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Mixed-effects regression of single-cell data accounts for confounding variation and reveals an expanded CD4+ T cell population in rheumatoid arthritis. Pinpointing culprits in single-cell data: New techniques analyzing single cells are being applied to clinical samples. These techniques generate large datasets, and it can be challenging to identify rare cell types associated with disease. Fonseka et al. developed a simple statistical method to do just that while simultaneously controlling for confounding biological and technical variation. Using their method on single-cell mass and flow cytometry data revealed an expanded CD4+ T cell subset in the blood of rheumatoid arthritis patients that was later seen to contract upon treatment. The authors' method performed better than the current gold standard and could be a potentially widely applied tool for the analysis of high-dimensional single-cell data. High-dimensional single-cell analyses have improved the ability to resolve complex mixtures of cells from human disease samples; however, identifying disease-associated cell types or cell states in patient samples remains challenging because of technical and interindividual variation. Here, we present mixed-effects modeling of associations of single cells (MASC), a reverse single-cell association strategy for testing whether case-control status influences the membership of single cells in any of multiple cellular subsets while accounting for technical confounders and biological variation. Applying MASC to mass cytometry analyses of CD4+ T cells from the blood of rheumatoid arthritis (RA) patients and controls revealed a significantly expanded population of CD4+ T cells, identified as CD27− HLA-DR+ effector memory cells, in RA patients (odds ratio, 1.7; P = 1.1 × 10−3). The frequency of CD27− HLA-DR+ cells was similarly elevated in blood samples from a second RA patient cohort, and CD27− HLA-DR+ cell frequency decreased in RA patients who responded to immunosuppressive therapy. Mass cytometry and flow cytometry analyses indicated that CD27− HLA-DR+ cells were associated with RA (meta-analysis P = 2.3 × 10−4). Compared to peripheral blood, synovial fluid and synovial tissue samples from RA patients contained about fivefold higher frequencies of CD27− HLA-DR+ cells, which comprised ~10% of synovial CD4+ T cells. CD27− HLA-DR+ cells expressed a distinctive effector memory transcriptomic program with T helper 1 (TH1)– and cytotoxicity-associated features and produced abundant interferon-γ (IFN-γ) and granzyme A protein upon stimulation. We propose that MASC is a broadly applicable method to identify disease-associated cell populations in high-dimensional single-cell data. [ABSTRACT FROM AUTHOR]

Objective: To develop an objective, readily measurable pharmacodynamic biomarker of glucocorticoid (GC) activity. Methods: Genes modulated by prednisolone were identified from in vitro studies using peripheral blood mononuclear cells from normal healthy volunteers. Using the criteria of a >2‐fold change relative to vehicle controls and an adjusted P value cutoff of less than 0.05, 64 up‐regulated and 18 down‐regulated genes were identified. A composite score of the up‐regulated genes was generated using a single‐sample gene set enrichment analysis algorithm. Results: GC gene signature expression was significantly elevated in peripheral blood leukocytes from normal healthy volunteers following oral administration of prednisolone. Expression of the signature increased in a dose‐dependent manner, peaked at 4 hours postadministration, and returned to baseline levels by 48 hours after dosing. Lower expression was detected in normal healthy volunteers who received a partial GC receptor agonist, which is consistent with the reduced transactivation potential of this compound. In cohorts of patients with systemic lupus erythematosus and patients with rheumatoid arthritis, expression of the GC signature was negatively correlated with the percentages of peripheral blood lymphocytes and positively correlated with peripheral blood neutrophil counts, which is consistent with the known biology of the GC receptor. Expression of the signature largely agreed with reported GC use in these populations, although there was significant interpatient variability within the dose cohorts. Conclusion: The GC gene signature identified in this study represents a pharmacodynamic marker of GC exposure. [ABSTRACT FROM AUTHOR]

Introduction: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We evaluated the effect of concomitant methotrexate (MTX) or glucocorticoid (GC) use on tofacitinib clinical efficacy.Methods: Data were pooled from two open-label, long-term extension studies of tofacitinib 5 or 10 mg twice daily in patients with RA. Response according to Clinical Disease Activity Index (CDAI) was assessed separately in patients who discontinued (no MTX/GC use within 30 days prior to year-3 visit; assessment at month 3/year 3) or initiated (on/before year 3; assessment at initiation and year 3) MTX/GC.Results: By year 3, among patients receiving background MTX at baseline, 186/1608 (11.6%) discontinued MTX, and 319/1434 (22.2%) patients receiving GC at baseline discontinued GC. Overall, 70.4/69.1% of patients who discontinued/continued MTX and 72.7/65.9% who discontinued/continued GC achieved CDAI remission or low disease activity (LDA) at year 3. Month 3 remission/LDA rates were maintained at year 3 in the majority of patients, irrespective of MTX/GC discontinuation/continuation. By year 3, 6.2% of patients receiving tofacitinib without MTX at baseline had initiated concomitant MTX, and 25.1% receiving tofacitinib without GC initiated GC; 69.0% and 45.4% initiating MTX or GC, respectively, had a CDAI-defined incomplete response prior to initiation. RA signs/symptoms improved following MTX initiation; only modest improvement was observed with GC initiation.Conclusions: Patients achieving remission/LDA with tofacitinib may discontinue MTX or GC and maintain treatment response. Patients with an incomplete response may benefit from adding concomitant MTX.Funding: Pfizer Inc.Trial registration: Study A3921024 [NCT00413699] and Study A3921041 [NCT00661661]. [ABSTRACT FROM AUTHOR]

