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OBJECTIVE To examine the impact of major therapeutic change (MTC) on clinical response across a broad range of disease activity in US veterans with rheumatoid arthritis (RA). METHODS This historical cohort analysis evaluated patient visits from the Veterans Affairs RA registry between January 1, 2006 and September 30, 2017. Eligible patient visits were a rheumatology visit with 3 disease activity measures, including the Disease Activity Score in 28 joints, the Clinical Disease Activity Index, and the Routine Assessment of Patient Index Data 3; the follow-up visit for all 3 disease activity measures was 2-6 months later. The full population and a subset of patients with active disease (≥6 tender joints, ≥6 swollen joints) were evaluated. Clinical outcome was based on the American College of Rheumatology criteria for 20% improvement in disease activity (ACR20). The effect of MTC on ACR20 response was presented as crude descriptive statistics and evaluated using standardized regression for population- and disease activity-level conditional effects. RESULTS The full population comprised 1,208 patients (6,138 visits) and the active disease subpopulation included 383 patients (1,109 visits). Overall, visits with MTC were associated with increased likelihood of ACR20 response across all disease activity measures for the full population. Risk ratios for overall risk of ACR20 response for visits with MTC versus those without MTC ranged from 1.67 to 2.22 across disease activity measures among the full population and from 1.51 to 1.60 for the subpopulation with active disease. CONCLUSION MTC was associated with clinical improvement, even among patients with longstanding RA who had received multiple prior therapies, which emphasizes the utility of therapy modifications for patients with established and active RA.

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.

PurposeRheumatoid arthritis (RA) is associated with a higher risk of diabetes mellitus (DM). Our aim was to determine associations between inflammatory disease activity (including evaluation of specific cytokines and chemokines) and incident DM.MethodsParticipants were adults with physician-confirmed RA from Veteran’s Affairs Rheumatoid Arthritis Registry. Disease activity and clinical assessments occur longitudinally as part of clinical care. Thirty cytokines and chemokines were measured in banked serum obtained at the time of enrolment. Cytokine/chemokine values were log-adjusted and standardised (per SD). Incident DM was defined based on validated algorithms using diagnostic codes and medications. Multivariable Cox proportional hazard models evaluated associations between clinical factors and incident DM. Independent associations between cytokines/chemokines and incident DM were assessed adjusting for age, sex, race, smoking, body mass index (BMI) and medication use at baseline.ResultsAmong 1866 patients with RA without prevalent DM at enrolment, there were 130 incident cases over 9223 person-years of follow-up. High Disease Activity Score (DAS28)-C reactive protein (CRP), obese BMI, older age and male sex were associated with greater risk for incident DM while current smoking and methotrexate use were protective. Patients using methotrexate were at lower risk. Several cytokines/chemokines evaluated were independently associated (per 1 SD) with DM incidence including interleukin(IL)-1, IL-6 and select macrophage-derived cytokines/chemokines (HR range 1.11–1.26). These associations were independent of the DAS28-CRP.ConclusionsHigher disease activity and elevated levels of cytokines/chemokines are associated with a higher risk of incident DM in patients with RA. Future study may help to determine if targeted treatments in at-risk individuals could prevent the development of DM.

OBJECTIVE To determine the performance of administrative-based algorithms for classifying interstitial lung disease (ILD) complicating rheumatoid arthritis (RA). METHODS Participants in a large, multicenter RA registry were screened for ILD using codes from the International Classification of Diseases, Ninth Revision (ICD-9) and the ICD-10. Medical record review confirmed ILD among participants screening positive and a random sample of those screening negative. ICD and procedure codes, provider specialty, and dates were extracted from Veterans Affairs administrative data to construct ILD algorithms. Performance of these algorithms against medical record review was assessed by sensitivity, specificity, positive predictive value (PPV), negative predictive value, and kappa using inverse probability weighting to account for sampling methods. RESULTS Medical records of 536 RA patients were reviewed, confirming 182 (stringent definition) and 203 (relaxed definition) cases of ILD. Initially, we identified ≥2 ICD codes from inpatient or outpatient encounters as optimal discriminating factors (specificity 96.0%, PPV 65.5%; κ = 0.70). Subsequently, we constructed a set of ICD-9 and ICD-10 codes that improved algorithm specificity (specificity 96.8%, PPV 69.5%; κ = 0.72). Algorithms that included a pulmonologist diagnosis or chest computed tomography plus pulmonary function testing or lung biopsy had improved performance (specificity 98.0%, PPV 77.4%; κ = 0.75). PPV increased with exclusion of other ILD causes (78.5%) in comparison with the relaxed ILD definition (82.4%) and in sensitivity analyses (83.4-86.3%). Gains in specificity and PPV with greater algorithm requirements were accompanied by declines in sensitivity. CONCLUSION Administrative algorithms with optimal combinations of ICD codes, provider specialty, diagnostic testing, and exclusion of other ILD causes accurately classify ILD in RA.

OBJECTIVE: In rheumatoid arthritis, whether women are less likely to achieve low disease activity is unclear. We evaluated sex differences in remission and low disease activity, comparing different clinical and imaging measures.METHODS: We used data from the Veterans Affairs Rheumatoid Arthritis (VARA) registry and from 2 clinical trials. Remission and low disease activity were defined using composite scores, individual items (tender joints, swollen joints, erythrocyte sedimentation rate [ESR], C-reactive protein [CRP] level, and evaluator/patient global assessment), and magnetic resonance imaging (MRI). In the VARA registry, we assessed the likelihood of point remission at any time during follow-up using logistic regression, and time to sustained remission (2 consecutive visits) using Cox proportional hazards models. In the clinical trials, logistic regression models evaluated the likelihood of low clinical and MRI activity at 52 weeks.RESULTS: Among 2,463 patients in VARA, women (10.2%) were less likely to be in Disease Activity Score in 28 joints (DAS28)-ESR remission in follow-up (odds ratio [OR] 0.71 [95% confidence interval (95% CI) 0.55-0.91]; P < 0.01) and had a longer time to sustained DAS28-ESR remission. This difference was not observed for DAS28-CRP, Clinical Disease Activity Index, or Routine Assessment of Patient Index Data 3. Women were more likely to achieve favorable individual components except for an ESR CONCLUSION: The comparison of remission rates between men and women varies based on the disease activity measure, with sex-specific differences in ESR resulting in reliably lower rates of remission among women. There were no differences in MRI measures.

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-1β, 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.

OBJECTIVES: We aimed to assess whether serum cytokine/chemokine concentrations predict incident cancer in RA patients. METHODS: Data from cancer-free enrollees in the Veterans Affairs Rheumatoid Arthritis (VARA) Registry were linked to a national VA oncology database and the National Death Index (NDI) to identify incident cancers. Seventeen serum cytokines/chemokines were measured from enrollment serum and an overall weighted cytokine/chemokine score (CK score) was calculated. Associations of cytokines/chemokines with all-site, lung, and lymphoproliferative cancers were assessed in Cox regression models accounting for relevant covariates including age, sex, RA disease activity, and smoking. RESULTS: In 1,216 patients, 146 incident cancers (42 lung and 23 lymphoproliferative cancers) occurred over 10,072 patient-years of follow-up with a median time of 4.6 years from enrollment (cytokine/chemokine measurement) to cancer incidence. In fully adjusted models, CK score was associated with a higher risk of all-site (aHR 1.32, 95% CI 1.01-1.71, p

Summary An informatics-driven population bone health clinic was implemented to identify, screen, and treat rural US Veterans at risk for osteoporosis. We report the results of our implementation process evaluation which demonstrated BHT to be a feasible telehealth model for delivering preventative osteoporosis services in this setting. Purpose An established and growing quality gap in osteoporosis evaluation and treatment of at-risk patients has yet to be met with corresponding clinical care models addressing osteoporosis primary prevention. The rural bone health tea m (BHT) was implemented to identify, screen, and treat rural Veterans lacking evidence of bone health care and we conducted a process evaluation to understand BHT implementation feasibility. Methods For this evaluation, we defined the primary outcome as the number of Veterans evaluated with DXA and a secondary outcome as the number of Veterans who initiated prescription therapy to reduce fracture risk. Outcomes were measured over a 15-month period and analyzed descriptively. Qualitative data to understand successful implementation were collected concurrently by conducting interviews with clinical personnel interacting with BHT and BHT staff and observations of BHT implementation processes at three site visits using the Promoting Action on Research Implementation in Health Services (PARIHS) framework. Results Of 4500 at-risk, rural Veterans offered osteoporosis screening, 1081 (24%) completed screening, and of these, 37% had normal bone density, 48% osteopenia, and 15% osteoporosis. Among Veterans with pharmacotherapy indications, 90% initiated therapy. Qualitative analyses identified barriers of rural geography, rural population characteristics, and the infrastructural resource requirement. Data infrastructure, evidence base for care delivery, stakeholder buy-in, formal and informal facilitator engagement, and focus on teamwork were identified as facilitators of implementation success. Conclusion The BHT is a feasible population telehealth model for delivering preventative osteoporosis care to rural Veterans.

