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Background: Diabetes is common in patients with rheumatoid arthritis (RA). Interleukin (IL)-6 is implicated in both the pathogenesis of RA and in glucose homeostasis; this post hoc analysis investigated the effects of IL-6 receptor vs. tumour necrosis factor inhibition on glycosylated haemoglobin (HbA1c) in patients with RA with or without diabetes., Methods: Data were from two placebo-controlled phase III studies of subcutaneous sarilumab 150/200 mg q2w + methotrexate or conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and a phase III monotherapy study of sarilumab 200 mg q2w vs. adalimumab 40 mg q2w. Patients with diabetes were identified by medical history or use of antidiabetic medication (patients with HbA1c ≥ 9% were excluded from all three studies). HbA1c was measured at baseline and weeks 12/24. Safety and efficacy were assessed in RA patients with or without diabetes., Results: Patients with diabetes (n = 184) were older, weighed more and exhibited higher RA disease activity than patients without diabetes (n = 1928). Regardless of diabetes status, in patients on background csDMARDs, least squares (LS) mean difference (95% CI) in change from baseline in HbA1c for sarilumab 150 mg/200 mg vs. placebo at week 24 was - 0.28 (- 0.40, - 0.16; nominal p <  0.0001) and - 0.42 (- 0.54, - 0.31; nominal p <  0.0001), respectively. Without csDMARDs, LS mean difference for sarilumab 200 mg vs. adalimumab 40 mg at week 24 was - 0.13 (- 0.22, - 0.04; nominal p = 0.0043). Greater reduction in HbA1c than placebo or adalimumab was observed at week 24 with sarilumab in patients with diabetes and/or baseline HbA1c ≥ 7%. There was no correlation between baseline/change from baseline in HbA1c and baseline/change from baseline in C-reactive protein, 28-joint Disease Activity Score, or haemoglobin, nor between HbA1c change from baseline and baseline glucocorticoid use. Medical history of diabetes or use of diabetes treatments had limited impact on safety and efficacy of sarilumab and was consistent with overall phase III findings in patients with RA., Conclusions: In post hoc analyses, sarilumab was associated with a greater reduction in HbA1c than csDMARDs or adalimumab, independent of sarilumab anti-inflammatory effects. Prospective studies are required to further assess these preliminary findings., Trial Registration: ClinTrials.gov NCT01061736: date of registration February 03, 2010; ClinTrials.gov NCT01709578: date of registration October 18, 2012; ClinTrials.gov NCT02332590: date of registration January 07, 2015.

Objective: Phase III clinical trials of the tumour necrosis factor inhibitors SB4, SB2, and SB5 (biosimilars to etanercept, infliximab, and adalimumab, respectively) have demonstrated efficacy in moderate-to-severe rheumatoid arthritis (RA). Data from these trials were used to identify baseline characteristics associated with radiographic progression and to build a matrix risk model for its prediction., Methods: Patients with radiographic progression and baseline demographic and disease characteristic data were pooled across the 3 phase III studies of each biosimilar and its reference product. Baseline demographics and disease characteristics were evaluated for their relationship with radiographic progression (1-year mean change in mTSS > 0); 3 factors were selected based on strongest Pearson's correlation coefficient with the change in modified Total Sharp Score. Univariate logistic regression was performed to assess the association between each baseline factor and the rate of radiographic progression, with subsequent matrix model development performed using multivariate logistic regression., Results: A total of 1371 patients were included in the analysis, with a radiographic progression rate of 27.4%. The 3 baseline predictors of radiographic progression, based on Pearson's correlation coefficient, were 28 swollen joint count (SJC28), C-reactive protein (CRP), and physician global assessment (PhGA). A matrix model showed that the predicted risk of radiographic progression was higher with the increased level of SJC28, CRP, and PhGA (P < 0.001)., Conclusions: In this pooled analysis of phase III clinical trial data of biosimilars for RA, identifiable baseline factors (SJC28, CRP, and PhGA) associated with radiographic progression were similar to those described in prior studies. Even though radiographic progression was minimal, a small number of patients who have increased SJC28, CRP, and PhGA at baseline should be closely monitored and follow treat-to-target approach., Clinical Trial Registration Numbers: EudraCT 2012-005026-30. Registered 30 April 2013, https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-005026-30/results EudraCT 2012-005733-37. Registered 10 July 2013, https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-005733-37/results EudraCT 2013-005013-13. Registered 01 April 2014, https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-005013-13/results.

