Are prognostic factors adequately selected to guide treatment decisions in patients with rheumatoid arthritis? A collaborative analysis from three observational cohorts.

OBJECTIVE: To investigate the impact of indicators of unfavorable prognosis ("poor prognostic factors") on the achievement of low disease activity (LDA)/remission in patients with rheumatoid arthritis (RA). METHODS: Biologic DMARD-naïve patients with RA from three observational cohorts were examined. N = 713 patients started their 1st csDMARD, n = 1613 switched to the 2nd csDMARD and n = 388 to the 1st TNF-inhibitor. High disease activity (DAS28 > 5.1), autoantibodies (RF/ACPA positive), prevalent erosions, functional limitation (HAQ ≥ 1.2), comorbidities, obesity (BMI > 30 kg/m2), and smoking were evaluated as prognostic factors. Generalized regression analyses were applied to investigate prognostic factors regarding the achievement of LDA (DAS28 < 3.2) or remission (DAS28 < 2.6) within six months. RESULTS: At baseline, RF/ACPA positivity was most frequent in all cohorts (60.3-75.3%), followed by DAS28 > 5.1 (35-57.7%), HAQ ≥ 1.2 (40.5-52.5%), ≥ 2 comorbidities (31.4-54.1%) and erosions (17.1-46.1%). Remission was achieved by 39% (1st-csDMARD), 26% (2nd-csDMARD) and 30% (1st-TNFi). In adjusted regression models DAS28 > 5.1 (OR: 0.41 [0.30;0.56]), HAQ ≥ 1.2 (0.56 [0.42;0.74]), current smoking (0.72 [0.53;0.97], obesity (0.66 [0.49;0.89] and ≥ 2 comorbidities (0.57 [0.40;0.80]) were independently associated with a lower chance to achieve remission within six months (ORs for 2nd-csDMARD). The proportion of patients in LDA/remission declined by 6-12%-points if DAS28 > 5.1 was present at baseline and by 15-27%-points if functional limitation, comorbidities and obesity were additionally present. In all cohorts RF/ACPA positivity and erosions were not associated with achieving LDA/remission. CONCLUSIONS: While RF/ACPA status and erosions do not affect the achievement of LDA/remission, high disease activity, functional limitation, comorbidities and obesity should be considered as unfavorable prognostic factors in patients starting the 1st or 2nd DMARD strategy.

Long-term effectiveness of tocilizumab in patients with rheumatoid arthritis, stratified by number of previous treatment failures with biologic agents: results from the German RABBIT cohort.

In Germany, Tocilizumab (TCZ) is used for the treatment of rheumatoid arthritis both in biologic-naïve patients and those with previous failures of biologic disease-modifying antirheumatic drugs (bDMARDs). The long-term effectiveness and retention rates of TCZ in patients with different numbers of prior bDMARD failures has rarely been investigated. We included 885 RA patients in the analyses, enrolled with the start of TCZ between 2009 and 2015 in the German biologics register RABBIT. Patients were stratified according to prior bDMARD failures: no prior bDMARD or 1, 2 or ≥ 3 bDMARD failures. We applied Kaplan-Meier methods and Cox-regression to examine treatment adherence as well as linear mixed effects models to investigate effectiveness over 3 years of follow-up. Compared to biologic-naïve patients, those with prior bDMARD failures at start of TCZ were younger but had significantly longer disease duration and more comorbidities. DAS28 at baseline and loss of physical function were highest in patients with ≥ 3 bDMARD failures. During follow-up, patients with up to two bDMARD failures on average reached low disease activity (LDA, DAS28 < 3.2). Those with ≥ 3 prior bDMARDs had a slightly lower response. However, after 3 years, nearly 50% of them achieved LDA. Treatment continuation on TCZ therapy was similar in patients with ≤ 2 bDMARD failures but significantly lower in those with ≥ 3 bDMARD failures. TCZ seems to be similarly effective in patients with no, one or two prior bDMARD failures. The majority of patients achieved LDA already after 6 months and maintained it over a period of 3 years. TCZ proved effective even in the high-risk group of patients with more than two prior bDMARD failures.

Plasmablasts With a Mucosal Phenotype Contribute to Plasmacytosis in Systemic Lupus Erythematosus.

OBJECTIVE: To analyze the composition of known plasmacytosis in systemic lupus erythematosus (SLE) to obtain further insight into the nature of underlying mechanisms. METHODS: Plasmablasts from patients with active SLE, patients with inactive/treated SLE, and healthy controls were characterized by flow cytometry, enzyme-linked immunospot assay, and Transwell migration assays and compared to vaccination-induced plasmablasts. Serum cytokine levels were analyzed by Luminex assay, and histologic analysis of kidney biopsy specimens was performed. RESULTS: Circulating plasmablasts in SLE expressed markers of mucosal immune reactions. IgA, CCR10, and ß7 integrin were expressed by 48%, 40%, and 38% of plasmablasts, respectively, with varying coexpression patterns. Consistent with mucosal homing, some SLE plasmablasts migrated toward the mucosal chemokine CCL28 and secreted polymeric IgA. SLE plasmablasts shared phenotypic characteristics with antigen-specific plasmablasts induced by oral, but not parenteral, vaccinations. Autoreactive antibody-secreting cells of the IgG and IgA isotypes were detectable, but only the emergence of phenotypically mucosal plasmablasts was positively associated with serum interleukin-2 and platelet-derived growth factor BB levels. CONCLUSION: Our data suggest that distinct plasmablast differentiation pathways jointly contribute to peripheral plasmacytosis in SLE, i.e., a cytokine-amplified mucosal "steady-state" plasmablast response, and an autoreactive plasmablast response, representing conventional autoimmunity. Our results indicate an overly activated mucosal immune system in patients with SLE, with both immunologic and clinical implications.