinumab+MTX group had higher levels of gastrointestinal disorders., Conclusion: Females and males with PsA had differences in baseline characteristics, treatment responses and adverse events during therapy. A better understanding of sex-based differences in PsA may help optimise treatment., Competing Interests: Competing interests: MK received consulting fees or honoraria from Amgen, Janssen-Cilag, Lilly, Novartis and UCB and received travel support from UCB. UK received grant and research support and consultancy fees from AbbVie, Amgen, Biocad, Biogen, BMS, Chugai, Eli Lilly, Fresenius, Gilead, Grünenthal, GSK, Hexal, Janssen, MSD, Novartis, onkowissen.de, Pfizer, Roche, UCB and Viatris and participated on a data safety monitoring or advisory board for the COPAGO trial, conducted by the German Ministry of Health. GRB received fees or honoraria for serving as a speaker and/or consultant from Abbvie, Galapagos, Janssen, Lilly, Novartis and UCB, meeting or travel support from Abbvie and Lilly and is the editor-in-chief of RMD Open. DMK received honoraria for serving as a speaker for Sanofi-Aventis. SF received scientific grants from Novartis, honoraria or fees for serving as a speaker and/or consultant from Abbvie, AstraZeneca, Chugai, Galapagos, Novartis, NovoNordisc and UCB, and travel or meeting support from Abbvie, Galapagos, Janssen Cilag, Novartis, SOBI and UCB. RB received honoraria or fees for serving as a speaker and/or consultant from Abbvie, BMS, Chugai, GSK, Galapagos, Novartis, Roche and Vifor and meeting or travel support from Chugai and Galapagos. MS received research support from Charité. FB received research support for this study from Janssen Cilag, consulting fees or honoraria from Abbvie, Acelyrin, Amgen, Janssen Cilag, Lily, Novartis, Pfizer and UCB, and meeting or travel support from Abbvie and UCB. ACF, TR, HK and JB have no competing interests to declare., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To investigate long-term effectiveness and safety of subcutaneous tocilizumab (TCZ-SC) in the routine clinical care of patients with rheumatoid arthritis (RA)., Methods: ARATA (ML29087) was a prospective, multicentre, observational study of adult patients with active RA initiating therapy with TCZ-SC. The primary effectiveness outcome was the proportion of patients achieving DAS28-ESR <2.6 at week 104. Additional efficacy outcomes included individual DAS28-dcrit responses (improvement of ≥1.8 from baseline), CDAI remission (≤2.8), and patient-reported outcomes (PROs), including Work Productivity and Activity Impairment scores. Adverse event rates were used to evaluate safety and tolerability., Results: Between May 2014 and July 2018, 114 study centres in Germany enrolled 1,300 patients with RA who received at least one dose of TCZ-SC (mean age 57.3 [SD 12.5] years, mean DAS28-ESR of 4.9 [SD 1.3]). At week 104, 58.7% (365/622) patients achieved DAS28-ESR <2.6, 64.0% had an individual DAS28-dcrit response, and 31.4% (241/767) achieved CDAI remission. PROs, including patient global assessment, pain, and fatigue, showed marked improvements from baseline. Work outcomes, including absenteeism (missed work) and presenteeism (productivity while at work), also improved. Injection reactions were rare and no new safety signals occurred. Patients expressed a high level of satisfaction with treatment. Baseline patient characteristics and outcomes were similar for ARATA and ICHIBAN (an observational study of TCZ-IV in Germany), despite different formulations and time periods., Conclusions: The safety and effectiveness of TCZ-SC is maintained over 2 years during routine clinical care. TCZ-SC represents a convenient and effective option for RA patients who prefer SC administration.

Objective: The Assessment of Spondyloarthritis international Society Health Index (ASAS HI) measures global functioning and health in patients with axial spondyloarthritis (axSpA) covering domains of physical, emotional, and social functioning. The main aim of this study was to investigate the sensitivity to change of ASAS HI in comparison with established variables of disease activity, function, and mental health., Methods: Patients with axSpA from the disease register RABBIT-SpA with follow-up time of at least 12 months and available ASAS HI questionnaires were included. Patients received questionnaires addressing disease activity (Bath Ankylosing Spondylitis Disease Activity Index [BASDAI], Ankylosing Spondylitis Disease Activity Score [ASDAS]), physical function (Bath Ankylosing Spondylitis Functional Index [BASFI]), mental health (5-item World Health Organization Well-Being Index [WHO-5]), and global functioning (ASAS HI). Standardized response means (SRMs) were calculated to compare the sensitivity to change of different variables., Results: Six hundred and sixty-seven patients were included, 552 treated with biologic disease-modifying antirheumatic drugs (bDMARDs) and 115 with conventional synthetic DMARDs and/or nonsteroidal antiinflammatory drugs (control group). Between baseline and month 12, the mean ASAS HI declined from 6.9 to 5.1 in the bDMARD group and from 5.9 to 5.6 in the conventionally treated group. In the bDMARD group, the SRM of ASAS HI was 0.52, compared to 0.59 for BASFI, 0.65 for WHO-5, 0.73 for BASDAI, and 0.90 for ASDAS. The following ASAS HI domains were most frequently affected: pain (78% agreed), maintaining body position (75%), and energy/drive (73%). In the patients receiving bDMARDs, there was an improvement in all items. In the control group, the largest improvement was seen in pain., Conclusion: As expected, ASDAS and BASDAI as disease activity scores showed high sensitivity to change, whereas changes in physical function (BASFI), mental health (WHO-5), and the broader concept of functioning and health (ASAS HI) were moderate., (Copyright © 2023 by the Journal of Rheumatology.)