Background: The interleukin-6 receptor inhibitor sarilumab demonstrated efficacy in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or as monotherapy in patients with moderately to severely active rheumatoid arthritis (RA) with an inadequate response (IR) or intolerant (INT) to methotrexate (MTX) or tumour necrosis factor (TNF)-α inhibitors. This analysis investigated the efficacy and safety of sarilumab in patient subgroups., Methods: Data were included from phase III studies: two placebo-controlled studies of subcutaneous sarilumab 150/200 mg every 2 weeks (q2w) either + MTX in MTX-IR patients (52 weeks) or + csDMARDs in TNF-IR/INT patients (24 weeks), and a monotherapy study of sarilumab 200 mg q2w vs. adalimumab 40 mg q2w in MTX-IR/INT patients (24 weeks). Prespecified and post hoc subgroups included patient demographics, disease characteristics, and prior treatments. Prespecified and post hoc endpoints included clinical, radiographic, and physical function measures, and p values are considered nominal. Safety was assessed during double-blind treatment., Results: The superiority of sarilumab (either as monotherapy vs. adalimumab or in combination with csDMARDs vs. placebo + csDMARDs) across clinical endpoints was generally consistent across subgroups defined by patient demographics, disease characteristics, and prior treatments, demonstrating the benefit of sarilumab treatment for a wide range of patient types. Interaction p values of < 0.05 were consistently observed across studies only for baseline anti-cyclic citrullinated peptide antibody (ACPA) status for American College of Rheumatology 20% response, but not American College of Rheumatology 50% or 70% response. Adverse events and worsening laboratory parameters occurred more frequently in sarilumab-treated vs. placebo-treated patients and were more frequent in the small number of patients ≥ 65 years (n = 289) vs. patients < 65 years (n = 1819). Serious infections occurred in six patients aged ≥ 65 years receiving sarilumab, although the incidence of serious infections was generally higher in patients aged ≥ 65 years regardless of treatment., Conclusions: Apart from ACPA status, there were no consistent signals indicating differential effects of sarilumab in any of the subpopulations assessed. Sarilumab demonstrated consistent efficacy and safety across a wide range of patients with RA., Trial Registration: ClinicalTrials.gov NCT01061736, registered on February 03, 2010; ClinicalTrials.gov NCT01709578, registered on October 18, 2012; ClinicalTrials.gov NCT02332590, registered on January 07, 2015.

Background: ABP 710 is being developed as a biosimilar to infliximab reference product (RP). Analytical similarity and pharmacokinetic equivalence between the two have been previously demonstrated. Here we report results from a comparative clinical study that evaluated the efficacy and safety of ABP 710 relative to the RP in patients with rheumatoid arthritis (RA)., Methods: In this multicenter, randomized, double-blind, 50-week equivalence study, patients with moderate to severe active RA despite methotrexate received 3-mg/kg infusions of ABP 710 or RP at predetermined intervals based on initial randomization and then with re-randomization at week 22. The primary endpoint was response difference (RD) of ACR20 at week 22, with clinical equivalence evaluated based on 90% CI of - 15%, 15%. Secondary endpoints included Disease Activity Score 28-joint count C-reactive protein (DAS28-CRP), ACR20, ACR50, and ACR70 across time, as well as safety and immunogenicity assessments., Results: A total of 558 patients were randomized for the initial treatment (ABP 710 n = 279; RP n = 279). The estimated RD of ACR20 at week 22 was 9.37% with 90% CI (2.67%, 15.96%). The lower bound was within the pre-specified criteria, thus confirming non-inferiority; the upper bound exceeded the pre-specified criteria by 0.96% such that superiority could not be ruled out statistically. In a post hoc analysis with adjustment for random imbalance in baseline factors, the CI of RD was narrowed (0.75%, 13.62%). Changes from baseline in DAS28-CRP as well as ACR20, ACR50, and ACR70 response rates across time and hybrid ACR evaluations were similar for the initial and initial/re-randomized treatment groups. Adverse events and incidence of anti-drug antibodies were similar between treatment groups., Conclusions: These efficacy and safety results support similarity with no clinically meaningful differences between ABP 710 and infliximab RP. Although we were unable to statistically confirm non-superiority, post hoc analysis was supportive of non-superiority. DAS28-CRP, ACR20, ACR50, ACR70, and hybrid ACR evaluations over the entire study were consistently comparable as were safety and immunogenicity., Trial Registration: ClinicalTrials.gov. Identifier: NCT02937701. Registered August 30, 2016.

