Methrotexate Treatment Inmunomodulates Abnormal Cytokine Expression by T CD4 Lymphocytes Present in DMARD-Naïve Rheumatoid Arthritis Patients

CD4(+)T-lymphocytes are relevant in the pathogenesis of rheumatoid arthritis (RA), however, their potential involvement in early RA remains elusive. Methotrexate (MTX) is a commonly used disease-modifying antirheumatic drug (DMARD), but its mechanism has not been fully established. In 47 new-onset DMARD-naïve RA patients, we investigated the pattern of IFNγ, IL-4 and IL-17A expression by naïve (T(N)), central (T(CM)), effector memory (T(EM)) and effector (T(E)) CD4(+) subsets; their STAT-1, STAT-6 and STAT-3 transcription factors phosphorylation, and the circulating levels of IFNγ, IL-4 and IL-17. We also studied the RA patients after 3 and 6 months of MTX treatment and according their clinical response. CD4(+)T-lymphocyte subsets and cytokine expression were measured using flow cytometry. New-onset DMARD-naïve RA patients showed a significant expansion of IL-17A(+), IFNγ(+) and IL-17A(+)IFNγ(+) CD4(+)T-lymphocyte subsets and increased intracellular STAT-1 and STAT-3 phosphorylation. Under basal conditions, nonresponder patients showed increased numbers of circulating IL-17A producing T(N) and T(MC) CD4(+)T-lymphocytes and IFNγ producing T(N), T(CM), T(EM) CD4(+)T-lymphocytes with respect to responders. After 6 months, the numbers of CD4(+)IL-17A(+)T(N) remained significantly increased in nonresponders. In conclusion, CD4(+)T-lymphocytes in new-onset DMARD-naïve RA patients show IL-17A and IFNγ abnormalities in T(N), indicating their relevant role in early disease pathogenesis. Different patterns of CD4(+) modulation are identified in MTX responders and nonresponders.