Validation of the rheumatic disease comorbidity index.

OBJECTIVE: There is no consensus on which comorbidity index is optimal for rheumatic health outcomes research. We compared a new Rheumatic Disease Comorbidity Index (RDCI) with the Charlson-Deyo Index (CDI), Functional Comorbidity Index (FCI), Elixhauser Total Score (ETS), Elixhauser Point System (EPS), and a simple comorbidity count (COUNT) using a US cohort of rheumatoid arthritis (RA) patients. METHODS: Using administrative diagnostic codes and patient self-reporting, we tested predictive values of the RDCI, CDI, FCI, ETS, EPS, and COUNT for 2 outcomes: all-cause mortality and physical functioning. Indices were compared using 3 models: bare (consisting of age, sex, and race), administrative (bare plus visit frequency, body mass index, and treatments), and clinic (administrative plus erythrocyte sedimentation rate, nodules, rheumatoid factor positivity, and patient activity scale). RESULTS: The ETS and RDCI best predicted death, with FCI performing the worst. The FCI best predicted function, with ETS and RDCI performing nearly as well. CDI predicted function poorly. The order of indices remained relatively unchanged in the different models, though the magnitude of improvement in Akaike's information criterion decreased in the administrative and clinic models. CONCLUSION: The RDCI and ETS are excellent indices as a means of accounting for comorbid illness when the RA-related outcomes of death and physical functioning are studied using administrative data. The RDCI is a versatile index and appears to perform well with self-report data as well as administrative data. Further studies are warranted to compare these indices using other outcomes in diverse study populations.

Rheumatoid factor as a potentiator of anti-citrullinated protein antibody-mediated inflammation in rheumatoid arthritis.

OBJECTIVE: The co-occurrence of rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) positivity in rheumatoid arthritis (RA) is well described. However, the mechanisms underlying the potential interaction between these 2 distinct autoantibodies have not been well defined. The aim of this study was to evaluate the epidemiologic and molecular interaction of ACPAs and RF and its association with both disease activity and measures of RA-associated inflammation. METHODS: In a cohort of 1,488 US veterans with RA, measures of disease activity and serum levels of cytokines and multiplex ACPAs were compared between the following groups of patients: double-negative (anti-cyclic citrullinated peptide [anti-CCP]-/RF-), anti-CCP+/RF-, anti-CCP-/RF+, or double-positive (anti-CCP+/RF+). Additional studies were performed using an in vitro immune complex (IC) stimulation assay in which macrophages were incubated with ACPA ICs in the presence or absence of monoclonal IgM-RF, and tumor necrosis factor α production measured as a readout of macrophage activation. RESULTS: Compared with the double-negative subgroup (as well as each single-positive subgroup), the double-positive subgroup exhibited higher disease activity as well as higher levels of C-reactive protein and inflammatory cytokines (all P < 0.001). In vitro stimulation of macrophages by ACPA ICs increased cytokine production, and the addition of monoclonal IgM-RF significantly increased macrophage tumor necrosis factor α production (P = 0.003 versus ACPA ICs alone). CONCLUSION: The combined presence of ACPAs and IgM-RF mediates increased proinflammatory cytokine production in vitro and is associated with increased systemic inflammation and disease activity in RA. Our data suggest that IgM-RF enhances the capacity of ACPA ICs to stimulate macrophage cytokine production, thereby providing a mechanistic link by which RF enhances the pathogenicity of ACPA ICs in RA.

Association of rheumatoid arthritis susceptibility gene with lipid profiles in patients with rheumatoid arthritis.