Background: The long-term safety was assessed in patients with psoriatic arthritis who were treated with ixekizumab in three clinical trials (SPIRIT-P1/-P2/-P3)., Methods: Integrated safety data from three trials (controlled and uncontrolled), including two pivotal phase 3, randomized, double-blind clinical trials: SPIRIT-P1 and SPIRIT-P2, were assessed. Safety data were integrated from the all ixekizumab exposure safety population (defined as all patients receiving ≥ 1 dose of ixekizumab). We report exposure-adjusted incidence rates (IRs) per 100 patient-years (PY) at 1-year intervals up to 3 years for adverse events., Results: Total exposure to IXE reached 1822.2 PY (1118 patients). The IRs/100 PY for the following treatment discontinuations were as follows: adverse events (5.3); serious infections (1.3); injection-site reactions (12.7); infections (34.2); and deaths (0.3). The IRs for treatment-emergent adverse events decreased or remained stable over time, the most common being upper respiratory tract infection, nasopharyngitis, and injection-site reactions. The IRs for serious adverse events and serious infections remained stable over time, whereas for injection-site reactions and general infections, IRs decreased with longer ixekizumab exposure. Opportunistic infections were limited to oral and esophageal candida and localized herpes zoster. No suicide or self-injury-related behaviors were reported. The IRs/100 PY for safety topics of special interest included inflammatory bowel disease (adjudicated; 0.1), depression (1.6), malignancies (0.7), and major adverse cardiovascular events (0.6)., Conclusions: The findings of this integrated safety analysis in patients with psoriatic arthritis are consistent with the known safety profile of ixekizumab. No unexpected safety signals were observed with ixekizumab treatment in patients with psoriatic arthritis., Trial Registration: SPIRIT-P1 (NCT01695239; Registered August 08, 2012), SPIRIT-P2 (NCT02349295; September 23, 2014), and SPIRIT-P3 (NCT02584855; August 04, 2015).

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: Sarilumab is a human monoclonal antibody directed against the alpha subunit of the interleukin-6 receptor complex. In the MOBILITY phase III randomized controlled trial (RCT), sarilumab + methotrexate (MTX) treatment resulted in clinical improvements at 24 weeks that were maintained at 52 weeks in adults with rheumatoid arthritis (RA), who have inadequate response to MTX (MTX-IR). These analyses indicate the effects of sarilumab + MTX versus placebo on patient-reported outcomes (PROs) in this RCT., Methods: Patients (n = 1197) were randomized to receive placebo, sarilumab 150 or 200 mg subcutaneously + MTX every 2 weeks for 52 weeks; after 16 weeks, patients without ≥20 % improvement from baseline in swollen or tender joint counts on two consecutive assessments were offered open-label treatment. PROs included patient global assessment of disease activity (PtGA), pain, health assessment questionnaire disability index (HAQ-DI), Short Form-36 Health Survey (SF-36), and functional assessment of chronic illness therapy-fatigue (FACIT-F). Changes from baseline at weeks 24 and 52 were analyzed using a mixed model for repeated measures. Post hoc analyses included percentages of patients reporting improvements equal to or greater than minimal clinically important differences (MCID) and normative values in the FACIT-F and SF-36. Pearson correlation between observed PRO scores and clinical measures of disease activity was tested at week 24., Results: Both doses of sarilumab + MTX vs placebo + MTX resulted in improvement from baseline by week 24 in PtGA, pain, HAQ-DI, SF-36 and FACIT-F scores (p < 0.0001) that was clinically meaningful, and persisted until week 52. In post hoc analyses, the percentages of patients with improvement equal to or greater than the MCID across all PROs were greater with sarilumab than placebo (p < 0.05), with differences ranging from 11.6 to 26.2 %, as were those reporting equal to or greater than normative scores., Conclusions: In this RCT in patients with MTX-IR RA, sarilumab + MTX resulted in sustained improvement in PROs that were clinically meaningful, greater than placebo + MTX, and complement the previously reported clinical efficacy and safety of sarilumab., Trial Registration: ClinicalTrials.gov. NCT01061736 . February 2, 2010.

