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Background Despite a paucity of evidence to support a multitude of educational innovations, curricular leaders are pressured to find innovative solutions to better prepare medical students for an evolving twenty-first century health care system. As part of this effort, this study directly compared student-rated effectiveness scores of six different learning modalities. Methods Study participants included 286 medical students enrolled in the second-year rheumatology core at a single academic medical center between 2013 and 2017. Students were surveyed at the end of the core with a 15-item questionnaire, and student perceived effectiveness of six different learning modalities were compared. Results The modality that outperformed all others was Live Patient Encounters (LPE), with significantly higher student-rated effectiveness scores when compared to the referent modality of Problem-Based Learning (PBL). Using a 5-point Likert scale with responses ranging from “not effective” to “highly effective,” LPE received a mean effectiveness score of 4.77 followed by Augenblick (4.21), PBL (4.11), Gout Racer video game (3.49), Rheumatology Remedy e-module (3.49), and simulation knee injection (3.09). Conclusions Technologically advanced novel learning strategies were outperformed in this study by the more traditional active learning modality of LPE. This finding highlights the importance of testing innovative learning strategies at the level of the learner. Three additional conclusions can be drawn from this result. First, conflation of technology with innovation may lead to a myopic view of educational reform. Second, human factors seem to be responsible for the success of LPE and may have far-reaching educational rewards. Third, further applications of LPE should be tested in non-rheumatologic curricula. The relevance of this study is innately tied to the humanities-based application. While a formal qualitative analysis was not performed in this study, preliminary results suggest that live, structured patient interactions in the pre-clinical years of medical education may not only promote the learning of important educational objectives but also foster professional development, empathy, reflection, leadership, agency, and interpersonal skills. This “win-win” scenario (if true) would stand out as a rarity among strategic educational initiatives.

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.

Systemic bone loss is associated with airway inflammatory diseases; yet, strategies to halt disease progression from inhalant exposures are not clear. Vitamin D might be a potentially protective approach against noxious respirable environmental exposures. We sought to determine whether vitamin D supplementation represents a viable lung- and bone-protective strategy following repetitive inhalant treatments with organic dust extract (ODE) or lipopolysaccharide (LPS) in mice. C57BL/5 mice were maintained on diets with low (1 IU/D/g) or high (10 IU/D/g) vitamin D for 5 weeks and treated with ODE from swine confinement facilities, LPS, or saline daily for 3 weeks per established intranasal inhalation protocol. Lungs, hind limbs, and sera were harvested for experimental outcomes. Serum 25-hydroxyvitamin D levels were tenfold different between low and high vitamin D treatment groups with no differences between inhalant agents and saline treatments. Serum calcium levels were not affected. There was no difference in the magnitude of ODE- or LPS-induced inflammatory cell influx or lung histopathology between high and low vitamin D treatment groups. However, high vitamin D treatment reversed the loss of bone mineral density, bone volume, and bone micro-architecture deterioration induced by ODE or LPS as determined by micro-CT analysis. Bone-resorbing osteoclasts were also reduced by high vitamin D treatment. In the low vitamin D treatment groups, ODE induced the greatest degree of airway inflammatory consequences, and LPS induced the greatest degree of bone loss. Collectively, high-concentration vitamin D was protective against systemic bone loss, but not airway inflammation, resulting from ODE- or LPS-induced airway injury.

