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Objective Three 6-12-month, double-blind, randomized, controlled trials have shown leflunomide (LEF; 20 mg/day, loading dose 100 mg x 3 days) to be effective and safe for the treatment of rheumatoid arthritis (RA). This analysis of the North American trial assessed whether the clinical benefit evident at month 12 was sustained over 24 months of treatment with LEF as compared with the efficacy and safety of methotrexate (MTX), an equivalent disease-modifying antirheumatic drug, at 24 months. Methods The year-2 cohort, comprising patients continuing into the second year of treatment with > or = 1 dose of study medication and > or = 1 followup visit after week 52, consisted of 235 patients (LEF n = 98; placebo n = 36; MTX n = 101). The mean (+/- SD) maintenance dose of LEF was 19.6 +/- 1.99 mg/day in year 2 and that of MTX was 12.6 +/- 4.69 mg/week. Statistical analyses used an intent-to-treat (ITT) approach. Statistical comparisons of the active treatments only were prospectively defined in the protocol. Results In total, 85% and 79% of LEF and MTX patients, respectively, who entered year 2 completed 24 months of treatment. From month 12 to month 24, the American College of Rheumatology improvement response rates of > or = 20% (LEF 79% versus MTX 67%; P = 0.049), > or = 50% (LEF 56% versus MTX 43%; P = 0.053), and > or = 70% (LEF 26% versus MTX 20%; P = 0.361) were sustained in both of the active treatment groups. The mean change in total Sharp radiologic damage scores at year 2 compared with year 1 and baseline (LEF 1.6 versus MTX 1.2) showed statistically equivalent sustained retardation of radiographic progression in the active treatment groups. Maximal improvements evident at 6 months in the Health Assessment Questionnaire (HAQ) disability index (HAQ DI) and the physical component score of the Medical Outcomes Survey 36-item short form were sustained over 12 months and 24 months; improvement in the HAQ DI with LEF4(-0.60) was statistically significantly superior to that with MTX (-0.37) at 24 months (P = 0.005). Over 24 months in the ITT cohort, serious treatment-related adverse events were reported in 1.6% of the LEF-treated patients and 3.7% of the MTX-treated patients. Frequently reported adverse events included upper respiratory tract infections, diarrhea, nausea and vomiting, rash, reversible alopecia, and transient liver enzyme elevations. Conclusion The safety and efficacy of LEF and MTX were maintained over the second year of this 2-year trial. Both active treatments retarded radiographic progression over 24 months. LEF was statistically significantly superior to MTX in improving physical function as measured by the HAQ DI over 24 months of treatment. Results indicate that LEF is a safe and effective initial treatment for active RA, with clinical benefit sustained over 2 years of treatment without evidence of new or increased toxicity.

Rat Chromosome 10 (RNO10) harbors Cia5, a non-MHC quantitative trait locus (QTL) that regulates the severity of type II collagen-induced arthritis (CIA) in DAxF344 and DAxBN F2 rats. CIA is an animal model with many features that resemble rheumatoid arthritis. To facilitate analysis of Cia5 independently of the other CIA regulatory loci on other chromosomes, DA recombinant QTL speed congenic rats, DA.F344(Cia5), were generated. These QTL congenic rats have a large chromosomal segment containing Cia5 (interval sizeor =80.1 cM) from CIA-resistant F344 rats introgressed into their genome. Phenotypic analyses of these rats for susceptibility and severity of CIA confirmed that Cia5 is an important disease-modifying locus. CIA severity was significantly lower in the Cia5 congenic rats than in DA controls. We also generated DA Cia5 speed sub-congenic rats, DA.F344(Cia5a), which had a smaller segment of the F344 genome, Cia5a, comprising only the distal q-telomeric end (interval sizeor = 22.5 cM) of Cia5, introgressed into their genome. DA.F344(Cia5a) sub-congenic rats also exhibited reduced CIA disease severity compared with the parental DA rats. The regulatory effects in both congenic strains were sex influenced. The disease-ameliorating effect of the larger fragment, Cia5, was greater in males than in females, but the effect of the smaller fragment, Cia5a, was greater in females. We also present an improved genetic linkage map covering the Cia5/Cia5a region, which we have integrated with two rat radiation hybrid maps. Comparative homology analysis of this genomic region with mouse and human chromosomes was also undertaken. Regulatory loci for multiple autoimmune/inflammatory diseases in rats (RNO10), mice (MMU11), and humans (HSA17 and HSA5q23-q31) map to chromosomal segments homologous to Cia5 and Cia5a.

Objective Collagen-induced arthritis (CIA) is a polygenic model of experimentally induced autoimmunity and chronic joint inflammation. This study maps genetic loci that regulate CIA susceptibility in DA/Bkl (DA) and BN/SsNHsd (BN) rats. Methods Genome scans covering chromosomes 1–20 and interval mapping techniques using 159 simple sequence-length polymorphism markers were used to identify quantitative trait loci (QTLs) that regulate CIA in (DA × BN)F2 hybrids. Serum antibody titers to type II collagen were determined by enzyme-linked immunosorbent assay. Results DA rats were high responders to porcine type II collagen (PII) and developed severe CIA (100%). BN rats were low responders to PII and resistant to CIA (0%). BN genes strongly repressed PII-induced CIA. Only 12% of (DA × BN)F1 rats (7 of 60) and 31% of (DA × BN)F2 rats (307 of 1,004) developed CIA. Three new QTLs (Cia11, Cia12, and Cia13) with significant logarithm of odds (LOD) scores of 5.6, 4.6, and 4.5, respectively, plus a suggestive QTL (Cia14*, LOD 3.0) regulating arthritis severity were identified on chromosomes 3, 12, 4, and 19. A new QTL, Ciaa3, associating with anticollagen antibody titer (antibody to PII LOD 6.5; antibody to rat type II collagen LOD 5.2) mapped to chromosome 9. Of 10 CIA QTLs previously identified in (DA × F344) and (DA × ACI) rats, only Cia1 in the major histocompatibility complex and a region coincident to Cia5 on chromosome 10 (LOD >8.0) influenced CIA severity in (DA × BN)F2 rats. Conclusion Since CIA exhibits many of the pathologic features of rheumatoid arthritis, the data indicate that the variety of genetic elements regulating human autoimmune and rheumatic diseases may be much larger and more varied than originally envisioned.

