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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

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 non‐active patients. The found discriminative effect of MTX may suggest a higher effectiveness of low‐dose MTX therapy in active RA patients.