Rheumatoid Arthritis: Costenbader KH

Costenbader KH, Manson JE. · No affiliation provided · Arthritis Rheum. · Pubmed #18311757 links to  free full text

This publication has no abstract.

Costenbader KH, Kountz DS. · Harvard Medical School, Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, MA USA. · J Fam Pract. · Pubmed #17605944 No free full text.

Abstract: Rheumatoid arthritis (RA) is a complex disease to diagnose and manage. The classes of drugs that are used to treat RA are directed at the immune response that occurs during the disease process. Prompt initiation of pharmacologic treatment may delay or prevent disease progression. The primary care clinician is responsible for recognizing and diagnosing RA at its onset and for ensuring that patients receive prompt treatment to avoid debilitating and progressive joint damage. While a specialist in rheumatology will prescribe disease-modifying antirheumatic drugs for RA patients, the specialist and the primary care clinician share responsibility for monitoring patient progress, RA complications, and adverse effects of the drugs.

Todd DJ, Costenbader KH, Weinblatt ME. · Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA. · Int J Clin Pract. · Pubmed #17313619 No free full text.

Abstract: Over the past decade, biological immunotherapy has revolutionised the treatment of rheumatoid arthritis (RA). The most widely used of these therapies targets tumour necrosis factor-alpha (TNF-alpha). Approximately 20% of patients fail to respond to TNF-alpha antagonism, however, and a significant number of additional patients become refractory to anti-TNF-alpha therapy over time. Thus investigators have sought to target other pathogenic elements of RA using novel biological therapies. Abatacept is the first immunotherapy directed against the process of T-cell costimulation. Abatacept has shown clinical effectiveness in RA by improving disease activity, quality of life measures and radiographic progression of disease. In this article, we review the immunology of T-cell activation and costimulation, define the role of abatacept in this process, and discuss the clinical trials that led to the approval of abatacept as the latest biological therapy in RA in the USA and Canada. We also address the role of abatacept in the greater context of biological therapy for RA.

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.

Costenbader KH, Coblyn JS. · Department of Medicine, Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. · South Med J. · Pubmed #15954510 No free full text.

Abstract: Rheumatoid arthritis, a chronic inflammatory polyarthritis that destroys synovial joints, is associated with systemic as well as local inflammation and with an increased risk of cardiovascular disease and death not fully explained by traditional cardiac risk factors. Statins (HMG-coA reductase inhibitors), medications originally designed to lower cholesterol, have been shown to have powerful effects on decreasing cardiovascular mortality rates in the general and high-risk populations. Not all of this protective benefit appears to be mediated by lowered cholesterol levels. Statins also influence multiple steps in the inflammatory process, including leukocyte migration and adhesion, T-cell stimulation, nitric oxide bioavailability, generation of free radicals, and angiogenesis. Recent studies show that statins may provide mild anti-inflammatory benefit in rheumatoid arthritis, in addition to reducing cardiovascular risk.

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.

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.

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.

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.

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.

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.

Lee DM, Phillips R, Hagan EM, Chibnik LB, Costenbader KH, Schur PH. · Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Smith 552B, 1 Jimmy Fund Way, Boston, Massachusetts 02115, USA. · Ann Rheum Dis. · Pubmed #18390910 No free full text.

Abstract: OBJECTIVE: To determine the significance of quantitative levels of antibodies to cyclic citrullinated peptides (anti-CCP) in a population of patients with rheumatoid arthritis (RA). METHODS: A total of 241 consecutive sera from patients with RA sent from a large rheumatology clinic for laboratory testing were selected for precisely quantifying anti-CCP antibody titres with the anti-CCP2 assay. Patient charts were reviewed for demographic information, smoking history, clinical diagnosis, rheumatoid factor (RF) titre, radiographic information and other laboratory information (erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level). Correlations with anti-CCP titre and RF titre, disease parameters and smoking history were assessed. RESULTS: We confirm previous findings that anti-CCP seropositivity is associated with a higher incidence of erosions in patients with RA (56% vs 20% CCP+ vs CCP-, kappa = 0.297, p<0.001). We also found a moderate correlation between anti-CCP titre and RF titre. However, we failed to find an association between anti-CCP titre and presence of erosions, between anti-CCP titre and CRP or ESR level, or between anti-CCP titre and age or disease duration. Interestingly, we did find significantly higher anti-CCP titres in patients with a history of smoking (452 units/ml vs 229 units/ml, smokers vs non-smokers, respectively; p = 0.02). CONCLUSIONS: Although anti-CCP titres were not associated with clinical parameters of disease, they are increased in patients with RA with exposure to tobacco. By contrast, no elevation in RF was noted in patients with a history of smoking. These observations are consistent with a pathogenic contribution of smoking to RA and suggest the immune stimulus for anti-CCP is distinct from that for RF.

