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IntroductionRheumatoid arthritis (RA) is a complex and clinically heterogeneous autoimmune disease. Currently, the relationship between pathogenic molecular drivers of disease in RA and therapeutic response is poorly understood.MethodsWe analyzed synovial tissue samples from two RA cohorts of 49 and 20 patients using a combination of global gene expression, histologic and cellular analyses, and analysis of gene expression data from two further publicly available RA cohorts. To identify candidate serum biomarkers that correspond to differential synovial biology and clinical response to targeted therapies, we performed pre-treatment biomarker analysis compared with therapeutic outcome at week 24 in serum samples from 198 patients from the ADACTA (ADalimumab ACTemrA) phase 4 trial of tocilizumab (anti-IL-6R) monotherapy versus adalimumab (anti-TNFα) monotherapy.ResultsWe documented evidence for four major phenotypes of RA synovium – lymphoid, myeloid, low inflammatory, and fibroid - each with distinct underlying gene expression signatures. We observed that baseline synovial myeloid, but not lymphoid, gene signature expression was higher in patients with good compared with poor European league against rheumatism (EULAR) clinical response to anti-TNFα therapy at week 16 (P =0.011). We observed that high baseline serum soluble intercellular adhesion molecule 1 (sICAM1), associated with the myeloid phenotype, and high serum C-X-C motif chemokine 13 (CXCL13), associated with the lymphoid phenotype, had differential relationships with clinical response to anti-TNFα compared with anti-IL6R treatment. sICAM1-high/CXCL13-low patients showed the highest week 24 American College of Rheumatology (ACR) 50 response rate to anti-TNFα treatment as compared with sICAM1-low/CXCL13-high patients (42% versus 13%, respectively, P =0.05) while anti-IL-6R patients showed the opposite relationship with these biomarker subgroups (ACR50 20% versus 69%, P =0.004).ConclusionsThese data demonstrate that underlying molecular and cellular heterogeneity in RA impacts clinical outcome to therapies targeting different biological pathways, with patients with the myeloid phenotype exhibiting the most robust response to anti-TNFα. These data suggest a path to identify and validate serum biomarkers that predict response to targeted therapies in rheumatoid arthritis and possibly other autoimmune diseases.Trial registrationClinicalTrials.gov NCT01119859

Objective To assess the risk of major adverse cardiovascular events (MACE) in patients with rheumatoid arthritis (RA) treated with tocilizumab compared to those treated with the tumor necrosis factor inhibitor etanercept. Methods This randomized, open‐label, parallel‐group trial enrolled patients with active seropositive RA (n = 3,080) who had an inadequate response to conventional synthetic disease‐modifying antirheumatic drugs and who had at least 1 cardiovascular (CV) risk factor. Patients were randomly assigned 1:1 to receive open‐label tocilizumab at 8 mg/kg/month or etanercept at 50 mg/week. All patients were followed up for a mean of 3.2 years. The primary end point was comparison of time to first occurrence of MACE. The trial was powered to exclude a relative hazard ratio for MACE of 1.8 or higher in the tocilizumab group compared to the etanercept group. Results By week 4 of treatment, the serum low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, and triglyceride levels were a median 11.1%, 5.7%, and 13.6% higher, respectively, in patients receiving tocilizumab compared to those receiving etanercept (each P < 0.001). During follow‐up, 83 MACE occurred in the tocilizumab group compared to 78 MACE in the etanercept group. The estimated hazard ratio for occurrence of MACE in the tocilizumab group relative to the etanercept group was 1.05 (95% confidence interval 0.77–1.43). Results were similar in sensitivity analyses and in the on‐treatment population analysis. Adverse events occurred more frequently in the tocilizumab group, including serious infection and gastrointestinal perforation. Conclusion The results of this trial, which provide insights into the CV safety of tocilizumab as compared to etanercept, ruled out a risk for occurrence of MACE of 1.43 or higher in patients treated with tocilizumab. This result should be interpreted in the context of the clinical efficacy and non‐CV safety of tocilizumab.

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Objective. To evaluate associations between lipid levels, inflammation, and rheumatoid arthritis (RA) disease activity, at baseline and during treatment, with the risk of major adverse cardiovascular events (MACE) in tocilizumab-treated patients with RA.Methods. In retrospective post hoc analyses, data were pooled for 3,986 adult patients with moderate to severe RA who received >1 dose of tocilizumab (4 mg/kg or 8 mg/kg) intravenously every 4 weeks in randomized controlled trials and extension studies. Cox proportional hazards modeling was used to evaluate associations between baseline characteristics and posttreatment changes in laboratory and disease characteristics (week 24) and change in disease activity and laboratory values from baseline to week 24 with the risk of future MACE during extended followup.Results. We identified 50 independently adjudicated cases of MACE during 14,683 patient-years of followup (0.34 MACE cases/100 patient-years). At baseline, age, a history of cardiac disorders, the Disease Activity Score in 28 joints (DAS28), and the total cholesterol:high-density lipoprotein cholesterol ratio were independently associated with MACE in multivariable models (P < 0.05 for all). During treatment, a higher DAS28 and higher swollen and tender joint counts at week 24 were associated with future MACE. In separate models, greater reductions in the DAS28 and joint counts from baseline to week 24 were inversely associated with future MACE; changes in lipid parameters were not statistically significantly associated with the risk of MACE.Conclusion. In this population of patients treated with tocilizumab, an association was observed between the baseline total cholesterol:high-density lipoprotein cholesterol ratio and an increased risk of MACE. The risk of MACE while receiving treatment, however, was associated with control of disease activity but not lipid changes. Larger studies are needed to confirm these findings.Patients with rheumatoid arthritis (RA) have approximately double the risk of myocardial infarction (MI) and stroke compared with that in the general population (1,2). Several studies suggest that the increased incidence of cardiovascular disease (CVD) in RA is not completely explained by traditional CV risk factors such as diabetes mellitus, hypertension, smoking, and dyslipidemia (3-5). Indeed, the HLA-DRB1 shared epitope, higher erythrocyte sedimentation rates (ESRs), and RA comorbidities such as vasculitis and pulmonary disease are associated with an increased risk of CVDrelated mortality (4,6). In a population-based incidence cohort of RA patients with high ESRs, those with much lower total cholesterol and low-density lipoprotein