An informatics-driven population bone health clinic was implemented to identify, screen, and treat rural US Veterans at risk for osteoporosis. We report the results of our implementation process evaluation which demonstrated BHT to be a feasible telehealth model for delivering preventative osteoporosis services in this setting.An established and growing quality gap in osteoporosis evaluation and treatment of at-risk patients has yet to be met with corresponding clinical care models addressing osteoporosis primary prevention. The rural bone health tea m (BHT) was implemented to identify, screen, and treat rural Veterans lacking evidence of bone health care and we conducted a process evaluation to understand BHT implementation feasibility.For this evaluation, we defined the primary outcome as the number of Veterans evaluated with DXA and a secondary outcome as the number of Veterans who initiated prescription therapy to reduce fracture risk. Outcomes were measured over a 15-month period and analyzed descriptively. Qualitative data to understand successful implementation were collected concurrently by conducting interviews with clinical personnel interacting with BHT and BHT staff and observations of BHT implementation processes at three site visits using the Promoting Action on Research Implementation in Health Services (PARIHS) framework.Of 4500 at-risk, rural Veterans offered osteoporosis screening, 1081 (24%) completed screening, and of these, 37% had normal bone density, 48% osteopenia, and 15% osteoporosis. Among Veterans with pharmacotherapy indications, 90% initiated therapy. Qualitative analyses identified barriers of rural geography, rural population characteristics, and the infrastructural resource requirement. Data infrastructure, evidence base for care delivery, stakeholder buy-in, formal and informal facilitator engagement, and focus on teamwork were identified as facilitators of implementation success.The BHT is a feasible population telehealth model for delivering preventative osteoporosis care to rural Veterans.

Background A previous analysis of the Veterans Affairs Rheumatoid Arthritis (VARA) registry showed that more than half of the patients with rheumatoid arthritis (RA) did not receive a major therapeutic change (MTC) despite moderate or severe disease activity. We aimed to empirically determine disease activity thresholds associated with a decision by rheumatologists and nurse practitioners to institute a MTC in patients with RA and to report the impact of that change on RA disease activity. Methods We analyzed data from the VARA registry between January 1, 2006, and September 30, 2017. Eligible patients had a visit with 3 disease activity measures (DAMs) recorded: Disease Activity Score for 28 joints (DAS28), Clinical Disease Activity Index (CDAI), and Routine Assessment of Patient Index Data 3 (RAPID3). The Youden Index was used to identify disease activity thresholds that best discriminated rheumatologist/nurse practitioner decision to initiate MTC. Clinical outcome was 20% improvement in the American College of Rheumatology criteria (ACR20 response). The effect of MTC on ACR20 response was presented as crude descriptive statistics and evaluated using G-computation for marginal and conditional effects with established disease activity level combined with an empirical threshold from Youden analysis. Results The study population comprised 1776 patients (12,094 visits: 3077 with MTC, 9017 without MTC). Empirical thresholds (95% bootstrap confidence interval with 1000 replications) for MTC were 4.03 (3.70–4.36) for DAS28, 12.9 (10.4–15.4) for CDAI, and 3.81 (3.32–4.30) for RAPID3. Visits with MTC had increased likelihood of ACR20 response: risk ratios for ACR20 response for visits with MTC vs without MTC ranged 1.2–2.6 across DAMs; risk differences ranged 0.2–14.5%. Conclusions MTC was associated with clinical improvement across all DAMs with the greatest change in patients with RA disease activity above the Youden threshold identified in this work. Trial registration VARA Registry, https://www.hsrd.research.va.gov/research/abstracts.cfm?Project_ID=2141698764

INTRODUCTION/OBJECTIVES: Assess the impact of chronic lung diseases (CLD) on survival in rheumatoid arthritis (RA). METHOD: Among participants in the Veterans Affairs Rheumatoid Arthritis (VARA) Registry, a prospective cohort of U.S. Veterans with RA, we identified CLD and cardiovascular disease (CVD) using administrative and registry data. Demographics, smoking status, RA characteristics including Disease Activity Score in 28 joints (DAS28), and disease-modifying anti-rheumatic drug (DMARD) use were obtained from registry data, which was linked to the National Death Index to obtain vital status. We evaluated associations of CLD with survival using multivariable Cox regression models. RESULTS: Among a large (n=2,053), male predominant (91%) RA cohort, 554 (27%) had CLD at enrollment. Mortality risk was increased 1.51-fold (95% CI 1.26–1.81) in RA patients with CLD after multivariable adjustment, a risk that was similar to that observed with CVD (HR CLD alone 1.46 [1.03–2.06]; CVD alone 1.62 [1.35–1.94]). Survival was significantly reduced in those with interstitial lung disease (ILD) as well as other forms of CLD. Mortality risk with methotrexate and biologic use was not different in those with CLD compared to those without (p interaction ≥ 0.15) using multiple exposure definitions and propensity score adjustment. CONCLUSIONS: Mortality risk is significantly increased in RA patients with CLD. This risk is attributable not only to ILD but also to other chronic lung conditions and does not appear to be substantially greater in those receiving methotrexate or biologic therapies. Comorbid lung disease should be targeted as a means of improving long-term outcomes in RA.

Objective.To evaluate the effect of access to and distance from rheumatology care on the use of disease-modifying antirheumatic drugs (DMARD) in US veterans with inflammatory arthritis (IA).Methods.Provider encounters and DMARD dispensations for IA (rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis) were evaluated in national Veterans Affairs (VA) datasets between January 1, 2015, and December 31, 2015.Results.Among 12,589 veterans with IA, 23.5% saw a rheumatology provider. In the general IA population, 25.3% and 13.6% of veterans were exposed to a synthetic DMARD (sDMARD) and biologic DMARD (bDMARD), respectively. DMARD exposure was 2.6- to 3.4-fold higher in the subpopulation using rheumatology providers, compared to the general IA population. The distance between veterans’ homes and the closest VA rheumatology site was < 40 miles (Near) for 55.9%, 40–99 miles (Intermediate) for 31.7%, and ≥ 100 miles (Far) for 12.4%. Veterans in the Intermediate and Far groups were less likely to see a rheumatology provider than veterans in the Near group (RR = 0.72 and RR = 0.49, respectively). Exposure to bDMARD was 34% less frequent in the Far group than the Near group. In the subpopulation who used rheumatology care, the bDMARD exposure discrepancy did not persist between distance groups.Conclusion.Use of rheumatology care and DMARD was low for veterans with IA. DMARD exposure was strongly associated with rheumatology care use. Veterans in the general IA population living far from rheumatology sites accessed rheumatology care and bDMARD less frequently than veterans living close to rheumatology sites.