Objective To evaluate the efficacy and safety of the Prosorba column as a treatment for rheumatoid arthritis (RA) in patients with active and treatment-resistant (refractory) disease. Methods A sham-controlled, randomized, double-blind, multicenter trial of Prosorba versus sham apheresis was performed in patients with RA who had failed to respond to treatment with methotrexate or at least 2 other second-line drugs. Patients received 12 weekly treatments with Prosorba or sham apheresis, with efficacy evaluated 7–8 weeks after treatment ended. Patients were characterized as responders if they experienced improvement according to the American College of Rheumatology (ACR) response criteria at the efficacy time point. A data safety monitoring board (DSMB) evaluated interim analyses for the possibility of early completion of the trial. Results Patients in the trial had RA for an average of 15.5 years (range 1.7–50.6) and had failed an average of 4.2 second-line drug treatments prior to entry. After the completion of treatment of 91 randomized patients, the DSMB stopped the trial early due to successful outcomes. Of the 47 patients in the Prosorba arm, 31.9% experienced ACR-defined improvement versus 11.4% of the 44 patients in the sham-treated arm (P = 0.019 after adjustment for interim analysis). When results from 8 additional patients, who had completed blinded treatments at the time of DSMB action, were added to the analysis (n = 99), results were unchanged. The most common adverse events were a short-term flare in joint pain and swelling following treatment, a side effect that occurred in most subjects at least once in both treatment arms. Other side effects, although common, occurred equally as frequently in both treatment groups. Conclusion Apheresis with the Prosorba column is an efficacious treatment for RA in patients with active disease who have failed other treatments.

Objective To identify novel non-major histocompatibility complex (non-MHC) genetic loci controlling the severity of homologous rat type II collagen-induced arthritis (CIA). Methods We conducted a genome-wide scan to identify CIA regulatory quantitative trait loci (QTL) in an F2 cross between DA (CIA highly susceptible) and ACI (CIA resistant) inbred rats immunized with homologous rat type II collagen (RII). These strains share the MHC/RT1av1 haplotype required for susceptibility to RII-induced CIA. Results F2 females had higher median arthritis scores than did males. Relative resistance in the males was determined by inheriting either a DA or an ACI Y chromosome and was independent of the source of the X chromosome. In addition, a major QTL was localized on chromosome 2 (Cia7, logarithm of odds score 4.6). Cia7 is in a region that shows linkage conservation with chromosomal regions that regulate autoimmune diabetes and experimental autoimmune encephalomyelitis in mice and multiple sclerosis in humans. Conclusion Sex chromosomes and Cia7 play an important role in regulating CIA in response to RII. This rat model should facilitate positional cloning and functional characterization of regulatory genes that may play a role in several forms of autoimmune disease, including rheumatoid arthritis.

Adjuvant-induced arthritis (AIA) in rats is a widely used autoimmune experimental model with many features similar to rheumatoid arthritis (RA). To identify potential genetic regulatory mechanisms in RA, we conducted genome-wide linkage analysis in F2 progeny of arthritis-susceptible Dark Agouti (DA) and relatively resistant Fischer 344 (F344) inbred rats. We compared the data with our previously reported investigation of collagen-induced arthritis (CIA), which was expanded in the follow-up study reported in this work. We found two quantitative trait loci (QTLs) in common, i.e., Aia1/Cia1 on chromosome 20, which includes the MHC, and Aia3/Cia3 on chromosome 4. We also identified a second unique QTL in AIA, Aia2, on chromosome 4. Interestingly, the QTL region on chromosome 4 (Aia3/Cia3), like the MHC, appears to be involved in several other autoimmune diseases in rats, including insulin-dependent diabetes, thyroiditis, and experimental autoimmune uveitis. Moreover, an analysis of conserved synteny among rats, mice, and humans suggested that Aia2 and Aia3/Cia3, like Aia1/Cia1, contain candidate genes for several autoimmune/inflammatory diseases in mice and humans, including diabetes, systemic lupus erythematosus, inflammatory bowel disease, asthma/atopy, multiple sclerosis, and RA. The rat models appear to provide a powerful complementary approach to identify and characterize candidate genes that may contribute to autoimmune diseases in several species.

Drug-induced pulmonary disease is a well-recognized complication of MTX treatment of rheumatic diseases. Physicians involved in the management of patients receiving MTX should be aware of this potentially life-threatening complication. The prompt evaluation of new pulmonary symptoms in patients receiving MTX is important in the early recognition of this drug-induced complication. The characteristic symptoms are shortness of breath, nonproductive cough, fatigue, and fever. If an MTX-induced pulmonary reaction is suspected and abnormalities are noted on lung examination, chest radiography should be performed. In the presence of an abnormal chest radiograph, MTX should be discontinued, supportive measures instituted, and the diagnosis of the patient's pulmonary complaints investigated by specifically looking for features of the underlying rheumatic process, infection, and other medical conditions. Patients with severe pulmonary compromise should be hospitalized and given supplemental oxygen and high-dose corticosteroids. Most patients recover from their illness. No risk factors have been identified that consistently identify patients at the greatest risk for MTX-induced pulmonary toxicity. All patients receiving MTX should be educated concerning this potentially life-threatening drug toxicity and instructed to contact their physician immediately if significant pulmonary symptoms develop.