Background: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). The aim of this study was to explore the safety and efficacy of open-label tofacitinib following blinded treatment with adalimumab or tofacitinib for moderate to severe RA., Methods: Analyses included patients treated with adalimumab 40 mg once every 2 weeks or tofacitinib 10 mg twice daily (BID) with background methotrexate (MTX) in a 12-month randomized study (NCT00853385), who subsequently received tofacitinib 10 mg BID (with/without background MTX) in an open-label extension (NCT00413699). Patients with treatment-related serious adverse events (AEs) and serious or recurrent infections in the index study were excluded from the extension study. Exposure-adjusted incidence rates of safety-related events were assessed in 3-month and 12-month periods in the year before and in the year after switching. Efficacy was assessed 3 months before, at the time of, and 3 months after switching., Results: There were 233 (107 adalimumab to tofacitinib 10 mg BID, 126 blinded to open-label tofacitinib 10 mg BID) patients included in these analyses. Patients in both treatment sequences had similar incidence rates (per 100 patient-years) of discontinuation due to AEs, serious AEs, and serious infections in the year before and in the year after switching. Incidence rates of AEs were increased in the first 3 months after switching compared with the last 3 months before switching in both treatment groups. Switching from either blinded adalimumab or tofacitinib to open-label tofacitinib resulted in numerically higher incidence of responders for signs and symptoms of disease and improved physical function., Conclusions: Treatment can be directly switched from adalimumab to tofacitinib. A similar safety and efficacy profile was seen when patients received open-label tofacitinib after receiving either blinded adalimumab or tofacitinib., Trial Registration: ClinicalTrials.gov Identifiers: NCT00853385 , registered 27 February 2009; NCT00413699 , registered 18 December 2006.

Introduction: Systemic sclerosis is an autoimmune disease characterized by inflammation and fibrosis of the skin and internal organs. We sought to assess the clinical and molecular effects associated with response to intravenous abatacept in patients with diffuse cutaneous systemic., Methods: Adult diffuse cutaneous systemic sclerosis patients were randomized in a 2:1 double-blinded fashion to receive abatacept or placebo over 24 weeks. Primary outcomes were safety and the change in modified Rodnan Skin Score (mRSS) at week 24 compared with baseline. Improvers were defined as patients with a decrease in mRSS of ≥30% post-treatment compared to baseline. Skin biopsies were obtained for differential gene expression and pathway enrichment analyses and intrinsic gene expression subset assignment., Results: Ten subjects were randomized to abatacept (n = 7) or placebo (n = 3). Disease duration from first non-Raynaud's symptom was significantly longer (8.8 ± 3.8 years vs. 2.4 ± 1.6 years, p = 0.004) and median mRSS was higher (30 vs. 22, p = 0.05) in the placebo compared to abatacept group. Adverse events were similar in the two groups. Five out of seven patients (71%) randomized to abatacept and one out of three patients (33%) randomized to placebo experienced ≥30% improvement in skin score. Subjects receiving abatacept showed a trend toward improvement in mRSS at week 24 (-8.6 ± 7.5, p = 0.0625) while those in the placebo group did not (-2.3 ± 15, p = 0.75). After adjusting for disease duration, mRSS significantly improved in the abatacept compared with the placebo group (abatacept vs. placebo mRSS decrease estimate -9.8, 95% confidence interval -16.7 to -3.0, p = 0.0114). In the abatacept group, the patients in the inflammatory intrinsic subset showed a trend toward greater improvement in skin score at 24 weeks compared with the patients in the normal-like intrinsic subset (-13.5 ± 3.1 vs. -4.5 ± 6.4, p = 0.067). Abatacept resulted in decreased CD28 co-stimulatory gene expression in improvers consistent with its mechanism of action. Improvers mapped to the inflammatory intrinsic subset and showed decreased gene expression in inflammatory pathways, while non-improver and placebos showed stable or reverse gene expression over 24 weeks., Conclusions: Clinical improvement following abatacept therapy was associated with modulation of inflammatory pathways in skin., Trial Registration: ClinicalTrials.gov NCT00442611. Registered 1 March 2007.

