Rheumatoid Arthritis: Karlson EW

Liao KP, Alfredsson L, Karlson EW. · Brigham and Women's Hospital, Boston, Massachusetts 02141, USA. · Curr Opin Rheumatol. · Pubmed #19318947 No free full text.

Abstract: PURPOSE OF REVIEW: To examine new environmental factors and provide updates on known risk factors for rheumatoid arthritis (RA) in the past 2 years (2006-2008). This review is timely given the expanding information on treatment, pathogenesis and genetic risk factors for RA. RECENT FINDINGS: High consumption of red meat does not increase risk of RA, whereas alcohol intake may be protective. The role of vitamin D and oral contraceptives as modifiers of disease risk remains equivocal. Other factors associated with increased risk of RA include higher birthweight, living in the northeastern United States compared with other regions of the country, and lower socioeconomic status. Duration of breastfeeding is inversely associated with RA risk. Several studies have now demonstrated that anti-citrullinated protein antibody positive RA has a specific association with environmental risk factors such as smoking. SUMMARY: Recent studies have increased our understanding of environmental exposures that modify risk for RA such as smoking and alcohol intake. Other factors such as birthweight, breastfeeding, socioeconomic status and region of birth have also been demonstrated to contribute to risk. ACPA status is associated with specific environmental factors and is therefore important to incorporate into present and future studies.

Costenbader KH, Karlson EW. · Division of Rheumatology, Immunology and Allergy, Section of Clinical Sciences, PBB-B3, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA. · Lupus. · Pubmed #17153844 No free full text.

Abstract: Cigarette smoking has been causally linked to the development of multiple autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, Graves' hyperthyroidism, and primary biliary cirrhosis, among others. We review the known biologic effects of cigarette smoke, in particular its actions on the immune system, and the epidemiologic evidence associating smoking with increased risk of each of these autoimmune diseases. Interactions between cigarette smoking and genetic and immunologic factors, such as the human leukocyte antigen (HLA)-shared epitope, rheumatoid factor, anti-cyclic citrullinated peptide antibodies, and anti-double stranded DNA antibodies, may point to mechanisms in disease pathogenesis.

Costenbader KH, Karlson EW. · Brigham and Women's Hospital, Division of Rheumatology, Immunology and Allergy, Department of Medicine, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA. · Arthritis Res Ther. · Pubmed #16542469 links to  free full text

Abstract: Rheumatoid arthritis is a systemic autoimmune disease characterized by chronic, destructive, debilitating arthritis. Its etiology is unknown; it is presumed that environmental factors trigger development in the genetically predisposed. Epstein-Barr virus, a nearly ubiquitous virus in the human population, has generated great interest as a potential trigger. This virus stimulates polyclonal lymphocyte expansion and persists within B lymphocytes for the host's life, inhibited from reactivating by the immune response. In latent and replicating forms, it has immunomodulating actions that could play a role in the development of this autoimmune disease. The evidence linking Epstein-Barr virus and rheumatoid arthritis is reviewed.

Phillips K, Husni ME, Karlson EW, Coblyn JS. · Robert B. Brigham Multipurpose Arthritis and Musculoskeletal Diseases Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. · Arthritis Rheum. · Pubmed #11932873 No free full text.

Abstract: OBJECTIVES: There is little established information regarding the safety of antitumor necrosis factor therapies used outside the setting of clinical trials. This study evaluated the long-term safety and tolerability of open-label use of etanercept when used to treat patients with a variety of systemic rheumatic diseases. Reduction of concomitant corticosteroid and disease-modifying antirheumatic drug was also assessed. METHODS: Retrospective medical record review of 180 patients who were started on etanercept between December 1998 and April 2000 at an academic medical center. RESULTS: Most patients (81%) remained on therapy for longer than 6 months, and a significant number (43%) of patients for longer than 12 months. Etanercept was prescribed for rheumatoid arthritis (RA) in 144 patients and for diseases other than RA, including ankylosing spondylitis, psoriatic arthritis, and polymyositis, in 36 patients. Fifty-six percent of patients taking corticosteroids were able to reduce their dose and 51% of patients were able to taper their methotrexate dosages. Forty-three patients (26%) discontinued etanercept. Reasons for discontinuing therapy included serious adverse events (2.9%), of which infection was most common. These included a psoas abscess secondary to Mycobacterium avium-intracellulare, septic wrist, bacteremia, and septic total hip replacement. Two deaths associated with infection were seen. CONCLUSIONS: The majority of the studied patients tolerated etanercept for longer than 6 months. Many of these patients were able to subsequently taper or even discontinue corticosteroid and methotrexate therapy. Serious infections occurred in this patient population. Our results underscore the value of long-term observation under the conditions of clinical practice beyond controlled clinical trials.