Objective To describe the clinical, laboratory, radiologic, and histopathologic features of methotrexate (MTX)-induced lung injury in a combined cohort of selected patients with rheumatoid arthritis (RA) and all cases reported in the English-language literature. Methods Retrospective combined cohort review and abstraction from the medical literature. Case reports were obtained from 6 centers that had 4 or more cases of potential MTX lung injury per site. RA patients who were seen between 1981 and 1993 and who satisfied predetermined criteria for the presence of MTX lung injury were identified. Results Twenty-seven patients satisfied the criteria for definite MTX lung injury, and 2 for probable MTX lung injury. Predominant clinical features of MTX lung injury included shortness of breath in 27 patients (93.1%), which was present for 23.5 +/- 22.3 days (mean +/- SD), cough in 24 (82.8%), present for 26.9 +/- 28.5 days, and fever in 20 (69.0%), present for 10.4 +/- 12.8 days. Five patients (17.2%) died, compared with 12 of 68 (17.6%) reported in the medical literature. Four of the 6 patients who were re-treated with MTX after an initial pulmonary event developed recurrent lung toxicity, resulting in 2 deaths, compared with a recurrence rate of 3 of 6 in the literature. Conclusion MTX lung injury is most often a subacute process, in which symptoms are commonly present for several weeks before diagnosis. Approximately 50% of the cases are diagnosed within 32 weeks from initiation of MTX treatment. A patient who recovers from MTX lung injury should not be re-treated. Earlier recognition and drug withdrawal may avoid the serious and sometimes fatal outcome that has been observed in this and other studies.

Objective: To assess the accuracy of International Classification of Diseases, Ninth Revision, and Current Procedural Terminology codes for identifying cardiovascular (CV) events (myocardial infarction [MI], stroke, coronary artery bypass graft [CABG], and percutaneous coronary intervention [PCI]) in enrollees of the Veterans Affairs Rheumatoid Arthritis (VARA) registry.Design: We performed a validation study from VARA enrollment until 6/1/2010 to compare the accuracy of CV events in those with and without CV-event coding in inpatient and outpatient records to evaluate for CV events +/- 3 months of the coding. The positive predictive value (PPV) was calculated, and codes with a PPV ≥50% were included in a composite coding algorithm.Results: We evaluated 107 individuals for 21 CV-event codes and 60 individuals without CV-event coding. The PPV varied between 0-100%. Composite coding algorithms’ PPV ranged from 70-100%.Conclusions: Validation of these algorithms allows for identification of acute CV events with known accuracy. The sensitivity and PPV of coding algorithms for CABG and PCI exceed that of stroke and MI.

The purpose of this analysis was to examine discontinuation and reasons for discontinuation from disease-modifying anti-rheumatic (DMARD) therapies in the RADIUS 2 registry, a long-term, open-label, observational study of patients with moderate to severe rheumatoid arthritis (RA).Patients who participated in RADIUS 2 initiated etanercept (ETN) therapy at study entry and were followed for 5 years. In this post hoc analysis, patients who had received ETN continuously from entry to month 4 were categorised by treatment at month 4: ETN monotherapy, ETN+methotrexate (MTX), ETN+MTX+other DMARDs (OTH), or ETN+OTH. Outcomes were assessed at month 4 and at the time of any subsequent treatment change, and included Clinical Disease Activity Index (CDAI) and Health Assessment Questionnaire Disability Index (HAQ-DI).Of 3,484 patients analysed (982 ETN; 1,356 ETN+MTX; 537 ETN+MTX+OTH; 609 ETN+OTH), baseline demographic and clinical characteristics were similar across treatments. No treatment change occurred in 62.3%, 49.9%, 33.3%, and 37.1% of ETN, ETN+MTX, ETN+MTX+OTH, and ETN+OTH patients, respectively. The mean time on therapy from month 4 was longer for patients receiving ETN (23.3 months) or ETN+MTX (23.7 months) than those receiving ETN+MTX+OTH (18.0 months) or ETN+OTH (18.3 months). The greatest improvements in CDAI and HAQ-DI were seen in patients who continued on ETN. The most common reasons for discontinuing DMARD therapy were cost and ineffective treatment.Most patients who had received ≥4 months of ETN continued on ETN throughout the 5-year observation period. Patients with greatest clinical and disability improvements tended to continue on ETN.

Objective. To evaluate the efficacy of an anti-CD5 ricin-linked immunoconjugate (CD5-IC) in patients with rheumatoid arthritis (RA). Methods. A total of 104 evaluable patients were enrolled in a multicenter, double-blind, multiple-dose, placebo-controlled study of CD5-IC. Results. Treatment with CD5-IC in doses up to 8 mg/m2/day for 4 days in 1 month failed to produce marked or prolonged T cell depletion and was no more effective than placebo in ameliorating disease manifestations. An unexpectedly high placebo response was observed in 48% of the patients. Adverse events were correlated with the dose of CD5-IC, but the treatment was generally well-tolerated. Conclusion. At the doses used in this study, CD5-IC was ineffective for treating RA.

