The Immunosuppressive Effect of Methotrexate in Active Rheumatoid Arthritis Patients vs. its Stimulatory Effect in Nonactive Patients, as Indicated by Cytometric Measurements of CD4 + T Cell Subpopulations

Abstract

This cytometric study assesses the effects of methotrexate (MTX) on the expanded CD4+ lymphocyte population in active and nonactive rheumatoid arthritis (RA) patients. In the active patients, MTX was found to reduce the predominant CD4+ CD28+ subpopulation (by 30%), and the minor subpopulation of CD4+ CD28- (by 34%). The incidence of CD25 phenotype was downregulated by 15%. These reductions can be attributed to immunosuppression through apoptosis, which was demonstrated by MTX-induced fluorescein diacetate (FDA) hyperpolarization (an established indicator of early apoptosis). In contrast, in nonactive RA patients, the major CD4+ CD28+ subpopulation of small lymphocytes appeared to be activated by MTX, subsequently transforming into a major hyperblast population, whereas the minor CD4+ CD28- subpopulation was not affected by MTX treatment. The activation by MTX in this group of patients is evidenced by MTX-induced FDA depolarization (an indicator of early activation). Thus, MTX immunosuppressive effect on CD4+ subsets was found in active patients, whereas immunostimulation by MTX was shown in nonactive patients. The found discriminative effect of MTX may suggest a higher effectiveness of low-dose MTX therapy in active RA patients.

Distinct Effects of Anti-Tumor Necrosis Factor Combined Therapy on TH1/TH2 Balance in Rheumatoid Arthritis Patients

“…The evaluation of apoptosis induction by anti-TNF agents plus MTX might be useful to assess the clinical improvements in RA patients after the administration of therapy. MTX alone previously has been demonstrated to induce apoptosis (8,10,12). Here, we show that the apoptotic effect may be strengthened by combined anti-TNF and MTX therapy.…”

“…LCA may aid in analyzing this mechanism in individual cells. We assume that the local decrease in inflammatory cells and the treatment efficiency in patients receiving combined therapy are due to an increased induction of apoptosis, especially of the TH1 subset, which previously was reported to be more sensitive to apoptotic triggers (1,11,12), resulting in a shift in TH1/TH2 balance.…”

Immunological evaluation of rheumatoid arthritis patients treated with itolizumab

“…41 Moreover, in another study where the effect of MTX in RA patients was evaluated, a decrease in the Th17 subpopulation was seen after 12 weeks of treatment. 42 As the majority of the biological drugs approved for RA treatment focus on inflammatory cytokines, changes in the immune cell profile are insufficiently studied when these drugs are combined with MTX.…”

Demodex folliculorum in patients with rheumatoid arthritis

“…According to drug history, our RA patients had used only methotrexate, sulfasalazine and leflunomide as DMDs. It is known that these three medications have immunosuppressive effects in addition to their immunomodulatory activities (Wahl et al 1998, Goldenber 1999, Herman et al 2004. Many studies also show that treatments with methotrexate, steroid and leflunomide increase the rate of infection in patients with RA (Van der Veen et al 1994, Schnabel et al 1996, Hernandez-Cruz et al 1998, Lee and Chang 2003, Ulusoy et al 2005.…”