Background: The role of methotrexate in combination with biological agents in patients with psoriatic arthritis remains unclear. The MUST phase 3b trial aimed to compare the efficacy of ustekinumab plus placebo with ustekinumab plus methotrexate in patients with active psoriatic arthritis., Methods: In this investigator-initiated, randomised, multicentre, placebo-controlled, phase 3b non-inferiority trial done in 22 centres in Germany, patients with active psoriatic arthritis received open-label ustekinumab and were randomly assigned (1:1) to masked concomitant therapy with placebo or methotrexate (ongoing or new). The primary outcome was non-inferiority of mean Disease Activity Score-28 joints (DAS28) at week 24 for ustekinumab monotherapy (ustekinumab plus placebo) versus ustekinumab combination therapy (ustekinumab plus methotrexate), stratified by previous methotrexate treatment. The key secondary analysis was non-inferiority of DAS28 at week 52. The primary analysis was based on a stratified van Elteren test with an α of 2·5% and a non-inferiority margin of 12·5% by Mann-Whitney estimator. Adverse events and serious adverse events were assessed. This study is registered with ClinicalTrials.gov, NCT03148860., Findings: Between Jan 24, 2017, and April 12, 2021, 186 patients with active psoriatic arthritis were screened, of whom 173 (93%) patients were enrolled and randomly assigned (1:1) to receive concomitant methotrexate therapy (n=88) or placebo (n=85). 84 patients were receiving methotrexate at baseline, and 89 patients had no previous methotrexate treatment. 166 (96%) patients (87 in the ustekinumab plus methotrexate group and 79 in the ustekinumab plus placebo group) were included in the safety and efficacy analyses at week 24 (69 [42%] female; 97 [58%] male; mean age 48·2 years [SE 1·1]). Ustekinumab plus placebo was non-inferior to ustekinumab plus methotrexate in DAS28 at week 24 (2·9 [SD 1·31] vs 3·1 [1·42]); the stratified Mann-Whitney estimator for treatment comparison was 0·5426 (95% CI 0·4545-0·6307). Non-inferiority for ustekinumab plus placebo was also observed in DAS28 at week 52. Serious adverse events occurred in seven (9%) patients in the ustekinumab plus placebo group and eight (9%) patients in the ustekinumab plus methotrexate group. No specific serious adverse events affected more than one patient, and there were no deaths., Interpretation: Interleukin (IL)-12 and IL-23 inhibition with ustekinumab is an effective treatment for psoriatic arthritis independent of methotrexate use; concomitant methotrexate did not increase efficacy of ustekinumab (based on DAS28). On the basis of these data, there is no evidence to support the addition or maintainance of methotrexate when initiating ustekinumab in patients with active psoriatic arthritis., Funding: Janssen Cilag., Competing Interests: Declaration of interests MK received grants or contracts from BMS, Bionorica, Iron4u, Janssen-Cilag, LEO, Novartis, and Pfizer and received travel support or honoraria or fees for serving as a speaker, consultant and/or advisory board member from Abbvie, Lilly, Janssen-Cilag, Novartis, Pfizer, and UCB. GRB received honoraria or fees for serving as a speaker and/or consultant from Abbvie, Amgen, BMS, Galapagos, Lilly, MSD, Pfizer, Roche, and Sanofi. UK received scientific grants from AbbVie, Amgen, Biogen, Fresenius, GSK, Hexal, Novartis, Pfizer and honoraria or fees for serving as a speaker and/or consultant from Abbvie, Biocad, Biogen, Chugai, Eli Lilly, Fresenius, Hexal, Janssen, MSD, Novartis, Pfizer, Roche, and UCB. JR received scientific grants from Novartis and Sobi, and honoraria or fees for serving as a speaker and/or consultant from Abbvie, Biogen, BMS, Chugai, GSK, Janssen, Lilly, MSD, Novartis, Roche, Sanofi, Sobi, and UCB. SM-P received honoraria or fees for serving as a speaker and/or consultant from AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Janssen, and Novartis. HB received travel support or honoraria or fees for speaking from Janssen Cilag and research support from the Fraunhofer Cluster of Excellence for Immune-mediated diseases (CIMD). FB received research support from Janssen Cilag, the Fraunhofer Cluster of Excellence for Immune-mediated diseases (CIMD), and LOEWE Zentrum Translational Medicine and Pharmacology, grants or contracts from BMS, Bionorica, Iron4u, Janssen-Cilag, LEO, Novartis, and Pfizer, and meeting support or honoraria or fees for serving as a speaker, consultant, and/or advisory board member from Abbvie, Affibody, Amgen, Boehringer Ingelheim, Galapagos, GSK, Janssen Cilag, Lilly, MoonLake, MSD, Novartis, Pfizer, Sandoz, Sanofi, and UCB. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: The optimal dose of rituximab in combination with leflunomide in patients with rheumatoid arthritis (RA) is not known., Methods: In Part 1 (previously reported) of the investigator-initiated AMARA study (EudraCT 2009-015950-39; ClinicalTrials.gov NCT01244958), improvements at week (W)24 were observed in patients randomized to rituximab + leflunomide compared with placebo + leflunomide. In the study reported here (Part 2), Part 1 responders received rituximab 500 or 1000 mg at W24/26 plus ongoing leflunomide. Patients were randomized at baseline to their eventual W24 treatment group. The Part 2 primary outcome was the mean Disease Activity Score-28 joints (DAS28) at W52, based on the last observation carried forward (LOCF) analyses and a two-sided analysis of variance. Patient-reported outcomes (PROs) and adverse events were evaluated., Results: Eighty-three patients received rituximab at W24/26 (31 rituximab→rituximab 1000 mg; 29 rituximab→rituximab 500 mg; 10 placebo→rituximab 1000 mg; 13 placebo→rituximab 500 mg). At W52, there were no significant differences in DAS28 between rituximab doses in patients originally treated with rituximab or those originally treated with placebo. In the Part 1 placebo group, the higher rituximab dose was associated with greater improvements in ACR response rates and some PROs. Adverse events were similar regardless of rituximab dose., Conclusions: Retreatment with rituximab 500 mg and 1000 mg showed comparable efficacy, whereas an initial dose of rituximab 500 mg was associated with lower response rates versus 1000 mg. Reduced treatment response with the lower dose in patients initially treated with placebo may have been influenced by small numbers and baseline disease activity.

Introduction: The objective of this work was to assess the efficacy and safety of risankizumab in psoriatic arthritis (PsA) over 76 weeks., Methods: In this double-blind, dose-ranging phase 2 study, adults with active PsA were randomized 2:2:2:1:2 to risankizumab 150 mg at weeks 0, 4, 8, 12, and 16 (arm 1), 150 mg at weeks 0, 4, and 16 (arm 2), 150 mg at weeks 0 and 12 (arm 3), 75 mg at week 0 (arm 4), or placebo (arm 5). Patients completing week 24 could receive risankizumab 150 mg in a 52-week open-label extension study. Efficacy assessments included American College of Rheumatology (ACR) responses, Psoriasis Area Severity Index (PASI) responses, minimal disease activity (MDA), and 28-joint Disease Activity Score based on C-reactive protein (DAS28[CRP])., Results: Of 185 randomized patients, 173 (93.5%) completed week 16 and 145 (78.4%) entered the open-label extension. Significantly more patients in each risankizumab arm achieved ACR20 at week 16 versus placebo (primary endpoint: pooled arms 1 + 2 [59.5%] versus placebo [35.7%]; treatment difference [90% CI] 24.0 [9.3, 38.7]; P = 0.007). Similarly, significantly more patients in most risankizumab arms achieved ACR20/50/70, PASI75/90/100, MDA, and greater improvements in DAS28(CRP) versus placebo at week 16. These benefits of risankizumab were maintained long term. Treatment-emergent adverse events were comparable across treatment arms. Risankizumab 150 mg was well tolerated over 76 weeks., Conclusions: Risankizumab improved joint and skin symptoms versus placebo in patients with active PsA over 16 weeks; improvements were sustained long term. Risankizumab was well tolerated over the long term with no new safety findings., Trial Registration Numbers: NCT02719171 and NCT02986373., (© 2022. The Author(s).)

Objectives: To examine the safety and effectiveness of long-term tocilizumab treatment in elderly patients with rheumatoid arthritis (RA) and patients with age-associated comorbidities., Methods: ICHIBAN (NCT01194401) was a prospective, non-interventional study that observed adult patients with active moderate-to-severe RA in German rheumatology clinics and practices for up to two years. Patients were to be treated according to the tocilizumab label. Here, we present safety and effectiveness data analysed according to patient age., Results: Of the 3,164 patients treated with at least one dose of tocilizumab, 924 patients were <50 years old, 1496 patients were 50-65 years old, and 744 patients were >65 years old at baseline. Patients >65 years had the highest baseline DAS28-ESR, CDAI, and HAQ-DI scores, along with the highest burden of comorbidities, such as diabetes, coronary heart disease, anaemia, and renal insufficiency. Under treatment with tocilizumab, patients >65 years had similar improvements in DAS28-ESR, CDAI and patient-reported outcomes (fatigue, pain, sleeplessness) with similar glucocorticoid savings compared to patient groups <65 years. Patients >65 years with late-onset RA achieved similar reductions in disease activity compared to early-onset patients. Despite numerically higher rates of adverse events (AEs), serious AEs and serious infections in patients >65 years, there were similar rates of AEs leading to withdrawal., Conclusions: Elderly patients in ICHIBAN experienced improvements similar to younger patients in most effectiveness endpoints with only slightly higher rates of AEs, indicating an overall net-positive risk-benefit ratio of tocilizumab treatment regardless of patient age.