OBJECTIVE: RA patients have an increased risk of cardiovascular (CV) disease, although the mechanisms are unclear. As RA and CV disease may be associated through lipid profiles, we examined whether single nucleotide polymorphisms (SNPs) associated with RA susceptibility were associated with low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglyceride (TG) levels in RA subjects. METHODS: Patients (n = 763) enrolled in the Veterans Affairs RA registry who were not on hydroxymethylglutaryl-CoA reductase inhibitor were genotyped for human leukocyte antigen shared epitope (HLA-DRB1-SE) and SNPs in the following genes: CTLA-4 (cytotoxic T-lymphocyte antigen 4), IL-10, PTPN22 (protein tyrosine phosphatase, non-receptor type 22), REL (c-Rel), STAT4 (signal transducer and activator of transcription protein), TNF- and TRAF1 (TNF receptor-associated factor 1). Other covariates included patient characteristics (age, gender, race, smoking status, education, BMI, modified CharlsonDeyo comorbidity index), CV characteristics (hypertension, diabetes, alcohol abuse), pharmacologic exposures (MTX, anti-TNF, glucocorticoids) and RA severity/activity markers (RA disease duration, mean DAS, CRP, RF positivity, anti-CCP positivity). Multivariate linear regression was performed to determine the factors associated with LDL, HDL and TG levels. RESULTS: The REL SNP rs9309331 homozygous minor allele was associated with higher LDL levels. Caucasian race and increasing BMI were associated with lower HDL. Factors associated with higher TG were diabetes, Caucasian race and higher BMI. CONCLUSION: The REL SNP rs9309331 was associated with LDL levels in our study. This association is a possible explanation of the increased risk of RA patients for CV disease and requires further inquiry.

Cardiovascular events are not associated with MTHFR polymorphisms, but are associated with methotrexate use and traditional risk factors in US veterans with rheumatoid arthritis.

OBJECTIVE: C677T and A1298C polymorphisms in the enzyme methylenetetrahydrofolate reductase (MTHFR) have been associated with increased cardiovascular (CV) events in non-rheumatoid arthritis (RA) populations. We investigated potential associations of MTHFR polymorphisms and use of methotrexate (MTX) with time-to-CV event in data from the Veterans Affairs Rheumatoid Arthritis (VARA) registry. METHODS: VARA participants were genotyped for MTHFR polymorphisms. Variables included demographic information, baseline comorbidities, RA duration, autoantibody status, and disease activity. Patients' comorbidities and outcome variables were defined using International Classification of Diseases-9 and Current Procedural Terminology codes. The combined CV event outcome included myocardial infarction (MI), percutaneous coronary intervention, coronary artery bypass graft surgery, and stroke. Cox proportional hazards regression was used to model the time-to-CV event. RESULTS: Data were available for 1047 subjects. Post-enrollment CV events occurred in 97 patients (9.26%). Although there was a trend toward reduced risk of CV events, MTHFR polymorphisms were not significantly associated with time-to-CV event. Time-to-CV event was associated with prior stroke (HR 2.01, 95% CI 1.03-3.90), prior MI (HR 1.70, 95% CI 1.06-2.71), hyperlipidemia (HR 1.57, 95% CI 1.01-2.43), and increased modified Charlson-Deyo index (HR 1.23, 95% CI 1.13-1.34). MTX use (HR 0.66, 95% CI 0.44-0.99) and increasing education (HR 0.87, 95% CI 0.80-0.95) were associated with a lower risk for CV events. CONCLUSION: Although MTHFR polymorphisms were previously associated with CV events in non-RA populations, we found only a trend toward decreased association with CV events in RA. Traditional risk factors conferred substantial CV risk, while MTX use and increasing years of education were protective.

Body mass index and the rheumatoid arthritis swollen joint count: an observational study.

OBJECTIVE: Obesity is a prevalent condition and a serious health concern. The relationship between obesity and rheumatoid arthritis (RA) disease activity and severity has not been adequately examined, and there are concerns that periarticular adipose tissue may reduce the utility of the joint examination. METHODS: We used a cross-sectional study to compare the performance of swollen joint count (SJC) in subjects with RA across body mass index (BMI) strata. Specifically, regression techniques tested for associations of SJC and 7 RA disease activity/severity measures (including high-sensitivity C-reactive protein level, radiographic changes, and Multidimensional Health Assessment Questionnaire scores) within BMI quartiles. We also evaluated the association of BMI with radiographic evidence of RA in multivariate analyses and the association of BMI with SJC. Clinical and laboratory data from 980 Veterans Affairs Rheumatoid Arthritis registry participants were analyzed using linear and logistic regression. RESULTS: Associations were evident between SJC and 6 of the 7 examined RA disease activity/severity measures. SJC predicts RA disease activity/severity in more obese subjects at least as well as in subjects with lower BMIs, and there was a trend toward better performance in individuals with higher BMIs. Subjects with higher BMIs were marginally less likely to be characterized by radiographic changes (odds ratio 0.98, P = 0.051). We found no association between BMI and SJC. CONCLUSION: BMI does not obscure the relationship of SJC and objective disease activity measures. There is a borderline association of higher BMI and the likelihood of radiographic changes characteristic of RA after controlling for clinical characteristics.

