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Background Biologic disease modifying agents (bDMARDs) are an integral part of rheumatoid arthritis treatment guidelines but are associated with significant cost in the US. We present the trends in total spending and unit cost of conventional DMARDs (cDMARDs) as compared to bDMARDs in Medicare program. Methods We used the Medicare drug spending data for the year 2012–2017 covering all part B (fee-for-service) and part D drugs. Total spending was calculated by summing spending across various drug formulations and unit drug cost by dividing total spending by number of doses dispensed. We present the 6-year trends in total spending, total beneficiary count and unit costs of each of the commonly used cDMARDs and bDMARDs. Results Between 2012 and 2017, the total spending on the cDMARDs increased 5-folds from $98 million to $579 million; this was fraction of total spending on bDMARDs which increased from $4.3 to $10.0 billion. This increase was driven largely by unit costs of drug rather than number of beneficiaries. There was a 6-fold increase in the unit cost of generic hydroxychloroquine followed by methotrexate and leflunomide. Amongst bDMARDs, adalimumab and etanercept unit cost increased by 2-folds. The increase was less pronounced for office-administered products. Conclusions Despite the availability of several generic cDMARDs over decades, there were steep increases in the unit cost of these agents to “keep pace” with the increases in bDMARDs. As the number of elderly rheumatoid arthritis patients increases, policy interventions might be required to reduce the spending on both biologics and conventional DMARDs.

OBJECTIVE: Certain non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with an increased risk of myocardial infarction (MI), a risk linked to cyclo-oxygenase-2 inhibition. There are limited studies assessing the risk of MI associated with meloxicam, an increasingly popular drug with COX-2 inhibiting properties. METHODS: A nested matched case-control study using The Health Improvement Network, a UK population-based database was conducted. NSAID users between 35 and 89 years of age with at least one year enrollment in the cohort were included. Incident MI cases were matched on age, sex, practice and event date with up to 4 controls. NSAID exposure was categorized as remote (between 60 days and 1 year), recent (between 1 and 60 days) or current relative to the event date. Current users were further classified as naproxen (negative control), diclofenac (positive control), meloxicam or other NSAID users. Multivariable conditional logistic regression was conducted to determine the risk of MI for each NSAID use categories compared with that of remote users. RESULTS: 9,291 MI cases were matched with 30,676 controls. The cases had a higher prevalence of traditional cardiac risk factors, chronic kidney disease and inflammatory arthritis and cardioprotective drug utilization. The adjusted odds ratio of MI for current user compared to remote users were: meloxicam 1.38 (1.17–1.63), naproxen 1.12 (0.96–1.30) and diclofenac 1.37 (1.25–1.50). CONCLUSIONS: In this large population-based study, meloxicam increased the risk of MI by 38%. This study warrants cautious use of this increasingly popular drug.

ObjectivesTo evaluate if optimal dose of either oral or injectable regimens of methotrexate (MTX) of 25 mg/week was used in the comparator arms of studies comparing biologic drugs with MTX in rheumatoid arthritis (RA).MethodsA systematic literature search was carried out in MEDLINE, EMBASE and the Cochrane Library databases for randomised controlled trials comparing biologics with MTX in RA. A systematic review was performed among studies that met predefined criteria focusing on assessment of dose of MTX used in the comparator arm. Study authors were contacted when necessary. Study quality was assessed.ResultsA total of 3276 references were identified and 13 trials were included. We obtained maximal dose and regimen for all. The maximal dose of MTX used in the comparator arm of the trials was no more than 20 mg/week in any trial and for all but one trial, MTX was given orally and not by injection. The trial that used an injectable form reached a maximum of 15 mg/week.ConclusionsA suboptimal dose of MTX was used in biological clinical trials performed in RA, particularly regarding route of administration. This may have biased findings in favour of biological agents.