Objectives: To assess whether tocilizumab treatment is associated with changes in depression symptoms in patients with rheumatoid arthritis (RA) during routine daily care., Methods: We retrospectively analysed data from a German non-interventional study (ARATA) of adult, tocilizumab-naïve RA patients who initiated subcutaneous tocilizumab and were followed for 52 weeks. The Beck Depression Inventory II (BDI-II) was used to assess symptoms of depression and create baseline subgroups of no (BDI-II<14), mild (14-19), moderate (20-28), and severe (≥29) depression. Other key outcomes included Disease Activity Score-28 joints (DAS28), patient-reported outcomes (PROs), and adverse events. Mixed model repeated measures (MMRM) assessed the impact of DAS28 on BDI-II over time, and Pearson correlation analyses evaluated associations between changes from baseline., Results: Of 474/1155 ARATA patients who completed the BDI-II at baseline, 47.7% had evidence of depression: 18.4% mild, 17.7% moderate, and 11.6% severe. 229 patients (48.3%) completed the BDI-II at both baseline and week 52. Two-thirds of patients with moderate or severe depression at baseline improved to a milder or no depression subgroup at week 52 (44/65 [67.7%]). Improvements in disease activity and PROs were observed in all subgroups, but patients with depression had lower response and higher adverse events rates. We observed an association between DAS28 and BDI-II over time in MMRM analyses, but the Pearson correlation for change from baseline was weak (r=0.10)., Conclusions: Depression is common in patients receiving routine care for RA. Improvements in depressive symptoms in RA during tocilizumab therapy appear to be distinct from changes in disease activity.

Objective: To investigate the efficacy and safety of rituximab + LEF in patients with RA., Methods: In this investigator-initiated, randomized, double-blind, placebo-controlled phase 3 trial, patients with an inadequate response to LEF who had failed one or more DMARD were randomly assigned 2:1 to i.v. rituximab 1000 mg or placebo on day 1 and 15 plus ongoing oral LEF. The primary efficacy outcome was the difference between ≥50% improvement in ACR criteria (ACR50 response) rates at week 24 (P ≤ 0.025). Secondary endpoints included ACR20/70 responses, ACR50 responses at earlier timepoints and adverse event (AE) rates. The planned sample size was not achieved due to events beyond the investigators' control., Results: Between 13 August 2010 and 28 January 2015, 140 patients received rituximab (n = 93) or placebo (n = 47) plus ongoing LEF. Rituximab + LEF resulted in an increase in the ACR50 response rate that was significant at week 16 (32 vs 15%; P = 0.020), but not week 24 (27 vs 15%; P = 0.081), the primary endpoint. Significant differences favouring the rituximab + LEF arm were observed in some secondary endpoints, including ACR20 rates from weeks 12 to 24. The rituximab and placebo arms had similar AE rates (71 vs 70%), but the rituximab arm had a higher rate of serious AEs (SAEs 20 vs 2%), primarily infections and musculoskeletal disorders., Conclusion: The primary endpoint was not reached, but rituximab + LEF demonstrated clinical benefits vs LEF in secondary endpoints. Although generally well tolerated, the combination was associated with additional SAEs and requires monitoring., Trial Registration: EudraCT: 2009-015950-39; ClinicalTrials.gov: NCT01244958., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: We aimed to measure long-term effectiveness and safety of tocilizumab in patients with rheumatoid arthritis in daily German practice., Methods: ICHIBAN was a prospective, multi-centre, non-interventional study (ML22928) that enrolled adult patients with active moderate to severe rheumatoid arthritis. Patients were to be treated according to tocilizumab label and observed for up to two years. Effectiveness outcomes included DAS28-ESR remission, EULAR response, CDAI and HAQ., Results: Overall, 3164 patients received at least one dose of tocilizumab. Patient mean age was 55.5±13.1 years (74.8% female). At baseline, 72.1% of patients had at least one comorbidity. Approximately 50.9% of patients received concomitant csDMARDs, mostly methotrexate, and 80.7% received concomitant glucocorticoids (GCs). In patients receiving GCs at baseline, the mean dose decreased from 9.32±16.36 mg/d to 4.60±4.48 mg/d at week 104. In the effectiveness population with no prior TCZ (n=2902), 61.4% of patients achieved the primary outcome, DAS28-ESR remission. Improvements were seen as early as week 4. At week 104, 77.9% of patients had DAS28-ESR low disease activity, 89.6% achieved good or moderate EULAR response, and 29.5% achieved a CDAI-based remission. Effectiveness outcomes were similar in all previous therapy subgroups. The incidence of serious infections was similar to the rates in former studies involving tocilizumab. Patients receiving GC at baseline experienced slightly higher rates of treatment-related serious adverse events, mainly infections. No new safety signals were observed., Conclusions: Long-term effectiveness and safety in ICHIBAN were in line with previously reported tocilizumab efficacy and safety studies.

Background/objective: FKB327 is a biosimilar of the antitumour necrosis factor adalimumab reference product (RP). A randomised, double-blind (DB) phase 3 study compared the efficacy of FKB327 with the RP in patients with active rheumatoid arthritis (RA) inadequately controlled with methotrexate (MTX). A subsequent randomised open-label extension (OLE) study with treatment switching assessed long-term safety, efficacy, pharmacokinetics and immunogenicity of FKB327 compared with the RP., Methods: Patients with moderate-to-severe, active RA on a stable dose of MTX were randomised 1:1 to receive FKB327 or the RP (40 mg subcutaneously every other week) for 24 weeks. Patients who completed the DB study were enrolled in the OLE and rerandomised 2:1 to receive FKB327 or the RP; two-thirds continued on the same treatment and one-third switched for 30 weeks. All patients received FKB327 through Week 76. Long-term efficacy, safety and immunogenicity were assessed., Results: Of 728 patients in the DB study, 645 were enrolled in the FKB327-OLE study. The American College of Rheumatology (ACR)20 response rates for all treatment groups at Week 30 in the OLE ranged from 83.2% to 85.9%. ACR20 response rates remained stable for all patients regardless of single- or double-switching treatment and were similar for all treatment sequences through Week 76. The safety profile and incidence of antidrug antibodies were comparable across sequences., Conclusion: Efficacy, safety and immunogenicity were similar among patients with RA treated with FKB327 or the RP for up to 2 years, and were not affected by single- or double-switching treatment., Competing Interests: Competing interests: MG has received consultant fees from Fujifilm Kyowa Kirin Biologics Co., including for the design of this trial. HK has no conflicts of interest to report. YA is an employee of Fujifilm Kyowa Kirin Biologics Co. and has received personal fees from the company, both during the conduct of the study and outside the submitted work. RM is an employee and shareholder of Mylan Inc. RA has received consultant fees from Mylan Inc and has been a paid speaker for Mylan Inc., (© 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.)