Karlson EW, Lee IM, Cook NR, Manson JE, Buring JE, Hennekens CH. · Harvard Medical School, and Brigham and Women's Hospital, Boston, Massachusetts, USA. · Arthritis Rheum. · Pubmed #10323446 links to  free full text

Abstract: OBJECTIVE: To study the association of cigarette smoking with risk of rheumatoid arthritis (RA), among 377,481 female health professionals in the Women's 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.

Karlson EW, Chibnik LB, McGrath M, Chang SC, Keenan BT, Costenbader KH, Fraser PA, Tworoger S, Hankinson SE, Lee IM, Buring J, De Vivo I. · Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. · Arthritis Res Ther. · Pubmed #19555469 links to  free full text

Abstract: INTRODUCTION: Rheumatoid arthritis (RA) is more common in females than males and sex steroid hormones may in part explain this difference. We conducted a case-control study nested within two prospective studies to determine the associations between plasma steroid hormones measured prior to RA onset and polymorphisms in the androgen receptor (AR), estrogen receptor 2 (ESR2), aromatase (CYP19) and progesterone receptor (PGR) genes and RA risk. METHODS: We genotyped AR, ESR2, CYP19, PGR SNPs and the AR CAG repeat in RA case-control studies nested within the Nurses' Health Study (NHS), NHS II (449 RA cases, 449 controls) and the Women's Health Study (72 cases, and 202 controls). All controls were matched on cohort, age, Caucasian race, menopausal status, and postmenopausal hormone use. We measured plasma dehydroepiandrosterone sulfate (DHEAS), testosterone, and sex hormone binding globulin in 132 pre-RA samples and 396 matched controls in the NHS cohorts. We used conditional logistic regression models adjusted for potential confounders to assess RA risk. RESULTS: Mean age of RA diagnosis was 55 years in both cohorts; 58% of cases were rheumatoid factor positive at diagnosis. There was no significant association between plasma DHEAS, total testosterone, or calculated free testosterone and risk of future RA. There was no association between individual variants or haplotypes in any of the genes and RA or seropositive RA, nor any association for the AR CAG repeat. CONCLUSIONS: Steroid hormone levels measured at a single time point prior to RA onset were not associated with RA risk in this study. Our findings do not suggest that androgens or the AR, ESR2, PGR, and CYP19 genes are important to RA risk in women.

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.

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Lee YC, Raychaudhuri S, Cui J, De Vivo I, Ding B, Alfredsson L, Padyukov L, Costenbader KH, Seielstad M, Graham RR, Klareskog L, Gregersen PK, Plenge RM, Karlson EW. · Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. · Arthritis Rheum. · Pubmed #19404952 No free full text.

