Immune response profiling in early rheumatoid arthritis: discovery of a novel interaction of treatment response with viral immunity

Abstract

IntroductionIt remains challenging to predict the outcomes of therapy in patients with rheumatoid arthritis (RA). The objective of this study was to identify immune response signatures that correlate with clinical treatment outcomes in patients with RA.MethodsA cohort of 71 consecutive patients with early RA starting treatment with disease-modifying antirheumatic drugs (DMARDs) was recruited. Disease activity at baseline and after 21 to 24 weeks of follow-up was measured using the Disease Activity Score in 28 joints (DAS28). Immune response profiling was performed by analyzing multi-cytokine production from peripheral blood cells following incubation with a panel of stimuli, including a mixture of human cytomegalovirus (CMV) and Epstein-Barr virus (EBV) lysates. Profiles identified via principal components analysis (PCA) for each stimulus were then correlated with the ΔDAS28 from baseline to follow-up. A clinically meaningful improvement in the DAS28 was defined as a decrease of ≥1.2.ResultsA profile of T-cell cytokines (IL-13, IL-4, IL-5, IL-2, IL-12, and IFN-γ) produced in response to CMV/EBV was found to correlate with the ΔDAS28 from baseline to follow-up. At baseline, a higher magnitude of the CMV/EBV immune response profile predicted inadequate DAS28 improvement (mean PCA-1 scores: 65.6 versus 50.2; P = 0.029). The baseline CMV/EBV response was particularly driven by IFN-γ (P = 0.039) and IL-4 (P = 0.027). Among patients who attained clinically meaningful DAS28 improvement, the CMV/EBV PCA-1 score increased from baseline to follow-up (mean +11.6, SD 25.5), whereas among patients who responded inadequately to DMARD therapy, the CMV/EBV PCA-1 score decreased (mean -12.8, SD 25.4; P = 0.002). Irrespective of the ΔDAS28, methotrexate use was associated with up-regulation of the CMV/EBV response. The CMV/EBV profile was associated with positive CMV IgG (P <0.001), but not EBV IgG (P = 0.32), suggesting this response was related to CMV exposure.ConclusionsA profile of T-cell immunity associated with CMV exposure influences the clinical response to DMARD therapy in patients with early RA. Because CMV latency is associated with greater joint destruction, our findings suggest that changes in T-cell immunity mediated by viral persistence may affect treatment response and possibly long-term outcomes of RA.

Autoimmune arthritis induces paired immunoglobulin‐like receptor B expression on CD4+ T cells from SKG mice

“…Previously, we and others have described an association of latent CMV–triggered immunosenescence with RA, in particular in patients with more severe disease . LIR‐1, an inhibitory receptor associated with T‐cell compartment deviations characteristically induced in CMV infection, was found to be up‐regulated on CD8 + T cells from RA patients .This prompted us to investigate the expression of its murine ortholog PIR‐B in an animal model of RA.…”

Latent Cytomegalovirus Infection in Rheumatoid Arthritis and Increased Frequencies of Cytolytic LIR‐1+CD8+ T Cells

“…Latent CMV infection and RA share several phenotypical features in the T cell compartment. In addition, the clinical impact of CMV infection on the RA disease course has previously been reported . We describe herein a population of CD8+ T cells in CMV‐positive RA patients that exhibits proinflammatory, cytolytic, and antiviral features and is functionally inhibited due to up‐regulated expression of LIR‐1.…”

“…In healthy individuals, expression of LIR-1 on CD81 T cells is up-regulated by CMV infection, possibly with the goal of limiting collateral tissue damage due to the longstanding immune response against the latent virus or, alternatively, as a homeostatic mechanism (6)(7)(8). We found that the frequency of LIR-11CD81 T cells was significantly higher in CMV-positive RA patients than in CMVpositive healthy controls and that it increased not only with age, but also with higher levels of disease activity.…”

“…Clinically, CMV infection can cause organ‐specific or systemic infections in immunocompromised patients. We and other investigators have shown that the presence of a latent CMV infection influences the clinical course and outcome of rheumatoid arthritis (RA), the prototypical T cell–mediated autoimmune disease with severe perturbations of immune homeostasis, particularly in various T lymphocyte compartments. Similar observations have been reported in other autoimmune diseases, such as psoriasis , granulomatosis with polyangiitis , Alzheimer's disease , and systemic lupus erythematosus .…”

How Herpesviridae Combined with other Viral Infections can Trigger and Drive Rheumatoid Arthritis

“…In this context the high serum levels of TNFalpha in the synovial fluid that characterize RA is believed to be protective. This seems to be the case at the early RA stage since the level of TNF-alpha and IFN-gamma produced by T lymphocytes in response to infections, such as CMV/EBV, correlated with the activity of joint inflammation Davis, et al [15]. However, it should be mentioned that, although elevated in the synovial fluids, the serum levels of TNF-alpha is similar to that observed in controls Bucht et al [16], and that IFN-gamma producing T cells in RA patients were absent or present only in small quantities in the joint tissues.…”