Association of a Type 2–Polarized T Cell Phenotype With Methotrexate Nonresponse in Patients With Rheumatoid Arthritis

• Published in: Arthritis & rheumatology (Hoboken, N.J.) N.J.), 2020-07, Vol.72 (7), p.1091-1102
• Main Authors: Slauenwhite, Drew, McAlpine, Sarah M., Hanly, John G., Malik, Anikó, Haidl, Ian D., Marshall, Jean S., Issekutz, Thomas B.
• Format: Article
• Language: English
• Subjects: Apoptosis; Arthritis; CD4 antigen; CD8 antigen; Cell death; Costimulator; Effector cells; Erythrocyte sedimentation rate; Erythrocytes; Flow cytometry; Health services; Immune checkpoint inhibitors; Immunofluorescence; Inflammatory diseases; Interferon; Interleukins; Joint diseases; Lymphocytes; Lymphocytes T; Medical treatment; Methotrexate; Mucin; Patients; PD-1 protein; Peripheral blood; Phenotypes; Proteins; Rheumatoid arthritis
• ISSN: 2326-5191; 2326-5205
• DOI: 10.1002/art.41223

Objective Rheumatoid arthritis (RA) is a chronic inflammatory disease mediated through complex immunologic pathways. Among RA patients receiving low‐dose methotrexate (MTX) monotherapy, approximately one‐half exhibit a meaningful clinical response within the first 6 months of starting treatment. Whether baseline immune phenotypes differ between subsequent MTX responders and nonresponders is unknown. This study utilized comprehensive T cell immunophenotyping to identify specific immunologic pathways associated with MTX‐nonresponsive joint inflammation in patients with RA. Methods In total, 32 patients with recent‐onset RA were treated with MTX therapy. After 6 months, 15 patients were categorized as responders and 17 as nonresponders. Comprehensive blood T cell immunophenotyping, using multiparameter immunofluorescence flow cytometry analyses, was performed at baseline and following 6 months of treatment. Results Baseline measures of disease activity (Disease Activity Score in 28 joints [DAS28], C‐reactive protein level, and erythrocyte sedimentation rate) did not differ between MTX responders and nonresponders following MTX treatment. Frequencies of CD4+ and CD8+ T cells were skewed to favor higher CD4:CD8 T cell ratios in MTX responders compared to nonresponders (P < 0.05). The proportion of inducible costimulator–expressing Treg cells was significantly greater among MTX nonresponders. Interleukin‐13 (IL‐13)–producing, but not interferon‐γ– or IL‐17–producing, CD4+ effector memory T (Tem) cells were significantly more frequent in MTX nonresponders (P < 0.05). The ratio of IL‐13+:IL‐17+ Tem cells among CD4+ Tem cells was 1.9‐fold higher in MTX nonresponders compared to responders (P < 0.05). Both the CD4:CD8 T cell ratio and the frequency of IL‐13+CD4+ Tem cells correlated with changes in the DAS28 score following MTX treatment, whereas T cell expression of immune checkpoint inhibitor markers (CTLA‐4, programmed death 1, and T cell immunoglobulin and mucin domain–containing protein 3) did not differ between MTX responders and nonresponders. Conclusion We observed a bias toward type 2–polarized T cell inflammatory responses in the peripheral blood of MTX‐nonresponsive RA patients. Targeting the IL‐13+CD4+ T cell pathway could be a new therapeutic strategy in RA patients whose disease remains resistant to MTX.