Gingival tissue, an extrasynovial source of malondialdehyde-acetaldehyde adducts, citrullinated and carbamylated proteins.

BACKGROUND AND OBJECTIVE: Postranslational modification of proteins can lead to the production of autoantibodies and loss of immune tolerance. This process has been hypothesised to be a critical factor in the pathogenesis of rheumatoid arthritis. The objective of this study was to demonstrate that inflamed human gingival tissue provides an extrasynovial source of malondialdehyde-acetaldehyde adducts, citrullinated and carbamylated proteins all of which are considered to be linked to the development of rheumatoid arthritis. Identification of such modified proteins in inflamed gingiva may explain, in part, how inflammation of the periodontal tissues may influence the development of rheumatoid arthritis. MATERIAL AND METHODS: Gingival biopsies of healthy, mild and moderate periodontitis were triple stained with antibodies against malondialdehyde-acetaldehyde adducts, citrullinated and carbamylated proteins. RESULTS: Assessment of healthy gingival tissue revealed negligible staining for carbamylated, malondialdehyde-acetaldehyde (MAA), or citrullinated proteins. Mild periodontitis was positive for all three modifications. Furthermore, there was an increase in staining intensity for carbamylated, citrullinated and MAA-modified proteins in moderate periodontitis. Negative staining results were observed for the isotype controls. CONCLUSION: This study provides evidence for the presence of citrullinated, carbamylated and MAA adduct modified proteins in inflamed periodontal tissues. The potential for these proteins to play a role in autoimmunity in a multi-system inflammatory syndromic disease model now needs to be determined.

TLR4 Asp299Gly polymorphism may be protective against chronic periodontitis.

BACKGROUND AND OBJECTIVE: Periodontitis results from interplay between genetic and environmental factors. Single nucleotide polymorphisms (SNPs) in the coding region of the toll-like receptor 4 gene (TLR4) may be associated with periodontitis, although previous studies have been inconclusive. Moreover, the interaction between environmental factors, such as cigarette smoking (a major risk factor for periodontitis), and Porphyromonas gingivalis (a major periodontal pathogen) with the TLR4 coding region Asp299Gly SNP (rs4986790; a SNP associated with lipopolysaccharide-mediated inflammatory responses in periodontitis), have been largely ignored in previous reports. Therefore, the objective of this study was to examine the association between TLR4 Asp299Gly (rs4986790) with alveolar bone height loss (ABHL) and periodontitis, accounting for interactions between this SNP with smoking and P. gingivalis prevalence. The CD14/-260 SNP (rs2569190) served as a control, as a recent meta-analysis suggested no relationship between this SNP and periodontitis. MATERIAL AND METHODS: This multicenter study included 617 participants who had rheumatoid arthritis or osteoarthritis. This report presents a secondary outcome from the primary case-control study examining the relationship of periodontitis with established rheumatoid arthritis. The Centers for Disease Control/American Academy of Periodontology case definitions of periodontitis were used for this analysis. Participants received a full-mouth clinical periodontal examination and panoramic radiograph. Percentage ABHL was measured on posterior teeth. The TLR4 Asp299Gly and CD14/-260 SNPs were selected a priori and genotypes were determined using the ImmunoChip array (Illumina(®) ). Minor allele frequencies and associations with periodontitis and ABHL did not differ according to rheumatoid arthritis vs. osteoarthritis status; therefore, data from these two groups were pooled. The presence of P. gingivalis was detected in subgingival plaque by PCR. Multivariate ordinal logistic regression examined associations between the SNPs and periodontitis or ABHL. SNP interactions with smoking and P. gingivalis were analyzed. RESULTS: A significant, negative interaction was observed between the TLR4 SNP and the presence of P. gingivalis (p = 0.045) with respect to periodontitis. The TLR4 minor variant was also associated with less ABHL: 16.8% of individuals with low ABHL, 9.0% with moderate ABHL and 11.2% with high ABHL had the minor allele [p = 0.029; odds ratio = 0.58 (95% confidence interval: 0.36-0.95)]. The interaction between the TLR4 SNP and smoking was not significant with respect to periodontitis or ABHL. The CD14 SNP was not associated with periodontitis or ABHL. CONCLUSION: The TLR4 Asp299Gly SNP significantly interacted with P. gingivalis in conferring a decreased risk of periodontitis and may be protective against ABHL, a feature of periodontitis. Agents blocking TLR4 signaling, a strategy currently under investigation for the treatment of other inflammatory conditions, may warrant investigation in the context of periodontitis related to the presence of P. gingivalis.