Objective. We aimed to examine whether the current users of specific NSAIDs have an increased risk of venous thromboembolism (VTE) among knee OA patients. Methods. We conducted a population-based case-control study using The Health Improvement Network, a database of patient records from general practices in the UK. For every VTE case, we identified five controls matched on age, sex and calendar year of study enrolment. We used conditional logistic regression to assess the association between current use of specific NSAIDs and risk of VTE relative to remote NSAID users. Results. Among knee OA patients with at least one NSAID prescription, we identified 4020 incident cases of VTE and 20 059 matched controls. Adjusted odd ratios (ORs) relative to the remote users were 1.38 (95% CI: 1.32, 1.44) for recent users and 1.43 (95% CI: 1.36, 1.49) for current users. Among the current NSAID users, the risk of VTE was increased with diclofenac [OR 1.63 (95% CI: 1.53, 1.74)], ibuprofen [OR = 1.49 (95% CI: 1.38, 1.62)], meloxicam [OR = 1.29 (95% CI: 1.11, 1.50)] and coxibs [celecoxib, OR = 1.30 (95% CI: 1.11, 1.51); rofecoxib, OR = 1.44 (95% CI: 1.18, 1.76)]; naproxen did not increase VTE risk [OR = 1.00 (95% CI: 0.89, 1.12)]. Conclusion. Compared with the remote users of NSAIDs, the risk of VTE increased for current users of diclofenac, ibuprofen, meloxicam, and coxibs, but not for naproxen, in the knee OA population. Clinicians should consider the risk profile for specific NSAIDs when recommending their use.

Background:Emergency department (ED) visits for acute gout increased by approximately 20% between 2006 and 2014 in the United States. (1) Reducing ED length of stay (LOS) can help improve health outcomes, and reduce ED crowding and cost of care for patients with gout.Objectives:The aim of our study was to assess ED LOS and to identify factors associated with prolonged ED LOS in patients with acute gout.Methods:In this retrospective analysis, we included the first ED visit of adult patients (>18years) with acute gout who presented to the 3 EDs affiliated with Lifespan Health Systems, the largest healthcare provider in Rhode Island. Our study period was 3/30/2015 to 9/30/2017.We calculated ED LOS as the time spent by patients in the ED until they were discharged. Patients presenting to the ED and subsequently admitted to the hospital were excluded given the differential effect of systems factors in these patients. We assessed the following factors’ association with being in the upper quartile of ED LOS: (a) Patient factors – demographics, comorbidities and clinical presentation of gout (number of joints involved, severity as gauged by an ED triage nurse on a scale of 1 to 5; 1 being the worst) and (b) systems factors – time of day, day of the week, and time of year at presentation to the ED, teaching versus non-teaching hospital setting, and performing an arthrocentesis. We performed univariate and multivariable analyses to identify factors associated with prolonged ED LOS in patients with acute gout.Results:A total of 355 patients (mean age 56.6 ± 16.03 years, 81.3% males) were included. The median ED LOS was 2.65 hours (1.75, 4.3 hours). A quarter of the patients spent more than 4.3 hours in the ED; the national average across all medical illnesses being 3.7 hours (2). In the univariate analysis, older age (> 65 years), comorbidities (hypertension, congestive heart failure), worse ED severity score, procedural delays, and teaching hospital setting were associated with being in the upper quartile of ED LOS. In a multivariable analysis, age >65 years, procedural delays, and worse ED acuity score continued to be associated with longer ED LOS.Conclusion:In our study settings, patients with acute gout spent a longer time in the ED than the national median of 120-150 minutes. (2) We noted that older age and higher acuity score in addition to procedural delays led to longer length of stay in the ED. The results of our study should guide future interventions to reduce ED LOS for patients with acute gout.References:[1] Mithal, A., & Singh, G. (2018). OP0185 Emergency department visits for gout: a dramatic increase in the past decade[2]Centers for Disease Control and Prevention. (2014). QuickStats: median emergency department (ED) wait and treatment times, by triage level–National Hospital Ambulatory Medical Care Survey, United States, 2010-2011. Morb Mortal Wkly Rep, 63,439. (https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6319a8.htm)Disclosure of Interests:None declared

Biologic anti-rheumatic drugs are used with less frequency among older patients compared to young patients. This population is less represented in studies performed to evaluate the efficacy and safety of this drugs. We aimed to assess the efficacy and safety of biological agents between the older RA patients compared to young.A comprehensive, systematic search was conducted in major indexing databases using key terms for RA and each biological agent. The review process was completed by 2 investigators. Both randomized controlled trials and observational studies of at least 6-month duration conducted in adult RA patients were included. Outcomes of interest were clinical efficacy and safety. Effect-estimates were pooled using random-effects modeling if 4 or more studies used the same scale and time-frame for measuring outcomes.24 studies (16 focusing on anti-TNF agents) representing 63,705 patients (24% were older) were included. Older RA patients had worse baseline RA disease activity, longer disease duration at the time of enrollment in the trial (14.4 ± 3.6 vs. 10.9 ± 3.6 years; p 0.001) and higher steroid use (73.2 vs. 64.7%, p 0.001) than younger. 5 out of 6 studies assessing anti-TNF agents showed worse efficacy outcomes in older patients. The pooled OR of infection and ADRs with anti-TNF agents in older compared to young RA patients was OR 1.59 (95% CI: 1.45-1.76) and 1.40 (95% CI: 1.23-1.61) respectively.Older patients had worse safety and efficacy with biological agents but also had worse baseline disease activity. There was significant heterogeneity in reporting outcomes and very limited studies in biological agents other than anti-TNF drugs.