Objective: To compare the efficacy, serum drug concentrations, immunogenicity, and safety of FKB327 with the adalimumab reference product (RP) in combination with methotrexate in patients with moderate-to-severe, active rheumatoid arthritis (RA)., Methods: Patients were randomized 1:1 in a double-blind study (NCT02260791), received 40 mg of FKB327 or RP by subcutaneous injection every other week for 24 weeks (Period I), then re-randomized 2:1, remaining on the same study drug or switching to the other up to week 54 in an open-label extension (Period II, NCT02405780). Efficacy was evaluated using American College of Rheumatology (ACR20) response rate difference at week 24 with equivalence margins of ± 13% and - 12% to + 15% using 95% and 90% confidence intervals (CIs), respectively. Efficacy, serum drug concentrations, immunogenicity, and safety were compared at week 54., Results: A total of 730 patients were randomized in Period I (n = 367 FKB327, n = 363 RP), and 645 transitioned to Period II (n = 216 FKB327-FKB327, n = 108 FKB327-RP, n = 108 RP-FKB327, n = 213 RP-RP). At week 24, ACR20 response rates were 74.1% with FKB327 versus 75.7% with RP. 95% and 90% CI of the response rate difference were - 7.9 to 4.7% and - 7.3 to 3.6%, respectively, meeting predefined equivalence margins. The ACR20 response rate remained over 70% of patients to week 54 with all treatment sequences. In Period I, mean trough serum drug concentrations were slightly higher for patients receiving FKB327 than those receiving RP. Mean concentrations were stable over time and reflected steady state in Period II. The proportions of patients with samples positive for neutralizing antidrug antibodies (ADAs) were comparable (57.7% with FKB327 vs. 55.5% with RP) at week 24, and no consistent difference in ADA were seen between continuous and switched treatments in Period II. Efficacy was slightly reduced in the small proportion of patients with high ADA titers in all treatment groups. No clinically significant differences were observed in the incidence of commonly reported treatment-emergent adverse events between the treatments across Periods I and II., Conclusion: FKB327 was equivalent to RP in clinical efficacy and demonstrated comparable safety and immunogenicity in patients with moderate-to-severe RA. No effect of switching between FKB327 and RP was observed., Trial Registration: ClinicalTrials.gov, NCT02260791, Registered 29 July 2014. ClinicalTrials.gov, NCT02405780, Registered 17 July 2015.

Background: Gastroenterological and rheumatological diseases often have a systemic character, with disease manifestations beyond the area affected by the disease. Common disease-relevant pathophysiological pathways, e.g. chronic inflammation, may present primarily as rheumatological or gastroenterological disease. Knowledge of disease-specific symptoms and signs beyond one's own area of expertise my lead to an earlier and more precise diagnosis, with the chance of a more focused therapy., Aim: The aim of this overview is to sensitize orthopedists as well as rheumatologists to gastroenterological signs and symptoms and give them a clinical guide to approaching an interdisciplinary patient. Targeted, clinically relevant questions are discussed and common disease entities are presented.

Objectives: To evaluate early and late responses in biological-naïve patients with rheumatoid arthritis (RA) initiating tocilizumab and early tocilizumab non-responders who switched to rituximab., Methods: In this open-label, non-randomised phase 3 study, RA patients with inadequate response to conventional synthetic DMARDs received tocilizumab 8 mg/kg intravenously at study begin and weeks 4, 8 and 12. After evaluation at week 16, early responders (Disease Activity Score based on 28 joints-erythrocyte sedimentation rate [DAS28-ESR] <2.6) completed the study; partial responders (DAS28-ESR decrease >1.2 or DAS28-ESR ≥2.6-≤3.2) were to continue tocilizumab through week 28; non-responders (DAS28-ESR decrease ≤1.2) switched to rituximab (1000 mg, weeks 16 and 18) with safety follow-up through week 66., Results: Of 519 patients, 222 (42.8%) achieved early DAS28-ESR remission at week 16; 240 patients continued treatment, 213 (41.0%) received tocilizumab, and 27 (5.2%) switched to rituximab. At week 32 DAS28-ESR remission was achieved by 117/213 patients (54.9%) who continued tocilizumab and 4/27 patients (14.8%) who switched to rituximab; good EULAR response was achieved by 66.7% and 25.9% and CDAI remission by 19.2% and 14.8% of patients, respectively. Serious adverse events occurred through week 32 in 45/490 patients (9.2%) who received tocilizumab (serious infections, 2.7%) and through week 66 in 8/27 patients (29.6%) who switched to rituximab., Conclusions: Early response to tocilizumab was observed in 42.8% of patients. Half of early partial responders benefitted from continuing tocilizumab. Switching non-responders to rituximab seems feasible. No new safety signals were observed in patients treated with tocilizumab or switched to rituximab.

Objective: To evaluate the safety, efficacy and therapeutic mechanism of BI 655064, an antagonistic anti-CD40 monoclonal antibody, in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX-IR)., Methods: In total, 67 patients were randomised to receive weekly subcutaneous doses of 120 mg BI 655064 (n=44) or placebo (n=23) for 12 weeks. The primary endpoint was the proportion of patients who achieved 20% improvement in American College of Rheumatology criteria (ACR20) at week 12. Safety was assessed in patients who received at least one dose of study drug., Results: At week 12, the primary endpoint was not met, with 68.2% of patients treated with BI 655064 achieving an ACR20 vs 45.5% with placebo (p=0.064); using Bayesian analysis, the posterior probability of seeing a difference greater than 35% was 42.9%. BI 655064 was associated with greater changes in CD40-CD40L pathway-related markers, including reductions in inflammatory and bone resorption markers (interleukin-6, matrix metalloproteinase-3, receptor activator of nuclear factor-κB ligand), concentration of autoantibodies (immunoglobulin [Ig]G rheumatoid factor [RF], IgM RF, IgA RF) and CD95+ activated B-cell subsets. No serious adverse events (AEs) related to BI 655064 treatment or thromboembolic events occurred; reported AEs were mainly of mild intensity., Conclusion: Although blockade of the CD40-CD40L pathway with BI 655064 in MTX-IR patients with RA resulted in marked changes in clinical and biological parameters, including reductions in activated B-cells, autoantibody production and inflammatory and bone resorption markers, with a favourable safety profile, clinical efficacy was not demonstrated in this small phase IIa study., Trial Registration Number: NCT01751776., Competing Interests: Competing interests: SD, RP, AP, HK, ED and BK report no disclosures; UM-L reports being an advisor for Boehringer Ingelheim; RA and CS report having received research/grant support from Boehringer Ingelheim; SV, MR, BR, AGE, RV, PB, DJ, JSF, SJP and JS report being employed by Boehringer Ingelheim., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To determine the repeatability and response to therapy of dynamic contrast-enhanced (DCE) MRI biomarkers of synovitis in the hand and wrist of rheumatoid arthritis (RA) patients, and in particular the performance of the transfer constant K trans , in a multicentre trial setting., Methods: DCE-MRI and RA MRI scoring (RAMRIS) were performed with meticulous standardisation at baseline and 6 and 24 weeks in a substudy of fostamatinib monotherapy in reducing synovitis compared with placebo or adalimumab. Analysis employed statistical shape modelling to avoid biased regions-of-interest, kinetic modelling and heuristic analyses. Repeatability was also evaluated., Results: At early study termination, DCE-MRI data had been acquired from 58 patients in 19 imaging centres. K trans intra-subject coefficient of variation (N = 14) was 30%. K trans change demonstrated inferiority of fostamatinib (N = 11) relative to adalimumab (N = 10) after 6 weeks (treatment ratio = 1.92, p = 0.003), and failed to distinguish fostamatinib from placebo (N = 10, p = 0.79). RAMRIS showed superiority of fostamatinib relative to placebo at 6 weeks (p = 0.023), and did not distinguish fostamatinib from adalimumab at either 6 (p = 0.175) or 24 (p = 0.230) weeks., Conclusion: This demonstrated repeatability of K trans and its ability to distinguish treatment groups show that DCE-MRI biomarkers are suitable for use in multicentre RA trials., Key Points: • DCE-MRI biomarkers are feasible in large multicentre studies of joint inflammation. • DCE-MRI K trans showed fostamatinib inferior to adalimumab after 6 weeks. • K trans repeatability coefficient of variation was 30% multicentre.