Objective SB5 is a biosimilar agent for adalimumab ( ADA). The aim of this study was to evaluate the efficacy, pharmacokinetics ( PK), safety, and immunogenicity of SB5 in comparison with reference ADA in patients with rheumatoid arthritis ( RA). Methods In this phase III, randomized, double-blind, parallel-group study, patients with moderately to severely active RA despite treatment with methotrexate were randomized 1:1 to receive SB5 or reference ADA at a dosage of 40 mg subcutaneously every other week. The primary efficacy end point was the response rate based on the American College of Rheumatology 20% improvement criteria ( ACR20) at week 24 in the per-protocol set (completer analysis). Additional end points included efficacy, PK, safety, and immunogenicity assessments. Results Of the 544 patients randomized to receive a study drug, the full analysis set comprised 542 patients (269 in the SB5 group, 273 in the reference ADA group) and the per-protocol set comprised 476 patients (239 receiving SB5, 237 receiving reference ADA). The ACR20 response rate at week 24 in the per-protocol set was equivalent between those receiving SB5 and those receiving reference ADA (72.4% and 72.2%, respectively); the difference in the ACR20 response rate (0.1%, [95% confidence interval −7.83%, 8.13%]) was within the predefined equivalence margin (±15%). Similar results were seen in the full analysis set (missing data being considered a nonresponse). The SB5 and reference ADA treatment groups were comparable across other end points, including the ACR 50% and ACR 70% improvement response rates, Disease Activity Score in 28 joints based on the erythrocyte sedimentation rate, PK data, incidence of treatment-emergent adverse events, and the antidrug antibody response. Subgroup analyses showed that the efficacy and safety of SB5 and reference ADA were comparable regardless of antidrug antibody status. Conclusion The ACR20 response rate at week 24 was equivalent between patients treated with the biosimilar agent SB5 and those treated with reference ADA. SB5 and reference ADA were both well tolerated, with comparable safety profiles, in patients with RA. [ABSTRACT FROM AUTHOR]

Objective This 24-week, phase IIb, double-blind study was undertaken to evaluate the efficacy and safety of mavrilimumab (a monoclonal antibody to granulocyte-macrophage colony-stimulating factor receptor α) and golimumab (a monoclonal antibody to tumor necrosis factor [anti- TNF]) in patients with rheumatoid arthritis ( RA) who have had an inadequate response to disease-modifying antirheumatic drugs ( DMARDs) (referred to as DMARD- IR) and/or inadequate response to other anti- TNF agents (referred to as anti- TNF- IR). Methods Patients with active RA and a history of DMARD- IR (≥1 failed regimen) or DMARD- IR (≥1 failed regimen) and anti- TNF- IR (1-2 failed regimens) were randomized 1:1 to receive either mavrilimumab 100 mg subcutaneously every other week or golimumab 50 mg subcutaneously every 4 weeks alternating with placebo every 4 weeks, administered concomitantly with methotrexate. The primary end points were the American College of Rheumatology 20% improvement ( ACR20), 50% improvement, and 70% improvement response rates at week 24, percentage of patients achieving a Disease Activity Score in 28 joints using C-reactive protein level ( DAS28- CRP) of <2.6 at week 24, percentage of patients with a score improvement of >0.22 on the Health Assessment Questionnaire ( HAQ) disability index ( DI) at week 24, and safety/tolerability measures. This study was not powered to formally compare the 2 treatments. Results At week 24, differences in the ACR20, ACR50, and ACR70 response rates between the mavrilimumab treatment group (n = 70) and golimumab treatment group (n = 68) were as follows: in all patients, −3.5% (90% confidence interval [90% CI] −16.8, 9.8), −8.6% (90% CI −22.0, 4.8), and −9.8% (90% CI −21.1, 1.4), respectively; in the anti- TNF- IR group, 11.1% (90% CI −7.8, 29.9), −8.7% (90% CI −28.1, 10.7), and −0.7% (90% CI −18.0, 16.7), respectively. Differences in the percentage of patients achieving a DAS28- CRP of <2.6 at week 24 between the mavrilimumab and golimumab groups were −11.6% (90% CI −23.2, 0.0) in all patients, and −4.0% (90% CI −20.9, 12.9) in the anti- TNF- IR group. The percentage of patients achieving a >0.22 improvement in the HAQ DI score at week 24 was similar between the treatment groups. Treatment-emergent adverse events were reported in 51.4% of mavrilimumab-treated patients and 42.6% of golimumab-treated patients. No deaths were reported, and no specific safety signals were identified. Conclusion The findings of this study demonstrate the clinical efficacy of both treatments, mavrilimumab at a dosage of 100 mg every other week and golimumab at a dosage of 50 mg every 4 weeks, in patients with RA. Both regimens were well-tolerated in patients who had shown an inadequate response to DMARDs and/or other anti- TNF agents. [ABSTRACT FROM AUTHOR]