Background The ability to assess rheumatoid arthritis (RA) disease activity using administrative data could provide a potential mechanism to identify patients with high disease activity who may be candidates for enhanced RA treatment. The Veterans Affairs rheumatoid arthritis (VARA) registry is a prospective observational cohort that collects RA disease activity measurements including the 28 joint count disease activity score (DAS28) at twelve US Veterans Affairs (VA) Medical Centers. Objectives This study used VA administrative data to develop a model to predict DAS28 in US Veterans. Results We identified 1,582 US Veterans with RA who fulfilled enrollment criteria. The average age was 62.7±11.0 years, 91% male, with a disease duration 13.7±12.1 years with 78% and 74% seropositive for rheumatoid factor and anti-CCP antibodies respectively. Of the 1,275 variables evaluated, 175 had prevalence of 1% or more for consideration in the model. Of these 175 candidate variables, 32 remained in the final model. The key variables associated with disease activity were related to number of clinic visits (rheumatology, primary care, and ancillary services), numbers of laboratory tests, medication changes, imaging episodes, and surgery. The association of the predicted and observed DAS28 was relatively limited with unadjusted and adjusted R-square as 0.24 and 0.22 respectively. The model was very sensitive for detection of high/moderate disease (sensitivity =91.3%) but the specificity was only 25.3%.US Veterans with RA enrolled in the VARA registry with administrative data available for the year prior to DAS28 measurement and were evaluated. Patients were excluded if they had cancer, organ transplantation, or other autoimmune diseases. We identified 1,275 administrative data elements with suspected association with disease activity to investigate for association with DAS28 score. Least absolute shrinkage and selection operator (LASSO) was used to develop a model for the prediction of DAS28 as a continuous variable. The sensitivity, specificity, positive and negative predictive values were calculated. For these calculations, we defined high/moderate disease as DAS28>3.2 and low disease as DAS28≤3.2 in a categorical manner. Conclusions While there were multiple administrative elements that correlated with disease activity measured by DAS28, it was not possible to develop a strong predictive model using available administrative data. These observations suggest that the continued direct observation of disease activity remains the most effective measure to identify RA patients with high disease activity. However the transient nature of RA disease activity may predicate the need to refine our model to account for disease duration. Additionally a single point-in-time measurement may not be indicative of patient disease activity over a long period of time. The development of other methods that can extract information from provider assessment of disease from electronic medical records has the potential to meet this critical need. 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, M. Trivedi Shareholder of: Amgen, Employee of: Amgen, B. Sauer Grant/research support from: Amgen

Background Systems to electronically retrieve disease activity measures in medical records would significantly aid rheumatoid arthritis (RA) management and enhance epidemiologic research. As part of the national VA rheumatoid arthritis (VARA) registry our clinic measures 28 joint disease activity score (DAS28) by manual extraction (ManEx). Objectives 1. To develop a natural language processing (NLP) system to extract core measures from patient clinic note text and erythrocyte sedimentation rate (ESR) from the laboratory data to calculate DAS28. 2. To compare the accuracy and precision of the NLP DAS28 with ManEx DAS28. 3. To validate these findings in a second RA cohort. Methods An NLP application used clinical notes between January 1, 2015 and September 30, 2015 for RA patients in VARA (n=207) at our single site to extract tender joint count (TJC), swollen joint count (SJC), and patient global assessment (PtGA) from note text. The ESR value within 2 weeks closest to the clinic visit was combined with TJC, SJC, and PtGA to calculate DAS28. During the same observation period, ManEx of DAS28 observations were also identified. Discrepancies between ManEx and NLP were resolved by investigator review of the clinic notes. An analysis of all notes identified either by ManEx or NLP were evaluated for accuracy (% of values correctly detected in all notes) and precision (% of retrieved values by either ManEx or NLP correctly identified by that specific method). The NLP system was validated in a second cohort of RA patients in VARA (n=214) at our site between April 1, 2014 to December 31, 2014. Results The derivation set contained a total of 472 notes; 440 (93%) identified by both ManEx and NLP; 20 (4%) by ManEx alone and 12 (3%) notes by NLP alone. The accuracy and precision for TJC, SJC, PtGA, ESR and DAS28 are as noted in the table. Failure of NLP to detect core measures was because of use of incorrect note template (n=5, 1.0%) and template modification (n=18, 3.8%); however, when detected NLP precision was near 100%. Failure of ManEx was a result of missed notes (n=19, 4.0%) and data entry errors (n=13, 2.8%). Similar results were seen in the validations set of notes (n=484). Conclusions This accurate and precise NLP system can retrieve DAS28 from clinic notes to aid in clinical care and research activities. This method can be implemented at other VARA sites and other research networks to collect RA outcomes. Disclosure of Interest None declared

Background Epidemiologic research would be significantly enhanced if accurate and reliable methods were available to assess rheumatoid arthritis (RA) disease activity using administrative data. The VA rheumatoid arthritis (VARA) registry is a prospective observational cohort that collects RA disease activity including the 28 joint count disease activity score (DAS28) and clinical disease activity index (CDAI). VA administrative data are available and can be employed to develop models to estimate RA disease activity measured by DAS28 and CDAI. Objectives 1. Use administrative data to develop models that predict disease activity. 2. Assess the accuracy of the model under different conditions including defining administrative variables as continuous (CON) and/or categorical (CAT) and stratifying by different disease durations. 3. Describe the accuracy of the models for predicting disease activity for both DAS28 and CDAI. Methods US Veterans with RA enrolled in the VARA registry without cancer, organ transplantation, or other autoimmune diseases were included in the model if they were enrolled in VA with one year of administrative data available before the first DAS28. We identified 1,275 administrative data elements with suspected association with disease activity for prediction modeling. The least absolute shrinkage and selection operator (LASSO) was used for variable selection and model development. A series of LASSO models were developed that varied the input variables. Variables were required to have ≥1% prevalence in the cohort to be included in model selection. Sub-analysis was also performed in patients with ≤2 years and ≤5 years of disease duration. Results There were 1,582 US Veterans with RA who fulfilled enrollment criteria. The average age was 62.7±11.0 years, 91% male, with a disease duration 13.7±12.1 years with 78% and 74% seropositive for rheumatoid factor and anti-CCP antibodies respectively. The adjusted r-square for the six models tested ranged from 0.20–0.24 for DAS28 and 0.17 to 0.24 for CDAI. When stratified by disease duration, the r-square associations for patients with and without ≤2 and ≤5 years of RA duration were 0.29–0.31 versus 0.22–0.27 for DAS28 and CDAI respectively. Conclusions The multiple models tested yielded very similar results with limited association of predicted disease activity with actual measured disease activity by DAS28 and CDAI in VARA. The use of CON versus CAT variables, multiple definitions for disease activity, and limitation of disease duration to early RA did drastically affect prediction accuracy. Future research should investigate additional strategies to collect components of disease activity measures directly from medical records. Disclosure of Interest G. Cannon Grant/research support from: Amgen, C.-C. Teng: None declared, N. Accortt Shareholder of: Amgen, Employee of: Amgen, D. Collier Shareholder of: Amgen, Employee of: Amgen, M. Trivedi Shareholder of: Amgen, Employee of: Amgen, B. Sauer Grant/research support from: Amgen