Introduction: A 28-week study suggested efficacy of the anti-interleukin-17A monoclonal antibody secukinumab in active ankylosing spondylitis (AS). MRI-assessed inflammation was reduced at weeks 6, 28., Objective: To analyse the longer-term effects of secukinumab on MRI inflammatory and non-inflammatory spinal lesions in relation to its clinical efficacy in subjects with active AS., Methods: Spinal MRI results (baseline, week 94) for 13 subjects with AS initially treated with secukinumab 2×10 mg/kg intravenously (n=10) or placebo (n=3) and receiving a secukinumab maintenance dose of 3 mg/kg IV every 4 weeks up to week 94 were evaluated by the Berlin score; inflammatory/non-inflammatory (fatty) changes were assessed at vertebral edges (VEs). Results were compared with clinical outcomes., Results: Most of the 13 subjects assessed at week 94 had sustained clinical responses: 8 (62%) achieved Assessment of SpondyloArthritis international Society 20% (ASAS20), including 6 (46%) achieving ASAS40 responses, corresponding to 75% and 83% reductions in the Berlin score, respectively. In the 10 subjects treated with secukinumab throughout the study period, 79/91 (87%) inflammatory VEs at baseline resolved by week 94; new fatty lesions occurred in 39/796 (4.9%) of VEs; 87/124 (70%) VEs with fatty lesions at baseline remained unchanged; 30% were no longer visible., Conclusions: In this pilot study, secukinumab treatment up to 2 years yielded sustained clinical improvement accompanied by regression of spinal inflammation. The impact of secukinumab on the development of fatty changes and bone formation in AS will be assessed in larger trials., Trial Registration Number: This study is registered with ClinicalTrials.gov, number NCT00809159., (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: Evaluate efficacy of infliximab with response-driven dosing in patients with active RA., Research Design and Methods: Patients (n = 203) with active RA despite methotrexate + etanercept/adalimumab, participated in this active-infliximab-switch study. Infliximab 3 mg/kg was infused at Weeks 0, 2, 6, 14, and 22 with escalation to 5 or 7 mg/kg depending on EULAR response at Weeks 14 and 22. The primary endpoint was EULAR response at Week 10. Safety was assessed through Week 30. Infliximab levels and antibodies to infliximab (ATI) were measured at Weeks 0, 6, 14, and 26., Clinical Trial Registration: NCT 00714493, EudraCT 2007-003288-36., Results: Of 197 evaluable patients, 120/77 previously received etanercept/adalimumab. Baseline mean (SD) swollen and tender joint counts were 17.3 (10.54) and 30.2 (16.89), respectively; mean DAS28-ESR was 6.19 (0.981). At Week 10, 98 (49.7%; 95% CI: 42.6%, 56.9%) patients achieved EULAR response, with a significantly improved DAS28-ESR score (mean [SD] change -1.1 [1.15]; p < 0.001). EULAR response was achieved by 41.7%/62.3% of patients previously receiving etanercept/adalimumab (p = 0.006). At Week 26, 51.8% (95% CI: 44.6%, 58.9%) of patients achieved or maintained EULAR response. Infliximab dose was escalated in 100 patients, 52% of whom achieved EULAR response at Week 26. Median serum concentration levels at Week 26 showed that dose escalation helped EULAR non-responders achieve levels similar to or higher than the levels seen in responders. ATI were associated with lower serum concentrations of infliximab, consistent with lower efficacy rates among ATI-positive patients., Conclusion: Infliximab, in treat-to-target settings with individual dose escalation, demonstrated significant efficacy at Weeks 10 and 26 in patients switched to infliximab after inadequate response to etanercept/adalimumab. The observed efficacy indicated that the switch to infliximab and ability to increase dose in a targeted fashion were beneficial., Key Limitations: Given the relatively short duration of study follow-up, these safety findings require confirmation in a longer-term study.

Objective: To evaluate the longer-term safety and efficacy of secukinumab, a fully human monoclonal antiinterleukin-17A antibody, in patients with rheumatoid arthritis., Methods: In this 52-week, double-blind, placebo-controlled (up to Week 20) study (NCT00928512), patients responding inadequately to disease-modifying antirheumatic drugs (DMARD) or biologics were randomized to receive monthly subcutaneous injections of secukinumab (25, 75, 150, or 300 mg), or placebo. The efficacy and safety results up to Week 20 have been reported previously. Here, efficacy results from Week 20 to 52 and safety results from Week 20 to 60 are presented., Results: Of 237 patients randomized, 174 (73.4%) completed the study. Patients with improved American College of Rheumatology (ACR) and 28-joint Disease Activity Score (DAS28) C-reactive protein (CRP) responses at Week 16 sustained their responses through Week 52. In patients taking 150 mg of secukinumab, responses were improved through Week 52 (ACR50: Week 16 = 45%, Week 52 = 55%; DAS28-CRP ≤ 2.6: Week 16 = 25%, Week 52 = 40%). The rate of adverse events (AE) from weeks 20 to 60 was 64.8%, with most AE being mild to moderate in severity. The overall rate of infections was 31.9%, most being mild. The most predominant infection was nasopharyngitis, and was not associated with dose or concurrent neutropenia. Serious AE were reported in 21 patients (8.9%). There were 3 reports of malignancies (ovarian, lung, basal cell), and no deaths between weeks 20 and 60., Conclusion: Patients with active RA who failed to respond to DMARD and other biologics showed an improvement after longterm treatment with 150 mg of secukinumab. The frequency of AE remained stable over time and secukinumab had a consistent safety profile over 60 weeks.

The German Society of Rheumatology approved new German guidelines for the sequential medical treatment of rheumatoid arthritis (RA) based on the European League Against Rheumatism (EULAR) recommendations for the management of RA published in 2010. An update of the EULAR systematic literature research was performed in Medline, Embase, and Cochrane databases. Meta-analyses, controlled trials, cohort studies, and registry data addressing traditional and biologic disease-modifying antirheumatic drugs, glucocorticoids, and treatment strategies published between January 2009 and August 2011 were included. Two reviewers independently evaluated and compared the additional data that had been published after the time limit set by the EULAR recommendations. A national guideline working group developed an adapted set of recommendations. The new German guidelines were accepted by vote using an informal Delphi approach. Twelve recommendations and the resulting updated treatment algorithm were developed and approved as a practical orientation for rheumatologists. These recommendations are based on a successive treatment with traditional and biologic disease-modifying drugs depending on the individual progress of the disease and distinct patient characteristics. The German guidelines have been developed on the basis of the internationally well-recognized EULAR recommendations. In addition, more recent evidence from a systematic literature research was considered. They have been developed and approved by a group of national experts aiming at guidance for rheumatologists to reach best medical practice.