Genetic variants associated with methotrexate efficacy and toxicity in early rheumatoid arthritis: results from the treatment of early aggressive rheumatoid arthritis trial.

Methotrexate (MTX) has emerged as first-line therapy for early moderate-to-severe rheumatoid arthritis (RA), but individual variation in treatment response remains unexplained. We tested the associations between 863 known pharmacogenetic variants and MTX response in 471 Treatment of Early Aggressive Rheumatoid Arthritis Trial participants with early RA. Efficacy and toxicity were modeled using multiple regression, adjusted for demographic and clinical covariates. Penalized regression models were used to test joint associations of markers and/or covariates with the outcomes. The strongest genetic associations with efficacy were in CHST11 (five markers with P<0.003), encoding carbohydrate (chondroitin 4) sulfotransferase 11. Top markers associated with MTX toxicity were in the cytochrome p450 genes CYP20A1 and CYP39A1, solute carrier genes SLC22A2 and SLC7A7, and the mitochondrial aldehyde dehydrogenase gene ALDH2. The selected markers explained a consistently higher proportion of variation in toxicity than efficacy. These findings could inform future development of personalized therapeutic approaches.

Folic acid pathway single nucleotide polymorphisms associated with methotrexate significant adverse events in United States veterans with rheumatoid arthritis.

OBJECTIVES: Methotrexate (MTX) is the cornerstone medication in the treatment of rheumatoid arthritis (RA). We examined whether single nucleotide polymorphisms (SNPs) in enzymes of the folic acid pathway (folylpoly-gamma-glutamate synthetase [FPGS], gamma-glutamyl hydrolase [GGH], and methylenetetrahydrofolate reductase [MTHFR]) associate with significant adverse events (SigAE). METHODS: Patients (n=319) enrolled in the Veterans Affairs RA (VARA) registry taking MTX were genotyped for HLA-DRB1-SE and the following SNPs: FPGS (rs7033913, rs10760503, rs10106), GGH (12548933, rs7010484, rs4617146, rs719235, rs11988534), MTHFR (rs1801131, rs1801133). AE were abstracted from the medical record using a structured instrument. SigAE were defined as an AE leading to MTX discontinuation. Covariates included: age, gender, race, RA antibody status, tobacco, RA disease duration between diagnosis and MTX course, Charlson-Deyo comorbidity index, glucocorticoids, use of prior RA medications, and mean 4-variable disease activity score. Cox regression was performed to determine factors associated with time-to-SigAE. A p-value ≤ 0.005 established significance in the final model. RESULTS: The presence of ≥ 1 copy of the minor allele in MTHFR rs1801131 was associated with an increased hazard ratio (HR) of SigAE (HR 3.05, 95% CI 1.48-6.29, p-value 0.003 and HR 3.88, 95% CI 1.62-9.28, p-value 0.002 for heterozygotes and homozygotes for the minor allele, respectively). An interaction term, between FPGS rs7033913 heterozygotes and GGH rs11988534 homozygotes for the minor allele, had a p-value <0.0001. CONCLUSIONS: RA subjects taking MTX may have decreased time-to-SigAE with ≥ 1 copy of the minor allele in MTHFR rs1801131. Further investigation is warranted, as these SNPs may indicate susceptibility to MTX toxicity.

Supervised machine learning and logistic regression identifies novel epistatic risk factors with PTPN22 for rheumatoid arthritis.

