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Objective: Many types of treatment are available for patients with rheumatoid arthritis (RA), however, some patients fail to achieve remission. This report aims to determine the safety and efficacy of using repository corticotropin injection (RCI) as an adjunctive therapy in patients with RA refractory to at least three therapeutics with different mechanisms of action. Method: In this open-label, interventional, single-group study, patients received 80 U RCI twice weekly via subcutaneous injection over 12 weeks. Changes in the Ritchie-Camp Articular Index and health assessment questionnaire scores were monitored for changes from baseline measures. Results: Eight patients were enrolled and consisted of seven females and one male with an average age of 64.6 years and disease duration of 20.9 years. Use of RCI resulted in significant improvement in swollen and tender joint counts. The disease activity score 28 and the physician and patient visual analog scale scores were significantly reduced at treatment week 12. The reduction in health assessment questionnaire scores did not reach statistical significance after RCI treatment. Once RCI therapy was discontinued, all improvements in disease activity score 28, physician and patient visual analog scale, and tender and swollen joint counts achieved during treatment were lost by the week 16 follow-up visit. Conclusion: While larger clinical trials are necessary to further confirm the efficacy of RCI in patients with refractory RA, the response of patients with refractory RA in this study suggests that RCI can be an effective add-on therapy for patients who have exhausted several classes of treatments. Furthermore, this study suggests that RCI has an alternative mode of action, compared to other available antirheumatic drugs. [ABSTRACT FROM AUTHOR]

Objectives. The B-cell chemokine, CXCL13, is a proposed serum biomarker of synovitis in RA. Its behaviour in the context of B-cell depletion therapy and reconstitution was studied during treatment of RA with rituximab.Methods. Serum samples from 20 RA patients were analysed for CXCL13, RF-IgM and anti-CCP by ELISA before and 2 and 6 months following rituximab treatment. B cells were monitored by flow cytometry. Gene expression in blood and synovial biopsies was determined by qPCR.Results. Patients with detectable B cells at 6 months had significantly higher levels of CXCL13 and RF-IgM and slightly higher levels of anti-CCP throughout the study, including at baseline, compared with patients with undetectable B cells at 6 months. Conversely, 10 of 12 patients with high baseline CXCL13 had detectable circulating B cells at 6 months, whereas no B cells could be detected at 6 months in patients with low baseline CXCL13. Synovial CXCL13 expression at baseline correlated significantly with serum CXCL13 levels, and the synovium of patients with high serum CXCL13 expressed elevated levels of IL-1β, IL-8, MMP1 and MMP3. In addition, synovial CXCL13 expression correlated significantly with several synovial inflammatory markers.Conclusions. Serum CXCL13 is predictive of the rate of B-cell repopulation following a course of rituximab in RA. Serum CXCL13 correlates with synovial CXCL13 measured at a single joint, suggesting synovitis as an important source of circulating CXCL13. Within the synovium, CXCL13 expression is highly correlated with markers of synovitis.Trial Registration. ClinicalTrials.gov, http://clinicaltrials.gov/, NCT00147966. [ABSTRACT FROM PUBLISHER]

Abstract: IL-17AA, IL-17FF, and IL-17AF are proinflammatory cytokines that have been implicated in the pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA). In order to measure the levels of these cytokines in synovial fluid and serum samples from RA patients, immunoassays specific for IL-17AA, FF, and AF were developed. Although these assays could tolerate up to 50% pooled normal human serum, false positive reactivity was problematic in patient samples suggesting interference from heterophilic antibodies. We therefore evaluated the ability of several commercially available heterophilic antibody blocking agents to reduce false positive reactivity by testing them against samples that were confirmed as false positives in the IL-17AA, FF, and AF assays. Several of the blockers performed well, including HBR-1, HBR-9, HBR-11, HBR-Plus, Serum Cytokine Assay Diluent, and IIR. We chose to move forward using IIR blocker for sample analysis and verified that IIR had no effect on the assay standard curves and did not affect IL-17 quantitation in plasma from ex vivo stimulated human whole blood. IL-17FF and IL-17AF were below the limits of quantitation of the assays (12.3 and 10.5pg/ml, respectively) in synovial fluid and serum samples from patients with RA and osteoarthritis (OA). For the more sensitive IL-17AA assay (1.6pg/ml limit of quantitation), low levels of IL-17AA were measurable in 48% of RA synovial fluid samples (mean, 7.9pg/ml; median, <1.6pg/ml; range, <1.6–29.7pg/ml; n=23) but not in synovial fluid from patients with OA (n=33). For serum samples, however, IL-17AA was below the limit of detection for both RA and OA patients. When these same serum samples were analyzed in the absence of a heterophilic antibody blocker, false positive reactivity yielded apparent mean IL-17AA levels of 43.3pg/ml (28% positive; n=50) and 14.8pg/ml (12% positive; n=50) for RA and OA patients, respectively, results that could potentially be interpreted as consistent with disease biology. These studies demonstrate the importance of ensuring that HAb interference is well controlled, particularly when measuring low concentrations of cytokines in samples from patients with autoimmune disease. [Copyright &y& Elsevier]

Abstract: Tumor necrosis factor-superfamily (TNF-SF) members, lymphotoxin (LT)-α and LTβ, are proinflammatory cytokines associated with pathology in rheumatoid arthritis. LTα3 homotrimers are secreted, whereas LTα1β2 heterotrimers are expressed on the surface of activated lymphocytes. As many TNF-SF members are actively cleaved from cell membranes, we determined whether LTαβ heterotrimers are also cleaved, and are biologically active in rheumatoid arthritis (RA) patients. LTαβ heterotrimers were detected in culture supernatants from activated human T-helper (Th) 0, Th1, and Th17 cells, together with LTα3 and TNFα. The heterotimers were actively cleaved from the cell surface by ADAM17 metalloproteinase (MMP) and MMP-8, and cleavage was inhibited by TAPI-1, a TNF-α converting enzyme (TACE) inhibitor. Soluble LTαβ was detected in serum from both normal donors and RA patients, and was elevated in synovial fluid from RA patients compared to osteoarthritis (OA) patients. Levels of LTαβ in RA patient synovial fluid correlated with increased TNFα, IL-8, IL-12, IL-1β, IFN-γ, and IL-6 cytokines. Moreover, recombinant LTα1β2-induced CXCL1, CXCL2, IL-6, IL-8, VCAM-1, and ICAM-1 from primary synovial fibroblasts isolated from RA patients. Therefore, soluble LTαβ in synovial fluid is associated with a proinflammatory cytokine milieu that contributes to synovitis in RA. [Copyright &y& Elsevier]