OBJECTIVE Many veterans enrolled in Veterans Affairs (VA) health care systems also receive care through other health care systems. Both VA and non-VA health care use must therefore be considered when conducting research in this population. This study characterized dual-care utilization in veterans with rheumatoid arthritis (RA) and explored associations with RA disease activity. METHODS Through a questionnaire mailed to RA patients at 3 VA sites, veterans reported medical services by non-VA primary care and subspecialty providers, comorbidities, non-VA medications, and hospitalizations. Disease Activity Score in 28 joints (DAS28) and Multidimensional Health Assessment Questionnaire (MD-HAQ) scores were recorded during VA clinic visits, and respondent groups were compared. RESULTS Of the 510 participants surveyed, 318 (62%) responded. Respondents were older (ages 69 versus 66 years; P = 0.006), more likely nonsmokers (80% versus 67%; P = 0.001), and had lower disease activity (DAS28 3.3 versus 3.8; P

Background This study developed and validated a claims-based statistical model to predict rheumatoid arthritis (RA) disease activity, measured by the 28-joint count Disease Activity Score (DAS28). Method Veterans enrolled in the Veterans Affairs Rheumatoid Arthritis (VARA) registry with one year of data available for review before being assessed by the DAS28, were studied. Three models were developed based on initial selection of variables for analyses. The first model was based on clinically defined variables, the second leveraged grouping systems for high dimensional data and the third approach prescreened all possible predictors based on a significant bivariate association with the DAS28. The least absolute shrinkage and selection operator (LASSO) with fivefold cross-validation was used for variable selection and model development. Models were also compared for patients with 5.1) activity. Results There were 1582 Veterans who fulfilled inclusion criteria. The adjusted r-square for the three models tested ranged from 0.221 to 0.223. The models performed slightly better for patients with

Objective To compare persistence and adherence to triple therapy with the nonbiologic disease-modifying antirheumatic drugs (DMARDs) methotrexate (MTX), hydroxychloroquine, and sulfasalazine, versus a tumor necrosis factor inhibitor (TNFi) plus MTX in patients with rheumatoid arthritis (RA). Methods Administrative and laboratory data were analyzed for US Veterans with RA initiating triple therapy or TNFi + MTX between January 2006 and December 2012. Treatment persistence 365 days postindex was calculated using 3 definitions. Definition 1 required no gap in therapy of ≥90 days for any drug in the original combination. Definition 2 required no added or switched DMARD, no decrease to nonbiologic DMARD monotherapy, and no termination of all DMARD therapies. Definition 3 was similar to definition 2 but allowed a switch to another drug within the same class. Adherence used a proportion of days covered of ≥80%. Propensity-weighted analysis with matched weights was used to balance covariates. Results The analysis included 4,364 RA patients (TNFi + MTX, n = 3,204; triple therapy, n = 1,160). In propensity-weighted analysis, patients in the TNFi + MTX group were significantly more likely than patients in the triple therapy group to satisfy all persistence criteria in definition 1 (risk difference [RD] 13.1% [95% confidence interval (95% CI) 9.2–17.0]), definition 2 (RD 6.4% [95% CI 2.3–10.5]), and definition 3 (RD 9.5% [95% CI 5.5–13.6]). Patients in the TNFi + MTX group also exhibited higher adherence during the first year (RD 7.2% [95% CI 3.8–10.5]). Conclusion US Veterans with RA were significantly more likely to be persistent and adherent to combination therapy with TNFi + MTX than triple therapy with nonbiologic DMARDs.

Background Osteoporosis is inadequately treated in primary care settings. Under-recognition of the condition among male Veterans may contribute to this problem. In order to improve understanding of bone health in older male patients, we developed the “Musculoskeletal (MSK) Education Week”, a multidisciplinary clinical training initiative within a primary care ambulatory rotation for internal medicine (IM) residents at the Salt Lake City VA Medical Center. The objective of this study was to evaluate the impact of this program on trainees’ recognition of osteoporosis or treatment of this condition following the training experience. Methods We examined several clinical behaviors of post-graduate year 1 (PGY-1) IM trainees following their participation in the MSK Education Week between July 1–April 30, 2014. To determine the prevalence of these clinical behaviors, we conducted an observational study of patients age 50 and older enrolled at the Salt Lake City VA Healthcare System from July 1, 2013 to May 31, 2014. We used time-dependent multivariable Cox proportional hazard models to evaluate the impact of the training program on 4 osteoporosis-related outcomes: (1) completion of dual energy X-ray absorptiometry (DXA) scan, (2) diagnosis of osteopenia, (3) diagnosis of osteoporosis, and (4) initiation of osteoporosis medications. Results Twenty-six PGY-1 IM residents participated in the MSK Education Week, and 43,678 Veterans were identified over these periods of observation. In the Veterans cohort, 1154 had an encounter with a provider who had completed the training (and were therefore “exposed” to the training) and 42,524 Veterans did not. After adjusting for confounders, the effect of the provider training program was significant for DXA (HR = 1.78, 95% CI: 1.11, 2.87), osteoporosis diagnosis (HR = 3.90, 95% CI: 2.09, 7.29), and initiation of medications (HR = 2.87, 95% CI: 2.02, 4.09) outcomes. Conclusions We have shown that IM residents’ participation in the MSK Education Week was associated with significantly improvements in their completion of DXA scans, diagnosis of osteoporosis, and initiation of fracture-reducing medications in a population of US Veterans. Long-term follow up is needed to determine whether these initial results are followed by actual reductions in osteoporotic fractures.

Background Our recent work showed that 41% of patients with moderate/severe rheumatoid arthritis (RA) by Disease Activity Score for 28 joint count (DAS28) did not have changes in RA therapy as recommended by current guidelines (1). Reasons identified for the decision not to escalate therapy was provider’s opinion that RA disease was adequately controlled despite moderate/severe disease activity by DAS28, and that changes in therapy may not produce significant improvements in disease activity (1). Objectives 1) Compare short-term differences in ACR20 response between patients with and without a major therapeutic change (MTC) over a range of disease activity; 2) Determine whether ACR20 responses vary by disease activity measures (DAMs) used to assess disease activity (i.e., DAS28, Clinical Disease Activity Index [CDAI], Routine Assessment of Patient Index Data 3 [RAPID3]). Methods Each clinic visit for US Veterans enrolled in the VA Rheumatoid Arthritis (VARA) registry was evaluated if the visit had: 1) a complete set of DAMs (DAS28, CDAI, RAPID3) recorded; 2) two other visits with all DAMs during the preceding 18 months separated by at least 60 days and one visit with all DAMs between 60 and 180 days following the visit date; 3) clinical data available for 18 months prior to visit date; and 4) ≥6 tender and ≥6 swollen joints at visit date. Each patient was assessed for MTC within 1 week before and 30 days after visit date. MTC was defined as any of the following: 1) initiation of new biologic or nonbiologic disease-modifying antirheumatic drug (DMARD) or prednisone (as new agent or after 90-day gap during baseline); 2) escalation of DMARD dose by ≥25%; or 3) increase in monthly average prednisone dose by 25%; and/or 4) injection of 2 or more joints with corticosteroids. Clinical improvement was defined as an ACR20 response comparing each eligible visit DAM to the first follow-up visit DAM observed between 60 and 180 days of the eligible visit date. ACR20 response was compared between eligible visits with and without a MTC and stratified by quartiles of disease activity by each DAM. The Generalized Estimating Equations (GEE) model was fitted using the exchangeable working covariance structure to account for clustering of visits within patients. Models for each DAM were adjusted for age, disease duration, race, seropositive status, comorbidities, disease stability, and recent medication changes in the observations period prior to the visit date. Results There were 383 patients (92% were male, mean age was 62.9 years, mean disease duration was 12.5 years, 83% tested positive for rheumatoid factor, and 79% positive for anti-cyclic citrullinated peptide antibodies) who contributed 1,193 eligible visits. Visits with a MTC had a higher rate of ACR20 response in comparison to visits without a MTC at all levels of disease activity. A MTC at a visit with the highest disease activity (quartile 4) consistently had the largest proportion of follow-up visits with an ACR20 response. The overall effect for MTC was statistically significant across all 3 DAMs. Across quartiles, the MTC group consistently had a higher proportion of follow-up visits with ACR20 response compared to the group without a MTC. Risk Ratios from the adjusted analysis are presented in the table. Conclusion All patients with active RA have a significant potential to benefit with a MTC. This potential for improvement was seen across all degrees of disease activity and with all three DAMs. Reference [1] Stever, et al. Utility of administrative and clinical data to predict major change in medical treatment in US Veterans enrolled in the Veterans Affairs Rheumatoid Arthritis (VARA) registry. Clin Exp Rheumatol; 2018Epub ahead of print. Disclosure of Interests Grant Cannon Grant/research support from: Amgen Inc., Wei Chen Grant/research support from: Amgen Inc., Jincheng Shen: None declared, Neil Accortt Shareholder of: Amgen Inc., Employee of: Amgen Inc., David Collier Shareholder of: Amgen Inc., Employee of: Amgen Inc., Brian Sauer Grant/research support from: Amgen Inc.