Background: To evaluate the utility of the recently introduced SOLAR score (sonography of large joints in Rheumatology), which has been validated in RA patients, in a cohort of patients with Psoriatic Arthritis (PsA) and Ankylosing Spondylitis (AS) presenting with involvement of large peripheral joints., Methods: The recently established SOLAR score has been designed to determine the degree of inflammation in the shoulder, the elbow, the hip and the knee joint in patients suffering from RA. Since large joints are frequently involved in PsA and AS, synovitis and synovial vascularity were scored semiquantitatively (grade 0-3) by grey scale (GSUS) and power Doppler ultrasound (PDUS) utilizing the validated scoring system. Each joint was scanned from different angles, the knee joint for example was divided into four areas to score for synovitis: the suprapatellar longitudinal, the medial longitudinal, the lateral longitudinal, and the posterior region. Each area was scored from 0-3, so a maximum score of 12 could be achieved. PsA and AS patients presenting with peripheral joint disease involving large joints were examined at baseline, 3 and 6 months after initiation of local or systemic therapy (DMARDs/Biologics). For evaluation of the inflammatory status, the erythrocyte sedimentation rate (ESR) was determined., Results: A cohort of 126 patients were enclosed, and 83 of these were followed for 6 months. At baseline before modification of the therapy, patients received DMARDs (n = 83), DMARDs plus biologics (n = 30), or biologic monotherapy (n = 29). Following intervention, all US scores demonstrated a marked improvement. The GSUS and the PDUS scores for all joint areas, except the PDUS score of the hip, exhibited a significant improvement (p < 0.05), while the GSUS of the knee showed even a highly significant (p < 0.001) change. The ESR displayed a significant decrease from 27 to 19 mm (p < 0.002) representing good treatment response., Conclusion: The SOLAR score, which has been recently introduced for RA patients, is a very suitable instrument for the qualitative and quantitative evaluation of large joint involvement in PsA and AS patients and allows for treatment monitoring.

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: Compare effectiveness of celecoxib versus diclofenac plus omeprazole in improving arthritis signs and symptoms in patients at high gastrointestinal (GI) risk who were enrolled in the CONDOR (Celecoxib vs Omeprazole and Diclofenac in Patients With Osteoarthritis and Rheumatoid Arthritis) trial., Methods: CONDOR was a 6-month, prospective, double-blind, triple-dummy, parallel-group, randomized, multicenter trial comparing celecoxib 200 mg twice daily versus diclofenac slow release (SR) 75 mg twice daily plus omeprazole 20 mg daily. Patients were Helicobacter pylori negative, had osteoarthritis (OA) or rheumatoid arthritis (RA), were aged ≥60 years, were with or without a history of gastroduodenal ulceration, or were ≥18 years with previous gastroduodenal ulceration. Patients' Global Assessment of Arthritis was determined at each study visit., Results: A total of 4484 patients were randomized to treatment (2238 celecoxib, 2246 diclofenac SR) and included in the intention-to-treat analyses. Least squares mean (LSM) (standard error [SE]) for Patients' Global Assessment of Arthritis was 3.219 (0.017) and 3.221 (0.017) at baseline for celecoxib and diclofenac SR (p=0.90). Improvement in both groups was similar in months 2, 4, and 6; at month 1 the LSM (SE) was 2.647 (0.017) and 2.586 (0.017) for celecoxib and diclofenac (p=0.0025). LSM difference (SE) from baseline to final visit demonstrated an improvement of 0.75 (0.02) in celecoxib-treated patients and 0.77 (0.02) in diclofenac SR-treated patients (p=0.42)., Conclusions: Celecoxib and diclofenac plus omeprazole were shown to have similar efficacy in patients with OA and/or RA at increased GI risk who were enrolled in the CONDOR trial., Trial Registry: Trial was registered under ClinicalTrials.gov identifier NCT00141102.

Purpose: To determine the sensitivity to change of the US7 score among RA patients under various therapies and to analyze the effect of each therapeutic option over 1 year. To estimate predictors for development of destructive bone changes., Methods: Musculoskeletal ultrasound (US7 score), DAS28, CRP and ESR were performed in 432 RA patients at baseline and after 3, 6 and 12 months. The cohort was divided into four sub-groups: first-line DMARDs (Group 1; 27.3%), therapy switch: DMARDs to second DMARDs (Group 2; 25.0%), first-line biologic after DMARDs therapy (Group 3; 35.4%) and therapy change from biologic to second biologic (Group 4; 12.3%)., Results: The US7 synovitis and tenosynovitis sum scores in grey-scale (GSUS) and power Doppler ultrasound (PDUS) as well as ESR, CRP decreased significantly (p<0.05) after 12 months in group 1 to 3. Group 1+2 also illustrated a significant change of DAS28 after 1 year (p<0.001). Only in Group 4, the US7 erosion sum score decreased significantly from 4.3 to 3.6 (p=0.008) after 1 year. Predictors capable of forecasting US erosions after one year were: higher score of US7 synovitis (p<0.001), of US7 erosions in GSUS (p<0.001), as well as of DAS28 (p<0.001) at baseline., Conclusions: The comparable developments of the US7 score with clinical and laboratory data illustrates its potential to reflect therapeutic response. Therefore, the novel US7 score is sensitive to change. Patients who switched from one biologic to another exhibited a significant decline in erosions after 12 months, while the erosions scores in the other groups were stable.

Objectives: Multifocal musculoskeletal inflammation is common in ankylosing spondylitis (AS) and is effectively treated by expensive anti-TNF (tumour necrosis factor) therapy. This study evaluated assessment of response by whole-body (WB) MRI compared with clinical assessment in AS patients during etanercept therapy., Methods: Ten patients with AS underwent a 12-month therapy with etanercept. Clinical markers were monitored [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and C-reactive protein (CRP)] and patients underwent WBMRI (1.5 T, STIR and T1-weighted) at three different time points (0, 26 and 52 weeks). WBMRI was evaluated and correlated with clinical scores., Results: The BASDAI index decreased under therapy from 5.5 ± 0.5 (week 0) to 1.7 ± 0.5 (week 52, P < 0.05). CRP declined from 15.7 ± 2.2 mg/dl (week 0) to 0.9 ± 0.9 mg/dl (week 52, P < 0.05). In WBMRI, the sum of all lesions showed a significant decrease from week 0 (38.9 ± 3.4) to week 52 (2.2 ± 0.9, 94.3 % reduction). WBMRI detected more areas of synovitis and enthesitis than clinical examination alone., Conclusions: AS activity significantly decreased under etanercept therapy, which was proven by clinical examination and WBMRI. WBMRI detected more inflammatory lesions than clinical examination alone. The results suggest that WBMRI improves the detection of inflammatory changes and the assessment of their course under therapy., Key Points: • Multifocal musculoskeletal inflammation in AS is effectively treated by anti-TNF therapy. • Inflammatory lesions can be assessed by clinical examination and whole-body MRI. • AS activity significantly decreased under therapy as shown by WBMRI/clinical examination. • WBMRI detected more inflammatory lesions than clinical examination alone. • WBMRI improves detection of inflammatory changes and may help evaluation of therapy.

Objective: To assess the safety and efficacy of secukinumab, a fully human monoclonal anti-interleukin-17A antibody, in patients with rheumatoid arthritis (RA)., Methods: Patients (n=237) with inadequate response to methotrexate were randomly assigned to receive monthly subcutaneous injections of secukinumab 25 mg, 75 mg, 150 mg, 300 mg or placebo. The primary endpoint was the American College of Rheumatology 20% response (ACR20) at week 16., Results: Demographics and baseline characteristics were comparable across all treatment groups. The primary efficacy endpoint was not achieved: the proportion of ACR20 responders at week 16 with secukinumab 25-300 mg was 36.0-53.7% versus placebo (34%). Disease activity score in 28 joints (DAS28)-C-reactive protein (CRP) was a secondary endpoint and clinically relevant decreases with secukinumab 75-300 mg were reported versus placebo. Serum high sensitivity CRP levels at week 16 were significantly reduced with secukinumab 75 mg, 150 mg and 300 mg doses versus placebo. The safety profile of secukinumab was consistent with that seen with other biological agents. Most adverse events (AE) were mild to moderate in severity. Infections were slightly more frequent with secukinumab than placebo. Six serious AE were reported: secukinumab 75 mg (one), secukinumab 300 mg (four) and placebo (one)., Conclusions: ACR20 response rates differed between secukinumab 75 mg, 150 mg and 300 mg doses and placebo; however, the primary efficacy endpoint was not achieved. Greater decreases in DAS28 were observed with secukinumab 75 mg, 150 mg and 300 mg than placebo. There were no unexpected safety signals and no specific organ-related toxicities. Further trials with secukinumab in the treatment of RA are warranted.