Abstract: OBJECTIVE: Previous studies have demonstrated that the PRL -1149 T (minor) allele decreases prolactin expression and may be associated with autoimmune disease. The aim of this study was to determine the role of the PRL -1149 G/T polymorphism (rs1341239) in rheumatoid arthritis (RA) susceptibility. METHODS: We examined the association between PRL -1149 G/T and RA risk in 4 separate study populations, consisting of a total of 3,405 RA cases and 4,111 controls of self-reported white European ancestry. Samples were genotyped using 1 of 3 genotyping platforms, and strict quality control metrics were applied. We tested for association using a 2-tailed Cochran-Mantel-Haenszel additive, fixed-effects model. RESULTS: In the individual populations, odds ratios (ORs) for an association between PRL -1149 T and RA risk ranged from 0.80 to 0.97. In a joint meta-analysis across all 4 populations, the OR for an association between PRL -1149 T and RA risk was 0.90 (95% confidence interval 0.84-0.96, P=0.001). CONCLUSION: Our findings indicate a possible association between the PRL -1149 T allele and decreased RA risk. The effect size is small but similar to ORs for other genetic polymorphisms associated with complex traits, including RA.

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.

Liao KP, Gunnarsson M, Källberg H, Ding B, Plenge RM, Padyukov L, Karlson EW, Klareskog L, Askling J, Alfredsson L. · Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, MA 02114, USA. · Arthritis Rheum. · Pubmed #19248096 No free full text.

Abstract: OBJECTIVE: The co-occurrence of autoimmune diseases such as rheumatoid arthritis (RA) and type 1 diabetes mellitus (DM) has been reported in individuals and families. In this study, the strength and nature of this association were investigated at the population level in a Swedish case-control cohort. METHODS: For this case-control study, 1,419 patients with incident RA diagnosed between 1996 and 2003 were recruited from university, public, and private rheumatology units throughout Sweden; 1,674 matched control subjects were recruited from the Swedish national population registry. Sera from the subjects were tested for the presence of antibodies to cyclic citrullinated peptide (anti-CCP), rheumatoid factor (RF), and the 620W PTPN22 allele. Information on a history of diabetes was obtained by questionnaire, telephone interview, and/or medical record review. The prevalence of type 1 DM and type 2 DM was compared between patients with incident RA and control subjects and further stratified for the presence of anti-CCP, RF, and the PTPN22 risk allele. RESULTS: Type 1 DM was associated with an increased risk of RA (odds ratio [OR] 4.9, 95% confidence interval [95% CI] 1.8-13.1), and this association was specific for anti-CCP-positive RA (OR 7.3, 95% CI 2.7-20.0), but not anti-CCP-negative RA. Further adjustment for the presence of PTPN22 attenuated the risk of anti-CCP-positive RA in patients with type 1 DM to an OR of 5.3 (95% CI 1.5-18.7). No association between RA and type 2 DM was observed. CONCLUSION: The association between type 1 DM and RA is specific for a particular RA subset, anti-CCP-positive RA. The risk of developing RA later in life in patients with type 1 DM may be attributed, in part, to the presence of the 620W PTPN22 allele, suggesting that this risk factor may represent a common pathway for the pathogenesis of these 2 diseases.

Chibnik LB, Mandl LA, Costenbader KH, Schur PH, Karlson EW. · Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St., Boston, MA 02115, USA. · J Rheumatol. · Pubmed #19228654 No free full text.

Abstract: OBJECTIVE: Anti-cyclic citrullinated peptide (anti-CCP) antibodies are strongly associated with increased risk of rheumatoid arthritis (RA).While the anti-CCP level is commonly dichotomized for clinical use, the best threshold for and utility of the titer as a continuous variable to predict development of RA are uncertain. METHODS: Using data from the Nurses' Health Study and Nurses' Health Study II longitudinal cohorts, we examined the sensitivity, specificity, and hazard of RA at various thresholds of the anti-CCP. Incident RA was confirmed using the Connective Tissue Disease Screening Questionnaire and medical record review in 93 women from among 62,437 participants with blood samples. Three controls per case were randomly chosen, matching on cohort, age, and menopausal status. Stored plasma was tested for anti-CCP antibodies with the second-generation Diastat ELISA. Five threshold values were assessed for sensitivity, specificity, and time to diagnosis of RA. Hazard of RA was assessed with conditional logistic regression models adjusting for smoking and reproductive factors. RESULTS: Using the suggested threshold of >5 U/ml for anti-CCP positivity, specificity was 100%, but sensitivity was only 28%. A threshold of >2 U/ml had a higher sensitivity (51%), and similar specificity (80%), with an odds ratio of 11.2 (95% confidence interval 4.7-26.9) for RA. Anti-CCP level as an ordinal variable was strongly associated with time to RA onset, with higher values predicting shorter time to RA onset. CONCLUSION: A lower threshold for anti-CCP positivity was more sensitive in predicting RA development. Higher ranges of the level were informative in predicting time to RA onset.