Background The Veterans Affairs (VA) Rheumatoid Arthritis (RA) (VARA) registry is an observational cohort study of US Veterans with RA at 11 VA Medical Centers. VARA investigators capture clinical and laboratory disease activity measures (DAMs) during clinic visits via standardized templates in the electronic health record (EHR). Six clinical (tender/swollen joints, patient/provider global, MD-HAQ, pain) and 2 laboratory (ESR, CRP) DAMs are extracted post-visit using natural language processing (NLP). Objectives This analysis determined the impact of an audit, feedback and data correction system on the quantity and quality of DAMs collected in the VARA registry. Methods After September 2017, VARA site investigators were provided monthly feedback reports of incomplete/missing DAMs for the prior month to allow sites to correct data entry errors. Updated and/or corrected data were entered into the EHR via note addendums and then automatically re-extracted by NLP to complete the capture of DAM data. DAMs from October 1, 2016 to September 30, 2017 (pre-feedback implementation – Pre-IMP) was compared to October 1, 2017 to September 30, 2018 (post-feedback implementation – Post-IMP). Results During the pre-IMP period, there were 2,411 notes with DAMs collected on 1,116 unique patients compared to 2,873 notes on 1,208 unique patients in the post-IMP period - an increase of 92 (8.2%) unique patients and 460 (19.1%) notes. Enrollment in the VARA registry only increased by 121 (6.5%) during post-IMP period. During post-IMP period, there were 541 notes identified with deficiencies in clinical DAMs and monthly audit and feedback reports were provided to VARA sites to allow corrections. Individual site review resulted in 376 additional DAMs in 225 notes, with complete resolution of all error in 137 (25.3%) notes. The quantity of DAMs collected increased from 15,709 to 21,064, a 34.1% increase with the average number of DAMs collected per note rising from 4.9 to 5.6. The quality of data improved as demonstrated by the proportion of notes with all 6 clinical DAMs increasing from 52.5% to 81.1% and other improvements in quality/completeness as noted in table. Conclusion An audit, feedback, and efficient data collection system improved both the quantity and quality of DAMs collected. The improvement in the collection of DAMs in RA patients will further enhance epidemiologic and outcomes studies of RA and provide higher quality longitudinal data to enhance the care of RA patients. References [1] Fed Pract 2015; 32(5):24-29 Acknowledgement Work Support in Part by VA HSR&D and VA Specialty Care Centers of Innovation Disclosure of Interests Grant Cannon Grant/research support from: Amgen Inc., Jorge Rojas: None declared, Neill Bell: None declared, Namrata Singh: None declared, Ted Mikuls: None declared, Liron Caplan: None declared, Gail Kerr: None declared, Joshua Baker: None declared, Angelo Gaffo: None declared, Jennifer Barton: None declared, Deana Lazaro: None declared, J Steuart Richards: None declared, Brian Sauer Grant/research support from: Amgen Inc.

Background Delays in treatment for inflammatory arthritis (IA) are associated with unfavorable outcomes, including impaired quality of life, irreversible joint damage, and disability. Objectives To characterize treatment initiation patterns in patients with newly diagnosed rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). Methods Incident IA cases were identified between January 1, 2007 and December 31, 2015, in patients enrolled in the Veteran Health Administration, using International Classification of Diseases codes and natural language processing. Patterns of treatment initiation and non-treatment with disease modifying anti-rheumatic drugs (DMARDs) were assessed in the 12-month follow-up period after the incident diagnosis. Results The population consisted of 12, 118 IA patients (9,711 RA, 1,472 PsA, 935 AS), with 91.3% males and a mean age of 63.7. In total, 58.2% of patients initiated a DMARD within 12 months after diagnosis (RA 60.0%, PsA 64.3%, AS 29.6%) (Figure). A DMARD was dispensed ≤30 days after IA diagnosis in 41.2% of patients and ≤90 days in 50.0% of patients. Rheumatology specialty care was accessed during the study period, prior to DMARD dispensation, by 82.7% of patients exposed to a non-biologic DMARD and 90.0% of patients exposed to a biologic DMARD. The percentage of IA patients with DMARD exposure during the 12-month follow-up period increased from 48.8% in 2008 to 66.4% in 2015. Conclusion Approximately one-half of patients received treatment with a DMARD within 90 days after their initial IA diagnosis. DMARD treatment rates during the initial 12 months after diagnosis increased between 2007 and 2015, but non-treatment remained common, particularly in patients with AS. Timely access to a rheumatology provider is likely important for early DMARD treatment. References [1] Ng, et al. BMJ Open. 3:e002468. Disclosure of Interests Jessica A. Walsh Grant/research support from: Abbvie, Pfizer , Consultant for: Abbvie, Celgene, Lilly, Novartis , Shaobo Pei: None declared, Gopi Penmetsa: None declared, Brian Sauer Grant/research support from: Amgen, Vikas Patil: None declared, Jodi Walker Shareholder of: Abbvie, Employee of: Abbvie, Jerry Clewell Shareholder of: Abbvie, Employee of: Abbvie, Kevin Douglas Shareholder of: Abbvie, Employee of: Abbvie, Daniel Clegg Grant/research support from: Amgen grant, Grant Cannon Grant/research support from: Amgen Inc., Ahmad Halwani Grant/research support from: Bristol-Myers Squibb, Kyowa Hakko Kirin, Roche, Abbvie, Genentech, Immune Design, miRagen, Amgen, Seattle Genetics, Takeda, Pharmacyclics

Background: Significant improvements in secondary prevention of osteoporotic fractures have been noted with fracture liaison services. However, similar models for the primary prevention of such fractures have not been reported. Objective: To determine the impact of a Bone Health Team (BHT) on osteoporosis screening and treatment rates in U.S. veterans in primary care practices. Design: Historical cohort study of a primary care–based intervention of a BHT from February 2013 to February 2015. Setting: Community-based outpatient clinics of the Salt Lake City Veterans Affairs Health Care System. Participants: Men aged 70 years and older and women aged 65 years and older. Intervention: Enrollment in the BHT. Measurements: Rates of dual energy x-ray absorptiometry (DXA) completion, chart diagnosis of osteoporosis or osteopenia, completion of vitamin D measurement, and initiation of fracture reducing medication. Results: Our cohort consisted of 7644 individuals, 975 of whom were exposed to the BHT and 6669 of whom were not. Comparison of patients exposed to the BHT versus non-exposed subjects demonstrated a substantial increase in all outcome measures studied. Hazard ratios (HRs) from multivariable cox proportional hazard models were: measurement of vitamin D, HR = 1.619 ( P < .001); chart diagnosis of osteopenia, HR = 37.00 ( P < .001); chart diagnosis of osteoporosis, HR = 16.38 ( P < .001); osteoporosis medication, HR = 17.03 ( P < .001); and completion of DXA, HR = 139.9 ( P < .001). Conclusions and Relevance: The implementation of a dedicated BHT produced significantly increased rates of intermediate osteoporosis outcome measures in US veterans in primary care practices. Additional research describing medication adherence rates and cost-effectiveness is forthcoming.

Objective To examine the potential of circulating cytokines and chemokines as biomarkers of cancer mortality risk in patients with rheumatoid arthritis (RA). Methods Male participants in the Veterans Affairs RA registry were followed up from the time of enrollment until death or December 2013. Cytokines and chemokines were measured in banked serum obtained at the time of enrollment, using a bead-based multiplex assay, and a previously developed cytokine score was calculated. Vital status and cause of death were determined through the National Death Index. Associations of cytokines with cancer mortality were examined using multivariable competing-risks regression. Results Among 1,190 men with RA, 60 cancer deaths (30 of which were attributable to lung cancer) occurred over 5,307 patient-years of follow-up. The patients had a mean age of 64.5 years, had established disease (median duration 8.7 years), were seropositive for rheumatoid factor (81%) or anti–cyclic citrullinated peptide antibody (77%), and frequently had a history of smoking (82% current or former). Seven of 17 analytes examined were individually associated with cancer mortality. The cytokine score was associated with overall cancer (subhazard ratio [SHR] 1.42, 95% confidence interval [95% CI] 1.08–1.85) and lung cancer (SHR 1.86, 95% CI 1.57–2.19) mortality in multivariable analyses. Those in the highest quartile of cytokine scores had a >2-fold increased risk of overall cancer mortality (P = 0.039) and a 6-fold increased risk of lung cancer mortality (P = 0.028) relative to the lowest quartile. A synergistic interaction between current smoking and high cytokine score was observed. Conclusion Serum cytokines and chemokines are associated with cancer and lung cancer mortality in men with RA, independent of multiple factors including age, smoking status, and prevalent cancer.

