Detecting the earliest signs of rheumatoid arthritis: symptoms and examination.

Signs and symptoms often occur well in advance of a formal diagnosis of rheumatoid arthritis (RA). However, these do not necessarily represent symptoms that are included in classification criteria. Their intensity, frequency, and persistence over time seem to be important in the spectrum from preclinical autoimmunity to classifiable RA. Prospective study of signs and symptoms in individuals at risk for RA will help to determine their onset and relationship with epitope spreading, cytokine evolution, sensitive imaging, and their usefulness in discriminating between individuals patients who will develop incident inflammatory arthritis versus normal controls.

RFC1 80G>A is a genetic determinant of methotrexate efficacy in rheumatoid arthritis: a human genome epidemiologic review and meta-analysis of observational studies.

OBJECTIVE: Associations have been reported between candidate genes and the response to methotrexate (MTX) in rheumatoid arthritis (RA) patients, but most of the studies have been small and have yielded conflicting results. This study was undertaken to provide a systematic review of all genetic variant associations with MTX efficacy and toxicity, and to conduct a meta-analysis evaluating the most commonly studied single-nucleotide polymorphism for which prior cumulative analysis has been lacking. METHODS: A systematic review and meta-analysis were performed to identify genetic variant associations with MTX efficacy and toxicity. Studies were identified from the Medline, EMBase, HuGENet Navigator, and Cochrane Library databases through December 2012, and from the 2009-2011 abstracts of the American College of Rheumatology and the European League Against Rheumatism annual meeting proceedings. Additional unpublished genotype data from a Canadian cohort of patients with early RA were also included. RESULTS: Among the 87 identified studies examining genetic associations with MTX efficacy and toxicity, the reduced folate carrier 1 gene (RFC1) variant 80G>A (Arg(27) His, rs1051266) was selected for random-effects meta-analysis. RFC1 80G>A was associated with MTX efficacy in both the recessive model (odds ratio [OR] 1.42, 95% confidence interval [95% CI] 1.04-1.93) and the additive model (OR 1.28, 95% CI 1.10-1.49). Restriction of the sensitivity analyses to studies that involved Caucasian subjects only and that used similar outcome measures (MTX failure versus nonfailure) maintained and improved the associations in both models. No significant association between RFC1 80G>A and MTX toxicity was detected. CONCLUSION: In these analyses of available data from observational studies, RFC1 80G>A was found to be associated with MTX efficacy, but not toxicity, in RA patients. This variant merits further prospective analysis as a potential predictor of MTX efficacy. Variability in the definitions of response in pharmacogenetic studies is a source of data heterogeneity that should be addressed.

Association of granulomatosis with polyangiitis (Wegener's) with HLA-DPB1*04 and SEMA6A gene variants: evidence from genome-wide analysis.

OBJECTIVE: To identify genetic determinants of granulomatosis with polyangiitis (Wegener's) (GPA). METHODS: We carried out a genome-wide association study (GWAS) of 492 GPA cases and 1,506 healthy controls (white subjects of European descent), followed by replication analysis of the most strongly associated signals in an independent cohort of 528 GPA cases and 1,228 controls. RESULTS: Genome-wide significant associations were identified in 32 single-nucleotide polymorphic (SNP) markers across the HLA region, the majority of which were located in the HLA-DPB1 and HLA-DPA1 genes encoding the class II major histocompatibility complex (MHC) DPß chain 1 and DPα chain 1 proteins, respectively. Peak association signals in these 2 genes, emanating from SNPs rs9277554 (for DPß chain 1) and rs9277341 (DPα chain 1) were strongly replicated in an independent cohort (in the combined analysis of the initial cohort and the replication cohort, P = 1.92 × 10(-50) and 2.18 × 10(-39) , respectively). Imputation of classic HLA alleles and conditional analyses revealed that the SNP association signal was fully accounted for by the classic HLA-DPB1*04 allele. An independent single SNP, rs26595, near SEMA6A (the gene for semaphorin 6A) on chromosome 5, was also associated with GPA, reaching genome-wide significance in a combined analysis of the GWAS and replication cohorts (P = 2.09 × 10(-8) ). CONCLUSION: We identified the SEMA6A and HLA-DP loci as significant contributors to risk for GPA, with the HLA-DPB1*04 allele almost completely accounting for the MHC association. These two associations confirm the critical role of immunogenetic factors in the development of GPA.

Non-biologic disease-modifying antirheumatic drugs (DMARDs) improve pain in inflammatory arthritis (IA): a systematic literature review of randomized controlled trials.

Evidence supports early use of non-biologic DMARDs to prevent irreversible damage in inflammatory arthritides, including rheumatoid arthritis (RA), psoriatic arthritis (PsA), and possibly ankylosing spondylitis (AS). However, there is a paucity of data exploring their effects on pain as a primary outcome in these conditions. This systematic literature review investigated the effect of non-biologic DMARDs on pain levels in IA and examined whether disease duration impacted efficacy. We searched Medline, Embase, Cochrane Central, and Cochrane Database of Systematic Reviews, abstracts from the 2008 to 2010 American College of Rheumatology annual congresses, and citation lists of retrieved publications. Only randomized, double-blind controlled trials were analyzed. Quality was assessed with the Risk of Bias tool. Descriptive statistics were used in meta-analysis. 9,860 articles were identified, with 33 eligible for inclusion: 8 in AS, 6 in PsA, 9 in early RA (ERA), and 10 in established RA. In ERA and established RA, all studies of DMARDs (monotherapy and combination therapies) consistently revealed statistically significant reductions in pain except three oral gold studies. In AS, sulfasalazine studies showed significant pain reduction, whereas use of other DMARDs did not. In PsA, 5 of 6 studies reported VAS-pain improvement. From the studies included, we were unable to assess the influence of disease duration on pain outcomes in these rheumatic conditions. DMARDs improve pain in early and established RA. Sulfasalazine may improve pain in AS and PsA. Further study is needed to assess the relationship between disease duration and DMARD efficacy in reducing pain in these conditions.