Community-based outpatient clinics (CBOCs) have been established by the Department of Veterans Affairs (VA) to provide primary care services to veterans living in remote and rural regions. The objective of this study was to evaluate the cost effectiveness of training rural primary care providers to perform knee injections in CBOCs, thereby avoiding referring the patient to an urban medical center for an injection by rheumatology or orthopedic specialists.We developed a decision-analysis model to compare costs and outcomes between rural providers who are trained to perform knee injections versus those who are not trained, therefore requiring a referral to a specialist to provide the injections. The model was run separately using costs from the perspective of the VA as well from the patient's perspective. The effectiveness outcome was quality-adjusted life years (QALYs). Probabilistic sensitivity analyses were performed using 10,000 second-order Monte Carlo simulations.In our base-case analyses, the incremental cost-effectiveness ratio for trained rural providers was $21,190/QALY using costs from the perspective of the VA and $205/QALY using costs from the patient's perspective. Training rural providers was cost effective in 74.4% and 93.6% of 10,000 Monte Carlo simulations at a willingness-to-pay threshold of $50,000/QALY from the perspectives of the VA and the patient, respectively.Training rural providers to perform knee injections for patients with knee pain secondary to osteoarthritis appears cost effective using the commonly used threshold of $50,000/QALY if more than 20 such patients per year are seen at rural primary care clinics. These results provide support for our ongoing efforts to implement such a training program.

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 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.

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

Objective. To evaluate the safety and activity of an immunoconjugate of ricin A chain and anti-CD5 monoclonal antibody (anti-CD5 IC), with and without concomitant methotrexate and/or azathioprine, in the treatment of rheumatoid arthritis (RA). Methods. Seventy-nine patients with active RA were enrolled in 2 prospective open-label protocols. Results. Using composite criteria, response rates were 50–68% at 1 month and 22–25% at 6 months. Transient depletion of CD3/CD5 T cells was observed on days 2 and 5 of treatment, with reconstitution on day 15 or day 29. Treatment-associated adverse effects were common but resolved rapidly without sequelae. Conclusion. These findings suggest activity of anti-CD5 IC in active RA and warrant confirmation in a multicenter randomized study (currently underway).

Objective. To test for genetic differences in susceptibility to homologous (rat) type II collagen-induced arthritis (RII-CIA). Methods. Nine inbred and RT1-congenic rat strains were immunized with native rat type II collagen and evaluated for arthritis and IgG anti-RII serum antibody titers. Results. Only RT1av1 strains developed a high incidence of severe RII-CIA and high titers of IgG anti-RII serum antibody. Rats having RII-CIA-resistant haplotypes, RT1u,n,1 (which are known to develop CIA after immunization with heterologous type II collagen), were shown to also be susceptible to passive transfer of CIA with immune serum concentrates. Clinical expression of RII-CIA was down-regulated by non-RT1 genes of BN origin. No strong gender differences in anti-RII autoimmune responses were observed. Conclusion. Arthritogenic, autoimmune reactivity to homologous RII is under strict genetic control but occurs readily in RT1av1 rats.

To define the effects of incomplete Freund's adjuvant (ICFA) on subsequent arthritis induced by complete Freund's adjuvant (CFA) and type II collagen (CII) in DA and Lewis rats.ICFA was injected into DA and Lewis rats before CFA or CII injection.DA rats previously injected with ICFA had significantly less severe arthritis induced by CFA compared with those not receiving ICFA pretreatment (P0.01). ICFA had no significant impact on CFA-induced arthritis in Lewis rats or on CII-induced arthritis in DA rats.The injection of ICFA alone specifically suppresses subsequent CFA-induced arthritis in DA rats, but not in Lewis rats.

The prophylactic and therapeutic effects of gold sodium thiomalate, cyclosporin A, cyclophosphamide, and placebo on collagen-induced arthritis (CIA) were evaluated in DA rats. Prophylactic treatment with cyclosporin A and cyclophosphamide suppressed the arthritis incidence, clinical inflammation, destructive bone changes, and development of anti-collagen antibody in DA rats subsequently injected with porcine type-II collagen. Therapeutic treatment with cyclosporin A and cyclophosphamide had a definite suppression on established CIA when started 21 days after the initial collagen injection, but the suppression was less marked than that of prophylactic treatment. Gold had no impact on CIA in DA rats when administered either prophylactically or therapeutically.