Investigating genetic interactions (epistasis) has proven difficult despite the recent advances of both laboratory methods and statistical developments. With no 'best' statistical approach available, combining several analytical methods may be optimal for detecting epistatic interactions. Using a multi-stage analysis that incorporated supervised machine learning and methods of association testing, we investigated epistatic interactions with a well-established genetic factor (PTPN22 1858T) in a complex autoimmune disease (rheumatoid arthritis (RA)). Our analysis consisted of four principal stages: Stage I (data reduction)-identifying candidate chromosomal regions in 292 affected sibling pairs, by predicting PTPN22 concordance using multipoint identity-by-descent probabilities and a supervised machine learning algorithm (Random Forests); Stage II (extension analysis)-testing detailed genetic data within candidate chromosomal regions for epistasis with PTPN22 1858T in 677 cases and 750 controls using logistic regression; Stage III (replication analysis)-confirmation of epistatic interactions in 947 cases and 1756 controls; Stage IV (combined analysis)-a pooled analysis including all 1624 RA cases and 2506 control subjects for final estimates of effect size. A total of seven replicating epistatic interactions were identified. SNP variants within CDH13, MYO3A, CEP72 and near WFDC1 showed significant evidence for interaction with PTPN22, affecting susceptibility to RA.

Poor to modest agreement between rheumatoid arthritis response measures in clinical practice.

OBJECTIVE: To evaluate the agreement among several rheumatoid arthritis (RA) response measures in a clinical setting. METHODS: 529 patients with RA were seen at 2 regular visits where the following response measures were determined: ACR-20, EULAR good or moderate (EULAR-GM), Simplified Disease Activity Index moderate (SDAI-M), Clinical DAI moderate (CDAI-M), and Patient Reported Outcomes Index-M 20 (PRO-IM-20). Each measure was modified to include a "worse" response, i.e. the inverse of the respective guidelines for a positive improvement response.Introduced for comparison was the Real-time Assessment of Disease Activity in Rheumatoid Arthritis (RADARA), a response measure that registers improvement if the patient's tender and swollen joint counts and HAQ score all improve and worsening if all three increase. Contingency tables comparing the three responses (worse, no change, and improvement) along with Cohen's kappa were calculated. RESULTS: The mean (SD) baseline characteristics of the patients included: age 66.5 (10.7) years, RA duration 12.9 (11.0) years, 91.3% male, 84.1% rheumatoid factor positive, and a Disease Activity Score-28 of 3.5 (1.3). The percentage of patients who improved/worsened were as follows: ACR-20 4.7/9.1, EULAR-GM 23.4/26.3, SDAI-M 16.1/20.6, CDAI-M 16.3/20.0, PRO-IM-20 22.5/34.4, and RADARA 7.0/11.5. Agreement (kappa) was poor to slight (

Post-traumatic stress disorder and serum cytokine and chemokine concentrations in patients with rheumatoid arthritis✰.

OBJECTIVE: Although post-traumatic stress disorder (PTSD) is identified as a risk factor in the development of rheumatoid arthritis (RA), associations of PTSD with disease progression are less clear. To explore whether PTSD might influence disease-related measures of systemic inflammation in RA, we compared serum cytokine/chemokine (cytokine) concentrations in RA patients with and without PTSD. METHODS: Participants were U.S. Veterans with RA and were categorized as having PTSD, other forms of depression/anxiety, or neither based on administrative diagnostic codes. Multiplex cytokines were measured using banked serum. Associations of PTSD with cytokine parameters (including a weighted cytokine score) were assessed using multivariable regression, stratified by anti-CCP status and adjusted for age, sex, race, and smoking status. RESULTS: Among 1,460 RA subjects with mean (SD) age of 64 (11) years and disease duration of 11 (11) years, 91% were male, 77% anti-CCP positive, and 80% ever smokers. Of these, 11.6% had PTSD, 23.7% other depression/anxiety, and 64.7% had neither. PTSD, but not depression/anxiety, was associated with a higher cytokine score and number of high-concentration analytes in adjusted models, though this was limited to anti-CCP positive subjects. PTSD was associated with heightened expression of several individual cytokines including IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12, IL-17, IFN-γ, GM-CSF, MCP-1, and TNF-α. CONCLUSION: Anti-CCP positive RA patients with PTSD have higher serum cytokine concentrations than those without PTSD, demonstrating that systemic inflammation characteristic of RA is heightened in the context of this relatively common psychiatric comorbidity.

