Rheumatoid Arthritis: Shadick NA

Heller JE, Shadick NA. · Division of Rheumatology, Immunology and Allergy, Brigham & Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA. · Curr Opin Rheumatol. · Pubmed #17278922 No free full text.

Abstract: PURPOSE OF REVIEW: As biologics have improved the prognosis for rheumatoid arthritis, the prioritization of outcomes has shifted. Methods of quantifying concerns of particular importance to patients as a basis for better addressing the patient perspective in treatment are being developed. This review aims first to highlight some of the recent research in more traditional outcomes and then to focus on the rapid development of patient-centered outcomes over the last several years. RECENT FINDINGS: Clinical trials with combinations of biologics and other disease-modifying antirheumatic drugs have reported significant improvement in radiographs, inflammatory markers and joint exams in rheumatoid arthritis patients. Concomitantly, several studies have appeared in major journals, reporting that patients are emphasizing outcomes such as fatigue, return to normalcy and mental health that are less easily measured by the traditional outcomes markers. SUMMARY: Recent studies have shown both that rheumatologist and patient approaches to achieving wellness differ and providing patients with a sense of control in reaching that state of wellness leads to better outcomes. Current research is focused on evaluating how best to measure the patient assessments and incorporate the patient voice into the clinic.

Parker A, Izmailova ES, Narang J, Badola S, Le T, Roubenoff R, Ginsburg GS, Maier A, Coblyn JS, Shadick NA, Weinblatt ME. · Millennium Pharmaceuticals Inc., Cambridge, Massachusetts, USA. · J Rheumatol. · Pubmed #17696278 No free full text.

Abstract: OBJECTIVE: To evaluate peripheral blood expression of genes regulated by nuclear factor-kappaB (NF-kappaB), a key mediator of tumor necrosis factor-alpha (TNF-alpha) signaling, in patients with rheumatoid arthritis (RA) before and during treatment with anti-TNF-alpha or methotrexate (MTX). We analyzed association of gene expression with disease activity, rheumatoid factor (RF), age, sex, disease duration, treatment modality, and clinical response. METHODS: Sixty patients consented for RNA analysis at baseline and after 2 and 6 weeks of treatment. Disease activity was quantified using Disease Activity Score (DAS28) and C-reactive protein (CRP). Expression of 67 TNF-alpha-responsive, NF-kappaB-regulated genes was measured using Affymetrix arrays and RT-PCR. RESULTS: Expression of 34 genes was associated with DAS28-CRP, notably S100A12/calgranulin C, IL7R, and aquaporin 3. No association was observed with age, sex, RF, or disease duration. Expression of 16 genes changed in a manner that differed significantly between treatment groups. Eleven were reduced in anti-TNF-alpha-treated patients relative to MTX, while 5 were increased. The majority of these observations were confirmed using RT-PCR. Gene expression was not associated significantly with change in disease activity. CONCLUSION: NF-kappaB-dependent gene expression in peripheral leukocytes is highly correlated with RA activity as measured by DAS28-CRP. Expression of many genes responds differentially to anti-TNF-alpha versus MTX, suggesting fundamentally different effects on the NF-kappaB pathway. This peripheral blood expression signature provides candidate markers that could lead to development of a simple, minimally invasive pharmacodynamic assay for RA treatments directed at the NF-kappaB pathway. Combination of gene expression data with clinical scores and serum markers may provide more sensitive and predictive measures of RA disease activity.

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.

Stoll ML, Solomon DH, Batra KL, Simard JF, Karlson EW, Dellaripa PF, Weinblatt ME, Glass R, Shadick NA. · Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, USA. · J Clin Rheumatol. · Pubmed #19455057 No free full text.

This publication has no abstract.

Cui J, Taylor KE, Destefano AL, Criswell LA, Izmailova ES, Parker A, Roubenoff R, Plenge RM, Weinblatt ME, Shadick NA, Karlson EW. · Division of Rheumatology, Immunology & Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. · Mol Med. · Pubmed #19287509 links to  free full text