Adjuvant-induced arthritis (AIA) can be passively transferred in Dark Agouti (DA) rats by spleen and lymph node cells after culture with Concanavalin A (Con A). A model not requiring in vitro Con A expansion and activation would be important in investigations of anti-rheumatic drugs in AIA. A new model using irradiated recipients fills this need. Donor DA rats treated with 0.1 ml complete Freund's adjuvant (CFA) containing 7.5 mg M. butyricum/ml were sacrificed 11 days after CFA injection, donor spleen cells harvested, and donor spleen cells injected intravenously into recipient DA rats previously irradiated with 5 Gy. Recipient rats developed arthritis 4-14 days after spleen cell transfer. This model can now be used to further define the effects of anti-rheumatic drugs in the passive transfer of AIA by eliminating the need for the in vitro Con A-induced expansion and/or activation of donor cells.

Mouse strains B10, B10.RIII, RIIIS/J and the F1 and backcross progeny arising from them were tested for susceptibility to porcine type II collagen-induced arthritis (PII-CIA). The clinically severe arthritis of rapid onset that is characteristic of PII-immunized B10.RIII mice developed predominantly in hybrid offspring that had inherited at least one copy of wild type T cell receptor (TCR) genes (V beta b genotype) from the B10 or B10.RIII parent. The results indicate that, in the development of PII-CIA, mice expressing the H-2r/r haplotype preferentially utilize TCR V beta genes that are normally encoded within the TCR V beta genomic deletion region of RIIIS mice (V beta c). After aggressive immunization with PII, the use of alternative TCR V beta genes, encoded outside of the RIIIS deletion region, produced a high IgG antibody response that was cross-reactive with mouse type II collagen (MII) and equivalent to that of B10.RIII mice, but only a very mild, late onset arthritis of 56% (27/48) incidence in RIIIS male mice and 28% (10/35) incidence in RIIIS female mice. In comparison, B10.RIII mice routinely developed early onset of PII-CIA of significantly higher incidence (100%; p0.005) and four-fold greater severity, even after milder immunization protocols. The data are compatible with the proposal that the clinically weak CIA response of RIIIs mice may be primarily antibody driven while the severe CIA of B10.RIII mice reflects the added inflammatory effects of collagen-reactive effector-T cells in the joint.(ABSTRACT TRUNCATED AT 250 WORDS)

Objective.25-hydroxy-vitamin D (25-OH-D) insufficiency/deficiency is increasingly prevalent and has been associated with many chronic diseases, including rheumatoid arthritis (RA). Our purpose was to define the prevalence and associations of 25-OH-D insufficiency/deficiency in a cohort of US veterans with RA.Methods.Vitamin D status (25-OH-D) was assessed in patients with RA using radioimmunoassay on banked plasma collected at enrollment. Insufficiency was defined as concentrations < 30 ng/ml and deficiency as < 20 ng/ml. Associations of 25-OH-D insufficiency/deficiency with patient characteristics obtained at enrollment were examined using multivariate logistic regression, adjusting for age, sex, season of enrollment, and race.Results.Patients (850 men, 76% Caucasian) had a mean (SD) age of 64 (SD 11.3) years. The prevalences of 25-OH-D insufficiency and deficiency were 84% and 43%, respectively. After multivariate adjustment, both insufficiency and deficiency were more common with anti-cyclic citrullinated peptide antibody positivity and non-Caucasian race, and in the absence of vitamin D supplementation. 25-OH-D deficiency, but not insufficiency, was independently associated with higher tender joint counts and highly sensitive C-reactive protein levels.Conclusion.In a predominantly elderly, male RA population, 25-OH-D insufficiency was highly prevalent. With the increasing adverse health outcomes associated with hypovitaminosis D, screening and supplementation, particularly among minority, seropositive patients with RA, should be performed routinely.

Objectives. To examine the all-cause mortality rate and factors associated with mortality in US veteran men with RA. Methods. Men with RA were enrolled and followed until death or censoring. Vital status was ascertained through systematic record review and standardized mortality ratios (SMRs) were calculated using US life tables for men. Multivariate Cox proportional hazards regression was used to examine the independent associations of patient factors including socio-demographics, comorbidity, measures of RA disease activity/severity and medication use with mortality. Measures of RA disease activity and medications were examined as time-varying factors. Results. A total of 138 deaths were observed during 2314 patient-years of follow-up (n = 1015 patients), corresponding to a crude morality rate of 5.9 deaths per 100 patient-years (95% CI 5.0, 7.0) and an SMR of 2.1 (95% CI 1.8, 2.5). After multivariate adjustment, factors independently associated with higher mortality risk in men with RA included older age, Caucasian race, low body weight, an increased frequency of rheumatology visits, higher ESR and RF concentrations, increased DAS28, subcutaneous nodules and prednisone use. In contrast, MTX use [hazard ratio (HR) 0.63; 95% CI 0.42, 0.96] was associated with 40% lower mortality risk. Conclusion. Mortality rates among US male veterans with RA are more than twice those of age-matched men in the general population. These results suggest that optimizing disease control, particularly with regimens that include MTX and minimize glucocorticoid exposure, could improve long-term survival in this population.

Background As the Accreditation Council on Graduate Medical Education (ACGME) deliberates over further limiting duty hours of graduate medical education (GME) trainees, few large-scale studies have shown residents to be satisfied with the effect the 2003 standards have had on clinical care, education outcomes, or working environments. This study measures the effect of the 2003 duty hours limits on resident-reported satisfaction with GME training during their rotations through the Department of Veterans Affairs (VA) medical centers from 2001 through 2007. Method Self-reported satisfaction with clinical care and education environments were assessed by comparing responses to VA's annual Learners' Perceptions Survey administered before 2003 with responses administered after 2003. To measure duty hours effects on satisfaction, before-after differences were adjusted for covariate biases modeled after an exhaustive covariate search with 10-fold cross-validation. Because nonteaching controls are not available in satisfaction studies, we used a robust differencing variable technique to control before-after differences for trend biases in the simultaneous presence of missing data and possible model misspecification. Results There were 19,605 responders. Adjusting for covariate and trend biases, after the 2003 ACGME standards, 25% more residents in medicine specialties reported satisfaction with VA clinical environment and 11% more with VA preceptors and faculty. For surgery, 33% more residents reported satisfaction with VA clinical environment and 12% more with VA preceptors and faculty. Satisfaction with working environment was mixed. Conclusions The 2003 ACGME duty hours standards were associated with improved satisfaction for resident clinical training and learning environments.