Objective Unintentional weight loss is important and can be predictive of long-term outcomes in patients with rheumatoid arthritis (RA). This study was undertaken to assess how primary therapies for RA may influence changes in body mass index (BMI) in RA patients from a large administrative database. Methods Unique dispensing episodes of methotrexate, prednisone, leflunomide, and tumor necrosis factor inhibitors (TNFi) administered to RA patients were identified from the US Department of Veterans Affairs pharmacy databases. Values for C-reactive protein (CRP) level and BMI closest to the time point within 30 days of the treatment course start date and at follow-up time points were linked. Missing laboratory values were imputed. Weight loss was defined as a decrease in BMI of >1 kg/m2. Regression models were used to evaluate changes in BMI during each drug treatment as compared to treatment with methotrexate. To assess the impact of confounding by indication, propensity scores for use of each drug were incorporated in analyses using matched-weighting techniques. Results In total, 52,662 treatment courses in 32,859 RA patients were identified. At 6 months from the date of prescription fill, weight gain was seen among patients taking methotrexate, those taking prednisone, and those taking TNFi. On average, compared to methotrexate-treated patients, prednisone-treated patients had significantly more weight gain, while leflunomide-treated patients demonstrated weight loss. In multivariable models, more weight loss (β = −0.41 kg/m2, 95% confidence interval [95% CI] −0.46, −0.36; P

Objectives The aim was to estimate the impact of TNF inhibitor (TNFi) exposure on radiographic disease progression in US Veterans with RA during the first year after initiating therapy. Methods This historical longitudinal cohort design used clinical and claims data to evaluate radiographic progression after initiation of TNFi. US Veterans with RA initiating TNFi treatment (index date), ≥ 6 months pre-index and ≥ 12 months post-index VA enrolment/activity, and initial (6 months pre-index to 30 days post-index) and follow-up (10–18 months post-index) bilateral hand radiographs were eligible. The cumulative TNFi exposure and change in modified Sharp score (MSS) between initial and follow-up radiographs were calculated. The percentage of patients with clinically meaningful change in MSS (≥ 5) for each month of exposure was assessed using a longitudinal marginal structural model with inverse probability of treatment weights. Mean values and CIs were generated using 1000 bootstrapped samples. Results For 246 eligible patients, the mean (s.d.) age was 58 (11) years; 81% were male. The mean (s.d.) initial MSS was 19.6 (33.4) (range 0–214). The mean change (s.d.) in MSS was 0.3 (3.6) (median 0, range −19 to 22). Patients with the greatest exposure had the least radiographic progression for both crude and adjusted model analyses. Adjusted rates of MSS change ≥ 5 points (95% CI) were 10.6% (9.8%, 11.4%) for patients with 3 months of exposure compared with 5.4% (5.1%, 5.7%) for patients with 12 months of exposure. Conclusion One-year changes in radiographic progression were small. Patients with the greatest cumulative TNFi exposure experienced the least progression.

Objective.To evaluate associations of HLA-DRB1 haplotypes and shared epitope (SE) with rheumatoid arthritis (RA) severity and all-cause mortality in RA.Methods.Patients with RA from the Veterans Affairs Rheumatoid Arthritis (VARA) registry were followed from enrollment until death or December 31, 2013. Clinical characteristics, DNA, and serum were collected at enrollment. Radiographic damage, the presence or absence of subcutaneous nodules, disease activity measures, and functional status were assessed at enrollment and updated during followup. Sixteen HLA-DRB1 haplotypes and SE status were determined from banked DNA. Associations between HLA-DRB1 haplotypes, RA disease characteristics, and mortality were assessed in multivariable regression models.Results.Within VARA, 1443 participants had genotyping and accrued 6150 patient-years of followup. Haplotypes VKA, VRA, LRA, SRA, SRE, SKR, and SEA, and SE alleles were significantly associated with seropositivity for rheumatoid factor (RF) and/or anticyclic citrullinated peptide (anti-CCP). Haplotypes VKA and SKR were associated with higher RF concentrations, while VRA, DRE, and GRQ were associated with lower RF concentrations. Haplotypes VKA, VRA, and LRA were associated with higher concentrations of anti-CCP antibody, while haplotypes SRA, SRE, LEA, SKR, and SEA were significantly associated with lower anti-CCP concentrations. Haplotype VKA (OR 1.39, 95% CI 1.08–1.80) was associated with increased frequency of radiographic damage at enrollment but none of the haplotypes were associated with the presence of subcutaneous nodules. Haplotypes SKA (HR 1.52, 95% CI 1.26–1.83) was associated with higher mortality.Conclusion.HLA-DRB1 haplotypes are independently and variably associated with seropositivity, autoantibody concentrations, and outcomes in RA.

Background Current rheumatoid arthritis (RA) treatment guidelines recommend the use of disease activity measures (DAMs) to guide RA therapy. These guidelines recommend considering escalation of therapy in RA patients with high or moderate disease activity. Recent work by our group has demonstrated that many RA patients with high/moderate RA by Disease Activity Score with 28 joints (DAS28) did not have therapy escalated despite active disease (DAS28 ≥3.2). Objectives 1) To determine if the rate of major therapeutic change (MTC) for RA patients with high/moderate disease activity based on DAS28 was similar when measured using two other common DAMs; 2) to compare the ability of different DAMs to predict MTC across the full spectrum of RA disease activity. Methods US Veterans enrolled in the VA Rheumatoid Arthritis (VARA) registry with 1) a complete set of DAMs (DAS28, Clinical Disease Activity Index [CDAI], Routine Assessment of Patient Index Data 3 [RAPID3]) recorded (index date), 2) two other visits during the preceding 18 months separated by at least 60 days, and 3) clinical data available for 18 months prior to through 30 days following index date were eligible. Each patient was assessed for MTC within 1 week before and 30 days after index date. MTC was defined as any of the following: 1) initiation of new biologic or nonbiologic DMARD, 2) escalation of DMARD dose by ≥25%, 3) initiation of prednisone (as new agent or after 90 day gap during baseline), or 4) increase in monthly average prednisone dose by 25% and/or 5) injection of 2 or more joints with corticosteroids. MTC was analysed by DAM severity thresholds of 1) high, moderate, low, and remission, and 2) high, high/moderate, and high/moderate/low levels. Analyses of the latter thresholds included sensitivity, specificity, predictive values, and accuracy estimations for MTC at each DAM level. Results Of 1776 eligible patients, 89% were male, mean age was 63.4 years, mean disease duration was 13.4 years, 79% tested positive for rheumatoid factor, and 63% positive for anti-cyclic citrullinated peptide antibodies. Overall, 33.1% (591/1776) of patients had an MTC. A markedly larger percentage of patients with high disease activity had MTC (range 55.1%–43.5%) compared to patients with moderate disease (range 38.7%–27.8%) (table 1). Sensitivity, specificity, predictive values, and accuracy at each DAM threshold level varied markedly by DAM, with RAPID3 having a higher sensitivity, lower specificity, and less accuracy than DAS28 or CDAI (table 2). Conclusions Most patients with high/moderate disease activity did not have a MTC. This observation was consistent regardless of which DAM was utilised. MTC increased with disease activity with all DAMs; however, DAS28 and CDAI appeared to have greater accuracy than RAPID3 at predicting MTC at all disease severity thresholds. There is need for continued evaluation of DAM thresholds for defining disease activity for MTC decisions, better DAMs, and/or better application of DAMs in clinical practice to improve the treatment of patients with active RA. Acknowledgements This study was sponsored by Immunex, a subsidiary of Amgen. Medical writing assistance provided by Amgen. Disclosure of Interest G. Cannon Grant/research support from: Amgen, C.-C. Teng Grant/research support from: Amgen, N. Accortt Shareholder of: Amgen, Employee of: Amgen, D. Collier Shareholder of: Amgen, Employee of: Amgen, T.-C. Lin Shareholder of: Amgen, Employee of: Amgen, B. Sauer Grant/research support from: Amgen Inc.