Abstract: We carried out a genome-wide association study of genetic predictors of anti-cyclic citrullinated peptide antibody (anti-CCP) level in 531 self-reported non-Hispanic Caucasian Rheumatoid Arthritis (RA) patients enrolled in the Brigham Rheumatoid Arthritis Sequential Study (BRASS). For replication, we then analyzed 289 single nucleotide polymorphisms (SNPs) with P < 0.001 in BRASS in an independent population of 849 RA patients from the North American Rheumatoid Arthritis Consortium (NARAC). BRASS and NARAC samples were genotyped using the Affymetrix 100K and Illumina 550K platforms respectively. Association between SNPs and anti-CCP titer was tested using general linear models. The five most significant SNPs from BRASS all were within the major histocompatibility complex (MHC) region (P < or = 3.5 x 10(-6)). After controlling for the human leukocyte antigen shared epitope (HLA-SE), the top SNPs still yielded P values < 0.0002. In NARAC, a single SNP from the MHC region near BTNL2 and HLA-DRA, rs1980493 (r(2) = 0.85 with the top five SNPs from BRASS), was associated significantly with CCP titer (P = 6.1 x 10(-5)) even after adjustment for the HLA-SE (P = 0.0002). The top SNPs found in BRASS and NARAC had r(2) = 0.46 and 0.64, respectively, to HLA-DRB1 DR3 alleles. These results confirm that the most significant genome region affecting anti-CCP titers in RA is the MHC region. We identified a SNP in moderate linkage disequilibrium (LD) with HLA-DR3, which may influence anti-CCP titer independently of the HLA-SE.

Karlson EW, Chibnik LB, Tworoger SS, Lee IM, Buring JE, Shadick NA, Manson JE, Costenbader KH. · Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. · Arthritis Rheum. · Pubmed #19248103 No free full text.

Abstract: OBJECTIVE: To examine the association of biomarkers of inflammation with preclinical rheumatoid arthritis (RA). METHODS: A nested case-control study was performed using samples from 2 large, prospectively studied cohorts of women (the Women's Health Study [WHS] and the Nurses' Health Study [NHS]). Blood samples obtained prior to symptom onset in women who later developed RA were selected as incident RA cases, and 3 controls per case were randomly chosen, matched for age, menopausal status, postmenopausal hormone use, and day, time, and fasting status at the time of collection. Plasma was tested for levels of interleukin-6 (IL-6), soluble tumor necrosis factor receptor II (sTNFRII) (as a proxy for TNFalpha), and high-sensitivity C-reactive protein. Relationships between biomarkers and RA were assessed using conditional logistic regression models, adjusting for age, body mass index, smoking habits, ethnicity, and reproductive factors. RESULTS: In 93 incident cases in the NHS and 77 incident cases in the WHS, the mean time between blood collection and the onset of RA symptoms was 5.2 years (range 0.3-12 years). Median IL-6 and sTNFRII levels were significantly higher in preclinical RA cases compared with matched controls in the NHS (P = 0.03 and P = 0.003, respectively) though not in the WHS. Pooled analysis of the NHS and WHS cohorts demonstrated significant association of sTNFRII with RA (relative risk 2.0 [95% confidence interval 1.1-3.6], P for trend = 0.004), and a modest association of IL-6 with RA (relative risk 1.4 [95% confidence interval 0.8-2.5], P for trend = 0.06). CONCLUSION: Levels of sTNFRII, a biomarker typically associated with active RA, were elevated up to 12 years prior to the development of RA symptoms and were positively associated with incident RA in these nested case-control studies. Studies with repeated assessments of biomarkers prior to RA development may provide further insight into the timing of biomarker elevation in preclinical RA.

Lee YC, Cui J, Costenbader KH, Shadick NA, Weinblatt ME, Karlson EW. · Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. · Rheumatology (Oxford). · Pubmed #19193698 No free full text.

Abstract: OBJECTIVES: We examined the association between candidate single nucleotide polymorphisms (SNPs) and disease activity in RA patients on MTX. METHODS: Our population was drawn from the Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS), a prospective, observational cohort of RA patients. A total of 556 participants were genotyped using the Affymetrix 100K platform. Two hundred and sixty-two participants were on MTX therapy, including 120 on MTX monotherapy. The primary outcome was the disease activity score in 28 joints (DAS28-CRP). High disease activity was defined as DAS28-CRP >3.2. Low disease activity was defined as DAS28-CRP < or =3.2. We studied three candidate alleles in the ATIC, ITPA and MTHFR genes for association with DAS28-CRP. RESULTS: Among participants on MTX monotherapy, those carrying the minor allele of ATIC SNP rs4673993 were more likely to have low disease activity (P = 0.01). None of the other SNPs was associated with disease activity. Among patients on any MTX (combination or monotherapy), the minor allele of ATIC rs4673993 was also associated with low disease activity (P = 0.04). CONCLUSIONS: In this cross-sectional analysis, ATIC SNP rs4673993 was associated with low disease activity in patients on MTX. Further studies are needed to clarify the relationship between ATIC polymorphisms, disease activity and treatment response.

