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

Autor: Drew Slauenwhite, J G Hanly, Thomas B. Issekutz, Jean S. Marshall, Aniko Malik, Sarah M. McAlpine, Ian D. Haidl
Rok vydání: 2020
Předmět:
CD4-Positive T-Lymphocytes
Male
T-Lymphocytes
Programmed Cell Death 1 Receptor
CD8-Positive T-Lymphocytes
T-Lymphocytes
Regulatory
Gastroenterology
Arthritis
Rheumatoid
Immunophenotyping
T-Lymphocyte Subsets
Immunology and Allergy
Cytotoxic T cell
CTLA-4 Antigen
Treatment Failure
skin and connective tissue diseases
Hepatitis A Virus Cellular Receptor 2
Interleukin-13
medicine.diagnostic_test
Interleukin-17
Middle Aged
Flow Cytometry
Treatment Outcome
medicine.anatomical_structure
Antirheumatic Agents
Erythrocyte sedimentation rate
Rheumatoid arthritis
Female
medicine.drug
Adult
musculoskeletal diseases
medicine.medical_specialty
T cell
Immunology
CD4-CD8 Ratio
Inducible T-Cell Co-Stimulator Protein
Interferon-gamma
Immune system
Rheumatology
Internal medicine
medicine
Humans
Aged
business.industry
medicine.disease
Methotrexate
Case-Control Studies
business
Immunologic Memory
CD8
Zdroj: Arthritis & Rheumatology. 72:1091-1102
ISSN: 2326-5205
2326-5191
Popis: 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.
Databáze: OpenAIRE
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