Cigarette smoking, disease severity and autoantibody expression in African Americans with recent-onset rheumatoid arthritis.

OBJECTIVE: To examine the association of smoking with clinical and serological features in African Americans with recent-onset rheumatoid arthritis (RA) and to explore whether this association is dependent on the presence of the HLA-DRB1 shared epitope (SE). METHODS: In African Americans with recent-onset RA (n = 300), we examined the association of cigarette smoking (current versus past versus never and pack-years of exposure) with anti-cyclic citrullinated peptide antibody, rheumatoid factor (RF) (IgM and IgA), rheumatoid nodules and baseline radiographic erosions using logistic and cumulative logistic regression (adjusting for SE status). We also examined for evidence of interaction between smoking status and SE for all outcomes. RESULTS: Although there was no association with RF-IgA seropositivity, current smokers were approximately twice as likely as never smokers to have higher IgA-RF concentrations (based on tertiles; OR = 1.74; 95% CI 1.05 to 2.88) and nodules (OR = 2.43; 95% CI 1.13 to 5.22). These associations were most pronounced in those with more than 20 pack-years of exposure. There was no association of smoking status or cumulative tobacco exposure with anti-cyclic citrullinated peptide antibody, IgM-RF or radiographic erosions. There was also no evidence of a biological or statistical SE-smoking interaction for any of the outcomes examined. CONCLUSIONS: This is the first study to systematically examine the association of cigarette smoking with RA-related features in African Americans. Cigarette smoking is associated with both subcutaneous nodules and higher serum concentrations of IgA-RF in African Americans with RA, associations that may have important implications for long-term outcomes in this population.

Design and Rationale for the Veterans Affairs "Cooperative Study Program 594 Comparative Effectiveness in Gout: Allopurinol vs. Febuxostat" Trial.

BACKGROUND: Gout patients do not routinely achieve optimal outcomes related in part to suboptimal administration of urate lowering therapy (ULT) including first-line xanthine oxidase inhibitors allopurinol or febuxostat. Studies leading to the approval of febuxostat compared this agent to allopurinol in inappropriately low, fixed doses. We will compare allopurinol with febuxostat in gout using appropriately titrated doses of both agents and a "treat-to-target" strategy congruent with specialty guidelines. METHODS: We have planned and initiated the Veterans Affairs (VA) Cooperative Study Program (CSP) 594, Comparative Effectiveness in Gout: Allopurinol vs Febuxostat study. This large double-blind, non-inferiority trial will enroll 950 gout patients randomized to receive allopurinol or febuxostat. Patients will be followed for a total of 72 weeks encompassing 3 distinct 24-week study phases. During Phase I (0-24 weeks), participants will undergo gradual dose titration of ULT until achievement of serum uric acid (sUA) <6.0 mg/dL or <5.0 mg/dL if tophi are present. Dose escalation will not be allowed during final three study visits of Phase 2 (24-48 weeks) and during Phase 3 (48-72 weeks). The primary study outcome is the proportion of participants experiencing at least one gout flare during Phase 3. Subsequent to the 72-week study, participants will be followed passively for up to 10 years after the study to assess long-term health outcomes. CONCLUSION: With its completion, the VA Comparative Effectiveness in Gout: Allopurinol vs Febuxostat study will demonstrate the central role of gradual ULT dose escalation and a treat-to-target strategy in gout management.

Quality of care in gout: from measurement to improvement.