Rheumatoid arthritis is a chronic and highly morbid disease affecting approximately 1% of the world’s population. With the advent of disease-modifying antirheumatic drugs, patients are increasingly able to maintain control of their arthritis and prevent joint destruction. However, not all patients respond adequately to any single disease-modifying antirheumatic drug, and many newer parenteral therapies are cost prohibitive. Leflunomide, an inhibitor of pyrimidine biosynthesis, is the first oral disease-modifying antirheumatic drug to have been approved for rheumatoid arthritis in the USA in the last 15 years, and is now widely used in over 70 countries around the world. Leflunomide is efficacious when used as monotherapy or in combination with methotrexate to treat patients with rheumatoid arthritis, and is generally well tolerated. As clinical use increases, new ways to use leflunomide in order to minimize toxicity and maximize efficacy are being explored.

To develop a survey instrument designed to quantify supervision by attending physicians in nonprocedural care and to assess the instrument's feasibility and reliability.In 2008, the Department of Veterans Affairs (VA) Office of Academic Affiliations convened an expert panel to adopt a working definition of attending supervision in nonprocedural patient care and to construct a survey to quantify it. Feasibility was field-tested on residents and their supervising attending physicians at primary care internal medicine clinics at the VA Loma Linda Healthcare System in their encounters with randomly selected outpatients diagnosed with either major depressive disorder or diabetes. The authors assessed both interrater concurrent reliability and test-retest reliability.The expert panel adopted the VA's definition of resident supervision and developed the Resident Supervision Index (RSI) to measure supervision in terms of residents' case understanding, attending physicians' contributions to patient care through feedback to the resident, and attending physicians' time (minutes). The RSI was field-tested on 60 residents and 37 attending physicians for 148 supervision episodes from 143 patient encounters. Consent rates were 94% for residents and 97% for attending physicians; test-retest reliability intraclass correlations (ICCs) were 0.93 and 0.88, respectively. Concurrent reliability between residents' and attending physicians' reported time was an ICC of 0.69.The RSI is a feasible and reliable measure of resident supervision that is intended for research studies in graduate medical education focusing on education outcomes, as well as studies assessing quality of care, patient health outcomes, care costs, and clinical workload.

The effect of flurbiprofen on the passive transfer of adjuvant-induced arthritis was studied to determine if flurbiprofen acted in the donor and/or recipient arms of this model. Groups of donor and recipient rats were treated with either placebo or flurbiprofen 4 mg/kg. Joint scores were markedly decreased in recipient rats treated with flurbiprofen irrespective of the whether donor animals were treated with placebo or flurbiprofen (p less than 0.01). There was also a moderate decrease in the ability of donor cells from rats treated with flurbiprofen to suppress the severity of arthritis (p less than 0.01); however, this effect was less marked than that seen in recipient animals. These data imply that flurbiprofen may act at multiple sites in adjuvant-induced arthritis, but the major site of action of flurbiprofen in this model is in the recipient animals.

BackgroundGraduate medical education is based on an on-the-job training model in which residents provide clinical care under supervision. The traditional method is to offer residents graduated levels of responsibility that will prepare them for independent practice. However, if progressive independence from supervision exceeds residents' progressive professional development, patient outcomes may be at risk. Leaders in graduate medical education have called for “optimal” supervision, yet few studies have conceptually defined what optimal supervision means and whether optimal care is theoretically compatible with progressive independence, nor have they developed a test for progressive independence.ObjectiveThis research develops theory and analytic models as part of the Resident Supervision Index to quantify the intensity of supervision.MethodsWe introduce an explicit set of assumptions for an ideal patient-centered theory of optimal supervision of resident-provided care. A critical assumption is that informed attending staff will use available resources to optimize patient outcomes first and foremost, with residents gaining clinical competencies by contributing to optimal care. Next, we derive mathematically the consequences of these assumptions as theoretical results.ResultsUnder optimal supervision, (1) patient outcome is expected to be no worse than if residents were not involved, (2) supervisors will avoid undersupervising residents (when patients are at increased risk for poor outcomes) or oversupervising residents (when residents miss clinical opportunities to practice care), (3) optimal patient outcomes will be compatible with progressive independence, (4) progressive development can be inferred from progressive independence whenever residents contribute to patient care, and (5) analytic models that test for progressive independence will emphasize adjusting the association between length of graduate medical education training and supervision for case complexity and clinic workload, but not patient health outcomes.ConclusionAn explicit theoretical framework is critical to measure scientifically progressive independence from supervision using graduate medical education data.

