Association of Agricultural, Occupational, and Military Inhalants With Autoantibodies and Disease Features in US Veterans With Rheumatoid Arthritis.

OBJECTIVE: To determine the association of inhalant exposures with rheumatoid arthritis (RA)-related autoantibodies and severity in US veterans. METHODS: Participants in the Veterans Affairs Rheumatoid Arthritis (VARA) registry were mailed surveys assessing occupational, agricultural, and military inhalant exposures. Demographic characteristics, disease activity, functional status, and extraarticular features were obtained from the VARA registry, while HLA-DRB1 shared epitope (SE) status, anti-cyclic citrullinated peptide (anti-CCP) antibodies, and rheumatoid factor (RF) were measured using banked DNA/serum from enrollment. Associations between inhalant exposures and RA-related factors (autoantibodies, severity, and extraarticular features) were assessed using multivariable linear and logistic regression models adjusted for age, sex, race, and tobacco use and stratified by SE status. Adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS: Questionnaires were returned by 797 of 1,566 participants (50.9%). Survey respondents were older, more often White or male, and less frequently smokers, and had lower disease activity compared to nonrespondents. Anti-CCP positivity was more common among veterans exposed to burn pits (OR 1.66 [95% CI 1.02, 2.69]) and military waste disposal (OR 1.74 [95% CI 1.04, 2.93]) independent of other factors. Among participants who were positive for SE alleles, burn pit exposure (OR 5.69 [95% CI 2.73, 11.87]) and military waste disposal exposure (OR 5.05 [95% CI 2.42, 10.54]) were numerically more strongly associated with anti-CCP positivity. Several inhalant exposures were associated with the presence of chronic lung disease, but not with the presence of RF or the level of disease activity. CONCLUSION: Military burn pit exposure and military waste disposal exposure were independently associated with the presence of anti-CCP antibodies in RA patients. These findings are consistent with emerging evidence that various inhalant exposures influence autoantibody expression and RA risk.

Rheumatology Clinicians' Perceptions of Telerheumatology Within the Veterans Health Administration: A National Survey Study.

INTRODUCTION: The Department of Veterans Affairs Veterans Health Administration (VA) Strategic Plan (Fiscal Year 2018-2024) identified four priorities for care including easy access, timely and integrated care, accountability, and modernization, all of which can be directly or indirectly impacted by telemedicine technologies. These strategic goals, coupled with an anticipated rheumatology workforce shortage, has created a need for additional care delivery methods such as clinical video telehealth application to rheumatology (ie, telerheumatology). Rheumatology clinician perceptions of clinical usefulness telerheumatology have received limited attention in the past. The present study aimed to evaluate rheumatologists' perceptions of and experiences with telemedicine, generally, and telerheumatology, specifically, within the VA. MATERIALS AND METHODS: A 38-item survey based on an existing telehealth providers' satisfaction survey was developed by two VA rheumatologists with experience in telemedicine as well as a social scientist experienced in survey development and user experience through an iterative process. Questions probed VA rheumatology clinician satisfaction with training and information technology (IT) supports, as well as barriers to using telemedicine. Additionally, clinician perceptions of the impact and usefulness of and appropriate clinical contexts for telerheumatology were evaluated. The survey was disseminated online via VA REDCap to members of the VA Rheumatology Consortium (VARC) through a LISTSERV. The study protocol was approved by the host institution IRB through expedited review. Survey responses were analyzed using descriptive statistics. RESULTS: Forty-five anonymous responses (20% response rate) were collected. Of those who responded, 47% were female, 98% were between 35 and 64 years old, 71% reported working at an academic center, and the majority was physician-level practitioners (98%). Respondents generally considered themselves to be tech savvy (58%). Thirty-six percent of the sample reported past experience with telemedicine, and, of those, 29% reported experience with telerheumatology specifically. Clinicians identified the greatest barrier to effective telerheumatology as the inability to perform a physical exam (71%) but agreed that telerheumatology is vital to increasing access to care (59%) and quality of care (40%) in the VA. Overall, regardless of experience with telemedicine, respondents reported that telerheumatology was more helpful for management of rheumatologic conditions rather than initial diagnosis. CONCLUSIONS: While the majority of rheumatology clinicians did not report past experience with telerheumatology, they agreed that it has potential to further the VA mission of improved access and quality of care. Rheumatology clinicians felt the suitability of telerheumatology is dependent on the phase of care. As remote care technologies continue to be rapidly adopted into clinic, clinician perceptions of and experiences with telemedicine will need to be addressed in order to maintain high-quality and clinician- and patient-centric care within VA rheumatology.

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.

Prospective study of posttraumatic stress disorder and disease activity outcomes in US veterans with rheumatoid arthritis.