Gout is a growing health problem, affecting approximately 7% of men and 3% of women over the age of 65 years. Although effective therapies for gout management exist, quality in gout care has been too frequently characterized as being "suboptimal." This review examines issues pertinent to quality of care in gouty arthritis with a focus on initial reports examining suboptimal care, subsequent efforts to develop quality of care indicators for gout management, more recently published evidence-based recommendations for gout diagnosis and treatment, and an ongoing international initiative to develop core outcome measures for acute and chronic gout. "If you can not measure it, you can not improve it" - Lord Kelvin.

Salivary and serum procalcitonin and C-reactive protein as biomarkers of periodontitis in United States veterans with osteoarthritis or rheumatoid arthritis.

Serum procalcitonin (ProCT) is elevated in response to bacterial infections, whereas high sensitivity C-reactive protein (hsCRP) is a nonspecific inflammatory marker that is increased by excess adipose tissue. We examined the efficacy of ProCT and hsCRP as biomarkers of periodontitis in the saliva and serum of patients with arthritis, which is characterized by variable levels of systemic inflammation that potentially can confound the interpretation of inflammatory biomarkers. Blood and unstimulated whole saliva were collected from 33 patients with rheumatoid arthritis (RA) and 50 with osteoarthritis (OA). Periodontal status was assessed by full mouth examination and patients were categorized as having no/mild, moderate or severe periodontitis by standard parameters. Salivary and serum ProCT and hsCRP concentrations were compared. BMI, diabetes, anti-inflammatory medications and smoking status were ascertained from the patient records. Differences between OA and RA in proportionate numbers of patients were compared for race, gender, diabetes, adiposity and smoking status. Serum ProCT was significantly higher in arthritis patients with moderate to severe and severe periodontitis compared with no/mild periodontitis patients. There were no significant differences in salivary ProCT or salivary or serum hsCRP in RA patients related to periodontitis category. Most of the OA and RA patients were middle aged or older, 28.9% were diabetic, 78.3% were overweight or obese, and slightly more than half were either current or past smokers. The OA and RA groups differed by race, but not gender; blacks and males were predominant in both groups. The OA and RA groups did not differ in terms of controlled or uncontrolled diabetes, smoking status or BMI. The RA patients had been prescribed more anti-inflammatory medication than the OA patients. Our results demonstrate that circulating ProCT is a more discriminative biomarker for periodontitis than serum hsCRP in patients with underlying arthritis. Any elevation in salivary and serum hsCRP due to periodontitis apparently was overshadowed by differences among these patients in factors that influence CRP, such as the extent of inflammation between RA and OA, the extent of adipose tissue, the use of anti- inflammatory medications and smoking status. Although our study showed no differences in salivary ProCT related to severity of periodontitis, this biomarker also may be useful with further refinement.

Celastrol inhibits inflammatory stimuli-induced neutrophil extracellular trap formation.

Neutrophil extracellular traps (NETs) are web-like structures released by activated neutrophils. Recent studies suggest that NETs play an active role in driving autoimmunity and tissue injury in diseases including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). The purpose of this study was to investigate if celastrol, a triterpenoid compound, can inhibit NET formation induced by inflammatory stimuli associated with RA and SLE. We found that celastrol can completely inhibit neutrophil oxidative burst and NET formation induced by tumor necrosis factor alpha (TNFα) with an IC50 of 0.34 µM and by ovalbumin:anti-ovalbumin immune complexes (Ova IC) with an IC50 of 1.53 µM. Celastrol also completely inhibited neutrophil oxidative burst and NET formation induced by immunoglobulin G (IgG) purified from RA and SLE patient sera. Further investigating into the mechanisms, we found that celastrol treatment downregulated the activation of spleen tyrosine kinase (SYK) and the concomitant phosphorylation of mitogen-activated protein kinase kinase (MAPKK/MEK), extracellular-signal-regulated kinase (ERK), and NFκB inhibitor alpha (IκBα), as well as citrullination of histones. Our data reveals that celastrol potently inhibits neutrophil oxidative burst and NET formation induced by different inflammatory stimuli, possibly through downregulating the SYK-MEK-ERK-NFκB signaling cascade. These results suggest that celastrol may have therapeutic potentials for the treatment of inflammatory and autoimmune diseases involving neutrophils and NETs.