Background Rheumatoid arthritis (RA) patients are disproportionately older (33% >60 years). With improved biologic therapy for RA, there is a need to understand the efficacy and safety of biologic therapies in older RA (oRA) patients. Objectives To systematically review published literature to summarize the available evidence of efficacy and safety of biologic agents in oRA compared to young RA (yRA) patients. Methods A search in EMBASE, MedLine, Toxline, clinicaltrials.gov and Cochrane database was performed to identify clinical trials (RCT) and observational (OBS) studies of >6 months comparing the efficacy and safety of biologic agents in oRA relative to yRA. The biologics of interest were all anti-TNF agents, abatacept (ABA), tocilizumab (TCZ), rituximab (RTX) and tofacitinib (TOF). English language studies conducted in adult RA that reported age-associated outcomes were included. Studies assessing juveniles, inflammatory arthritis or not reporting older age outcomes were excluded. Safety outcomes included infections, adverse drug reactions (ADR), and malignancy. 2 independent rheumatologists reviewed abstracts, full text articles, and abstracted data from included articles. Conflicts were resolved by a 3rd reviewer. Abstracted data was summarized and evaluated for use within a meta-analysis Results Of 5353 abstracts, 187 were identified for full text review and 32 articles were included in this review. Articles were focused on efficacy (n=9), safety (n=15), or both (n=8). Most articles (n=22; 69%) focused on anti-TNF agents, then TCZ (n=4), ABA (n=2), TOF (n=2), RTX (n=1) and all biologics (n=1). Most studies were OBS studies (n=28, 88%) and fewer (n=4) were post-hoc analyses of RCT. In total, 99947 unique patients were identified, of which ∼24% were older. Most studies used valid definitions of RA and outcomes; only 25% of the studies have Out of the 12 efficacy studies focusing on anti-TNF agents, 9 (75%) showed a reduced efficacy in oRA on DAS28, HAQ, CDAI, SDAI, EULAR or ACR response scales relative to yRA. Studies focusing on TCZ (n=2) and RTX (n=1) also showed a reduced efficacy in oRA. OBS studies in ABA (n=2) showed comparable efficacy in oRA and yRA. Meta-analysis was limited by heterogeneity. Safety was the focus of anti-TNF (n=15), TCZ (n=3), 2 on TOF (n=2), 1 on ABA (n=1), RTX and all biologics (n=1) studies. Among these 23 safety studies, 74% (n=17) demonstrated worse safety outcomes in oRA. like in oRA. Of studies focusing on infection in anti-TNF agents, 82% (9 of 11) reported increased risk in oRA. Among the anti-TNF studies, 2 out of the 4 (50%) measured more ADR in oRA. A meta analysis of 4 studies reporting infectious outcomes in anti-TNF agents at >1 year found a pooled risk estimate was 1.59 (95% CI 1.45–1.76). Conclusions There is heterogeneity within the literature of biological agents in RA, particularly when age is considered. Given the anticipated population increase in the oRA, there is an urgent need for analysis of these medications in oRA patients for both safety and efficacy. Disclosure of Interest None declared

Bacterial and fungal infections are major causes of morbidity and mortality after liver transplantation (LT). The role of intestinal decontamination in the prevention of post-LT infections is controversial. Rifaximin is widely used for the treatment of hepatic encephalopathy. The effect of rifaximin on post-LT infections is unknown. The aim of our study was to determine the effect of rifaximin therapy in the pretransplant period on early bacterial infections (EBIs) and fungal infections within the first 30 days after LT. All adult patients who underwent LT at our institution (January 2009 to July 2011) were included in this retrospective cohort study. Patients receiving antibiotics other than pretransplant protocol antibiotics were excluded. Patients were stratified into 2 groups based on the presence or absence of rifaximin therapy for at least 2 days before LT. Infections were defined by the isolation of any bacterial or fungal organisms within 30 days of LT. Multivariate regression analysis, Student t tests, and Pearson's chi-square tests were used to compare the 2 groups. Two hundred sixty-eight patients were included, and 71 of these patients (26.5%) were on rifaximin at the time of LT. The 2 groups were comparable with respect to age, sex, race, and Model for End-Stage Liver Disease score. There were no significant differences in the rates of EBIs (30% for the non-rifaximin group and 25% for the rifaximin group, P = 0.48) or fungal infections between the 2 groups. There was no increase in antimicrobial resistance among the infecting organisms. There was no difference in survival between the rifaximin and non-rifaximin groups (98% versus 97%, P = 0.36). In conclusion, the use of rifaximin in the pre-LT period was not associated with an increased risk of bacterial or fungal infections in the early post-LT period. Liver Transpl 20:544–551, 2014. © 2014 AASLD.