Objective There has been limited investigation into cause-specific mortality and the associated risk factors in men with rheumatoid arthritis (RA). We investigated all-cause and cause-specific mortality in men with RA, examining determinants of survival. Methods Men from a longitudinal RA registry were followed from enrollment until death or through 2013. Vital status and cause of death were determined using the National Death Index. Crude mortality rates and standardized mortality ratios (SMRs) were calculated for all-cause, cardiovascular disease (CVD), cancer, and respiratory mortality. Associations with all-cause and cause-specific mortality were examined using multivariable Cox proportional hazards and competing-risks regression. Results There were 1,652 men with RA and 332 deaths. The leading causes of death were CVD (31.6%; SMR 1.77 [95% confidence interval (95% CI) 1.46–2.14]), cancer (22.9%; SMR 1.50 [95% CI 1.20–1.89]), and respiratory disease (15.1%; SMR 2.90 [95% CI 2.20–3.83]). Factors associated with all-cause mortality included older age, white race, smoking, low body weight, comorbidity, disease activity, and prednisone use. Rheumatoid factor concentration and nodules were associated with CVD mortality. There were no associations of methotrexate or biologic agent use with all-cause or cause-specific mortality. Conclusion Men in this RA cohort experienced increased all-cause and cause-specific mortality, with a 3-fold risk of respiratory-related deaths compared to age-matched men in the general population. Further studies are needed in order to examine whether interventions targeting potentially modifiable correlates of mortality might lead to improved long-term survival in men with RA.

Objective.Low body mass index (BMI) is a risk factor for poor longterm outcomes in rheumatoid arthritis (RA). The purpose of this study was to identify factors associated with longterm changes in BMI.Methods.Subjects with RA from the Veterans Affairs (VA) Rheumatoid Arthritis (VARA) Registry (n = 1474) were studied. Information on inflammatory markers, presence of erosions, and smoking status were extracted from the VARA database. BMI was extracted from VA electronic medical records within 14 days of each visit date. VA pharmacy records were queried to identify prescriptions for specific RA therapies within 1 month of the visit date. We used robust generalized estimating equations marginal regression models to calculate independent associations between clinical variables and BMI over time. Similar models determined predictors of change in weight and risk of weight loss over the subsequent study observation period.Results.Increasing age, active smoking, and the presence of erosions at baseline were associated with lower BMI. Weight decreased over time among older adults. Factors associated with greater reductions in BMI over time and a greater risk of weight loss were higher inflammatory markers, smoking, older age, higher BMI, and less subsequent improvement in inflammation. Methotrexate use was associated with a lower risk of weight loss. The use of prednisone or anti-tumor necrosis factor therapies was not associated with change in BMI or the risk of weight loss independent of other factors.Conclusion.Greater age, greater inflammatory activity, and active smoking are associated with greater weight loss in RA over time.

Objective To assess disease characteristics, disease activity, and treatment patterns in rheumatoid arthritis (RA) patients with comorbid hepatitis C virus (HCV) infection. Methods RA patients with concomitant HCV were identified within the Veterans Affairs Rheumatoid Arthritis Registry. HCV was defined as at least 1 diagnostic code present in medical record databases. Generalized estimating equations in linear regression models compared component and composite measures of disease activity between HCV-positive and HCV-negative patients over the study period, accounting for within-subject correlations. Similar analysis of pharmacy databases evaluated medication use within each group. Results Ninety-two of 1,706 registry participants (5.1%) were identified with concomitant HCV. At enrollment, HCV-positive patients were younger (mean ± SD 61.7 ± 7.1 years versus 67.5 ± 11.2 years; P < 0.001), more often African American (35% versus 15%; P < 0.001), and smokers (48% versus 26%; P < 0.001). In unadjusted and adjusted analyses incorporating all study visits, patient-reported outcomes (pain, tender joints, and patient global scores) were higher in HCV-positive patients, contributing to higher disease activity scores. There was no difference in physician-reported outcomes (swollen joints or physician global scores). HCV-positive patients had lower C-reactive protein levels (β −0.30 [95% confidence interval (95% CI) −0.53, −0.07], P = 0.01). Over all visits, HCV-positive patients were less likely to receive methotrexate (odds ratio [OR] 0.27 [95% CI 0.17, 0.40], P < 0.001), and more likely to receive prednisone (OR 1.41 [95% CI 1.02, 1.97], P = 0.04) and anti–tumor necrosis factor α (anti-TNFα) therapies (OR 1.51 [95% CI 1.04, 2.19], P = 0.03). Conclusion RA patients with concomitant HCV have higher disease activity scores, driven primarily by higher patient-reported measures. HCV-positive patients were more likely to be treated with prednisone and anti-TNFα therapies and less likely to receive methotrexate compared to HCV-negative patients.

Objective.To compare survival in American veterans with and without the HLA-B27 (B27) gene.Methods.Mortality was evaluated in a national cohort of veterans with clinically available B27 test results between October 1, 1999, and December 31, 2011. The primary outcome was the mortality difference between B27-positive and B27-negative veterans, adjusted for age, sex, race, and diagnoses codes for diseases that may have influenced both B27 testing and mortality, including psoriasis, inflammatory bowel disease, spondyloarthritis (SpA), and other types of inflammatory arthritis. The secondary outcomes were the adjusted mortality HR for B27+ and B27− veterans, in subgroups with and without SpA.Results.Among veterans with available B27 test results, 27,652 (84.7%) were B27− and 4978 (15.3%) were B27+. The mean followup time was 4.6 years. Mortality was higher in the B27+ group than in the B27− group (HR 1.15, 95% CI 1.03–1.27). Mortality was also higher in the B27+ subgroups with SpA (HR 1.35, 95% CI 1.06–1.72) and without SpA (HR 1.11, 95% CI 0.99–1.24), but the difference was significant only in the subgroup with SpA.Conclusion.B27 positivity was associated with an increased mortality rate in a cohort of veterans clinically selected for B27 testing, after adjustment for SpA. In the subgroup with SpA, the mortality rate was associated with B27 positivity, and in the subgroup without SpA, there was a nonsignificant association between B27+ and mortality.

This study examines: 1) alveolar bone loss (ABL), a hallmark of periodontitis, in anti-citrullinated protein antibody (ACPA)-positive rheumatoid arthritis (RA) patients versus control patients with osteoarthritis (OA); and 2) the association of ABL with RA disease activity and ACPA concentrations, including multiple antigen-specific ACPA.This multicenter case-control study includes 617 patients diagnosed with RA (n = 287) or OA (n = 330). Panoramic radiographs were taken; patients were categorized into low, moderate, or high tertiles based on mean percentage ABL. Serum ACPA was measured using second-generation anticyclic citrullinated peptide enzyme-linked immunosorbent assay and a multiplex platform to assess distinct antigen-specific ACPA. A generalized linear mixed model for binary data was used to compare stratified ABL in RA versus OA patients. Associations of moderate and high ABL (versus low) with RA disease activity and severity measures were examined using multivariate regression. Antigen-specific ACPA responses were compared among ABL tertiles using significance analysis of microarrays.ACPA-positive patients with RA had a significantly higher mean percentage of sites with ABL20% compared with patients with OA (P = 0.03). After multivariate adjustment, greater ABL was significantly associated with higher serum ACPA concentration (P = 0.004), 28-joint Disease Activity Score (P = 0.023), health assessment questionnaire disability (P = 0.05), tender joint count (P = 0.02) and joint space narrowing scores (P = 0.05) among patients with RA. ACPAs targeting citrullinated vimentin and histone were significantly higher in moderate and high ABL groups versus low, regardless of smoking status (q0.1%).Greater ABL was associated with higher ACPA, consistent with findings at articular sites. ACPA targeting could provide novel insight into important linkages between RA and periodontitis.

