O’Dell, James R.

Abstract Individuals who have serum elevations of anti-cyclic citrullinated protein (anti-CCP) antibodies are at risk for developing rheumatoid arthritis (RA), yet immunologic factors that lead to a transition from pre- to clinical RA remain unclear. Here, we used materials from anti-CCP antibody-positive individuals enrolled in a clinical trial that evaluated the efficacy of hydroxychloroquine to prevent clinical RA, and performed multi-modal single-cell profiling (transcriptome, surface proteins, T/B-cell receptor sequencing, and chromatin accessibility) on samples obtained at baseline and at RA onset in those who developed clinical RA (Converters) or follow-up point in matched Nonconverters. At both baseline and follow-up, Converters had expansions of peripheral helper T (Tph) cells and CD8 + T cells expressing GZMK and GZMB , along with elevated potentially autoreactive T-cell receptors in CD4 + T cells compared to Nonconverters. Induction of age-associated B cell signatures was observed in B cells of Converters prior to RA onset. Epigenetic profiling further identified chromatin accessibility changes in Converters over time, particularly within myeloid and NK cells. Lastly, predictive modeling using baseline immune features, including Tph cells, GZMK + XCL1 + CD8 + , and GZMB + CD57 + CD8 + T cells, together with clinical features such as anti-CCP3 levels, RF-positivity, and HLA shared epitope status, stratified RA risk and predicted time to onset. These findings define immune endotypes in pre-RA that could serve as targets for future preventive interventions and be used to stratify the risk of developing clinical RA in anti-CCP antibody-positive individuals.

Objective Individuals with serum elevations of anti–cyclic citrullinated peptide (anti‐CCP) antibodies are at increased risk for future rheumatoid arthritis (RA). No pharmacologic interventions have been approved for the prevention of RA in such at‐risk individuals. However, hydroxychloroquine (HCQ) is used without supporting clinical trial evidence. Methods In this phase 2 randomized trial, individuals at risk for RA with anti‐CCP3 ≥2 times the upper limit of normal (ULN) were assigned to receive HCQ or placebo for 12 months, with up to 24 months of postdrug follow‐up. The primary outcome was the development of clinical RA, as defined in the protocol, at 36 months. Secondary outcomes included safety, development of inflammatory arthritis (IA), and participant‐reported joint symptoms. Results Of 144 randomized participants, 71 were assigned to HCQ and 73 to placebo. In the modified intent‐to‐treat population, clinical RA occurred in 21 of 69 (30.4%) participants in the HCQ group and 24 of 73 (32.9%) in the placebo group. The risk of clinical RA at 36 months was 0.336 with HCQ and 0.394 with placebo (difference −0.058; 95% confidence interval −0.336 to 0.220; P = 0.52). Results for IA were similar. The occurrence and severity of joint symptoms were not observed to differ between groups. Adverse event incidence was similar between groups. Conclusion In this trial involving individuals with anti‐CCP3 levels ≥2 times the ULN, 12 months of HCQ did not prevent the development of clinical RA at 36 months. image

ObjectiveThe Outcome Measures in Rheumatology (OMERACT) 3×3 method analyzes the occurrence of benefit and harm simultaneously at the individual patient level. We applied this method to 2 recent rheumatoid arthritis (RA) trial data sets.MethodsThe Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) and the Rheumatoid Arthritis Comparison of Active Therapies (RACAT) randomized trial outcomes for safety were defined according to OMERACT as having no adverse events (AEs), non‐serious AEs, and serious AEs. Treatment efficacy was defined as good, moderate, or no response. A good treatment response without any AEs was labeled an unqualified success, and no treatment response but at least 1 AE was considered an unmitigated failure. The association between benefit and harm was assessed by chi‐square or exact tests, as appropriate.ResultsIn TEAR, 612 of 755 patients had response data at 48 weeks: 14% of patients experienced unqualified success and 9% had unmitigated failure, with no difference between the treatment arms. Treatment response and AE rates were not correlated. In RACAT, 309 of 353 patients had response data at 48 weeks: 6% of patients experienced unqualified success and 11% had unmitigated failure, with no differences between the treatment arms. Response and AE rates were negatively correlated. The frequency of AEs and serious AEs increased as response decreased (P = 0.008).ConclusionWe found some evidence that clinical response may be reduced by the co‐occurrence of AEs.

