Elizabeth W. Karlson

The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes

OBJECTIVE To develop a standardized nomenclature system for the neuropsychiatric syndromes of systemic lupus erythematosus (NPSLE). METHODS An international, multidisciplinary committee representing rheumatology, neurology, psychiatry, neuropsychology, and hematology developed case definitions, reporting standards, and diagnostic testing recommendations. Before and after the meeting, clinician committee members assigned diagnoses to sets of vignettes randomly generated from a pool of 108 NPSLE patients. To assess whether the nomenclature system improved diagnostic agreement, a consensus index was developed and pre- and postmeeting scores were compared by t-tests. RESULTS Case definitions including diagnostic criteria, important exclusions, and methods of ascertainment were developed for 19 NPSLE syndromes. Recommendations for standard reporting requirements, minimum laboratory evaluation, and imaging techniques were formulated. A short neuropsychological test battery for the diagnosis of cognitive deficits was proposed. In the postmeeting exercise, a statistically significant improvement in diagnostic agreement was observed. CONCLUSION The American College of Rheumatology (ACR) Nomenclature for NPSLE provides case definitions for 19 neuropsychiatric syndromes seen in SLE, with reporting standards and recommendations for laboratory and imaging tests. It is intended to facilitate and enhance clinical research, particularly multicenter studies, and reporting. In clinical settings, consultation with other specialists may be required. It should be useful for didactic purposes but should not be used uncritically or as a substitute for a clinical diagnosis. The complete case definitions are available on the ACR World Wide Web site: http://www.rheumatology .org/ar/ar.html.

Cardiovascular Morbidity and Mortality in Women Diagnosed With Rheumatoid Arthritis

Background—Rheumatoid arthritis may be associated with an increased risk of cardiovascular disease. We compared the incidence rates of myocardial infarction and stroke in subjects with and without rheumatoid arthritis. Methods and Results—A prospective cohort study was conducted among the 114 342 women participating in the Nurses’ Health Study who were free of cardiovascular disease and rheumatoid arthritis at baseline in 1976. All self-reported cases of rheumatoid arthritis were confirmed by medical record review. Fatal and nonfatal myocardial infarctions and strokes were similarly confirmed. Multivariate pooled logistic regression was used to adjust for potential cardiovascular risk factors. Five hundred twenty-seven incident cases of rheumatoid arthritis and 3622 myocardial infarctions and strokes were confirmed during 2.4 million person-years of follow-up. The adjusted relative risk of myocardial infarction in women with rheumatoid arthritis compared with those without was 2.0 (95% confidence interval [CI], 1.23 to 3.29). For stroke, the adjusted relative risk was 1.48 (95% CI, 0.70 to 3.12). Women who had rheumatoid arthritis for at least 10 years had a risk for myocardial infarction of 3.10 (95% CI, 1.64 to 5.87). Conclusion—In this large prospective cohort of women, participants with rheumatoid arthritis had a significantly increased risk of myocardial infarction but not stroke compared with those without rheumatoid arthritis. If these data are confirmed, aggressive coronary heart disease prevention strategies should be tested for persons with rheumatoid arthritis.

Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci

To identify new genetic risk factors for rheumatoid arthritis, we conducted a genome-wide association study meta-analysis of 5,539 autoantibody-positive individuals with rheumatoid arthritis (cases) and 20,169 controls of European descent, followed by replication in an independent set of 6,768 rheumatoid arthritis cases and 8,806 controls. Of 34 SNPs selected for replication, 7 new rheumatoid arthritis risk alleles were identified at genome-wide significance (P < 5 × 10−8) in an analysis of all 41,282 samples. The associated SNPs are near genes of known immune function, including IL6ST, SPRED2, RBPJ, CCR6, IRF5 and PXK. We also refined associations at two established rheumatoid arthritis risk loci (IL2RA and CCL21) and confirmed the association at AFF3. These new associations bring the total number of confirmed rheumatoid arthritis risk loci to 31 among individuals of European ancestry. An additional 11 SNPs replicated at P < 0.05, many of which are validated autoimmune risk alleles, suggesting that most represent genuine rheumatoid arthritis risk alleles.

Genetics of rheumatoid arthritis contributes to biology and drug discovery

A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ∼10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2, 3, 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation, cis-acting expression quantitative trait loci and pathway analyses—as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes—to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.

Two independent alleles at 6q23 associated with risk of rheumatoid arthritis

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, ∼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 × 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.

Replication of Putative Candidate-Gene Associations with Rheumatoid Arthritis in >4,000 Samples from North America and Sweden: Association of Susceptibility with PTPN22, CTLA4, and PADI4

Candidate-gene association studies in rheumatoid arthritis (RA) have lead to encouraging yet apparently inconsistent results. One explanation for the inconsistency is insufficient power to detect modest effects in the context of a low prior probability of a true effect. To overcome this limitation, we selected alleles with an increased probability of a disease association, on the basis of a review of the literature on RA and other autoimmune diseases, and tested them for association with RA susceptibility in a sample collection powered to detect modest genetic effects. We tested 17 alleles from 14 genes in 2,370 RA cases and 1,757 controls from the North American Rheumatoid Arthritis Consortium (NARAC) and the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) collections. We found strong evidence of an association of PTPN22 with the development of anti-citrulline antibody-positive RA (odds ratio [OR] 1.49; P=.00002), using previously untested EIRA samples. We provide support for an association of CTLA4 (CT60 allele, OR 1.23; P=.001) and PADI4 (PADI4_94, OR 1.24; P=.001) with the development of RA, but only in the NARAC cohort. The CTLA4 association is stronger in patients with RA from both cohorts who are seropositive for anti-citrulline antibodies (P=.0006). Exploration of our data set with clinically relevant subsets of RA reveals that PTPN22 is associated with an earlier age at disease onset (P=.004) and that PTPN22 has a stronger effect in males than in females (P=.03). A meta-analysis failed to demonstrate an association of the remaining alleles with RA susceptibility, suggesting that the previously published associations may represent false-positive results. Given the strong statistical power to replicate a true-positive association in this study, our results provide support for PTPN22, CTLA4, and PADI4 as RA susceptibility genes and demonstrate novel associations with clinically relevant subsets of RA.