OBJECTIVE Cross-sectional studies have demonstrated that obese patients with rheumatoid arthritis (RA) often report greater disability. The longitudinal effects of obesity, however, are not well-characterized. We evaluated associations between obesity, weight loss, and worsening of disability in patients of 2 large registry studies, which included patients who were followed for longer periods of time. METHODS This study included patients with RA from the National Data Bank for Rheumatic Diseases (FORWARD) (n = 23,323) and the Veterans Affairs RA (VARA) registry study (n = 1,697). Results of the Health Assessment Questionnaire (HAQ) or Multidimensional HAQ (MD-HAQ) were recorded through follow-up. Significant worsening of disability was defined as an increase of >0.2 in HAQ or MD-HAQ scores. The Cox proportional hazards model was used to evaluate the risk of worsening of disability from baseline and to adjust for demographics, baseline disability, comorbidity, disease duration, and other disease features. RESULTS At enrollment, disability scores were higher among severely obese patients compared to those who were overweight both in FORWARD (β = 0.17 [95% confidence interval (95% CI) 0.14, 0.20]; P < 0.001) and in the VARA registry (β = 0.17 [95% CI 0.074, 0.27]; P = 0.001). In multivariable models, patients who were severely obese at enrollment had a greater risk of progressive disability compared to overweight patients in FORWARD (HR 1.25 [95% CI 1.18, 1.33] P < 0.001) and in the VARA registry (HR 1.33 [95% CI 1.07, 1.66]; P = 0.01). Weight loss following enrollment was also associated with a greater risk in both cohorts. In the VARA registry, associations were independent of other clinical factors, including time-varying C-reactive protein and swollen joint count. CONCLUSION Severe obesity is associated with a more rapid progression of disability in RA. Weight loss is also associated with worsening disability, possibly due to it being an indication of chronic illness and the development of age-related or disease-related frailty.

Objective To examine the association of serum lipids, inflammation and seropositivity on coronary heart disease (CHD) and stroke in patients with rheumatoid arthritis (RA). Methods The incidence of hospitalised myocardial infarction (MI) or stroke was calculated in a cohort of patients with RA receiving care within the national Veterans Health Administration from 1998 to 2011. Cox proportional hazard models were used to examine the association between these outcomes and low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), C reactive protein (CRP) and erythrocyte sedimentation rate (ESR) as time-varying variables, divided into quintiles. Results There were 37 568 patients with RA in the cohort with mean age of 63 years (SD 12.1); 90% were men. There was a no clear association between LDL-C and CHD/stroke. Compared with lower HDL-C (2.17 mg/dL (vs CRP 47 mm/h compared with

OBJECTIVE Combination treatments for patients with rheumatoid arthritis (RA) with an inadequate response to methotrexate (MTX) alone include the addition of a tumor necrosis factor inhibitor (TNFi) or the addition of sulfasalazine (SSZ) and hydroxychloroquine to MTX (triple therapy). We compared persistence and adherence rates between these 2 combination therapies in US veterans and report the reasons for discontinuation of combination treatment in these groups. METHODS Using Veteran's Affairs clinical and administrative data from 2006 to 2012, veterans with RA escalating treatment from MTX to MTX-TNFi or triple therapy were examined for a 12-month period after combination initiation. Persistence was defined as treatment without a ≥90-day gap in therapy. Adherence was calculated using the proportion of days covered ≥80% at 12 months. Matching weights-adjusted models were applied to more closely mimic randomization in this study. The reasons that patients discontinued their combination regimens were identified by chart abstraction. RESULTS Full persistence at 1 year was 45% in the MTX-TNFi patients (n = 2,125) and 18% in the triple therapy patients (n = 171) (P < 0.001). Adherence was higher for the MTX-TNFi group (26%) than the triple therapy group (11%) (P < 0.0001). The triple therapy group was associated with significantly more treatment discontinuation, which was most often due to adverse drug events from SSZ. CONCLUSION Differences in persistence and adherence between the MTX-TNFi and triple therapy groups appear to be primarily related to adverse drug events that were most often attributed to SSZ.

Background Current guidelines encourage the measurement of rheumatoid arthritis (RA) disease activity and directing therapy to achieve a low disease state or remission (treat-to-target). Many RA patients with documented moderate to severe disease activity remain on their current therapy without change. Objectives This study investigated Veterans Affairs (VA) clinical data to identify patient factors associated with a major change in RA therapy and to determine the relative importance of these different factors. Methods US Veterans enrolled in the VARA registry were included if they had: 1) high/moderate disease activity (DAS28≥3.2) at index date, 2) 18 months of VA data prior to the index date and 3) two or more other DAS28 measured during the preceding 18 months separated by at least three months. A major change was report if within 7 days before to 90 days after the index date there was either: 1) initiation or escalation of DMARDs, 2) initiation or increase dose of prednisone and/or 3) ≥2 joint injections. Baseline DAS28 was estimated during the observation period prior to the index date using an area under the curve calculation and compared to the DAS28 at the index date. Patients were categorized as have a worsening or improvement of disease if the DAS28 at index date was 0.6 higher or lower than the average DAS28 during the observation period respectively. Other patients were categorized as no change in DAS28. Analyses of clinical variables including components of the DAS28 and patient and physician reported measures were compared in patients with and patients without a major change in therapy. Results Of 941 patients who met study criteria, only 388/941 (41.2%) had a major change of therapy. Patients with worsening DAS28 were more likely to have a major change 183/369 (49.5%) than no DAS28 change 170/454 (37.4%) and improved DAS28 35/118 (29.6%) (P Conclusions More than half of the patients with moderate disease activity did not have a major change in therapy. The likelihood of a major change in therapy increased with worsening disease activity. The clinical variables assessed were more strongly associated with change in therapy in patients with worsening of disease. Clinical disease activity measures are highly associated with the decision to initiate major changes. Future work will investigate the potential added value of administrative variables. This work emphasizes the need for methods to systematically collect and utilize clinical disease activity measurements, particularly longitudinally, to improve the treat-to-target strategy. Acknowledgements Work Sponsored by VA Specialty Care Centers of Innovation, VA Health Service Research and Development, and Amgen. Disclosure of Interest G. Cannon Grant/research support from: Amgen, C.-C. Teng Grant/research support from: Amgen, N. Accortt Shareholder of: Amgen, Employee of: Amgen, D. Collier Shareholder of: Amgen, Employee of: Amgen, S. Mehrotra Grant/research support from: Amgen, B. Sauer Grant/research support from: Amgen

Objective To evaluate the association of hydroxychloroquine (HCQ) use with lipid profiles in a Veterans Affairs Rheumatoid Arthritis (VARA) cohort. Methods Lipid profiles in HCQ users were compared with HCQ nonusers, adjusting for potential confounders (age, sex, race, disease activity, prednisone, disease-modifying antirheumatic drugs, diabetes mellitus, and statin use). Applying current National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) guidelines for reduction of cardiovascular disease (CVD) events risk, the frequency of target lipid profiles with HCQ status was evaluated. Varied periods of HCQ exposure were compared to ascertain pharmacologic associations with lipid values. CVDs were compared between HCQ users and nonusers. Results In an elderly, predominantly male VARA cohort, 1,011 patients had lipid profiles; 787 patients (77.8%) were white. Statin use was recorded in 11.6% of patients, diabetes mellitus in 33.5%, and CVD in 31.2%. HCQ users (n = 150) were older, had longer rheumatoid arthritis (RA) disease duration, and had lower disease activity. Optimum lipid profiles, including total cholesterol:high-density lipoprotein (HDL) and HDL:low-density lipoprotein ratios (P ≤ 0.001), were more frequent in HCQ users, with the exception of HDL (P = 0.165), and persisted in multivariate analyses. Similarly, more HCQ users had NCEP-ATP III target levels. Varied periods of HCQ exposure suggested lipid changes to occur early, but lost within a year of drug discontinuation. HCQ users had less prevalent CVD. Conclusion In RA patients, HCQ use of at least 3 months' duration was associated with better lipid profiles irrespective of disease activity or statin use. Given the increased CVD risks in RA and the relative low cost and toxicity of HCQ, continued use, regardless of treatment regimen, should be considered.

This is a cost-effectiveness analysis of training rural providers to identify and treat osteoporosis. Results showed a slight cost savings, increase in life years, increase in treatment rates, and decrease in fracture incidence. However, the results were sensitive to small differences in effectiveness, being cost-effective in 70 % of simulations during probabilistic sensitivity analysis. We evaluated the cost-effectiveness of training rural providers to identify and treat veterans at risk for fragility fractures relative to referring these patients to an urban medical center for specialist care. The model evaluated the impact of training on patient life years, quality-adjusted life years (QALYs), treatment rates, fracture incidence, and costs from the perspective of the Department of Veterans Affairs. We constructed a Markov microsimulation model to compare costs and outcomes of a hypothetical cohort of veterans seen by rural providers. Parameter estimates were derived from previously published studies, and we conducted one-way and probabilistic sensitivity analyses on the parameter inputs. Base-case analysis showed that training resulted in no additional costs and an extra 0.083 life years (0.054 QALYs). Our model projected that as a result of training, more patients with osteoporosis would receive treatment (81.3 vs. 12.2 %), and all patients would have a lower incidence of fractures per 1,000 patient years (hip, 1.628 vs. 1.913; clinical vertebral, 0.566 vs. 1.037) when seen by a trained provider compared to an untrained provider. Results remained consistent in one-way sensitivity analysis and in probabilistic sensitivity analyses, training rural providers was cost-effective (less than $50,000/QALY) in 70 % of the simulations. Training rural providers to identify and treat veterans at risk for fragility fractures has a potential to be cost-effective, but the results are sensitive to small differences in effectiveness. It appears that provider education alone is not enough to make a significant difference in fragility fracture rates among veterans.