Rosenau BJ, Costenbader KH, Schur PH. · Division of Rheumatology, Immunology, and Allergy, Department of Medicine and the Division of Laboratory Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. · Vasc Med. · Pubmed #18372435 No free full text.

Abstract: There has been considerable interest in the relationship between C-reactive protein (CRP) and atherosclerosis. We have previously demonstrated that individuals, especially those with rheumatoid arthritis and systemic lupus erythematosus, may produce antibodies to CRP. This study was therefore undertaken to determine the possible association between anti-CRP antibodies and atherosclerosis. A total of 103 individuals were identified with or without atherosclerosis, and without clinical rheumatic diseases. They were evaluated with respect to cholesterol, HDL, LDL, high-sensitivity (hs)CRP, and anti-CRP antibody levels, as well as use of statin medications. Individuals with atherosclerosis were much more likely to be taking a statin, and thus have lower lipid levels. However, there was no association between hsCRP or anti-CRP antibody levels with atherosclerosis, statin use, or each other. These observations suggest that anti-CRP antibody is not involved in atherosclerosis, and may represent an epiphenomenon.

Liao KP, Batra KL, Chibnik L, Schur PH, Costenbader KH. · Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. · Ann Rheum Dis. · Pubmed #18234714 No free full text.

Abstract: OBJECTIVE: The classification of rheumatoid arthritis (RA) is increasingly important as new therapies can halt the disease in its early stages. Antibodies to cyclic citrullinated peptides (anti-CCP) are widely used for RA diagnosis, but are not in the 1987 American College of Rheumatology (ACR) Criteria for RA Classification. We developed and tested the performance characteristics of new criteria for RA classification, incorporating anti-CCP. METHODS: We identified all subjects seen in our arthritis centre with rheumatoid factor (RF) and anti-CCP tested simultaneously between 1 January and 30 June 2004 and reviewed their medical records for the ACR criteria, rheumatologists' diagnoses, RF and anti-CCP. We revised the ACR criteria in two ways: (a) adding anti-CCP, and (b) replacing rheumatoid nodules and erosions with anti-CCP (CCP 6 criteria). We compared sensitivity and specificity of all criteria, in all subjects and in subjects with arthritis symptoms </=6 months. RESULTS: Medical records of 292 subjects were analysed: mean age was 54 years, 82% were women, and mean symptom duration was 4.1 years. 17% were RF positive and 14% were anti-CCP positive at initial testing. 78 (27%) had definite RA per treating rheumatologist at latest follow-up. The CCP 6 criteria increased sensitivity for RA classification for all subjects regardless of symptom duration: 74% vs 51% for ACR criteria with a loss in specificity (81% vs 91%). Sensitivity was greatly improved in subjects with symptoms < or =6 months: 25% vs 63% for ACR criteria with a decrease in specificity. CONCLUSIONS: The CCP 6 criteria improved upon the sensitivity of the ACR criteria, most remarkably for subjects with symptoms < or =6 months and could be used for the classification of subjects for RA in clinical studies.

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.

King JK, Costenbader KH. · Division of Rheumatology, University of California Los Angeles, 1000 Veteran Avenue, Rehab Center Room 32-59, Los Angeles, CA 90095, USA. · Clin Rheumatol. · Pubmed #17297594 No free full text.

