The influence of genetic variation in the HLA–DRB1 and LTA–TNF regions on the response to treatment of early rheumatoid arthritis with methotrexate or etanercept

Abstract

Objective. To examine the roles of specific genetic polymorphisms as predictors of response to treatment of early rheumatoid arthritis (RA).Methods. Subjects included 457 patients with early RA (duration of <3 years) who participated in a randomized controlled trial comparing weekly methotrexate and 2 dosages of etanercept (10 mg twice weekly and 25 mg twice weekly). Our primary outcome measure was achievement of 50% improvement in disease activity according to the criteria of the American College of Rheumatology (ACR50 response) after 12 months of treatment. Subjects were genotyped for HLA-DRB1 alleles and polymorphisms in the following genes: TNF, LTA, TNFRSF1A, TNFRSF1B, FCGR2A, FCGR3A, and FCGR3B. Univariate and multivariate analyses were performed to define the impact of specific polymorphisms and haplotypes on response to treatment. Covariates for the multivariate analyses included sex, ethnicity, age, disease duration, and baseline values for rheumatoid factor and the tender and swollen joint counts.Results. The presence of 2 HLA-DRB1 alleles encoding the shared epitope (SE) (compared with 1 or 0 copies) was associated with response to treatment with standard-dose etanercept (odds ratio [OR] 4.3, 95% confidence interval [95% CI] 1.8-10.3). Among Caucasian patients, 2 extended haplotypes that included the HLA-DRB1 alleles *0404 and *0101 (both of which encode the SE) and 6 single-nucleotide polymorphisms in the LTA-TNF region were associated with response to treatment. In a multivariate model that included treatment received and the aforementioned covariates, the ORs for the association of these haplotypes with achievement of an ACR50 response at 12 months were 2.5 (95% CI 0.8-7.3) and 4.9 (95% CI 1.5-16

Polymorphism at position +896 of the toll-like receptor 4 gene interferes with rapid response to treatment in rheumatoid arthritis

“…However, this study can only be regarded as hypothesis-generating, because the sample size was quite small and so far there are no publications supporting the finding, and because the exact role of 299Gly in TLR4 expression or signalling is still under investigation. 6 Previous studies have looked for genetic 12 and biochemical 13 markers that reliably predict the outcome of treatment for rheumatoid arthritis. If confirmed in larger studies, the TLR4 +896 polymorphism may become a part of such a profile.…”

A clinical pharmacogenetic model to predict the efficacy of methotrexate monotherapy in recent‐onset rheumatoid arthritis

“…Baseline variables possibly influencing the patient's disease state and MTX response were selected based on the literature (10)(11)(12)(13)(14)(15)(16)(17)(18)20,23,27,28). The following factors were iden-tified: sex; rheumatoid factor (RF) status; age; duration of joint symptoms; alcohol consumption; smoking; body mass index; menopausal status; hormone supplementation; scores for physician's assessment of disease activity, pain, patient's assessment of disease activity, patient's assessment of global health, and morning stiffness on a 0-100-point VAS; Health Assessment Questionnaire (HAQ) score (29); ESR; C-reactive protein level; DAS; SJC; RAI; kidney function (defined as creatinine clearance); anti-cyclic citrullinated peptide (anti-CCP) status; NSAID use; and the existence of comorbidity based on drug use (other than RA disease-related drugs).…”

“…Previously, the influences of demographic, clinical, immunologic, and genetic factors on the state of disease in patients with RA have been studied (10)(11)(12)(13)(14)(15)(16)(17)(18). Specifically, polymorphisms in genes coding for methylenetetrahydrofolate reductase (MTHFR), adenosine monophosphate deaminase (AMPD1), aminoimidazole carboxamide ribonucleotide transformylase (ATIC), serine hydroxymethyltransferase 1 (SHMT1), and inosine triphosphate pyrophosphatase (ITPA) demonstrate association with the MTX response (19)(20)(21)(22).…”

Genome-Wide Association Scan Identifies Candidate Polymorphisms Associated with Differential Response to Anti-TNF Treatment in Rheumatoid Arthritis

“…Of the markers present on the Illumina HapMap 300 chip, four SNP associations with TNF response have been reported previously in candidate gene studies: rs1800896 in IL10 (8,24), rs419598 in interleukin 1 receptor antagonist (IL1RN) (14), rs1041981 in LTA (25)(26)(27), and rs4149570 in TNFRSF1A (26). These markers were evaluated separately in view of their increased prior probability.…”