Rheumatoid Arthritis: Maher NE

Benito-Garcia E, Heller JE, Chibnik LB, Maher NE, Matthews HM, Bilics JA, Weinblatt ME, Shadick NA. · Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. · J Rheumatol. · Pubmed #16821266 No free full text.

Abstract: OBJECTIVE: Methylxanthines, like caffeine, have been thought to reverse the antiinflammatory effects of methotrexate (MTX) in rheumatoid arthritis (RA). We investigated whether patients with RA taking MTX with a higher dietary caffeine intake have a worse clinical response to MTX than those with a lower intake. METHODS: Patients with RA enrolled in a prospective cohort study and currently taking MTX were divided equally into low, moderate, and high caffeine consumers. MTX clinical response was defined by the Disease Activity Score (DAS)28, Multidimensional Health Assessment Questionnaire (MDHAQ) score, and duration of morning stiffness. Regression models were used to study the relationship between caffeine intake and MTX response adjusting for age, sex, and other relevant variables at study enrollment. RESULTS: Two hundred and sixty-four patients with RA taking MTX had an average caffeine intake of 211.7 mg and average MTX dose of 16.0 mg/wk. The low caffeine group comprised 87 patients, the moderate 86, and the high 91. In 3 multivariate models, there was no statistical difference in MTX efficacy between groups, as measured by DAS28 score, MDHAQ score, and duration of morning stiffness at study enrollment. Moderate and high caffeine group had higher DAS28 scores, physician's global assessment, and swollen joint counts, but differences were not significant. CONCLUSION: Caffeine intake among patients taking high doses of MTX for RA did not affect MTX efficacy and RA disease activity over time.

Agarwal SK, Glass RJ, Shadick NA, Coblyn JS, Anderson RJ, Maher NE, Weinblatt ME, Solomon DH. · Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. · J Rheumatol. · Pubmed #18634159 No free full text.

Abstract: OBJECTIVE: Tumor necrosis factor-alpha (TNF) inhibitors have transformed management of rheumatoid arthritis (RA); however, many patients discontinue TNF inhibitors. Our goal was to determine the discontinuation rate of TNF inhibitors and identify predictors associated with discontinuation. METHODS: Enrollees in the Brigham RA Sequential Study (BRASS) formed the eligible cohort. Patients reporting use of a TNF inhibitor with at least 6 months of followup were followed until reporting TNF inhibitor discontinuation or their last study visit if they continued therapy. Potential predictor variables, including demographic and clinical data assessed at baseline and 6 months prior to study endpoint, were identified using a Cox proportional regression. RESULTS: Among 961 patients in BRASS, 503 were using a TNF inhibitor with at least 6 months of followup in BRASS (mean length of followup 39 mo, SD 13). Two hundred ten patients (42%) reported discontinuation of TNF inhibitor. Higher physician global scores (hazard ratio 1.27, 95% CI 1.18-1.38) and RA Disease Activity Index scores (HR 1.13, 95% CI 1.05-1.22) 6 months prior to stopping the TNF inhibitor and higher number of TNF inhibitors used previously (HR 1.30, 95% CI 1.03-1.66) were associated with discontinuation of TNF inhibitor. Prior use of synthetic disease modifying antirheumatic drugs (HR 0.50, 95% CI 0.34-0.72) and more years of cumulative methotrexate use (HR 0.24, 95% CI 0.12-0.47) were inversely associated with discontinuation of TNF inhibitor. CONCLUSION: These data demonstrate that a significant number of patients with RA discontinue TNF inhibitors. Several easily characterized clinical variables have a modest predictive association with reduced probability of TNF inhibitor discontinuation.

Karlson EW, Chibnik LB, Cui J, Plenge RM, Glass RJ, Maher NE, Parker A, Roubenoff R, Izmailova E, Coblyn JS, Weinblatt ME, Shadick NA. · Division of Rheumatology, Allergy, and Immunology, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. · Ann Rheum Dis. · Pubmed #17666451 links to  free full text