BackgroundA Resident Supervision Index (RSI) developed by our research team quantifies the intensity of resident supervision in graduate medical education, with the goal of testing for progressive independence. The 4-part RSI method includes a survey instrument for staff and residents (RSI Inventory), a strategy to score survey responses, a theoretical framework (patient centered optimal supervision), and a statistical model that accounts for the presence or absence of supervision and the intensity of patient care.MethodsThe RSI Inventory data came from 140 outpatient encounters involving 57 residents and 37 attending physicians during a 3-month period at a Department of Veterans Affairs outpatient clinic. Responses are scored to quantitatively measure the intensity of resident supervision across 10 levels of patient services (staff is absent, is present, participated, or provided care with or without a resident), case discussion (resident-staff interaction), and oversight (staff reviewed case, reviewed medical chart, consulted with staff, or assessed patient). Scores are analyzed by level and for patient care using a 2-part model (supervision initiated [yes or no] versus intensity once supervision was initiated).ResultsAll resident encounters had patient care supervision, resident oversight, or both. Consistent with the progressive independence hypothesis, residents were 1.72 (P = .019) times more likely to be fully responsible for patient care with each additional postgraduate year. Decreasing case complexity, increasing clinic workload, and advanced nonmedical degrees among attending staff were negatively associated with supervision intensity, although associations varied by supervision level.ConclusionsThese data are consistent with the progressive independence hypothesis in graduate medical education and offer empirical support for the 4-part RSI method to quantify the intensity of resident supervision for research, program evaluation, and resident assessment purposes. Before informing policy, however, more scientific research in actual teaching settings is needed to better understand the relationships among patient outcomes, clinic workload, case complexity, and graduate medical education experience in resident supervision and professional development.

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 (p0.01), had lower mean OST index score (p0.05), and were more likely to have been prescribed prednisone (p0.01) 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 (p0.01). There was a significant but modest correlation between BMD and the OST index (r = 0.17, p0.01). 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.

A retrospective review of methotrexate (MTX) treatment assessed the clinical course in 124 rheumatoid arthritis (RA) patients. After 5 years, 39 (31%) patients continued MTX with clinical benefit. Although patients continuing MTX after 5 years were younger (45 +/- 13 v 54 +/- 12 yrs, P less than .001) and had a shorter disease duration of RA (9.3 +/- 8.1 v 14 +/- 11 yrs, P less than .05) than patients who discontinue the drug, these differences were not considered clinically significant. MTX was discontinued in 20 patients for a lack of clinical benefit, in 21 patients for non-drug-related reasons, and in 44 patients for suspected adverse drug reactions. The adverse drug reactions requiring permanent discontinuation of MTX were nausea, stomatitis, hair loss, rash, pulmonary reactions, elevated liver enzymes, hematologic abnormalities, and hepatic fibrosis. At least one adverse drug reaction was reported by 115 (93%) patients receiving MTX, but the majority did not require permanent drug discontinuation. Although the prevalence of adverse reactions increased with longer duration of therapy, no differences existed in the type of reactions reported over 5 years of treatment. There were no risk factors identified that were clearly associated with the development of toxicity. Long-term therapy was primarily limited by adverse reactions rather than loss of efficacy.

Despite the fact that almost all men will develop symptoms associated with benign prostatic hyperplasia within their lifetimes, no molecular markers for the disease or its likelihood to progress have been established. A marker of this type could be used to stratify patients into subpopulations as well as to identify individuals whose disease is most likely to progress. Several molecular biomarkers have high potential to fulfill these needs, although none is currently approved for the clinical setting. The future does look promising as research to find novel biologic biomarkers is progressing while existing markers are optimized and validated for clinical use.

One hundred five patients were enrolled in a 12-week, randomized, prospective, double-blind, placebo-controlled trial of recombinant human gamma-interferon (rHu gamma-IFN) for the treatment of rheumatoid arthritis. Fifty-four patients received rHu gamma-IFN and 51 received placebo. Forty-two patients in each group completed the 12-week trial. Some clinical improvement occurred in both groups of patients. Although the improvement with rHu gamma-IFN was greater than that with placebo, the differences were generally not statistically significant.

Collagen-Induced Arthritis (CIA) is a complex model of autoimmune-mediated arthritis that is regulated by multiple genetic and environmental factors. CIA is induced in rats by immunization with native type II collagen and develops joint pathology similar to that of rheumatoid arthritis. This chapter details methods for the extraction and purification of native type II collagen from sternal and articular cartilage, an arthritis induction protocol that has resulted in reproducible CIA expression in several rat strains from year to year and criteria for measuring clinical, radiographic and immunological outcome parameters characteristic of CIA.

To examine the association of race/ethnicity with measures of disease activity and severity among male US veterans with rheumatoid arthritis (RA).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.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.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.

To describe the initial assessment of early prostate cancer antigen (EPCA)-2 as a serum marker for the detection of prostate cancer and to examine its sensitivity and specificity.Serum samples were obtained from 385 men: those with prostate-specific antigen (PSA) levels less than 2.5 ng/mL, PSA levels of 2.5 ng/mL or greater with negative biopsy findings, benign prostatic hyperplasia, organ-confined prostate cancer, non-organ-confined disease, and prostate cancer with PSA levels less than 2.5 ng/mL. In addition, a diverse group of controls was assessed with an enzyme-linked immunosorbent assay to detect an epitope of the EPCA-2 protein, EPCA-2.22.Using a cutoff of 30 ng/mL, the EPCA-2.22 assay had a 92% specificity (95% confidence interval 85% to 96%) for healthy men and men with benign prostatic hyperplasia and 94% sensitivity (95% confidence interval [CI] 93% to 99%) for overall prostate cancer. The specificity for PSA in these selected groups of patients was 65% (95% CI 55% to 75%). Additionally, EPCA-2.22 was highly accurate in differentiating between localized and extracapsular disease (area under the curve 0.89, 95% CI 0.82 to 0.97, P0.0001) in contrast to PSA (area under the curve 0.62, 95% CI 0.50 to 0.75, P = 0.05).The results of our study have shown that EPCA-2 is a novel biomarker associated with prostate cancer that has high sensitivity and specificity and accurately differentiates between men with organ-confined and non-organ-confined disease.