Karlson EW, Shadick NA, Cook NR, Buring JE, Lee IM. · Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. · Arthritis Rheum. · Pubmed #18975365 No free full text.

Abstract: OBJECTIVE: Vitamin E supplements may reduce the risk of developing rheumatoid arthritis (RA) through antioxidant effects. Although previous observational studies have investigated this question, no randomized trial data are available. METHODS: The Women's Health Study is a randomized, double-blind, placebo-controlled trial designed to evaluate the benefits and risks of low-dose aspirin and vitamin E in the primary prevention of cardiovascular disease and cancer among 39,876 female health professionals age > or = 45 years throughout the US, conducted between 1992 and 2004. After excluding women with self-reported RA at baseline, 39,144 women were included in the present study. The primary end point, definite RA, was confirmed using a connective tissue disease screening questionnaire, followed by medical record review for American College of Rheumatology criteria. RESULTS: During an average followup of 10 years, 106 cases of definite RA occurred, 50 in the vitamin E group and 56 in the placebo group. Sixty-four (60%) RA cases were rheumatoid factor positive and 42 (40%) were rheumatoid factor negative. There was no significant association between vitamin E and risk of definite RA (relative risk [RR] 0.89, 95% confidence interval [95% CI] 0.61-1.31). There were also no significant risk reductions for either seropositive RA (RR 0.64, 95% CI 0.39-1.06) or seronegative RA (RR 1.47, 95% CI 0.79-2.72). CONCLUSION: Six hundred IU of vitamin E supplements taken every other day is not associated with a significant reduction in the risk of developing RA among women in a randomized, double-blind, placebo-controlled trial.

Raychaudhuri S, Remmers EF, Lee AT, Hackett R, Guiducci C, Burtt NP, Gianniny L, Korman BD, Padyukov L, Kurreeman FA, Chang M, Catanese JJ, Ding B, Wong S, van der Helm-van Mil AH, Neale BM, Coblyn J, Cui J, Tak PP, Wolbink GJ, Crusius JB, van der Horst-Bruinsma IE, Criswell LA, Amos CI, Seldin MF, Kastner DL, Ardlie KG, Alfredsson L, Costenbader KH, Altshuler D, Huizinga TW, Shadick NA, Weinblatt ME, de Vries N, Worthington J, Seielstad M, Toes RE, Karlson EW, Begovich AB, Klareskog L, Gregersen PK, Daly MJ, Plenge RM. · Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA. · Nat Genet. · Pubmed #18794853 No free full text.

Abstract: To identify rheumatoid arthritis risk loci in European populations, we conducted a meta-analysis of two published genome-wide association (GWA) studies totaling 3,393 cases and 12,462 controls. We genotyped 31 top-ranked SNPs not previously associated with rheumatoid arthritis in an independent replication of 3,929 autoantibody-positive rheumatoid arthritis cases and 5,807 matched controls from eight separate collections. We identified a common variant at the CD40 gene locus (rs4810485, P = 0.0032 replication, P = 8.2 x 10(-9) overall, OR = 0.87). Along with other associations near TRAF1 (refs. 2,3) and TNFAIP3 (refs. 4,5), this implies a central role for the CD40 signaling pathway in rheumatoid arthritis pathogenesis. We also identified association at the CCL21 gene locus (rs2812378, P = 0.00097 replication, P = 2.8 x 10(-7) overall), a gene involved in lymphocyte trafficking. Finally, we identified evidence of association at four additional gene loci: MMEL1-TNFRSF14 (rs3890745, P = 0.0035 replication, P = 1.1 x 10(-7) overall), CDK6 (rs42041, P = 0.010 replication, P = 4.0 x 10(-6) overall), PRKCQ (rs4750316, P = 0.0078 replication, P = 4.4 x 10(-6) overall), and KIF5A-PIP4K2C (rs1678542, P = 0.0026 replication, P = 8.8 x 10(-8) overall).

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.

Royle L, Campbell MP, Radcliffe CM, White DM, Harvey DJ, Abrahams JL, Kim YG, Henry GW, Shadick NA, Weinblatt ME, Lee DM, Rudd PM, Dwek RA. · Department of Biochemistry, Glycobiology Institute, University of Oxford, Oxford OX1 3QU, UK. · Anal Biochem. · Pubmed #18194658 No free full text.