Objective To determine the differences in carotid intima-media thickness (CIMT) between patients with psoriatic diseases with and without metabolic syndrome. Methods Eligible patients from the Cardiometabolic Outcome Measures in Psoriatic Arthritis Study database, which is comprised of both psoriasis and psoriatic arthritis (PsA) patients enrolled at 2 academic medical centers, were included. Detailed cardiovascular (CV) risk factors, including metabolic syndrome profiles, medication use, disease activity, and CIMT, were examined. Results A total of 343 patients with psoriatic disease were evaluated (42.28% with psoriasis and 57.72% with PsA). PsA patients were significantly older, with longer disease duration and higher blood pressure, body mass index, and C-reactive protein (CRP) level. PsA patients took more disease-modifying antirheumatic drugs (DMARDs) and corticosteroids and underwent more CV procedures. There were no differences in prior CV events, family history of CV risk, and Framingham/Adult Treatment Panel III Risk Score. PsA patients had a higher risk of metabolic syndrome (univariate odds ratio [OR] 1.78 [95% confidence interval (95% CI) 1.08–2.95], P = 0.025). Even after adjusting for age, CRP level, and diastolic blood pressure, PsA patients not taking DMARDs were twice as likely to have metabolic syndrome compared to psoriasis patients (adjusted OR 2.09 [95% CI 0.78–5.59], P = 0.049). PsA patients with metabolic syndrome had the thickest CIMT compared to any other group (P < 0.001). Conclusion PsA patients had an increased prevalence of metabolic syndrome with significantly greater CIMT measurements compared to patients with psoriasis. Furthermore, PsA patients with metabolic syndrome had the greatest CIMT measurements compared to PsA patients without metabolic syndrome and psoriasis patients with or without metabolic syndrome. Incremental increases in inflammatory pathways in PsA may contribute to a higher CV risk as compared to psoriasis patients.

Objective Up to 30% of patients with psoriasis suffer from concurrent psoriatic arthritis, and both the diseases have worse quality-of-life outcomes compared to the general population. There is limited literature comparing quality-of-life outcomes between these diseases. We seek to compare quality-of-life outcomes between both these groups. Methods The current study is a cross-sectional analysis of a cohort of 252 patients with psoriatic diseases, who were recruited from 2 tertiary-care centers. A self-administered questionnaire was used to collect demographic and validated quality-of-life data using short form-12 (SF 12), health assessment questionnaire (HAQ), and dermatology life quality index (DLQI). Univariate and multivariate analyses were conducted to compare the quality-of-life outcomes. Results We included 107 (42.5%) psoriatic arthritis and 145 (57.5%) psoriasis patients in the cohort. The groups had comparable gender distribution and co-morbid diseases prevalence, but arthritis patients were older and received biologics/DMARDs more frequently than psoriasis patients. The physical indices (identified by HAQ and SF 12 PCS) were worse for psoriatic arthritis, whereas the mental/psychometric indices (identified by DLQI and SF 12 MCS) were comparable between both the groups. Conclusions Despite aggressive therapy, physical quality of life was worse in psoriatic arthritis patients compared to psoriasis patients. The mental quality-of-life indices were comparable in both the groups and were still below the population norm. These results suggest need for screening for psoriatic arthritis in patients with psoriasis to reduce the burden of physical quality of life and screening for early signs of psychiatric illnesses in both these disease populations.