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.

Wolfe F, Petri M, Alarcón GS, Goldman J, Chakravarty EF, Katz RS, Karlson EW. · National Data Bank for Rheumatic Diseases, 1035 N. Emporia, Suite 288, Wichita, KS 67214, USA. · J Rheumatol. · Pubmed #19004039 No free full text.

Abstract: OBJECTIVE: To determine if fibromyalgia (FM) or fibromyalgia-ness (the tendency to respond to illness and psychosocial stress with fatigue, widespread pain, general increase in symptoms, and similar factors) is increased in patients with compared to those without systemic lupus erythematosus (SLE); to determine whether FM or fibromyalgia-ness biases the SLE Activity Questionnaire (SLAQ); and to determine if the SLAQ is overly sensitive to FM symptoms. METHODS: We developed a 16-item SLE Symptom Scale (SLESS) modeled on the SLAQ and used that scale to investigate the relation between SLE symptoms and fibromyalgia-ness in 23,321 patients with rheumatic disease. FM was diagnosed by survey FM criteria, and fibromyalgia-ness was measured using the Symptom Intensity (SI) Scale. As comparison groups, we combined patients with rheumatoid arthritis and noninflammatory rheumatic disorders into an "arthritis" group and also utilized a physician-diagnosed group of patients with FM. RESULTS: FM was identified in 22.1% of SLE and 17.0% of those with arthritis. The SI scale was minimally increased in SLE. The correlation between SLAQ and SLESS was 0.738. SLESS/SLAQ scale items (Raynaud's phenomenon, rash, fever, easy bruising, hair loss) were significantly more associated with SLE than FM, while the reverse was true for headache, abdominal pain, paresthesias/stroke, fatigue, cognitive problems, and muscle pain or weakness. There was no evidence of disproportionate symptom-reporting associated with fibromyalgia-ness. Self-reported SLE was associated with an increased prevalence of FM that was unconfirmed by physicians, compared to SLE confirmed by physicians. CONCLUSION: The prevalence of FM in SLE is minimally increased compared with its prevalence in patients with arthritis. Fibromyalgia-ness does not bias the SLESS and should not bias SLE assessments, including the SLAQ.

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).

Costenbader KH, Chang SC, Laden F, Puett R, Karlson EW. · Section of Clinical Sciences, Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115, USA. · Arch Intern Med. · Pubmed #18695080 No free full text.

Abstract: BACKGROUND: The geographic variation in rheumatoid arthritis (RA) incidence in the United States is unknown. METHODS: We studied residential region from January 1, 1921, to May 31, 1976, and RA risk in a prospective cohort of women, the Nurses' Health Study. Information on state of residence was collected at baseline in 1976 (when participants were aged 30-55 years) and on state of residence at birth, at age 15 years, and at age 30 years in 1992. Among 83,546 participants reporting residence for all 4 time points, 706 incident RA cases from June 1, 1976, to May 31, 2004, were confirmed by screening questionnaire and record review for American College of Rheumatology criteria. Residential region was classified as West, Midwest, mid-Atlantic, New England, and Southeast. Multivariate Cox proportional hazards regression models were used to assess relationships between region and RA risk, adjusting for age, smoking, body mass index, parity, breastfeeding, postmenopausal status, postmenopausal hormone use, father's occupation, race, and physical activity. Analyses were performed in participants who lived in the same regions, or moved, over time. RESULTS: Compared with those in the West, women in New England had a 37% to 45% elevated risk of RA in multivariate models at each time point (eg, state of residence in 1976: rate ratio [RR], 1.42; 95% confidence interval [CI], 1.10-1.82). In analyses of women who lived in the same region at birth, age 15 years, and age 30 years, living in the Midwest was associated with greater risk (RR, 1.47; 95% CI, 1.05-2.05), as was living in New England (RR, 1.40; 95% CI, 0.98-2.00). Compared with living in the West at birth, age 15 years, and age 30 years, RA risk was higher in the East. CONCLUSIONS: In this large cohort of US women, significant geographic variation in incident RA existed after controlling for confounders. Potential explanations include regional variation in behavioral factors, climate, environmental exposures, RA diagnosis, and genetic factors.