Comorbidity in rheumatoid arthritis.

It is increasingly clear that coexistent disease plays a pivotal role in RA outcome and that efforts aimed at specifically addressing these comorbidities need to be aggressively sought, investigated, and implemented once proven effective. RA-associated costs are currently increasing at twice the rate of the medical care index. Comorbidity in the setting of RA independently predicts disease-associated disability (a major cost component) and mortality, underscoring the need for a more comprehensive approach to RA, one that adequately addresses disease-specific comorbidities. At present, many primary and secondary preventative measures (Table 1) for RA-specific comorbidities remain largely unproved and require rigorous investigation in a randomized prospective fashion. Despite this ongoing need, advances are being made in our understanding of the underlying pathogenesis of these comorbid conditions and their relation with RA. This improved understanding should translate into further effective interventions. Bisphosphonates, for instance, have been shown to be effective in the prevention of GIOP and associated fractures. The past several years have seen other exciting therapeutic advances in RA. DMARD combinations have been shown to be more effective and no more toxic than MTX monotherapy. In addition to the recent release of COX-2 NSAIDs, three new disease-modifying agents (leflunomide, etanercept, and infliximab) have been added to the therapeutic armamentarium; these are options that have markedly changed the treatment landscape in RA. Although these important advances have generated much deserved optimism, the precise effect that these agents may have on RA-specific comorbidity remains to be seen. The next decade should prove to be an exciting time in RA management. Better identification, understanding, and management of RA comorbidities have great potential to improve quality of life and survival among our patients with RA.

Early rheumatoid arthritis in African-Americans: the CLEAR Registry.

African-Americans have been under-represented in genetic studies of rheumatoid arthritis (RA) susceptibility and severity. Genetic and non-genetic factors influencing the radiographic severity of RA and its response to treatment are poorly understood, particularly in African-Americans. The Consortium for the Longitudinal Evaluation of African-Americans with early RA (CLEAR) Registry, a collaborative effort among four institutions in the southeast USA, will hopefully provide a useful resource to study these issues.

TNF blockade in the treatment of rheumatoid arthritis: infliximab versus etanercept.

There is accumulating evidence that tumour necrosis factor (TNF) plays a major role in the pathogenesis of rheumatoid arthritis (RA). Recent biotechnological advances have allowed for the development of agents that directly target TNF, a pro-inflammatory cytokine. In the last 2 years, the US FDA and the EU's Commission of the European Communities have approved two biological agents for the treatment of refractory RA, etanercept and infliximab. Etanercept is a fusion protein, composed of the Fc portion of IgG1 and the extracellular domain of the TNF receptor (p75). Infliximab is a chimeric monoclonal antibody (mAb) composed of murine variable and human constant regions. In placebo-controlled trials, both agents have proven to be effective and well-tolerated in RA patients. This review evaluates the available TNF inhibitors, summarises pertinent clinical trials and underscores differences between the two agents in terms of molecular structure, efficacy, safety data, antigenicity and pharmacokinetics.

Risk of hospitalized bacterial infections associated with biologic treatment among US veterans with rheumatoid arthritis.