Introduction: This randomized, double-blind, phase II study evaluated the pharmacodynamics, safety and tolerability of ISIS 329993 (ISIS-CRPRx), an antisense oligonucleotide, in patients with active rheumatoid arthritis (RA)., Methods: Patients with active RA of at least six months duration were randomized into three cohorts to receive ISIS-CRPRx (100 mg, 200 mg or 400 mg) or placebo (3 active:1 placebo within each cohort) via subcutaneous (SC) injection on Days 1, 3, 5 and 8 and then once weekly for the next 11 weeks. The effects of study treatment on high-sensitivity C-reactive protein (hs-CRP) level were evaluated. An exploratory analysis on disease activity was assessed via the American College of Rheumatology 20% improvement criteria (ACR20). Safety was evaluated via adverse events and laboratory measures., Results: Fifty-one patients received one of the following treatments: ISIS-CRPRx 100 mg, n = 12; 200 mg, n = 13, 400 mg, n = 14; placebo n = 12. In the ISIS-CRPRx treatment groups there were dose-dependent reductions in hs-CRP. At Day 36 the mean percent change from baseline was: placebo: -14.4%; ISIS-CRPRx 100 mg: -19.5%; 200 mg: -56.6% and 400 mg: -76.7%, (P = 0.0015 placebo compared to 400 mg). There were no differences between treatment groups and placebo in the ACR20 at Day 36 or Day 92. There were no serious infections and no elevations in liver function tests, lipids, creatinine or other lab abnormalities related to ISIS-CRPRx., Conclusions: In this study, ISIS-CRPRx selectively reduced hs-CRP in a dose-dependent manner, and was well-tolerated in patients with RA. Its utility as a therapy in RA remains unclear., Trial Registration: Clinicaltrials.gov NCT01414101 . Registered 21 July 2011.

Introduction: Anti-TNF therapies have revolutionized the treatment of rheumatoid arthritis (RA), a common systemic autoimmune disease involving destruction of the synovial joints. However, in the practice of rheumatology approximately one-third of patients demonstrate no clinical improvement in response to treatment with anti-TNF therapies, while another third demonstrate a partial response, and one-third an excellent and sustained response. Since no clinical or laboratory tests are available to predict response to anti-TNF therapies, great need exists for predictive biomarkers., Methods: Here we present a multi-step proteomics approach using arthritis antigen arrays, a multiplex cytokine assay, and conventional ELISA, with the objective to identify a biomarker signature in three ethnically diverse cohorts of RA patients treated with the anti-TNF therapy etanercept., Results: We identified a 24-biomarker signature that enabled prediction of a positive clinical response to etanercept in all three cohorts (positive predictive values 58 to 72%; negative predictive values 63 to 78%)., Conclusions: We identified a multi-parameter protein biomarker that enables pretreatment classification and prediction of etanercept responders, and tested this biomarker using three independent cohorts of RA patients. Although further validation in prospective and larger cohorts is needed, our observations demonstrate that multiplex characterization of autoantibodies and cytokines provides clinical utility for predicting response to the anti-TNF therapy etanercept in RA patients.

The objective of this study was to evaluate the safety and possible efficacy of IFN-beta-1a for the treatment of patients with rheumatoid arthritis (RA). Twenty-two patients with active RA were enrolled in a phase II randomized, double-blind, placebo-controlled trial of 30 microg IFN-beta-1a by weekly self-injection for 24 weeks. The primary outcome of the study was safety. Secondary outcomes included the proportion of patients achieving an American College of Rheumatology (ACR) 20 response at 24 weeks. There were no significant differences in adverse events reported in the two groups. Fewer than 20% of patients in each arm of the study achieved an ACR 20 response at 24 weeks (P = 0.71). Sixty-nine percent of patients receiving IFN-beta and 67% receiving placebo terminated the study early, most of them secondary to a perceived lack of efficacy. Overall, IFN-beta-1a had a safety profile similar to that of placebo. There were no significant differences in the proportion of patients achieving an ACR 20 response between the two groups.