Mandl LA, Costenbader KH, Simard JF, Karlson EW. · Division of Rheumatology, Hospital for Special Surgery, Weill Cornell Medical College, New York City, New York 10021, USA. · Ann Rheum Dis. · Pubmed #18593757 No free full text.

Abstract: OBJECTIVES: The "fetal origins of adult disease" hypothesis suggests the uterine environment can influence the susceptibility of a fetus to future disease. We examine whether the fetal environment, as reflected by birthweight, could modulate an individual's future risk of rheumatoid arthritis (RA). METHODS: The relationship between birthweight and the risk of incident RA was studied in 87 077 women followed prospectively in the Nurses' Health Study cohort. New cases of RA diagnosed between 1976 and 2002 were confirmed in 619 women. The association between birthweight and the future development of RA was studied in age-adjusted and Cox proportional hazard models adjusting for age and potential confounders, including history of maternal diabetes, childhood socioeconomic status, prematurity, maternal and paternal smoking, as well as additionally adjusting for risk factors for RA including smoking, age at menarche, use of oral contraceptives, use of post-menopausal hormones, total lifetime breastfeeding, and body mass index (BMI) at age 18. RESULTS: In an age-adjusted model, birthweight >4.54 kg vs birthweight 3.2-3.85 kg was associated with a two-fold increased risk of RA (relative risk (RR) = 2.1, 95% CI 1.4 to 3.3). Further adjusting for potential confounders and risk factors did not change this relationship (RR = 2.0, 95% CI 1.3 to 3.0). Findings were similar when we limited cases to those with rheumatoid factor positive RA (RR = 2.1, 95% CI = 1.2 to 3.6). CONCLUSIONS: In this large prospective cohort, birthweight >4.54 kg was associated with a two-fold increased risk of adult onset RA, compared with those of average birthweight. Further study of this observation may provide insight into the pathogenesis of RA.

Källberg H, Jacobsen S, Bengtsson C, Pedersen M, Padyukov L, Garred P, Frisch M, Karlson EW, Klareskog L, Alfredsson L. · Institute of Environmental Medicine, Box 210, Karolinska Institutet, 17177 Stockholm, Sweden. · Ann Rheum Dis. · Pubmed #18535114 No free full text.

Abstract: OBJECTIVES: To determine the association between risk of rheumatoid arthritis (RA) and alcohol consumption in combination with smoking and HLA-DRB1 shared epitope (SE). METHODS: Data from two independent case-control studies of RA, the Swedish EIRA (1204 cases and 871 controls) and the Danish CACORA (444 cases and 533 controls), were used to estimate ORs of developing RA for different amounts of alcohol consumed. RESULTS: Alcohol consumption was significantly more common in controls (p<0.05) and dose-dependently associated with reduced risk of RA (p for trend <0.001) in both studies. Among alcohol consumers, the quarter with the highest consumption had a decreased risk of RA of the order of 40-50% compared with the half with the lowest consumption (EIRA, OR = 0.5 (95% CI 0.4 to 0.6); CACORA, OR = 0.6 (95% CI 0.4 to 0.9)). For the subset of RA that is seropositive for antibodies to citrullinated peptide antigens, alcohol consumption reduced the risk most in smokers carrying HLA-DRB1 SE alleles. CONCLUSIONS: The observed inverse association between alcohol intake and risk of RA and the recent demonstration of a preventive effect of alcohol in experimental arthritis indicate that alcohol may protect against RA. This highlights the potential role of lifestyle in determining the risk of developing RA, and emphasises the advice to stop smoking, but not necessarily to abstain from alcohol in order to diminish risk of RA. The evidence of potential RA prevention should prompt additional studies on how this can be achieved.