Abstract: Patients with systemic lupus erythematosus (SLE) are at increased risk of developing non-Hodgkin's lymphoma (NHL), but features of SLE associated with NHL are not well described. The objective of this study was to describe SLE characteristics, laboratory serologies, and medication histories in patients who subsequently develop NHL. Two thousand twenty patients with SLE were identified using the online Partners' patient database research tool between October 1992 and June 2005. We confirmed the diagnoses of SLE and NHL and sought details of medical history and treatment by medical record review. Eleven patients with NHL without coexisting rheumatoid arthritis, Sjögren's, or HIV were identified; seven of these (64%) had a diffuse large B cell lymphoma subtype, and 83% of those stained were Epstein-Barr virus (EBV) negative. The mean duration of SLE at NHL diagnosis was 17.8 years (range 1.6-41.8), and the mean Systemic Lupus International Collaborative Clinics/American College of Rheumatology damage index was 1.9. Seven patients (64%) had SLE hematologic involvement, four had anti-dsDNA antibodies, and four had anti-phospholipid antibodies. One patient had significant renal disease. All patients had arthritis and had received antimalarial therapy. Five of 11 patients had received other treatments for SLE, including cyclophosphamide, imuran, methotrexate, and/or sulfasalazine. Diffuse large B cell lymphoma was the most common subtype of NHL, and most were EBV negative. Although disease duration was fairly long and end organ damage moderately severe in this group of patients, renal disease and the use of immunosuppressive chemotherapeutic agents were rare and did not appear to confer an increased risk of NHL development.

Finckh A, Dehler S, Costenbader KH, Gabay C, Anonymous00135. · Division of Rheumatology, Department of Internal Medicine, University of Geneva, 26 Av. Beau-Sejour, 1211 Geneva 14, Switzerland. · Ann Rheum Dis. · Pubmed #17237117 No free full text.

Abstract: BACKGROUND: Smoking is a well-established environmental risk factor for the development of rheumatoid arthritis (RA). However, it remains unclear whether smoking influences RA disease progression and whether smokers have more radiographic damage progression than non-smokers over time. OBJECTIVE: To compare the rates of radiographic damage progression in current smokers and non-smokers in a large prospective RA cohort. METHODS: The SCQM-RA is a population-based registry monitoring disease activity, radiographic damage and symptoms at regular intervals. All patients in the SCQM-RA database with sequential plain radiographs were included. Joint erosions were assessed in 38 hand and foot joints with a validated scoring method. The rate of erosion progression was analysed using multivariate longitudinal regression models and adjusted for potential confounders. RESULTS: 2004 RA patients with a mean of 3.6 sequential radiographs and 3.1 years of follow-up were included. The 545 (27%) current smokers smoked on average 16 cigarettes per day and had a mean past smoking exposure of 20.6 pack-years. Radiographic joint damage progressed at a similar rate in current smokers and non-smokers (p = 0.26). However, smoking intensity was associated with a significant inverse dose-response; heavy smokers (>1 pack-day) progressed significantly less than non-smokers or moderate smokers (p<0.001). CONCLUSION: Radiographic joint damage progressed at an equivalent rate in smokers and non-smokers. Furthermore, a significant trend was observed for reduced radiographic progression and generally more favourable functional scores among heavy smokers, suggesting that cigarette smoke does not accelerate RA disease progression.

Costenbader KH, Feskanich D, Mandl LA, Karlson EW. · Division of Rheumatology, Immunology, and Allergy, Robert B. Brigham Arthritis and Musculoskeletal Diseases Clinical Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass 02115, USA. · Am J Med. · Pubmed #16750964 No free full text.

Abstract: BACKGROUND: Cigarette smoking has been associated with rheumatoid arthritis (RA), but the importance of smoking intensity, duration, and time since quitting, and whether the risk is primarily for rheumatoid factor (RF) seropositive versus seronegative RA are still unclear. METHODS: We conducted a prospective analysis of smoking and the risk of RA among 103,818 women in the Nurses' Health Study. A total of 680 RA cases, diagnosed from 1976 and 2002, were confirmed using a questionnaire and medical record review. Sixty percent were RF positive. Cox proportional hazards models calculated the relative risks (RRs) of RA with smoking, adjusting for reproductive and lifestyle factors. RESULTS: The RR of RA was significantly elevated among current (RR 1.43 [95% confidence interval 1.16-1.75]) and past smokers (RR 1.47 [95% confidence interval 1.23-1.76]), compared with never smokers. The risk of RA was significantly elevated with 10 pack-years or more of smoking and increased linearly with increasing pack-years (P trend <.01). A greater number of daily cigarettes and longer duration of smoking were associated with increased risk. The effect of smoking was much stronger among RF-positive cases than among RF-negative cases. The risk remained elevated in past smokers until 20 years or more after cessation. CONCLUSIONS: In this large cohort, past and current cigarette smoking were related to the development of RA, in particular seropositive RA. Both smoking intensity and duration were directly related to risk, with prolonged increased risk after cessation.

Costenbader KH, Glass R, Cui J, Shadick N. · No affiliation provided · JAMA. · Pubmed #17090761 No free full text.

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