Clinical and experimental evidence suggest that interleukin-17A (IL-17A; also known as IL-17) is an attractive therapeutic target in rheumatoid arthritis (RA). Rheumatoid synovial tissue produces IL-17A, which causes cartilage and bone degradation in synovial and bone explants. Overexpression of IL-17A induces synovial inflammation and joint destruction in animal RA models. These effects are attenuated in IL-17A-deficient animals and by agents that block IL-17A. Serum IL-17A levels and, to a greater extent, synovial fluid IL-17A levels are elevated in many patients with RA. In some RA cohorts, higher IL-17A levels have been associated with a more severe clinical course. Several IL-17A blockers, including the anti-IL-17A monoclonal antibodies secukinumab and ixekizumab, and the anti-IL-17 receptor subunit A monoclonal antibody brodalumab have been evaluated in phase II clinical trials. Of these, secukinumab is the most advanced with respect to clinical evaluation in RA, with phase III trials ongoing in patients on background methotrexate who had inadequate responses to previous tumor necrosis factor blocker therapy.

Objective: To compare the safety and efficacy of celecoxib versus diclofenac slow release (SR) plus omeprazole in elderly arthritis patients., Research Design and Methods: Patients aged≥65 years, with osteoarthritis and/or rheumatoid arthritis, at high gastrointestinal (GI) risk who participated in the CONDOR trial (Celecoxib vs. Omeprazole and Diclofenac in Patients With Osteoarthritis and Rheumatoid Arthritis) were included in this subanalysis. CONDOR was a 6-month prospective, double-blind, randomized, parallel-group, multicenter, international study comparing treatment with celecoxib 200 mg twice daily (BID) versus diclofenac SR 75 mg BID plus omeprazole 20 mg daily., Main Outcome Measures: The primary end point was a composite of Clinically Significant Upper and Lower GI Events adjudicated by an independent blinded expert committee. Efficacy was determined by the Patient's Global Assessment of Arthritis., Results: A total of 2446 patients aged≥65 years were included in the intent-to-treat (ITT) population (n=1219 celecoxib; n=1227 diclofenac). Eight patients in the celecoxib group and 52 in the diclofenac group were adjudicated as having Clinically Significant Upper and Lower GI events (adjusted odds ratio: 6.27; p<0.0001). Clinically significant reductions in hemoglobin (≥2 g/dL) and/or hematocrit (≥10%) were observed in 23 patients in the celecoxib group and in 76 in the diclofenac group (relative risk: 3.22 [95% confidence interval: 2.04-5.07]; p<0.0001). Incidence of moderate-to-severe abdominal symptoms and discontinuation of treatment due to GI adverse events (AEs) were lower in the celecoxib group. The Patient's Global Assessment of Arthritis score least squares mean change from baseline to final visit and percentage of patients rating treatment efficacy as good/very good at baseline and final visit were similar in both groups., Limitations: The dose of celecoxib used is consistent with the European label for the management of osteoarthritis and may not reflect what is commonly prescribed in current clinical practice in the United States. The data were obtained in a clinical trial setting where patients were enrolled based on specific inclusion and exclusion criteria; as such, the patients may not be broadly representative of the patient population in a general practice setting., Conclusions: Efficacy was comparable in the two treatment groups. There were fewer endpoints as well as fewer GI AEs reported in patients treated with celecoxib compared with diclofenac. These data may help physicians in their treatment decisions for elderly patients with arthritis.

Objective: To introduce and evaluate a new standardized ultrasound (US) score developed for large joints in patients with rheumatoid arthritis (RA)., Methods: A US score was designed to determine the degree of inflammation in the shoulder, the elbow, the hip, and the knee joint in patients with RA (Sonography of Large Joints in Rheumatology [SOLAR] score). Synovitis and synovial vascularity were scored semiquantitatively (grade 0-3) by gray-scale US (GSUS) and power Doppler US (PDUS). Patients with RA were examined at baseline and 3, 6, and 12 months after initiation of local or systemic therapy (disease-modifying antirheumatic drugs [DMARDs]/biologic agents). Erythrocyte sedimentation rate, anti-cyclic citrullinated peptide antibodies, and the clinical Disease Activity Score in 28 joints (DAS28) were determined., Results: A cohort of 199 patients were analyzed and followed up over 12 months. At baseline, before modification of the therapy, patients received either DMARDs (n = 131), DMARDs plus biologic agents (n = 46), biologic monotherapy (n = 8), or no DMARD therapy (n = 14). At baseline, the mean DAS28 score was 4.6 and decreased to 3.2 after 1 year of therapy (P < 0.001). All US scores demonstrated a statistically significant improvement except for the PDUS scores for the shoulder and the hip. In detail, the mean synovitis GSUS score for the knee decreased from 5.2 at baseline to 2.2 after 12 months of followup. The mean GSUS score for the shoulder fell from 2.6 to 1.6, for the elbow fell from 5.2 to 2.6, and for the hip fell from 2.2 to 0.4 (P < 0.05 for each)., Conclusion: The SOLAR score is a feasible tool for the qualitative and quantitative evaluation of large joint involvement in patients with RA using US., (Copyright © 2012 by the American College of Rheumatology.)

Background: Canakinumab is a fully human anti-interleukin IL-1beta monoclonal antibody, being investigated for the treatment of rheumatoid arthritis (RA). This multicenter, phase II, randomized, double-blind, placebo-controlled, parallel-group, dose-finding study investigated the efficacy and safety of canakinumab in patients with active RA despite ongoing therapy at stable doses of methotrexate., Methods: Patients were randomized to receive one of four regimens, in addition to methotrexate, for 12 weeks: canakinumab 150 mg subcutaneously (SC) every 4 weeks (q4wk), canakinumab 300 mg SC (2 injections of 150 mg SC) every 2 weeks, a 600 mg intravenous loading dose of canakinumab followed by 300 mg SC every 2 weeks', or placebo SC every 2 weeks., Results: Among 274 patients with evaluable efficacy data, the percentage of responders according to American College of Rheumatology 50 criteria (the primary endpoint, based on a 28-joint count) was significantly higher with canakinumab 150 mg SC q4wk than with placebo (26.5% vs. 11.4%, respectively; p = 0.028). Compared to placebo, this dosage of canakinumab was also associated with significantly more favorable responses at week 12 with respect to secondary endpoints including the Disease Activity Score 28, scores on the Health Assessment Questionnaire and Functional Assessment of Chronic Illness Therapy-Fatigue, swollen 28-joint count, and patient's and physician's global assessments of disease activity. No safety concerns were raised with canakinumab therapy, particularly with regard to infections. Few injection-site reactions occurred., Conclusion: The addition of canakinumab 150 mg SC q4wk improves therapeutic responses among patients who have active RA despite stable treatment with methotrexate., Trial Registration: (ClinicalTrials.gov identifier: NCT00784628).

