Pretreatment cytokine profiles of peripheral blood mononuclear cells and serum from patients with rheumatoid arthritis in different american college of rheumatology response groups to methotrexate.
OBJECTIVE
To determine the role of putative target cytokines for methotrexate (MTX) treatment in patients with rheumatoid arthritis (RA) as predictors for treatment outcome.


METHODS
Fifty consecutive patients with RA were characterized according to demographic and disease associated features and followed prospectively before and after 6 months of treatment with MTX. Before starting MTX treatment, serum was obtained from each patient and peripheral blood mononuclear cells (PBMC) were isolated. PBMC were cultured 2 days under resting conditions, and interleukin 1 receptor antagonist (IL-1ra), IL-1beta, soluble tumor necrosis factor receptor p55+75 (sTNFR p55+p75), and TNF-a release into cell culture supernatants and corresponding serum cytokine levels were determined by specific ELISA. Constitutive production and circulating levels of cytokines and cytokine inhibitors were correlated to the clinical response after 6 months of MTX treatment, and patients were categorized into 4 different groups according to the American College of Rheumatology (ACR) response criteria (ACR < 20, 20-50, 50-70, > 70% improvement from baseline).


RESULTS
Good (ACR 50-70) or excellent (ACR > 70) responses to MTX treatment were seen in groups of patients with a higher proportion of males (25 and 43%) associated with a significantly lower ratio of IL-1ra/IL-1beta (p < 0.00001) constitutively produced by PBMC (ratio < 100) compared with nonresponding (ACR < 20) patients (males 7.7%; ratio > 100). The ratios in 3 female poor responders (ACR 20-50) were in between. The decreased ratios of IL-1ra/IL-1beta in most good and excellent responders were due to an enhanced constitutive IL-1beta release from PBMC (p < 0.004) compared to the groups of non or poor responders. Much less pronounced, there was a slightly significant increase of sTNFR p55 shedding from PBMC and increase of sTNFR p75 serum levels in good and excellent responders (both p < 0.02). In contrast, there were no intergroup differences regarding constitutive IL-1ra release, sTNFR p75 shedding, and IL-1ra and sTNFR p55 serum levels and various demographic and disease associated characteristics of patients.


CONCLUSIONS
Determination of cellularly produced IL-1beta and even more of the IL-1ra/IL-1beta synthesis in PBMC may be useful to predict the outcome of RA patients undergoing treatment with MTX and may characterize a subset of RA that is more responsive to IL-1 directed therapeutic interventions.
Seitz
Michael
M
Department of Rheumatology and Clinical Immunology/Allergology, University Hospital, Bern, Switzerland. michael.seitz@insel.ch
Zwicker
Marianne
M
Villiger
Peter M
PM
D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000097:blood; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D015415:Biomarkers; D002478:Cells, Cultured; D015331:Cohort Studies; D018450:Disease Progression; D000068800:Etanercept; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000097:blood*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use*; D008875:Middle Aged; D011237:Predictive Value of Tests; D011446:Prospective Studies; D018124:Receptors, Tumor Necrosis Factor / Q000097:blood; D047889:Receptors, Tumor Necrosis Factor, Type II; D012795:Sialoglycoproteins / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D015703:Antigens, CD; D018501:Antirheumatic Agents; D015415:Biomarkers; C507763:IL1RN protein, human; D007074:Immunoglobulin G; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D018124:Receptors, Tumor Necrosis Factor; D047889:Receptors, Tumor Necrosis Factor, Type II; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept; D008727:Methotrexate