Methotrexate (MTX) has emerged as first-line therapy for early moderate-to-severe rheumatoid arthritis (RA), but individual variation in treatment response remains unexplained. We tested the associations between 863 known pharmacogenetic variants and MTX response in 471 Treatment of Early Aggressive Rheumatoid Arthritis Trial participants with early RA. Efficacy and toxicity were modeled using multiple regression, adjusted for demographic and clinical covariates. Penalized regression models were used to test joint associations of markers and/or covariates with the outcomes. The strongest genetic associations with efficacy were in CHST11 (five markers with P

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

Tumor necrosis factor-alpha (TNFa) plays a central role in rheumatoid arthritis (RA) pathogenesis. There are currently three available anti-TNFa agents for the treatment of RA--adalimumab, etanercept, and infliximab. These targeted therapies have select advantages over traditional disease-modifying antirheumatic drugs (DMARDs), agents that have long been the mainstay of RA treatment. Compared with conventional DMARDs, TNFa inhibitors display a rapid onset of action and have shown a significant effect in retarding the radiographic joint destruction that often characterizes RA disease progression. Although anti-TNFa drugs represent an important advance in RA treatment, postmarketing reports of serious infections, as well as other adverse events, highlight the need for continued postmarketing vigilance with the use of these agents. This review evaluates the unique attributes of the available TNFa inhibitors, focusing specifically on recent reports providing important insight into the understanding of drug-related efficacy and toxicity.

In the last decade, there have been substantial advances in the treatment of rheumatoid arthritis with the addition of several new disease-modifying agents to the therapeutic armamentarium. Biological agents targeting tumour necrosis factor (TNF) represent one such important addition. Infliximab, a chimeric anti-TNF monoclonal antibody, has shown remarkable promise in alleviating the signs and symptoms of rheumatoid arthritis in addition to retarding radiographic disease progression when used in combination with methotrexate. In its pivotal phase III trial, the addition of infliximab to patients with methotrexate-refractory disease was associated with substantial clinical benefit. Using American College of Rheumatology criteria for improvement, one-half of patients receiving infliximab (3 mg/kg every 8 weeks) plus methotrexate showed at least 20% improvement compared with only 20% of those receiving placebo plus methotrexate (p < 0.001) with over one-half of eventual responders obtaining criteria for improvement by the second week of observation. Although its use has been met with much deserved enthusiasm, recent reports have highlighted several potential serious adverse effects associated with infliximab (and other TNF antagonists), including infusion reactions, congestive heart failure, drug-induced lupus, and CNS demyelination. In addition, recent reports have cited the potential for reactivation of mycobacterial and fungal infection in patients receiving infliximab, mandating appropriate tuberculosis screening prior to drug initiation. Although the frequency of serious drug-related toxicity (requiring discontinuation of the agent) appears to be quite low, these reports underscore the need for caution and close surveillance with the administration of TNF inhibitors, particularly given that strategies aimed at preventing toxicity remain unproven. Despite its potential for toxicity, infliximab remains a valuable alternative for patients with rheumatoid arthritis.

Introduction Findings that African-American race/ethnicity is associated with higher concentrations of serum urate have not been adjusted for possible confounding factors or have not explored this question as a primary outcome. We tested this hypothesis in a bi-racial cohort of younger African-American and white men and women. Methods Data from 5,049 participants at the Coronary Artery Risk Development in Young Adults (CARDIA) cohort baseline (1985 to1986) and follow-up for up to 20 years of individuals without hyperuricemia (defined as a serum urate of 6.8 mg/dL or more) at baseline were utilized. We determined associations between race, serum urate and the development of hyperuricemia in sex-specific cross-sectional and longitudinal analyses. Confounding factors examined included: age at enrollment, body mass index, development of hypertension, glomerular filtration rate, medication use, diet and alcohol intake and menopausal symptoms in women. Results Referent to whites, African-American men and women had significantly lower concentrations of serum urate at baseline. African-American men had an essentially equal risk of developing incident hyperuricemia during follow-up compared with white men (multivariable adjusted HR = 1.12 (0.88 to1.40)). African-American women developed a significantly increased risk of hyperuricemia when compared to white women (HR = 2.31 (1.34 to 3.99)). Conclusions Young African-American men and women had lower concentrations of serum urate than whites. During longitudinal follow-up, African-American women had a significantly increased risk of developing hyperuricemia when compared with white women, a difference that was not observed in men. Differences in production of serum urate or a more rapid decline in fractional excretion of serum urate are potential, albeit still unproven, explanations for these findings in African-American women.