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.

Periodontitis (PD) has emerged as a risk factor in a number of health conditions including rheumatoid arthritis (RA) (1). Sharing both morphologic and histopathologic similarities with RA (2), PD is an inflammatory disease initiated by bacterial infection resulting in soft and hard tissue destruction and ultimately leading to tooth loss. In addition to shared inflammatory pathways, PD and RA share risk factors for susceptibility and progression, most notably cigarette smoking and, possibly, shared epitope-containing HLA-DRB1 alleles, the latter associated with localized aggressive periodontitis (3–10). Although a causal link between these conditions has not been established, several reports have demonstrated an increased PD prevalence in RA patients compared to controls (11–18). Growing evidence suggests that pathogens associated with PD could play a role in RA propagation. Chief among the organisms of interest is Porphyromonas gingivalis (P. gingivalis) (19). P. gingivalis is the only known pathogen expressing peptidylarginine deiminase (PPAD). Similar to its human counterpart, P. gingivalis-expressed PAD catalyzes the citrullination of arginine-containing peptides. This is noteworthy because citrullinated antigens are thought to drive adaptive immune responses that are nearly exclusive to RA. The potential role of P. gingivalis in RA pathogenesis has been borne out in epidemiologic investigations. Concentrations of circulating antibody to P. gingivalis have been demonstrated to be associated with the expression of anti-citrullinated peptide antibody (ACPA) (20–22). More recently, our group has shown that antibody to P. gingivalis is associated with the presence of RA-related autoantibody (a combination of rheumatoid factor [RF] and/or ACPA) among individuals at increased risk for disease but who have not yet developed RA symptoms (23), underscoring the potential role of this pathogen in RA development. As part of the present study, we conducted a large case-control investigation to examine the relationship of PD with established RA. We sought to examine the degree to which this relationship is impacted by shared genetic and/or environmental factors. We also sought to elucidate the degree to which the relationship of PD with RA may be related to infection and/or colonization with P. gingivalis. By using a rigorously selected control population, we attempted to mitigate issues of bias or unmeasured confounding that may have impacted other efforts often using healthy volunteers as comparators (16–18). Finally, using a multiplex approach, we examined the associations of PD and P. gingivalis with autoreactivity to several citrullinated autoantigens that have been implicated in RA disease pathogenesis.

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.

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.

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.

Objective The C-reactive protein (CRP) level and erythrocyte sedimentation rate (ESR) are important disease activity biomarkers in rheumatoid arthritis (RA). This study aimed to determine to what extent obesity biases these biomarkers. Methods Body mass index (BMI) associations with CRP level and ESR were assessed in 2 RA cohorts: the cross-sectional Body Composition (BC) cohort (n = 451), including whole-body dual x-ray absorptiometry measures of fat mass index; and the longitudinal Veterans Affairs Rheumatoid Arthritis (VARA) registry (n = 1,652), using multivariable models stratified by sex. For comparison, associations were evaluated in the general population using the National Health and Nutrition Examination Survey. Results Among women with RA and in the general population, greater BMI was associated with greater CRP levels, especially among women with severe obesity (P < 0.001 for BMI ≥35 kg/m2 versus 20–25 kg/m2). This association remained after adjustment for joint counts and patient global health scores (P < 0.001 in BC and P < 0.01 in VARA), but was attenuated after adjustment for fat mass index (P = 0.17). Positive associations between BMI and ESR in women were more modest. In men with RA, lower BMI was associated with higher CRP levels and ESR, contrasting with positive associations among men in the general population. Conclusion Obesity is associated with higher CRP levels and ESR in women with RA. This association is related to fat mass and not RA disease activity. Low BMI is associated with higher CRP levels in men with RA; this unexpected finding remains incompletely explained but likely is not a direct effect of adiposity.

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.

Background: Current ultrasonographic scoring systems used to assess the degree of finger joint synovitis in rheumatoid arthritis (RA) are not designed for distinguishing healthy or osteoarthritis (OA) patients from those with RA in clinical settings. Objective: To explore a novel scoring approach using structural and synovial ultrasonographic features to distinguish between healthy and OA finger joints and those with RA. Methods: 22 patients with RA, 16 healthy controls, and 14 OA controls received a comprehensive ultrasound of one hand, with scores assigned using a modification of a previously reported RA scoring system (Semiquantitative Synovial Score), and using the novel approach (Combined Structural/Synovial Score). The number of joints classified as supporting the diagnosis of RA (“RA-supported”) with each approach was recorded. Sensitivity and specificity for each scoring system were calculated with respect to the clinical diagnosis. Results: The Semiquantitative Synovial Score was highly sensitive (100%), but without specificity (0%) for the diagnosis of RA, when RA was defined as having more than 1 joint classified as “RA-supported.” The Combined Structural/Synovial Score had high sensitivity (95%) and moderate specificity (77%) when RA was defined as having any joint classified as “RA-supported”. Moderate sensitivity (73%) and high specificity (97%) were found when having more than 1 joint classified as “RA-supported” was required to diagnose RA. Conclusion: A novel structural and synovial hand joint scoring system was capable of distinguishing OA and healthy controls from RA subjects in this pilot evaluation. Prospective validation of this approach is planned.

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

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) ≤2.6); (2) remission for ≥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.

As the average age of the US population increases, the number of men with benign prostatic hyperplasia will also rise. Lower urinary tract symptoms are found in almost all men as they age, yet we do not have a dependable means to detect, classify, and predict potential response to therapy and disease progression. A molecular biomarker, JM-27, may address some of these needs. Serum levels of JM-27 detect disease and differentiate among disease states as classified by the associated symptoms. Although larger validation studies to more extensively characterize this test are under way, current data suggest that JM-27 differentiates men with highly symptomatic disease from those with asymptomatic disease.

Colon cancer–specific antigen (CCSA)-3 and CCSA-4 are novel colon cancer markers identified by focused proteomic analysis of nuclear structural proteins. The goal of these studies was to evaluate serum-based CCSA-3 and CCSA-4 in the detection of individuals with preneoplastic and neoplastic lesions using ELISAs. Serum samples from 107 subjects undergoing colonoscopy, 28 subjects with colorectal cancer, and 125 subjects with benign disease or other types of cancer were evaluated. Individuals who underwent colonoscopy were classified into mutually exclusive categories, including normal colon, hyperplastic polyp, nonadvanced adenoma, and advanced adenoma. Sensitivity and specificity for both CCSA-3 and CCSA-4 were evaluated using receiver operating characteristic (ROC) curves. At a cutoff of 2 μg/mL for CCSA-3 and 0.3 μg/mL for CCSA-4, each marker detected all 28 colorectal cancers, for a sensitivity of 100% (lower 95% confidence bound, 89.8%). The sensitivity for detection of the combined end point of colorectal cancer and advanced adenoma for CCSA-3 was 89.1% [95% confidence interval (95% CI), 76.4–96.4%] and for CCSA-4 was 84.8% (95% CI, 71.1–93.7%) and 91.3% (95% CI, 79.2–97.6%) for either marker positive. The specificity in individuals with normal, hyperplastic polyps, or nonadvanced adenomas was 82.0% (95% CI, 72.4–89.4%) and 91.0% (95% CI, 83.0–96.0%) for CCSA-3 and CCSA-4, respectively. ROC curves for CCSA-3 and CCSA-4 reveal an area under the curve of 0.94 (95% CI, 0.90–0.98%). In these initial analyses, CCSA-3 and CCSA-4 show promise as potential serum markers for detection of colorectal cancer and advanced adenomas. [Cancer Res 2007;67(12):5600–5]