Current insights and future prospects for the pathogenesis and treatment for rheumatoid arthritis.

Genetic, environmental, and epigenetic factors simultaneously or serially contribute to immune cells and resident joint tissue cell abnormalities, invariably leading to joint destruction. Understanding the immune cell dysfunction in earlier years has brought forward life-changing therapeutics to patients with rheumatoid arthritis (RA). Further advances in the understanding of the immune and joint tissue-resident cell signaling and metabolic defects should produce additional tools to treat people with RA and foretell those who will respond to each biological or small drug. This review presents the latest evidence on RA pathogenesis and outlines the prospects for achieving precision medicine.

Immunopathogenic Mechanisms and Novel Immune-Modulated Therapies in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease of unknown etiology. It is characterized by the presence of rheumatoid factor and anticitrullinated peptide antibodies. The orchestra of the inflammatory process among various immune cells, cytokines, chemokines, proteases, matrix metalloproteinases (MMPs), and reactive oxidative stress play critical immunopathologic roles in the inflammatory cascade of the joint environment, leading to clinical impairment and RA. With the growing understanding of the immunopathogenic mechanisms, increasingly novel marked and potential biologic agents have merged for the treatment of RA in recent years. In this review, we focus on the current understanding of pathogenic mechanisms, highlight novel biologic disease-modifying antirheumatic drugs (DMRADs), targeted synthetic DMRADs, and immune-modulating agents, and identify the applicable immune-mediated therapeutic strategies of the near future. In conclusion, new therapeutic approaches are emerging through a better understanding of the immunopathophysiology of RA, which is improving disease outcomes better than ever.

Association of anticyclic citrullinated peptide antibodies and/or rheumatoid factor status and clinical presentation in early arthritis: results from the ESPOIR cohort.

OBJECTIVE: To compare the initial clinical, biological, and radiographic findings of early arthritis by positivity for rheumatoid factor (RF) and/or anticyclic citrullinated peptide antibodies (anti-CCP), and to validate a patient profile based on this serologic information. METHODS: The ESPOIR cohort comprises patients presenting synovitis of at least 2 joints for 6 weeks to 6 months. Patients underwent testing for IgM rheumatoid factor (IgM-RF) and anti-CCP2 antibodies and were divided into 4 groups: RF- and anti-CCP- (group 1), RF+ and anti-CCP- (group 2), RF- and anti-CCP+ (group 3), RF+ and anti-CCP+ (group 4). We compared the groups in terms of clinical, biological, and radiographic features (baseline scores and 6-month and 12-month progression). RESULTS: Of the 813 recruited patients, 406 (50%) were in group 1, 91 (11.2%) in group 2, 34 (4.1%) in group 3, and 281 (34.6%) in group 4. Mean baseline erythrocyte sedimentation rate and C-reactive protein were higher for anti-CCP+ groups (groups 3 and 4) than for other groups (p < 0.001), and van der Heijde-modified Sharp score for radiographs was higher for group 4 than for other groups (p < 0.001). Clinical presentation was not consistently associated with serologic profile. Radiographic progression at 1 year was higher for anti-CCP+ groups than other groups (p < 0.001). CONCLUSION: The phenotype of patients with early arthritis with or without anti-CCP and/or RF positivity did not correspond to a particular clinical presentation. However, baseline acute-phase reactants and short-term radiographic progression were high in patients with anti-CCP positivity, which may be associated with the inflammatory process and progressive disease in patients with early arthritis.

Serum levels of anti-CCP antibodies, anti-MCV antibodies and RF IgA in the follow-up of patients with rheumatoid arthritis treated with rituximab.

Rheumatoid arthritis (RA) is characterized by the presence of circulating rheumatoid factor (RF) and anticitrullinated peptide antibodies (ACPA), which are positive in about 70-80% of patients. APCA have a higher specificity and therefore a higher diagnostic power than RF, but are less informative than RF in monitoring the course of the disease in patients under treatment. Recently, it has been reported that the anticitrullinated vimentin (a-MCV) antibody test can identify a particular subgroup of APCA that may be negative for anticyclic citrullinated peptide (a-CCP) antibodies. Concerning RF, the RF IgA isotype has been described as a more specific marker of erosive joint damage than total RF. The aim of our study was to monitor the levels of a-CCP, a-MCV, total RF and RF IgA in the follow-up of patients with RA treated with B-lymphocytedepletive rituximab (RTX), to detect any differences or peculiarities in patterns of these autoantibodies, especially in relation to their potential use as predictive markers of therapeutic response. We studied 30 patients with RA treated with RTX. All patients were previously unresponsive to at least 6 months of therapy with disease-modifying antirheumatic drugs (DMARDs; methotrexate, leflunomide, cyclosporine, chloroquine) and/or at least 6 months of therapy with anti-TNF biologics. The evaluation of response to RTX was made at month +6 using the EULAR criteria (DAS28). a-CCP, a-MCV, total RF and RF IgA were determined at baseline (before the first infusion of RTX) and after 1, 3 and 6 months. In serum samples obtained before treatment two cytokines essential for Blymphocyte proliferation, interleukin 6 (IL-6) and B-lymphocyte stimulator (BLyS) were also determined. In all patients a significant and consistent reduction in all the tested antibodies was found during follow-up, with no differences in respect of the degree of response to RTX. Of note, at baseline, generally a higher titre of all autoantibodies was seen in patients who then showed a better response to RTX. Finally, there were no differences in serum concentrations of IL-6 and BLyS in patients in relation to the presence or absence of the autoantibodies investigated, nor was there any significant correlation between the serum concentrations of the cytokines and the titres of the autoantibodies. Thus, neither a-MCV compared to a- CCP, nor RF IgA compared to routine total RF, provided any additional predictive information in the follow-up of patients with RA treated with RTX.