OBJECTIVE: The comparative risk of infection associated with non-anti-tumor necrosis factor (anti-TNF) biologic agents is not well established. Our objective was to compare risk for hospitalized infections between anti-TNF and non-anti-TNF biologic agents in US veterans with rheumatoid arthritis (RA). METHODS: Using 1998-2011 data from the US Veterans Health Administration, we studied RA patients initiating rituximab, abatacept, or anti-TNF therapy. Exposure was based upon days supplied (injections) or usual dosing intervals (infusions). Treatment episodes were defined as new biologic agent use. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for hospitalization for a bacterial infection were estimated from Cox proportional hazards models, adjusting for potential confounders. RESULTS: Among 3,152 unique RA patients contributing 4,158 biologic treatment episodes to rituximab (n = 596), abatacept (n = 451), and anti-TNF agents (n = 3,111), the patient mean age was 60 years and 87% were male. The most common infections were pneumonia (37%), skin/soft tissue (22%), urinary tract (9%), and bacteremia/sepsis (7%). Hospitalized infection rates per 100 person-years were 4.4 (95% CI 3.1-6.4) for rituximab, 2.8 (95% CI 1.7-4.7) for abatacept, and 3.0 (95% CI 2.5-3.5) for anti-TNF. Compared to etanercept, the adjusted rate of hospitalized infection was not different for adalimumab (HR 1.4, 95% CI 0.9-2.2), abatacept (HR 1.1, 95% CI 0.6-2.1), or rituximab (HR 1.4, 0.8-2.6), although it was increased for infliximab (HR 2.3, 95% CI 1.3-4.0). Infection risk was greater for those taking prednisone >7.5 mg/day (HR 1.8, 95% CI 1.3-2.7) and in the highest quartile of C-reactive protein (HR 2.3, 95% CI 1.4-3.8) and erythrocyte sedimentation rate (HR 4.1, 95% CI 2.3-7.2) compared to the lowest quartile. CONCLUSION: In older, predominantly male US veterans with RA, the risk of hospitalized bacterial infections associated with rituximab or abatacept was similar to etanercept.

Skeletal health among African Americans with recent-onset rheumatoid arthritis.

OBJECTIVE: African Americans with rheumatoid arthritis (RA) may be at increased fracture risk. We applied the World Health Organization (WHO) Fracture Risk Assessment Tool (FRAX) and National Osteoporosis Foundation (NOF) guidelines to a cohort of African Americans with early RA to identify which patients were recommended for osteoporosis treatment. METHODS: Risk factors and bone mineral density (BMD) were assessed in a cohort of African Americans with RA. The WHO FRAX tool estimated 10-year fracture risk. Patients were risk stratified using FRAX without BMD to identify which individuals might be most efficiently targeted for BMD testing. RESULTS: Participants (n = 324) had a mean age of 51 years and included 81% women. There were no associations of RA disease characteristics with BMD. The proportion of patients recommended for osteoporosis treatment varied from 3-86%, depending on age and body mass index (BMI). Ten-year fracture risk calculated with BMI only was generally the same or higher than fracture risk calculated with BMD; adding BMD data provided the most incremental value to risk assessment in patients 55-69 years of age with low/normal BMI, and in those > or =70 years of age with BMI > or =30 kg/m2. CONCLUSION: A high proportion of African Americans with RA were recommended for treatment under the 2008 NOF guidelines. FRAX without BMD identified low-risk patients accurately. Systematic application of FRAX to screen high-risk groups such as patients with RA may be used to target individuals for BMD testing and reduce the use of unnecessary tests and treatments.

Smoking interacts with genetic risk factors in the development of rheumatoid arthritis among older Caucasian women.

OBJECTIVE: To determine whether the impact of tobacco exposure on rheumatoid arthritis (RA) risk is influenced by polymorphisms at the HLA-DRB1 and glutathione S-transferase M1 (GSTM1) loci. METHODS: Subjects were participants from a case-control study nested within the Iowa Women's Health Study, a population based, prospective cohort study of postmenopausal women. Incident RA cases (n = 115) were identified and medical records reviewed to confirm RA diagnosis. Controls without RA (n = 466) were matched with RA cases by age and ethnic background. HLA-DRB1 typing classified subjects according to the presence of alleles encoding the RA "shared epitope" (SE) sequence. GSTM1 was genotyped using a multiplex polymerase chain reaction assay. Conditional logistic regression was used to estimate the odds ratios (ORs) and 95% confidence intervals. RESULTS: Strong positive associations of smoking (OR = 6.0, p = 0.004), SE positivity (OR = 4.6, p = 0.0006), and GSTM1 null genotype (OR = 3.4, p = 0.007) with risk of RA, and significant gene-environment interactions (smoking by SE interaction p = 0.034; smoking by GSTM1 interaction p = 0.047) were observed. Stratified analyses indicated that exposure to tobacco smoke primarily increased the risk of RA among subjects who lacked genetic risk factors for the disease (that is, SE negative or GSTM1 present). CONCLUSIONS: Although these findings require confirmation in other groups, the results support the importance of considering both genetic and environmental factors, and also their interaction, in studies of complex diseases like RA.