Adherence with bisphosphonate therapy in US veterans with rheumatoid arthritis.

OBJECTIVE: Pharmacy Benefits Management program data for patients enrolled in the Veterans Affairs Rheumatoid Arthritis (VARA) registry were linked with clinical data to determine bisphosphonate adherence and persistence among US veterans with rheumatoid arthritis (RA) and to determine factors associated with adherence. METHODS: The primary outcome measures were the duration of bisphosphonate therapy and the medication possession ratio (MPR). Patients with an MPR <0.80 were classified as nonadherent. Potential covariates considered in the analysis included patient demographics, RA disease activity and severity parameters, and factors associated with osteoporosis risk. Associations of patient factors with duration of therapy and adherence were examined using multivariable regression modeling. RESULTS: Bisphosphonates were prescribed to 573 (41.5%) of 1,382 VARA subjects. The mean ± SD duration of therapy for bisphosphonates was 39.2 ± 31.4 months. A longer duration of therapy correlated with older age, more years of education, and dual x-ray absorptiometry testing. The mean ± SD MPR of VARA subjects for bisphosphonate therapy was 0.69 ± 0.28; 302 (52.7%) were nonadherent. In multivariate analyses, nonadherence with bisphosphonate therapy was associated with a longer duration of RA disease (odds ratio [OR] 1.02, 95% confidence interval [95% CI] 1.00-1.04) and duration of bisphosphonate therapy >32 months (OR 1.63, 95% CI 1.04-2.57). Whites were less likely to have a low MPR compared with nonwhites (OR 0.52, 95% CI 0.30-0.88). CONCLUSION: Nonadherence with bisphosphonates was common in this cohort of RA patients and was associated with nonwhite ethnicity, a longer duration of RA disease, and a greater duration of bisphosphonate therapy.

Soluble CD14 and CD14 polymorphisms in rheumatoid arthritis.

OBJECTIVE: Soluble CD14 (sCD14) is involved in innate immune responses and has been implicated to play a pathogenic role in inflammatory diseases including rheumatoid arthritis (RA). No studies have identified the specific factors that influence sCD14 expression in RA. We used cross-sectional data to evaluate the relationship of sCD14 concentrations in RA with measures of disease activity and severity. We hypothesized that sCD14 concentrations would be elevated in subjects with greater RA disease severity and markers of disease activity, compared to subjects with lower disease activity. We also examined whether well-defined polymorphisms in CD14 are associated with sCD14 expression in RA. METHODS: Soluble CD14 concentrations were measured using banked serum from patients with RA (n = 1270) and controls (n = 186). Associations of patient factors including demographics, measures of RA disease activity/severity, and select CD14 single-nucleotide polymorphisms (SNP) with sCD14 concentration were examined in patients with RA using ordinal logistic regression. RESULTS: Circulating concentrations of sCD14 were higher in patients with RA compared to controls (p < 0.0001). Factors significantly and independently associated with higher sCD14 levels in patients with RA included older age, being white (vs African American), lower body mass index, elevated high sensitivity C-reactive protein, and higher levels of disease activity based on the Disease Activity Score (DAS28). There were no significant associations of CD14 tagging SNP with sCD14 level in either univariate or multivariable analyses. CONCLUSION: Circulating levels of sCD14 are increased in RA and are highest in patients with increased levels of RA disease activity. In the context of RA, sCD14 concentrations also appear to be strongly influenced by specific patient factors including older age and race but not by genetic variation in CD14.

Merging Veterans Affairs rheumatoid arthritis registry and pharmacy data to assess methotrexate adherence and disease activity in clinical practice.

