The impact of conventional DMARD and biological therapies on CD4+ cell subsets in rheumatoid arthritis: a follow-up study

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease characterized by abnormal prevalence of Th1, Th2, Th17, and regulatory (Treg) subsets. Some data suggest that these subsets are influenced by anti-RA agents. Follow-up studies monitoring T cell phenotype in response to therapy are limited. We investigated the alteration of CD4+ T cell subset distribution after the initiation of disease-modifying antirheumatic drug (DMARD) (with glucocorticosteroid (GCS) and methotrexate (MTX)) and anti-TNFα therapy. We enrolled 19 treatment naive (early) RA patients and initiated GCS (in a dose of 16 mg/day for 4 weeks; then 8 mg/day). MTX, 10 mg/week, was started at week 4. We also enrolled 32 RA patients unresponsive to DMARD and initiated anti-TNFα therapy: adalimumab (ADA), 40 mg/2 weeks, n = 12; etanercept (ETA), 50 mg/weeks, n = 12; or infliximab (IFX) on week 0, 2, and 6, 3 mg/kg bw, n = 8. Blood was taken before and 4 and 8 weeks after the initiation of therapy. Ten volunteers served as controls. The T cell phenotype was assessed with flow cytometry. In early RA, Th1, Th2, and Th17 prevalence was higher, while Treg prevalence was lower than normal. GCS alone decreased Th2 prevalence. GCS + MTX decreased Th17 prevalence. Immune phenotype in unresponsive RA before anti-TNF therapy was as in early RA. Four and 8 weeks after initiating anti-TNF therapy, Th1 prevalence was higher than baseline in ETA or IFX, while it was stable in ADA groups. Th2 prevalence was higher than normal in ADA or IFX, while normalized in ETA group. In each group, Treg prevalence increased, while Th17 prevalence was at the baseline. The proinflammatory immune phenotype is normalized only under GCS + MTX combination in early RA. Anti-TNFα therapy exhibit marked effects on all the cell populations investigated (except Th17); some slight differences in this action exist between ADA, ETA, and IFX therapy.

STAT6 and STAT1 Pathway Activation in Circulating Lymphocytes and Monocytes as Predictor of Treatment Response in Rheumatoid Arthritis

“…We found no association between the pSTAT1/pSTAT6 ratio at baseline and treatment response, but, however, the ratio increased during treatment with synthetic or biological DMARDs, and the increase was significant in lymphocytes during successful DMARD treatment in recent-onset RA. Our findings are consistent with results showing that a shift to the Th1 direction occurred in the Th1/Th2 cell ratio in patients with RA during either TNF blocker or glucocorticoid treatment [47], and that the expression of IFN-γ compared to that of IL-4 in peripheral blood mononuclear culture increased under treatment with the TNF antibody infliximab [48]. IFN-γ can suppress IL-4 -induced STAT6 activation, as observed in monocytes and Th1 cells [49,50].…”

Patients with the most advanced rheumatoid arthritis remain with Th1 systemic defects after TNF inhibitors treatment despite clinical improvement

“…Available data concerning the effect of the different therapeutic interventions on the Th17 cell population are still confusing. Several studies have shown an unchanged [13, 15, 20] or, alternatively, a decreased Th17 frequency following treatment with MTX and/or iTNF [13–16, 19, 20], and the latter findings are in accordance with the current study. Similarly to the recent work [20], monotherapy with MTX was able to effectively limit the Th17 population only in the patients with early disease.…”

“…Considering CD4 T cell subpopulations, a common disorder found in all RA patients irrespective of the disease duration was expansion of Th17 cells in circulation. This observation is in accordance with previous reports [11–20] and confirms that Th17 is a key effector cell in the pathogenesis of RA [21]. Its strong pro-inflammatory action has been attributed to secretion of IL-17 and, to a lesser extent, TNF-α and IL-6 [22].…”

Analysis of CXCR5+Th17 cells in relation to disease activity and TNF inhibitor therapy in Rheumatoid Arthritis

“…Szalay et al . analyzed proportions of CCR6 + Th17 cells in subjects with established RA before and after 8 weeks of anti-TNF therapy, and found no significant change in the Th17 population37, similar to our findings. In contrast, Lina et al .…”