Bacterial and fungal infections are major causes of morbidity and mortality after liver transplantation (LT). The role of intestinal decontamination in the prevention of post-LT infections is controversial. Rifaximin is widely used for the treatment of hepatic encephalopathy. The effect of rifaximin on post-LT infections is unknown. The aim of our study was to determine the effect of rifaximin therapy in the pretransplant period on early bacterial infections (EBIs) and fungal infections within the first 30 days after LT. All adult patients who underwent LT at our institution (January 2009 to July 2011) were included in this retrospective cohort study. Patients receiving antibiotics other than pretransplant protocol antibiotics were excluded. Patients were stratified into 2 groups based on the presence or absence of rifaximin therapy for at least 2 days before LT. Infections were defined by the isolation of any bacterial or fungal organisms within 30 days of LT. Multivariate regression analysis, Student t tests, and Pearson's chi-square tests were used to compare the 2 groups. Two hundred sixty-eight patients were included, and 71 of these patients (26.5%) were on rifaximin at the time of LT. The 2 groups were comparable with respect to age, sex, race, and Model for End-Stage Liver Disease score. There were no significant differences in the rates of EBIs (30% for the non-rifaximin group and 25% for the rifaximin group, P = 0.48) or fungal infections between the 2 groups. There was no increase in antimicrobial resistance among the infecting organisms. There was no difference in survival between the rifaximin and non-rifaximin groups (98% versus 97%, P = 0.36). In conclusion, the use of rifaximin in the pre-LT period was not associated with an increased risk of bacterial or fungal infections in the early post-LT period.

Background Observational studies, including recent large cohort studies that were unavailable for prior meta-analysis, have suggested an association between migraine headache and ischemic stroke. We performed an updated meta-analysis to quantitatively summarize the strength of association between migraine and ischemic stroke risk. Methods We systematically searched electronic databases, including MEDLINE and EMBASE, through February 2009 for studies of human subjects in the English language. Study selection using a priori selection criteria, data extraction, and assessment of study quality were conducted independently by reviewer pairs using standardized forms. Results Twenty-one (60%) of 35 studies met the selection criteria, for a total of 622,381 participants (13 case-control, 8 cohort studies) included in the meta-analysis. The pooled adjusted odds ratio of ischemic stroke comparing migraineurs with nonmigraineurs using a random effects model was 2.30 (95% confidence interval [CI], 1.91-2.76). The pooled adjusted effect estimates for studies that reported relative risks and hazard ratios, respectively, were 2.41 (95% CI, 1.81-3.20) and 1.52 (95% CI, 0.99-2.35). The overall pooled effect estimate was 2.04 (95% CI, 1.72-2.43). Results were robust to sensitivity analyses excluding lower quality studies. Conclusions Migraine is associated with increased ischemic stroke risk. These findings underscore the importance of identifying high-risk migraineurs with other modifiable stroke risk factors. Future studies of the effect of migraine treatment and modifiable risk factor reduction on stroke risk in migraineurs are warranted.

A man with liver cancer developed abdominal ecchymoses resembling the Cullen sign and flank ecchymoses resembling the Grey Turner sign.

Background Several residency program characteristics have been suggested as measures of program quality, but associations between these measures are unknown. We set out to determine associations between these potential measures of program quality. Methods Survey of internal medicine residency programs that shared an online ambulatory curriculum on hospital type, faculty size, number of trainees, proportion of international medical graduate (IMG) trainees, Internal Medicine In-Training Examination (IM-ITE) scores, three-year American Board of Internal Medicine Certifying Examination (ABIM-CE) first-try pass rates, Residency Review Committee-Internal Medicine (RRC-IM) certification length, program director clinical duties, and use of pharmaceutical funding to support education. Associations assessed using Chi-square, Spearman rank correlation, univariate and multivariable linear regression. Results Fifty one of 67 programs responded (response rate 76.1%), including 29 (56.9%) community teaching and 17 (33.3%) university hospitals, with a mean of 68 trainees and 101 faculty. Forty four percent of trainees were IMGs. The average post-graduate year (PGY)-2 IM-ITE raw score was 63.1, which was 66.8 for PGY3s. Average 3-year ABIM-CE pass rate was 95.8%; average RRC-IM certification was 4.3 years. ABIM-CE results, IM-ITE results, and length of RRC-IM certification were strongly associated with each other (p < 0.05). PGY3 IM-ITE scores were higher in programs with more IMGs and in programs that accepted pharmaceutical support (p < 0.05). RRC-IM certification was shorter in programs with higher numbers of IMGs. In multivariable analysis, a higher proportion of IMGs was associated with 1.17 years shorter RRC accreditation. Conclusions Associations between quality indicators are complex, but suggest that the presence of IMGs is associated with better performance on standardized tests but decreased duration of RRC-IM certification.