Costenbader KH, Chang SC, De Vivo I, Plenge R, Karlson EW. · Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. · Arthritis Res Ther. · Pubmed #18462498 links to  free full text

Abstract: INTRODUCTION: PTPN22, PADI-4, and CTLA-4 have been associated with risk for rheumatoid arthritis (RA). We investigated whether polymorphisms in these genes were associated with RA in Caucasian women included in two large prospective cohorts, adjusting for confounding factors and testing for interactions with smoking. METHODS: We studied RA risk associated with PTPN22 (rs2476601), PADI-4 (rs2240340), and CTLA-4 (rs3087243) in the Nurses' Health Study (NHS) and NHSII. Participants in NHS were aged 30 to 55 years at entry in 1976; those in NHSII were aged 25 to 42 years at entry in 1989. We confirmed incident RA cases through to 2002 in NHS and to 2003 in NHSII by questionnaire and medical record review. We excluded reports not confirmed as RA. In a nested case-control design involving participants for whom there were samples for genetic analyses (45% of NHS and 25% of NHSII), each incident RA case was matched to a participant without RA by year of birth, menopausal status, and postmenopausal hormone use. Genotyping was performed using Taqman single nucleotide polymorphism allelic discrimination on the ABI 7900 HT (Applied Biosystems, 850 Lincoln Centre Drive, Foster City, CA 94404 USA) with published primers. Human leukocyte antigen shared epitope (HLA-SE) genotyping was performed at high resolution. We employed conditional logistic regression analyses, adjusting for smoking and reproductive factors. We tested for additive and multiplicative interactions between each genotype and smoking. RESULTS: A total of 437 incident RA cases were matched to healthy female control individuals. Mean (+/- standard deviation) age at RA diagnosis was 55 (+/- 10), 57% of RA cases were rheumatoid factor (RF) positive, and 31% had radiographic erosions at diagnosis. PTPN22 was associated with increased RA risk (pooled odds ratio in multivariable dominant model = 1.46, 95% confidence interval [CI] = 1.02 to 2.08). The risk was stronger for RF-positive than for RF-negative RA. A significant multiplicative interaction between PTPN22 and smoking for more than 10 pack-years was observed (P = 0.04). CTLA-4 and PADI-4 genotypes were not associated with RA risk in the pooled results (pooled odds ratios in multivariable dominant models: 1.27 [95% CI = 0.88 to 1.84] for CTLA-4 and 1.04 [95% CI = 0.77 to 1.40] for PADI-4). No gene-gene interaction was observed between PTPN22 and HLA-SE. CONCLUSION: After adjusting for smoking and reproductive factors, PTPN22 was associated with RA risk among Caucasian women in these cohorts. We found both additive and multiplicative interactions between PTPN22 and heavy cigarette smoking.

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.

Costenbader KH, Feskanich D, Holmes M, Karlson EW, Benito-Garcia E. · Department of Medicine, Division of Rheumatology, Immunology, and Allergy, Section of Clinical Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. · Ann Rheum Dis. · Pubmed #17666449 links to  free full text

Abstract: OBJECTIVES: Vitamin D has immune-modulating effects and may protect against the development of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). METHODS: We identified incident cases of SLE and RA among 186 389 women followed from 1980 to 2002 in the Nurses' Health Study and Nurses' Health Study II cohorts. We excluded subjects where SLE or RA was not confirmed by medical record review, and those who failed to return questionnaires. Semi-quantitative food frequency questionnaires assessed vitamin D intake from food and supplements. We used cumulative-updated total energy-adjusted dietary exposures for each 2-year cycle. Relationships between vitamin D intake and incident SLE and RA were examined in age-adjusted and Cox proportional hazards models, adjusted for confounders. Results were pooled using meta-analysis random effects models. RESULTS: We confirmed 190 incident cases of SLE and 722 of RA with dietary information. Increasing levels of vitamin D intake had no relationship to the relative risk of developing either SLE or RA. CONCLUSIONS: Vitamin D intake was not associated with risk of SLE or RA in these large prospective cohorts of women.