ObjectiveTo develop a new evidence‐based, pharmacologic treatment guideline for rheumatoid arthritis (RA).MethodsWe conducted systematic reviews to synthesize the evidence for the benefits and harms of various treatment options. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology to rate the quality of evidence. We employed a group consensus process to grade the strength of recommendations (either strong or conditional). A strong recommendation indicates that clinicians are certain that the benefits of an intervention far outweigh the harms (or vice versa). A conditional recommendation denotes uncertainty over the balance of benefits and harms and/or more significant variability in patient values and preferences.ResultsThe guideline covers the use of traditional disease‐modifying antirheumatic drugs (DMARDs), biologic agents, tofacitinib, and glucocorticoids in early (<6 months) and established (≥6 months) RA. In addition, it provides recommendations on using a treat‐to‐target approach, tapering and discontinuing medications, and the use of biologic agents and DMARDs in patients with hepatitis, congestive heart failure, malignancy, and serious infections. The guideline addresses the use of vaccines in patients starting/receiving DMARDs or biologic agents, screening for tuberculosis in patients starting/receiving biologic agents or tofacitinib, and laboratory monitoring for traditional DMARDs. The guideline includes 74 recommendations: 23% are strong and 77% are conditional.ConclusionThis RA guideline should serve as a tool for clinicians and patients (our two target audiences) for pharmacologic treatment decisions in commonly encountered clinical situations. These recommendations are not prescriptive, and the treatment decisions should be made by physicians and patients through a shared decision‐making process taking into account patients’ values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies.

Objective To develop a new evidence‐based, pharmacologic treatment guideline for rheumatoid arthritis (RA). Methods We conducted systematic reviews to synthesize the evidence for the benefits and harms of various treatment options. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology to rate the quality of evidence. We employed a group consensus process to grade the strength of recommendations (either strong or conditional). A strong recommendation indicates that clinicians are certain that the benefits of an intervention far outweigh the harms (or vice versa). A conditional recommendation denotes uncertainty over the balance of benefits and harms and/or more significant variability in patient values and preferences. Results The guideline covers the use of traditional disease‐modifying antirheumatic drugs (DMARDs), biologic agents, tofacitinib, and glucocorticoids in early (<6 months) and established (≥6 months) RA. In addition, it provides recommendations on using a treat‐to‐target approach, tapering and discontinuing medications, and the use of biologic agents and DMARDs in patients with hepatitis, congestive heart failure, malignancy, and serious infections. The guideline addresses the use of vaccines in patients starting/receiving DMARDs or biologic agents, screening for tuberculosis in patients starting/receiving biologic agents or tofacitinib, and laboratory monitoring for traditional DMARDs. The guideline includes 74 recommendations: 23% are strong and 77% are conditional. Conclusion This RA guideline should serve as a tool for clinicians and patients (our two target audiences) for pharmacologic treatment decisions in commonly encountered clinical situations. These recommendations are not prescriptive, and the treatment decisions should be made by physicians and patients through a shared decision‐making process taking into account patients’ values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies.

Purpose Although preliminary studies suggest that non-Hodgkin's lymphoma (NHL) complicating rheumatoid arthritis (RA) may be a clinically distinct entity compared with that occurring in the general population, studies examining the impact of antecedent RA on survival are limited. In this prospective study, we examined the association of RA with survival in patients with NHL. Patients and Methods Using two large lymphoma registries, we identified patients with evidence of RA preceding NHL. Survival in RA patients was compared with that of controls using proportional hazards regression, adjusting for the effects of age, sex, lymphoma diagnosis-to-treatment lag time, calendar year, International Prognostic Index score, and NHL grade. Results The frequency of NHL subtypes was similar in RA patients (n = 65) and controls (n = 1,530). Compared with controls, RA patients with NHL had similar overall survival (hazard ratio [HR] = 0.95; 95% CI, 0.70 to 1.30) but were at lower risk of lymphoma progression or relapse (HR = 0.41; 95% CI, 0.25 to 0.68) or death related to lymphoma or its treatment (HR = 0.60; 95% CI, 0.37 to 0.98), but were more than twice as likely to die from causes unrelated to lymphoma (HR = 2.16; 95% CI, 1.33 to 3.50). Conclusion RA is associated with improved NHL-related outcomes, including a 40% reduced risk of death occurring as a result of lymphoma or its treatment and approximately a 60% lower risk of lymphoma relapse or progression compared with non-RA controls. However, the survival advantage gained in RA from the acquisition of lymphomas with favorable prognoses is negated through an increased mortality from other comorbid conditions.