OBJECTIVE: The Veterans Affairs (VA) Rheumatoid Arthritis (VARA) registry and the VA Pharmacy Benefits Management database were linked to determine the association of methotrexate (MTX) adherence with rheumatoid arthritis (RA) disease activity. METHODS: For each patient, the medication possession ratio (MPR) was calculated for the first episode of MTX exposure of a duration of ≥12 weeks for both new and established MTX users. High MTX adherence was defined as an MPR ≥0.80 and low MTX adherence was defined as an MPR <0.80. For each patient, the mean Disease Activity Score with 28 joints (DAS28) score, erythrocyte sedimentation rate (ESR), and C-reaction protein (CRP) level observed during registry followup were compared in high- versus low-adherence groups. RESULTS: In 455 RA patients, the prescribed doses of MTX (mean ± SD 16 ± 4 mg versus 16 ± 4 mg; P = 0.6) were similar in high-adherence patients (n = 370) in comparison to low-adherence patients (n = 85). However, the actual observed MTX doses taken by patients were significantly higher in the high-adherence group (mean ± SD 16 ± 5 mg versus 11 ± 3 mg; P < 0.001). DAS28 (mean ± SD 3.6 ± 1.2 versus 3.9 ± 1.5; P < 0.02), ESR (mean ± SD 24 ± 18 versus 29 ± 24 mm/hour; P = 0.05), and CRP level (mean ± SD 1.2 ± 1.3 versus 1.6 ± 1.5 mg/dl; P < 0.03) were lower in the high-adherence group compared to those with low MTX adherence. These variances were not explained by differences in baseline demographic features, concurrent treatments, or whether MTX was initiated before or after VARA enrollment. CONCLUSION: High MTX adherence was associated with improved clinical outcomes in RA patients treated with MTX. Adjustment for potential confounders did not alter the estimated effect of adherence. These results demonstrate the advantages of being able to merge clinical observations with pharmacy databases to evaluate antirheumatic drugs in clinical practice.

Anticitrullinated protein antibody (ACPA) in rheumatoid arthritis: influence of an interaction between HLA-DRB1 shared epitope and a deletion polymorphism in glutathione S-transferase in a cross-sectional study.

INTRODUCTION: A deletion polymorphism in glutathione S-transferase Mu-1 (GSTM1-null) has previously been implicated to play a role in rheumatoid arthritis (RA) risk and progression, although no prior investigations have examined its associations with anticitrullinated protein antibody (ACPA) positivity. The purpose of this study was to examine the associations of GSTM1-null with ACPA positivity in RA and to assess for evidence of interaction between GSTM1 and HLA-DRB1 shared epitope (SE). METHODS: Associations of GSTM1-null with ACPA positivity were examined separately in two RA cohorts, the Veterans Affairs Rheumatoid Arthritis (VARA) registry (n = 703) and the Study of New-Onset RA (SONORA; n = 610). Interactions were examined by calculating an attributable proportion (AP) due to interaction. RESULTS: A majority of patients in the VARA registry (76%) and SONORA (69%) were positive for ACPA with a similar frequency of GSTM1-null (53% and 52%, respectively) and HLA-DRB1 SE positivity (76% and 71%, respectively). The parameter of patients who had ever smoked was more common in the VARA registry (80%) than in SONORA (65%). GSTM1-null was significantly associated with ACPA positivity in the VARA registry (odds ratio (OR), 1.45; 95% confidence interval (CI), 1.02 to 2.05), but not in SONORA (OR, 1.00; 95% CI, 0.71 to 1.42). There were significant additive interactions between GSTM1 and HLA-DRB1 SE in the VARA registry (AP, 0.49; 95% CI, 0.21 to 0.77; P < 0.001) in ACPA positivity, an interaction replicated in SONORA (AP, 0.38; 95% CI, 0.00 to 0.76; P = 0.050). CONCLUSIONS: This study is the first to show that the GSTM1-null genotype, a common genetic variant, exerts significant additive interaction with HLA-DRB1 SE on the risk of ACPA positivity in RA. Since GSTM1 has known antioxidant functions, these data suggest that oxidative stress may be important in the development of RA-specific autoimmunity in genetically susceptible individuals.