Objective In disease-modifying antirheumatic drug-naive patients with early rheumatoid arthritis (RA) who had achieved sustained low disease activity (a Disease Activity Score in 28 joints using the erythrocyte sedimentation rate of ≤3.2 at both week 40 and week 52) after 1 year of treatment with certolizumab pegol (CZP) at a standard dose (200 mg every 2 weeks plus optimized methotrexate [MTX]), we evaluated whether continuation of CZP treatment at a standard dose or at a reduced frequency (200 mg every 4 weeks plus MTX) was superior to stopping CZP (placebo plus MTX) in maintaining low disease activity for 1 additional year. Methods A total of 293 patients from period 1 of our study were re-randomized 2:3:2 in period 2 to CZP at a standard dose (n = 84), CZP at a reduced frequency (n = 127), or placebo plus MTX (CZP stopped) (n = 82). The primary end point was the percentage of patients who maintained low disease activity throughout weeks 52-104 without flares. We used a hierarchical testing scheme, comparing CZP at a standard dose with CZP stopped. If P < 0.05 was achieved, then CZP at a reduced frequency was compared with CZP stopped (nonresponder imputation). Results The 293 patients from period 1 represented 36% fewer patients than projected, yielding a smaller number of patients eligible for period 2. Higher proportions of patients treated with the standard and reduced frequency regimens maintained low disease activity than those who had stopped CZP (48.8% and 53.2%, respectively, versus 39.2% [ P = 0.112 and P = 0.041, respectively; nominal P value, first hierarchical test not significant]). Similar trends were observed for radiographic nonprogression (change from baseline of ≤0.5 in modified Sharp/van der Heijde score; 79.2% and 77.9% of patients, respectively, versus 70.3%) and normative physical function (Health Assessment Questionnaire disability index score of ≤0.5; 71.4% and 70.6% of patients, respectively, versus 57.0%). Safety profiles were similar between all groups, with no new safety signals identified for continuing CZP to week 104. No deaths were reported. Conclusion The study failed to meet its primary end point. However, there were no clinically meaningful differences between the standard and reduced frequency doses of CZP plus MTX; both controlled RA more effectively than stopping CZP. [ABSTRACT FROM AUTHOR]

Background: To assess the effect of baricitinib on patient-reported outcomes (PROs) in patients with active rheumatoid arthritis and an inadequate response to methotrexate (MTX).Methods: In this double-blind phase 3 study, patients were randomised 3:3:2 to placebo (n=488), baricitinib 4 mg once daily (n=487), or adalimumab 40 mg biweekly (n=330) with background MTX. PROs included the SF-36, EuroQol 5-D (EQ-5D) index scores and visual analogue scale, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient's Global Assessment of Disease Activity (PtGA), patient's assessment of pain and Work Productivity and Activity Impairment Questionnaire-Rheumatoid Arthritis (WPAI-RA), and measures collected in electronic patient daily diaries: duration and severity of morning joint stiffness (MJS), Worst Ttiredness and Worst Joint Pain. The primary study endpoint was at week 12. Treatment comparisons were assessed with logistic regression for categorical measures or analysis of covariance for continuous variables.Results: Compared with placebo and adalimumab, baricitinib showed statistically significant improvements (p≤0.05) in HAQ-DI, PtGA, pain, FACIT-F, SF-36 physical component score, EQ-5D index scores and WPAI-RA daily activity at week 12. Improvements were maintained for measures assessed to week 52. Statistically significant improvement in patient diary measures (MJS duration and severity), worst tiredness and worst joint pain were observed for baricitinib versus placebo and adalimumab at week 12 (p≤0.05).Conclusions: Baricitinib provided significantly greater improvement in most PROs compared with placebo and adalimumab, including physical function MJS, pain, fatigue and quality of life. Improvement was maintained to the end of the study (week 52).Trial Registration: NCT01710358. [ABSTRACT FROM AUTHOR]