Abstract: BACKGROUND: HLA-DRB1 shared epitope (HLA-SE), PTPN22 and CTLA4 alleles are associated with cyclic citrullinated peptide (CCP) and rheumatoid arthritis (RA). OBJECTIVE: We examined associations between HLA-SE, PTPN22, CTLA4 genotypes and RA phenotypes in a large cohort to (a) replicate prior associations with CCP status, and (b) determine associations with radiographic erosions and age of diagnosis. METHODS: A total of 689 RA patients from the Brigham RA Sequential Study (BRASS) were genotyped for HLA-SE, PTPN22 (rs2476601) and CTLA4 (rs3087243). Association between genotypes and CCP, rheumatoid factor (RF) erosive phenotypes and age at diagnosis were assessed with multivariable models adjusting for age, sex and disease duration. Novel causal pathway analysis was used to test the hypothesis that genetic risk factors and CCP are in the causal pathway for predicting erosions. RESULTS: In multivariable analysis, presence of any HLA-SE was strongly associated with CCP+ (odds ratio (OR) 3.05, 95% CI 2.18-4.25), and RF+ (OR 2.53, 95% CI 1.83-3.5) phenotypes; presence of any PTPN22 T allele was associated with CCP+ (OR 1.81, 95% CI 1.24-2.66) and RF+ phenotypes (OR 1.84, 95% CI 1.27-2.66). CTLA4 was not associated with CCP or RF phenotypes. While HLA-SE was associated with erosive RA phenotype (OR 1.52, 95% CI 1.01-2.17), this was no longer significant after conditioning on CCP. PTPN22 and CTLA4 were not associated with erosive phenotype. Presence of any HLA-SE was associated with an average 3.6 years earlier diagnosis compared with absence of HLA-SE (41.3 vs 44.9 years, p = 0.002) and PTPN22 was associated with a 4.2 years earlier age of diagnosis (39.5 vs 43.6 years, p = 0.002). CTLA4 genotypes were not associated with age at diagnosis of RA. CONCLUSIONS: In this large clinical cohort, we replicated the association between HLA-SE and PTPN22, but not CTLA4 with CCP+ and RF+ phenotypes. We also found evidence for associations between HLA-SE, and PTPN22 and earlier age at diagnosis. Since HLA-SE is associated with erosive phenotype in unconditional analysis, but is not significant after conditioning on CCP, this suggests that CCP is in the causal pathway for predicting erosive phenotype.

Shadick NA, Heller JE, Weinblatt ME, Maher NE, Cui J, Ginsburg G, Coblyn J, Anderson R, Solomon DH, Roubenoff R, Parker A. · Division of Rheumatology, Immunology, Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. · Ann Rheum Dis. · Pubmed #17491100 No free full text.

Abstract: BACKGROUND: Certain sequences present in the hypervariable region of human leucocyte antigen (HLA)-DRB1 known as the shared epitope (SE) are hypothesised to increase the risk of rheumatoid arthritis (RA), whereas alleles encoding aspartic acid at position 70 (D70 alleles) may have a protective effect. METHODS: Patient HLA-DRB1 serotypes were assessed and the genotypes encoding the SE motif or the putatively protective D70 motif identified in a large RA cohort. Logistic regression was used to analyse associations of genotype with presence of disease, comorbidities and disease severity, and association between genotype and change in disease activity over time. RESULTS: The 689 patients enrolled had a mean (SD) age of 57.9 (13.7) years and mean (SD) disease duration of 15.3 (12.7) years. In a comparison with 482 ethnicity matched population-based controls, the D70 sequence exerted a strong protective effect (OR = 0.52, p<0.001) that remained significant when the SE at the same locus was accounted for (OR = 0.72, 95% CI 0.60 to 0.86, p<0.001). The SE assessed on all HLA-DRB1 serotypic backgrounds except DR1 was associated with RA susceptibility (additive OR = 2.43, p<0.001). Associations were found between SE and serum levels of rheumatoid factor (p<0.001, with correlation of 0.18) and anti-cyclic citrullinated peptide antibodies (p<0.001, with correlation of 0.25) but not with serum C-reactive protein. CONCLUSION: The D70 allele has a significant protective effect that is mitigated but still significant when the risk effect of the SE at the same locus is taken into account. The presence of the SE on DR4 is associated with greater RA susceptibility and certain disease-activity measures.

Shadick NA, Cook NR, Karlson EW, Ridker PM, Maher NE, Manson JE, Buring JE, Lee IM. · Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. · Arch Intern Med. · Pubmed #17159015 links to  free full text

Abstract: BACKGROUND: The purpose of this study was to examine whether levels of C-reactive protein (CRP), a sensitive marker of disease activity in rheumatoid arthritis (RA), are associated with increased risk of subsequent RA. METHODS: Eligible subjects were 39 876 healthy women from the Women's Health Study, a completed randomized trial of aspirin and vitamin E in cardiovascular disease and cancer prevention, begun in 1992. We included 27 939 women who provided blood samples at baseline that could be assayed for CRP. RESULTS: During 9.9 years of follow-up, 398 women reported a new diagnosis of RA. Of these, 90 cases were confirmed on medical chart review using American College of Rheumatology criteria. In age-adjusted analysis, the relative risks for developing confirmed, incident RA associated with increasing tertiles of CRP (first, second, and third) were 1.00 (reference value), 0.94 (0.54-1.61), and 1.29 (0.78-2.12) (P = .30 for trend). Further adjustment for randomized treatment, age, body mass index, and smoking demonstrated corresponding relative risks of 1.00 (reference value), 0.95 (0.55-1.65), and 1.33 (0.77-2.30) (P = .48 for trend). When we examined whether CRP levels predicted incident RA within 4 years, between 5 to 8 years, and 9 or more years after CRP measurement, we found no significant associations for any time period. CONCLUSIONS: In this prospective study of healthy women, a single CRP level did not predict increased risk of RA. Furthermore, CRP measurement closer to the time of diagnosis was not predictive. The consistency of this effect throughout different time periods from diagnosis suggests that CRP does not have a large effect in predicting incident RA.