Leflunomide is effective and well tolerated in the treatment of rheumatoid arthritis (RA), however, data on its use in early RA are scarce. This study seeks to evaluate effectiveness and safety of leflunomide in the treatment of early RA in daily practice. This prospective, open-label, non-interventional, multi-center study was carried out over 24 weeks including adults with early RA (< or =1 year since diagnosis). Leflunomide treatment was according to label instructions. Three hundred thirty-four patients were included. Disease activity score in 28 joints (DAS28) response (reduction in DAS28 of >1.2 or reduction of >0.6 and a DAS28 of < or =5.1) was 71.9% at week 12 and 84.6% at week 24. 25.0% of patients achieved clinical remission (DAS28 < or = 2.6). Most frequently reported adverse drug reactions (ADR) were diarrhea (3.0%), nausea (2.4%), hypertension (1.8%), and headache (1.5%). Serious ADR were reported in four patients (1.2%). Leflunomide showed the effectiveness which was to be expected from controlled studies without revealing any new or hitherto unknown side effects. Onset of action was quick and significant improvement of disease was seen after 12 weeks of therapy and at even higher rates after 24 weeks irrespective of the use of a loading dose. Interestingly, the DAS28-remission rate achieved was similar to the rate seen with methotrexate or biologic therapy in other studies.

Objective: Understanding of the molecular pathophysiology of spondylarthritis (SpA) remains largely elusive. This is related both to the complexity of the disease (axial versus peripheral disease, inflammation versus tissue remodeling) and to the difficulty in obtaining samples from primary disease sites. This study was undertaken to explore a gene expression approach for identifying novel candidate mediators of SpA., Methods: Sacroiliac joint fluid aspirates from 3 SpA patients with active sacroiliitis were studied by microarray analysis. The expression of selected candidate molecules in peripheral synovitis was confirmed by reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay., Results: Microarray analysis identified 4 sacroiliitis gene clusters, containing a total of 47 messenger RNA (mRNA) transcripts. Two clusters contained genes expressed in all sacroiliitis samples, corresponding to both known and unsuspected candidate mediators of SpA pathology. These included proinflammatory molecules as well as molecules involved in tissue remodeling, such as transforming growth factor beta2. Of the novel candidate genes selected for confirmation, interleukin-7 (IL-7) mRNA expression was higher in SpA peripheral synovial fluid and synovial tissue samples than in osteoarthritis samples, and similar to expression in rheumatoid arthritis (RA) samples. At the protein level, synovial fluid IL-7 levels were even higher in SpA than in RA, despite lower levels of tumor necrosis factor alpha and IL-1beta., Conclusion: In the present study, both known and unsuspected candidate mediators of SpA pathogenesis were identified, including IL-7. The specific overexpression of IL-7 at sites of peripheral synovitis in SpA suggests that further functional investigations of the role of this cytokine in SpA pathogenesis are warranted.

We evaluated the association of anti-cyclic citrullinated peptide (CCP) antibody titers with serological markers of disease activity. We also compared three different anti-CCP antibody ELISAs with an anti-citrullin ELISA and the IgM and the IgA rheumatoid factor (RF) in their performance of discriminating between rheumatoid arthritis (RA) and other rheumatic diseases. Sera from 333 consecutive patients of the Rheumaeinheit der Medizinischen Poliklinik Munchen, an outpatient clinic for rheumatic diseases, were collected and tested. Anti-CCP antibodies were assayed with three different commercially available ELISAs. Antifilaggrin antibodies were tested with a commercially available ELISA using in vitro deiminated recombinant rat filaggrin. IgA-RF was analyzed with an ELISA, whereas IgM-RF was measured by latex-enhanced turbidimetry. Rheumatoid arthritis (RA) was diagnosed in 87 patients according to the revised classification criteria of the American College of Rheumatology (ACR), probable RA was diagnosed in 23 patients in an early phase not (yet) fulfilling the ACR criteria, and 223 patients had other rheumatic diseases. Differences in sensitivity and specificity were calculated using McNemar's test. A measure of agreement (kappa statistic) was used to examine whether the tests tended to identify the same patients as positive or negative. Correlations between CCP titers and other tests were analyzed by Spearman nonparametric rank correlation. No significant differences in sensitivity and specificity were found between the tested CCP assays (80.0-80.9% and 97.3-98.1%, respectively). All three CCP tests were slightly but not significantly more sensitive and specific than the anti-citrullin assay (77% and 92%, respectively), comparably sensitive but significantly more specific compared with the IgM-RF (86% and 82%, respectively), and significantly more sensitive but comparably specific compared with the IgA-RF (63% and 94.4%, respectively) in detecting the patients with RA. There was no significant correlation between anti-CCP, anti-citrullin, or IgM-RF or IgA-RF antibody titers and C-reactive protein, erythrocyte sedimentation rate, or white blood cell count. A weak but significant linear correlation was found between anti-CCP titers and IgM-RF titers (r = 0.2, P = 0.03). We could not find a significant difference between the three tested anti-CCP assays and the anti-citrullin test in terms of sensitivity and specificity. Compared with the IgM-RF, all the anti-CCP assays were superior in specificity and comparable in sensitivity. Compared with the IgA-RF, they were more sensitive and comparably specific in the discrimination of patients with RA from other rheumatic diseases. No correlation of any tested autoantibody titer with serological parameters of inflammation was found.

We analyzed the clinical response and the time to relapse after discontinuation of continuous long-term infliximab therapy in patients with ankylosing spondylitis (AS). After 3 years of infliximab therapy, all AS patients (n = 42) discontinued treatment (time point (TP)1) and were visited regularly for 1 year in order to assess the time to relapse (TP2). Relapse was defined as an increase to a value >or= 4 on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and a physician's global assessment >or= 4 according to the recommendations of the Assessments in Ankylosing Spondylitis (ASAS) working group. After 52 weeks, 41 of the 42 patients (97.6%) had to be reinfused because of relapse. The mean change in the BASDAI between TP1 and TP2 was 3.6 +/- 1.7 and that in the physician's global assessment was 4.4 +/- 1.8 (both P < 0.001). The mean time to relapse was 17.5 weeks (+/- 7.9 weeks, range 7 to 45). Ten patients (24%) showed a relapse within 12 weeks and 38 patients (90.5%), within 36 weeks. After 52 weeks, only one patient had remained in ongoing remission without further treatment with anti-tumor-necrosis factor. Patients who were in partial remission according to the ASAS criteria and those with normal C-reactive protein levels at the time point of withdrawal had longer times to relapse after discontinuation of the treatment. Retreatment with infliximab was safe and resulted in clinical improvement in all patients to a state similar to that before the treatment was stopped. Discontinuation of long-term therapy with infliximab eventually led to relapse of disease activity in all patients but one.

Imaging-guided interventional procedures are becoming increasingly important in clinical rheumatology, since arthrocentesis of peripheral joints and the spine, as well as soft tissue injections, have a high rate of para-articular localisation when performed as blind techniques. Ultrasound-guided needle placement is the method of choice for interventional procedures on peripheral joints and for soft tissue injections. Fluoroscopy and computed tomography (CT) are not recommended for these indications due to the application of ionising radiation and the high procedural effort. By contrast, CT and magnetic resonance imaging are preferred for a variety of percutaneous procedures on the spine and sacroiliac joints. The increasing use of these methods for interventional purposes should improve both technical and procedural quality, thus ensuring cost-effectiveness and patient safety.

Arthropathy is a leading clinical manifestation of hereditary hemochromatosis (HH), but involvement of the ankle and hindfoot joints is rare. We describe 3 male patients who presented with symmetrical pain and swelling of the ankles. Radiographs and magnetic resonance imaging showed severe osteoarthritic degenerative changes with a radiological triad of joint space narrowing, subchondral sclerosis, and cyst formation. In all 3 cases a homozygous C282Y mutation in the HFE gene was detected and liver biopsies confirmed the diagnosis of HH. Other differential diagnoses could be excluded. Severe arthropathy of the ankle and hindfoot in comparatively young men can be a leading presentation of HH.