Introduction Minocycline and doxycycline are safe and moderately effective disease-modifying anti-rheumatic drugs (DMARDs) in the treatment of early, DMARD-naïve rheumatoid arthritis (RA), although little is known about their use outside clinical trials. We characterize the use of minocycline and doxycycline in community-dwelling RA patients by examining associated prescribing patterns, patient-level determinants of use, and side-effect profiles. Methods We studied 15,716 patients with RA observed between 1998 and 2009 while participating in a long-term US observational study. Results Minocycline or doxycycline was prescribed by 18% of rheumatologists (interquartile range one to two patients per physician) to 9% of RA patients. Significant differences between minocycline-treated and doxycycline-treated patients and nontreated patients included age (58.4 years vs. 59.8 years), RA duration (14.8 years vs. 13.7 years), Caucasian race (93.7% vs. 89.7%), lifetime DMARDs and biologics (3.3 vs. 2.5), prednisone use (40.1% vs. 35.3%), and Medical Outcomes Study 36-Item Short Form Survey physical component summary score (35.0 vs. 36.4). In multivariable Cox regression, patients initiating minocycline or doxycycline had increased disease activity, more comorbidities, and a greater number of prior nonbiologic DMARDs. Side effects were reported by 17.8% of minocycline users and 11.8% of doxycycline users. Skin complaints accounted for 54% of minocycline patient-reported side effects. The most commonly effected organ systems for doxycycline were gastrointestinal (35.4%) and skin (33.7%). Approximately 75% of side effects were of mild or moderate severity. Conclusions Rheumatologists have not embraced minocycline or doxycycline as primary treatment options for RA and reserve their use primarily in patients with long-standing, refractory disease. These drugs are generally well tolerated, with skin complaints, nausea, and dizziness being the most common patient-reported side effects.

Introduction The purpose of the present manuscript is to test the hypothesis that arthrotropic localization and synovial cell internalization account for the unique capacity of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-dexamethasone conjugate (P-Dex, a macromolecular prodrug of dexamethasone) to induce sustained amelioration of joint inflammation and inhibition of tissue damage in an animal model of inflammatory arthritis. Methods Rats with adjuvant-induced arthritis (AA) were treated with P-Dex, free dexamethasone, saline or HPMA homopolymer. To define the biodistribution of P-Dex, conjugates with different imaging labels were given to AA rats and analyzed. Isolated joint tissues were evaluated by fluorescence-activated cell sorting (FACS) and immunohistochemical staining. Cellular uptake of P-Dex and its effects on apoptosis and production of proinflammatory cytokines were examined using human monocyte-macrophages and fibroblasts. Results A single systemic administration of P-Dex completely suppressed AA for >20 days. Magnetic resonance imaging demonstrated higher HPMA copolymer influx into the inflamed joints than the normal joints. Immunohistochemistry and FACS analyses of arthritic joints revealed extensive uptake of the polymer conjugate by synovial fibroblasts and myeloid lineage cells. The capacity of P-Dex to suppress inflammation was confirmed in monocyte-macrophage cultures in which P-Dex treatment resulted in suppression of lipopolysaccharide-induced IL-6 and TNFα release. Similarly, TNFα-induced expression of matrix metalloproteinases (MMP1 and MMP3) in synovial fibroblasts from a rheumatoid arthritis patient was suppressed by P-Dex. P-Dex showed no detectable effect on monocyte apoptosis. Conclusions P-Dex provides superior and sustained amelioration of AA compared with an equivalent dose of free dexamethasone. The arthrotropism and local retention of P-Dex is attributed to the enhanced vascular permeability in arthritic joints and the internalization of P-Dex by synovial cells. The uptake and processing of P-Dex by macrophages and fibroblasts, and downregulation of proinflammatory mediators, provides an explanation for the sustained anti-inflammatory efficacy of P-Dex in this model of inflammatory arthritis.