Sex differences in pain scores and localization in inflammatory arthritis: a systematic review and metaanalysis.

OBJECTIVE: To systematically identify and examine reports of sex-stratified pain measurements in patients with inflammatory arthritis. METHODS: Data sources included PubMed (1950 to April 2010), Embase (1980 to April 2010), and manual searches of reference lists and conference abstracts. We included cohort studies and randomized trials comparing pain scores, treatment efficacy at reducing pain, or pain localization, between females and males with inflammatory arthritis [rheumatoid arthritis (RA), ankylosing spondylitis, psoriatic arthritis, and reactive arthritis]. RESULTS: Twenty-six cohorts and 1 randomized trial reported sex-stratified pain scores, and all but 1 cohort identified worse pain scores at enrollment in females. In a metaanalysis of mean visual analog scale (VAS) scores (0 to 10) in 16 RA cohort studies (reporting on 21,612 females and 6871 males), the standardized mean difference in VAS was 0.21 (95% CI 0.16, 0.26). Treatment with disease-modifying therapy results in improvement in mean scores for both sexes; however, female absolute scores remain higher. In 12 spondyloarthropathy cohorts reporting pain localization, females develop more peripheral arthritis during their disease course (68.9% vs 51.2%) but less inflammatory back pain (50.6% vs 66.4%). CONCLUSION: We identified important sex differences in pain scores in inflammatory arthritis, with higher pain levels in females. In spondyloarthritis, females develop more peripheral arthritis and have less frequent spinal involvement compared to males. These differences may affect a clinician's perception of disease severity and activity, and thus influence management decisions.

HLA markers for susceptibility and expression in scleroderma.

OBJECTIVE: Reported associations between HLA alleles and both susceptibility to and features of scleroderma have been conflicting. Our objective was (1) to determine the role of HLA alleles in the susceptibility to scleroderma; and (2) to determine the role of HLA alleles in various aspects of disease expression. METHODS: Consecutive patients were followed in the scleroderma clinic between 1996 and 1998. Clinical data were obtained through chart review. Healthy volunteers as well as cadaveric donors served as controls. Molecular HLA typing was performed (polymerase chain reaction/sequence-specific oligonucleotides). Statistical analysis included Fisher's exact test and multivariate analyses, using logistic and linear regression models. RESULTS: Ninety-five Caucasian patients (75 women, 20 men, age 43.9 yrs, disease duration 11.9 yrs) with scleroderma and 416 controls were studied. HLA-DRB1*01 and HLA-DRB1*11 were associated with susceptibility to scleroderma, whereas HLA-DRB1*07 was protective. HLA-A*30 and HLA-A*32 were also associated with susceptibility to scleroderma, while HLA-B*57 and HLA-Cw*14 were protective. HLA-B*62 and HLA-DRB1*07 had a significant correlation with the presence of diffuse skin involvement in both univariate and multivariate analyses. HLA-DRB1*11 was associated with high skin score values, while lower values were related to the presence of HLA-Cw*14 and HLA-DQB1*06. Both alleles retained significance in a linear regression model. High skin score values were related to the absence of anticentromere antibodies. Pulmonary fibrosis was associated with HLA-B*62 and HLA-Cw*0602, whereas pulmonary hypertension was associated with HLA-B*13 and HLA-B*65. CONCLUSION: HLA alleles play a role in susceptibility to scleroderma and its disease expression.

Automatic referral to cardiac rehabilitation.

OBJECTIVES: Cardiac rehabilitation (CR) remains underused and inconsistently accessed, particularly for women and minorities. This study examined the factors associated with CR enrollment within the context of an automatic referral system through a retrospective chart review plus survey. Through the Behavioral Model of Health Services Utilization, it was postulated that enabling and perceived need factors, but not predisposing factors, would significantly predict patient enrollment. SUBJECTS: A random sample of all atherosclerotic heart disease (AHD) patients treated at a tertiary care center (Trillium Health Centre, Ontario, Canada) from April 2001 to May 2002 (n = 501) were mailed a survey using a modified Dillman method (71% response rate). MEASURES: Predisposing measures consisted of sociodemographics such as age, sex, ethnocultural background, work status, level of education, and income. Enabling factors consisted of barriers and facilitators to CR attendance, exercise benefits and barriers (EBBS), and social support (MOS). Perceived need factors consisted of illness perceptions (IPQ) and body mass index. RESULTS: Of the 272 participants, 199 (73.2%) attended a CR assessment. Lower denial/minimization, fewer logistical barriers to CR (eg, distance, cost), and lower perceptions of AHD as cyclical or episodic reliably predicted CR enrollment among cardiac patients who were automatically referred. CONCLUSION: Because none of the predisposing factors were significant in the final model, this suggests that factors associated with CR enrollment within the context of an automatic referral model relate to enabling factors and perceived need. A prospective controlled evaluation of automatic referral is warranted.