Common variants at CD40 and other loci confer risk of rheumatoid arthritis

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 × 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 × 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 × 10−7 overall), CDK6 (rs42041, P = 0.010 replication, P = 4.0 × 10−6 overall), PRKCQ (rs4750316, P = 0.0078 replication, P = 4.4 × 10−6 overall), and KIF5A-PIP4K2C (rs1678542, P = 0.0026 replication, P = 8.8 × 10−8 overall).

Alcohol intake and risk of incident gout in men: a prospective study.

BACKGROUND The association between alcohol consumption and risk of gout has been suspected since ancient times, but has not been prospectively confirmed. Additionally, potential differences in risk of gout posed by different alcoholic beverages have not been assessed. METHODS Over 12 years (1986-98) we used biennial questionnaires to investigate the relation between alcohol consumption and risk of incident gout in 47?150 male participants with no history of gout at baseline. We used a supplementary questionnaire to ascertain whether reported cases of gout met the American College of Rheumatology survey gout criteria. FINDINGS We documented 730 confirmed incident cases of gout. Compared with men who did not drink alcohol, the multivariate relative risk (RR) of gout was 1.32 (95% CI 0.99-1.75) for alcohol consumption 10.0-14.9 g/day, 1.49 (1.14-1.94) for 15.0-29.9 g/day, 1.96 (1.48-2.60) for 30.0-49.9 g/day, and 2.53 (1.73-3.70) for > or =50 g/day (p for trend <0.0001). Beer consumption showed the strongest independent association with the risk of gout (multivariate RR per 12-oz serving per day 1.49; 95% CI 1.32-1.70). Consumption of spirits was also significantly associated with gout (multivariate RR per drink or shot per day 1.15; 95% CI 1.04-1.28); however, wine consumption was not (multivariate RR per 4-oz serving per day 1.04; 95% CI 0.88-1.22). INTERPRETATION Alcohol intake is strongly associated with an increased risk of gout. This risk varies substantially according to type of alcoholic beverage: beer confers a larger risk than spirits, whereas moderate wine drinking does not increase the risk.

Genetic variants at CD28, PRDM1, and CD2/CD58 are associated with rheumatoid arthritis risk

To discover new rheumatoid arthritis (RA) risk loci, we systematically examined 370 SNPs from 179 independent loci with P < 0.001 in a published meta-analysis of RA genome-wide association studies (GWAS) of 3,393 cases and 12,462 controls. We used Gene Relationships Across Implicated Loci (GRAIL), a computational method that applies statistical text mining to PubMed abstracts, to score these 179 loci for functional relationships to genes in 16 established RA disease loci. We identified 22 loci with a significant degree of functional connectivity. We genotyped 22 representative SNPs in an independent set of 7,957 cases and 11,958 matched controls. Three were convincingly validated: CD2-CD58 (rs11586238, P = 1 × 10−6 replication, P = 1 × 10−9 overall), CD28 (rs1980422, P = 5 × 10−6 replication, P = 1 × 10−9 overall) and PRDM1 (rs548234, P = 1 × 10−5 replication, P = 2 × 10−8 overall). An additional four were replicated (P < 0.0023): TAGAP (rs394581, P = 0.0002 replication, P = 4 × 10−7 overall), PTPRC (rs10919563, P = 0.0003 replication, P = 7 × 10−7 overall), TRAF6-RAG1 (rs540386, P = 0.0008 replication, P = 4 × 10−6 overall) and FCGR2A (rs12746613, P = 0.0022 replication, P = 2 × 10−5 overall). Many of these loci are also associated to other immunologic diseases.

A retrospective cohort study of cigarette smoking and risk of rheumatoid arthritis in female health professionals

OBJECTIVE To study the association of cigarette smoking with risk of rheumatoid arthritis (RA), among 377,481 female health professionals in the Womens Health Cohort Study. METHODS Subjects completed mailed questionnaires regarding demographics, health habits, including cigarette smoking history, and medical history, including RA diagnosis made by a physician and date of diagnosis. Of 7,697 women who self-reported RA, 3,416 reported seropositive RA. Cox proportional hazards regression models were used to retrospectively assess the associations of smoking intensity and duration with the risk of developing RA or seropositive RA. Cigarette smoking status was treated as a time-varying exposure in these regression models. RESULTS In multivariate analyses controlling for age, race, education, age at menarche, pregnancy history, menopausal status, and postmenopausal hormone use, duration of smoking was associated with a significantly increased risk of both RA and seropositive RA (both P < 0.01 for trend), after adjusting for smoking intensity. Women who smoked > or =25 cigarettes/day for more than 20 years experienced a 39% increased risk of RA and 49% increased risk of seropositive RA. However, smoking intensity (number of cigarettes/day) was unrelated to risk of RA or seropositive RA (both P = 0.3 for trend), after adjusting for duration of smoking. CONCLUSION Duration, but not intensity, of cigarette smoking is associated with a modest increased risk of RA in women.