De Pablo P, Dietrich T, Karlson EW. · Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. · Arthritis Rheum. · Pubmed #17665477 links to  free full text

Abstract: OBJECTIVE: To compare antioxidants and other novel and traditional cardiovascular disease (CVD) risk factors in participants with rheumatoid arthritis (RA) and non-RA controls in a large population sample. METHODS: The Third National Health and Nutrition Examination Survey (NHANES-III) was a cross-sectional population survey in which subjects ages >or=60 underwent a musculoskeletal examination. RA subjects were defined as those who met >or=3 of 6 available 1987 American College of Rheumatology (ACR) criteria. Non-RA subjects were defined as those who met no ACR criteria. We performed univariate and multivariate analyses of the association between RA and each novel and traditional CVD risk factor in RA versus non-RA subjects. RESULTS: The sample included 5,302 subjects ages >or=60, with 131 (2.5%) RA and 4,444 (84%) non-RA participants. A total of 727 subjects were excluded. Plasma levels of antioxidants alpha-carotene, beta-cryptoxanthin, lutein/zeaxanthin, and lycopene were significantly lower in RA subjects compared with non-RA subjects in multivariate analysis adjusting for potential confounders. Compared with non-RA participants, RA subjects were more likely to have increased C-reactive protein (CRP) levels in multivariate analysis adjusting for potential confounders. RA and non-RA participants had similar prevalence of traditional CVD risk factors and previous CVD. CONCLUSION: In this large population study, RA subjects had similar prevalence of previous CVD and traditional CVD risk factors as controls. Among novel CVD risk factors, plasma carotenoid levels were significantly lower and CRP level was significantly higher in RA compared with non-RA subjects after adjustment for potential confounders. Further research should evaluate whether these differences account for the observed increased incidence of CVD in individuals with RA.

Lee HS, Irigoyen P, Kern M, Lee A, Batliwalla F, Khalili H, Wolfe F, Lum RF, Massarotti E, Weisman M, Bombardier C, Karlson EW, Criswell LA, Vlietinck R, Gregersen PK. · Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York 11030, USA. · Arthritis Rheum. · Pubmed #17530703 links to  free full text

Abstract: OBJECTIVE: Recently, Swedish members of the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) provided evidence that smoking may trigger RA-specific immune reactions to citrullinated protein in carriers of HLA-DR shared epitope alleles. In an effort to confirm this interaction between smoking and shared epitope alleles, we performed a case-only analysis of 3 North American RA cohorts. METHODS: A total of 2,476 white patients with RA were studied, 1,105 from the North American Rheumatoid Arthritis Consortium (NARAC) family collection, 753 from the National Inception Cohort of Rheumatoid Arthritis Patients (Inception Cohort), and 618 from the Study of New Onset Rheumatoid Arthritis (SONORA). All patients were HLA-DRB1 typed, and tested for anti-cyclic citrullinated peptide (anti-CCP) and rheumatoid factor. Information about smoking history was obtained by questionnaire. RESULTS: A significant association was found between smoking and the presence of anti-CCP in the NARAC and the Inception Cohort, but not in the SONORA. The shared epitope alleles consistently correlated with anti-CCP in all 3 populations. Using multiple logistic regression analyses, shared epitope alleles were still the most significant risk factor for anti-CCP positivity. Weak evidence of gene-environment interaction between smoking and shared epitope alleles for anti-CCP formation was found only in the NARAC. CONCLUSION: Unlike the EIRA data, we could not confirm a major gene-environment interaction for anti-CCP formation between shared epitope alleles and smoking in 3 North American RA cohorts. Our data indicate a need for further studies to address the full range of environmental factors other than smoking that may be associated with citrullination and RA.