Abstract: We present a robust, fully automatable technology platform that includes computer software for the detailed analysis of low femtomoles of N-linked sugars released from glycoproteins. Features include (i) sample immobilization in 96-well plates, glycan release, and fluorescent labeling; (ii) quantitative HPLC analysis, including monosaccharide sequence, linkage, and arm-specific information for charged and neutral glycans; (iii) automatic structural assignment of peaks from HPLC profiles via web-based software that accesses our database (GlycoBase) of more than 350 N-glycan structures, including 117 present in the human serum glycome; and (iv) software (autoGU) that progressively analyzes data from exoglycosidase digestions to produce a refined list of final structures. The N-glycans from a plate of 96 samples can be released and purified in 2 or 3 days and profiled in 2 days. This strategy can be used for (i) identification and screening of disease biomarkers and (ii) monitoring the production of therapeutic glycoproteins, allowing optimization of production conditions. This technology is also suitable for preparing released glycans for other analytical techniques. Here we demonstrate its application to rheumatoid arthritis using 5 microl of patient serum.

Plenge RM, Cotsapas C, Davies L, Price AL, de Bakker PI, Maller J, Pe'er I, Burtt NP, Blumenstiel B, DeFelice M, Parkin M, Barry R, Winslow W, Healy C, Graham RR, Neale BM, Izmailova E, Roubenoff R, Parker AN, Glass R, Karlson EW, Maher N, Hafler DA, Lee DM, Seldin MF, Remmers EF, Lee AT, Padyukov L, Alfredsson L, Coblyn J, Weinblatt ME, Gabriel SB, Purcell S, Klareskog L, Gregersen PK, Shadick NA, Daly MJ, Altshuler D. · Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA. · Nat Genet. · Pubmed #17982456 links to  free full text

Abstract: To identify susceptibility alleles associated with rheumatoid arthritis, we genotyped 397 individuals with rheumatoid arthritis for 116,204 SNPs and carried out an association analysis in comparison to publicly available genotype data for 1,211 related individuals from the Framingham Heart Study. After evaluating and adjusting for technical and population biases, we identified a SNP at 6q23 (rs10499194, approximately 150 kb from TNFAIP3 and OLIG3) that was reproducibly associated with rheumatoid arthritis both in the genome-wide association (GWA) scan and in 5,541 additional case-control samples (P = 10(-3), GWA scan; P < 10(-6), replication; P = 10(-9), combined). In a concurrent study, the Wellcome Trust Case Control Consortium (WTCCC) has reported strong association of rheumatoid arthritis susceptibility to a different SNP located 3.8 kb from rs10499194 (rs6920220; P = 5 x 10(-6) in WTCCC). We show that these two SNP associations are statistically independent, are each reproducible in the comparison of our data and WTCCC data, and define risk and protective haplotypes for rheumatoid arthritis at 6q23.

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.

Sato M, Schneeweiss S, Scranton R, Katz JN, Weinblatt ME, Avorn J, Ting G, Shadick NA, Solomon DH. · Division of Pharmacoepidemiology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 1620 Tremont Street, Suite 3030, Boston, MA 02120, USA. · Arthritis Res Ther. · Pubmed #16542499 links to  free full text

Abstract: The objective of this work was to assess the convergent validity of a previously developed rheumatoid arthritis medical records-based index of severity (RARBIS) by comparing it with the 28-joint Disease Activity Score (DAS28). This study was conducted in subjects within the Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS). We selected 100 patients with rheumatoid arthritis (RA) from the BRASS with DAS28 scores equally distributed in four quartiles. The medical records were reviewed to calculate the RARBIS, which includes indicators from the following categories: prior surgical history, radiologic and laboratory findings, clinical and functional status, and extra-articular manifestations. The Spearman correlation between the RARBIS and the DAS28 was assessed in the total study population and in relevant subgroups. We re-weighted on subscales and recalculated the RARBIS score. This was performed based on findings of correlations between the DAS28 and subscales; and also the result from a multiple linear regression with the DAS28 (as a dependent variable) and five subscales (as independent variables). The mean RARBIS was 4.36 (range 0-11). Among the total study cohort, the RARBIS was moderately correlated with the DAS28 (r = 0.41, 95% confidence interval [CI] 0.23-0.56). In subgroup analyses, including age, gender, rheumatoid factor status, and disease duration, we found no statistically significant differences in the correlations. After re-weighting, the correlation between the RARBIS and the DAS28 was somewhat improved (r = 0.48, 95% CI 0.31-0.62). In conclusion, the RARBIS correlated moderately well with the DAS28 in this population. The RARBIS has both face and convergent validity for patients with RA and relevant subgroups and may have application for medical records studies in patients with RA.