OBJECTIVE: To examine the relationship between posttraumatic stress disorder (PTSD) and disease activity in US veterans with rheumatoid arthritis (RA). METHODS: US veterans with RA were enrolled in a longitudinal observational study and were categorized as having PTSD, other anxiety/depression disorders, or neither of these psychiatric diagnoses using administrative codes. Generalized linear mixed-effects models were used to examine the associations of the diagnostic groups with outcomes measured over a mean followup period of 3.0 years. RESULTS: At enrollment, 1,522 patients had a mean age of 63 years, they were primarily men (91%), and a majority (78%) reported white race. A diagnosis of PTSD was observed in 178 patients (11.7%), and other anxiety/depression diagnoses (excluding PTSD) were found in 360 patients (23.7%). The presence of a PTSD diagnosis was independently associated with higher values of self-reported pain, physical impairment, tender joint count, and worse patient global well-being scores compared to patients with no psychiatric diagnosis. There were no significant group differences in swollen joint count, erythrocyte sedimentation rate, or Disease Activity Score in 28 joints. There were no differences between any outcomes comparing those with PTSD and those with other anxiety/depression diagnoses. CONCLUSION: In this RA cohort, the diagnosis of PTSD was associated with worse patient-reported outcomes and tender joint counts, but not with other physician- or laboratory-based measures of disease activity. These results suggest that PTSD, along with other anxiety/depression disorders, may affect RA disease activity assessments that rely on patient-reported outcomes and the resulting treatment decisions.

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.

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.

Anti-CCP antibody and rheumatoid factor concentrations predict greater disease activity in men with rheumatoid arthritis.

OBJECTIVE: To examine associations of anti-cyclic citrullinated peptide (aCCP) antibody and rheumatoid factor (RF) concentrations with future disease activity in men with rheumatoid arthritis (RA). METHODS: Outcome measures were examined in male US veterans with RA and included (1) proportion of observations in remission (disease activity score (DAS28) < or =2.6); (2) remission for > or =3 consecutive months; and (3) area under the curve (AUC) for DAS28. The associations of autoantibody concentration (per 100 unit increments) with outcomes were examined using multivariate regression. RESULTS: 826 men with RA were included in the analysis; the mean (SD) age was 65 (10.5) years and follow-up was for 2.6 (1.3) years. Most were aCCP (75%) and RF (80%) positive. After multivariate adjustment, aCCP (OR 0.93; 95% CI 0.89 to 0.96) and RF concentrations (OR 0.92; 95% CI 0.90 to 0.94) were associated with a lower odds of remission, a lower proportion of observation in remission (p=0.017 and p=0.002, respectively) and greater AUC DAS28 (p=0.092 and p=0.007, respectively). Among patients with discordant autoantibody status, higher concentrations of both aCCP and RF trended towards an inverse association with remission (OR 0.93; 95% CI 0.83 to 1.05 and OR 0.80; 95% CI 0.59 to 1.10, respectively). CONCLUSIONS: Higher aCCP concentrations (particularly in RF-positive patients) are associated with increased disease activity in US veterans with RA, indicating that aCCP concentration is predictive of future disease outcomes in men.

Dual-energy X-ray absorptiometry and evaluation of the osteoporosis self-assessment tool in men with rheumatoid arthritis.

Males with rheumatoid arthritis (RA) are at risk for osteoporosis but infrequently undergo dual-energy X-ray absorptiometry (DXA). We examined the frequency of DXA in males enrolled in the Veterans Affairs Rheumatoid Arthritis Registry. The Osteoporosis Self-Assessment Tool (OST) index, a formula using age and weight, was calculated for all subjects. DXA was performed on 282 (35.5%) of the males who were younger (p < 0.01), had lower mean OST index score (p < 0.05), and were more likely to have been prescribed prednisone (p < 0.01) than subjects without DXA. Low bone mass (T-score < -1) was present in 73% of subjects with DXA; 37% of subjects with low-risk OST index scores had normal bone mineral density (BMD) compared with 5.6% of those with high-risk OST index scores (p < 0.01). There was a significant but modest correlation between BMD and the OST index (r = 0.17, p < 0.01). No OST score had a sensitivity and specificity of more than 80%. Association between OST index and BMD was strongest in non-Hispanic whites, subjects older than 60 yr, and smokers. DXA was underutilized in males with RA. The OST index correlated with low bone mass but could not reliably predict osteoporosis in this population.

Osteoporosis risk factor assessment increases the appropriate use of dual energy X-ray absorptiometry in men and reduces ethnic disparity.