Sex differences in gout epidemiology: evaluation and treatment.

BACKGROUND: Little is known about the characteristics, evaluation and treatment of women with gout. OBJECTIVE: To examine the epidemiological differences and differences in treatment between men and women in a large patient population. METHODS: The data from approximately 1.4 million people who were members of seven managed care plans in the USA for at least 1 year between 1 January 1999 and 31 December 2003 were examined. Adult members who had pharmacy benefits and at least two ambulatory claims specifying a diagnosis of gout were identified. In addition, men and women who were new users of urate-lowering drugs (ULDs) were identified to assess adherence with recommended surveillance of serum urate levels within 6 months of initiating urate-lowering treatment. RESULTS: A total of 6133 people (4975 men and 1158 women) with two or more International Classification of Disease-9 codes for gout were identified. As compared with men with gout, women were older (mean age 70 (SD 13) v 58 (SD 14), p<0.001) and had comorbidities and received diuretics more often (77% v 40%; p<0.001). Only 37% of new users of urate-lowering treatment had appropriate surveillance of serum urate levels post-initiation of urate-lowering treatment. After controlling for age, comorbidities, gout treatments, number of ULD dispensings and health plan, women were more likely (odds ratio 1.36, 95% confidence interval 1.11 to 1.67) to receive the recommended serum urate level testing. CONCLUSIONS: Women with gout were older, had greater comorbidities and more often used diuretics and received appropriate surveillance of serum urate levels, suggesting that the factors leading to gout as well as monitoring of treatment are very different in women and men.

Suboptimal physician adherence to quality indicators for the management of gout and asymptomatic hyperuricaemia: results from the UK General Practice Research Database (GPRD).

OBJECTIVES: : To examine adherence to validated quality indicators assessing the quality of allopurinol use in the treatment of gout and asymptomatic hyperuricaemia. METHODS: We determined physician adherence in the UK General Practice Research Database (GPRD) to three validated quality indicators developed to assess the quality of allopurinol prescribing practices. These indicators were developed to assess: (i) dosing in renal impairment; (ii) concomitant use with azathioprine or 6-mercaptopurine; and (iii) use in the treatment of asymptomatic hyperuricaemia. We also examined the association of patient-level factors (sociodemographics, comorbidity, follow-up duration and concomitant medicine use) with the treatment of asymptomatic hyperuricaemia using multivariable logistic regression. RESULTS: Of the 63 105 gout patients, 185 (0.3%) were eligible for Quality Indicator 1 and 52 (0.1%) were eligible for Quality Indicator 2. There were an additional 471 patients with asymptomatic hyperuricaemia eligible for Quality Indicator 3. Rates of practice deviation for the three individual quality indicators ranged from 25 to 57%. Male sex, older age, a history of chronic renal failure, and a greater number of concomitant medications were significantly associated with increased odds of inappropriate treatment for asymptomatic hyperuricaemia. Hypertension and diuretic use were associated with lower odds of this practice. CONCLUSIONS: One-quarter to one-half of all patients eligible for at least one of the validated quality of care indicators were subject to possible allopurinol prescribing error, suggesting that inappropriate prescribing practices are widespread with this agent. Future interventions aimed at reducing inappropriate allopurinol use are needed and should be targeted towards high-risk groups, including older men and those receiving multiple concomitant medications.