BACKGROUND: Male patients are frequently not tested for osteoporosis even in the presence of recognized risk factors for that disease. OBJECTIVES: To evaluate if the assessment of risk factors for osteoporosis increases the utility of dual energy X-ray absorptiometry (DXA) in men over the age of 50 attending a rheumatology clinic. METHODS: Men over 50 attending a rheumatology clinic completed a checklist of 10 risk factors for osteoporosis before seeing the physician. The physician reviewed the checklist and made a management decision. The checklists and medical records were reviewed for medical history and DXA results. Comparisons were made with DXA requests before the use of the checklist. RESULTS: Medical records of 183 men were reviewed, including 111 African Americans (AA) and 67 whites. Twenty-three percent of patients had rheumatoid arthritis (14% of AA, 37% of whites) and 27% of patients were on glucococorticoids. Before the use of the checklist, 14% of men had a DXA (6% of AA and 29% of whites) compared with 29% of patients (21% for AA and 42% for whites) after the checklist was instituted in the clinic. Sixty-three percent of AA with rheumatoid arthritis had DXA compared with 65% of whites. Thirteen patients had osteoporosis whereas 16 had osteopenia. CONCLUSIONS: The use of a check list of risk factors for osteoporosis may increase the appropriate use of DXA in male patients over the age of 50 at risk for osteoporosis.

The association of race and ethnicity with disease expression in male US veterans with rheumatoid arthritis.

OBJECTIVE: To examine the association of race/ethnicity with measures of disease activity and severity among male US veterans with rheumatoid arthritis (RA). METHODS: Measures of disease activity and severity were examined in a group of US veterans (n = 573) with RA, comparing measures in African American men (n = 79) with Caucasian men (n = 494). Dichotomous variables were compared using logistic regression while continuous variables were examined using linear regression, adjusting for the effects of age, disease duration, and smoking status. RESULTS: Compared to Caucasians, African Americans were slightly younger (65.0 vs 67.1 yrs; p = 0.09) at enrollment and had a similar age at disease onset (50.5 vs 50.6 years; p = 0.98). After adjusting for age, disease duration, and smoking status, there were no differences based on race/ethnicity in rheumatoid factor positivity, the presence of radiographic changes, physical functioning, swollen joint counts, Disease Activity Score (DAS28), or global well-being scores. In contrast, African Americans were about 50% less likely than Caucasians with RA to have subcutaneous nodules (adjusted OR 0.51, 95% CI 0.30-0.86) and had lower tender joint counts (p = 0.007), associations that were attenuated and not significant with further adjustment for collection site. CONCLUSION: With the possible exception of lower rates of rheumatoid nodules and lower tender joint counts in African Americans, there is little evidence to support the existence of important racial/ethnic differences in RA disease expression between African American and Caucasian men.

Rheumatic diseases in minority populations.

Rheumatic diseases are expressed in all ethnic populations, but differ in prevalence, genetic associations, clinical features, and responses to interventions. Most data describing these differences do so in reference to and comparisons with white populations. These are sparse data that evaluate differences within minority populations where there is more homogeneity of external factors, such as social, cultural, and behavioral attitudes. This article reviews the features that are unique to various rheumatic diseases within minority populations.

Elderly African-American and Caucasian men are infrequently screened for osteoporosis.

INTRODUCTION: To retrospectively examine the factors that initiated a request for dual x-ray absorptiometry (DXA) in elderly males in a rheumatology practice and to determine if there were differences between African Americans and Caucasians, MATERIALS AND METHODS: The records of 98 consecutive male patients in the rheumatology clinic were reviewed for demographic data and risk factors and treatment for osteoporosis. DXA results were noted and classified as normal, osteopenic or osteoporotic. RESULTS: There were 59 (60%) African Americans, 38 (39%) Caucasians and one (1%) Native American included for study. Fourteen patients had DXA-three (5%) among the African Americans and 11 (29%) among the Caucasians. Age was not found to be a significant predictor of obtaining DXA. Caucasians were 7.69 times more likely to have a DXA than African Americans. After adjusting for ethnicity, oral glucocorticoid use and rheumatoid arthritis were significant predictors of obtaining a DXA, although only 31% and 35% of patients on glucocorticoids or with rheumatoid arthritis, respectively, had DXA. Using a logistic regression model, ethnicity (odds ratio 4.61) remained the only significant predictor of requests for DXA. CONCLUSION: Male patients infrequently had DXA despite the presence of well-established risk factors for osteoporosis. Compared to Caucasians, fewer African Americans were screened even in the presence of similar risk factors for osteoporosis.

Erysipelothrix rhusiopathiae septic arthritis.

We describe herein the case of a man with Erysipelothrix rhusiopathiae septic arthritis and possible infective endocarditis. This is the first report in the English-language medical literature of septic arthritis caused by this organism.