Faculty Bibliography

Purpose: The etiology of RA remains unknown, but genetic and environmental factors have been implicated. An infectious trigger has been sought but conventional microbiologic techniques have been uninformative. The human intestine contains a dense, diverse and poorly characterized (>=80% uncultured) bacterial population whose collective genome (microbiome) is >=100 times larger than its human host. We (DRL) have recently shown in mice that gut-residing bacteria drive autoimmune arthritis via Th17 cell activation (Immunity 2010). Multiple lines of investigation also suggest a link between RA and oral microbes. Methods: As part of an NIH ARRA grant, the NYU Microbiome Center for Rheumatology and Autoimmunity was established to study gut and oral microbiota in RA and related conditions. A cross-sectional study and prospective proof-of-concept antibiotic intervention trial are ongoing. Fecal samples are collected, periodontal status assessed and oral samples obtained by subgingival biofilm collection. To date, oral/intestinal microbiomes have been analyzed in 8 RA patients, 3 psoriatic arthritis (PsA) patients and 9 healthy controls. Periodontal status was characterized in 30 RA, 4 PsA and 8 controls. DNA was purified and variable 16s rRNA gene regions amplified. PCR products were pyrosequenced (454 Life Sciences), and DNA sequences compared to the RDP and BLAST catalogs. rDNA-based phylogenetic trees were created, and the UNIFRAC metric used to compare bacterial communities across individuals. Sera from all subjects were evaluated for anti-citrullinated peptide antibodies (ACPA). Results: Prevotellaceae family was significantly overrepresented in fecal microbiota from ACPA+ RA patients (range 13%-85%; mean=38%) vs ACPA-individuals (mean=4.3%); p=0.003. One ACPA+ healthy individual and 1 ACPA+ PsA patient shared similar microbiomes with ACPA+ RA. Subgingival microbiomes in patients with new-onset drug-naive RA exhibited overabundance of the Spirochetaceae/Prevotellaceae/Porphyromonaceae families (mean=53%) compared to chronic-active RA and healthy controls (mean=18.5%). Periodontal assessment revealed 78% of examined sites bled upon probing in RA patients (mean age 39; 73% female), significantly more than controls (38% PsA, 12% healthy; p<0.001 vs RA); 66% of RA patients also presented with moderate periodontitis compared to PsA (25%) and controls (12%). Conclusions: This is the first study using high-throughput technologies to assess oral and intestinal microbiota in RA. Our data corroborate prior reports demonstrating an underappreciated high prevalence of periodontal disease at a young age in patients with RA. Moreover, our preliminary data suggest that ACPA generation may be associated with larger populations of Prevotellaceae in both oral and intestinal microbiomes. In response to such altered microbial flora, certain predisposed individuals may develop auto-inflammatory disease, through mechanisms that may include the generation of cyclic citrullinated peptides or Th17 cell activation in the intestinal mucosa. Thus, the oral and intestinal microbiota merit further investigation as potential triggers for autoimmunity and clinical RA

BACKGROUND: Relatively few studies have rigorously assessed the effectiveness of computer-based self-assessment in medical education. AIM: To assess whether an online self-assessment tool can be an effective adjunct to a traditional curriculum for second-year medical students. METHODS: The NYU School of Medicine Online Self-Assessment Tool (SOMOSAT) consists of >450 multiple-choice questions spanning disciplines of internal medicine, administered as separate modules focused on individual organ systems. Questions are coded on multiple dimensions, permitting second-year medical students to receive low-stakes, highly specific feedback regarding their knowledge and performance. Students can also review their answers to guide future study. We employed data collected during SOMOSAT operation to assess its utility and effectiveness. RESULTS: Overall, SOMOSAT accurately predicted student performance on future exams. SOMOSAT participants generally performed better than non-participants on subsequent graded course examinations (p < 0.05). Students using SOMOSAT subsequently experienced greater improvement in areas in which they initially performed poorly, compared with those in which they initially performed well. Students reported that SOMOSAT was most helpful in filling knowledge gaps, and providing opportunities to practice exam-style questions. CONCLUSION: The ability of SOMOSAT to enhance learning and exam performance suggests that web-based self-assessment tools can be effective adjuncts to traditional educational methods

OBJECTIVES: Reactivation of Mycobacterium tuberculosis (TB) is a significant problem with all available tumor necrosis factor (TNF) antagonists when used to treat rheumatoid arthritis (RA), psoriatic arthritis, psoriasis and other inflammatory diseases. Concerns have been raised regarding the appropriate management of patients with latent TB (LTB) exposure (or active TB infection) before initiating TNF antagonists since the safety data of combined therapy with two potentially hepatotoxic medications, methotrexate (MTX) and isoniazid (INH), is lacking. The goal of this study was to investigate the toxicity of MTX and INH therapy in RA patients before initiating TNF antagonists. METHODS: To investigate the toxicity of MTX and INH therapy in RA patients we performed a retrospective chart review of patients seen at the Bellevue Hospital Arthritis Clinic in New York City between 2002-2006. Forty-four patients who were concomitantly treated with both drugs were included. The primary outcome investigated was increase in liver function tests (LFT). RESULTS: Transient increases in LFT were seen in 11% of patients, but in no case was this more than twice the upper limit of normal values. All abnormal LFT resolved spontaneously without intervention. In addition, no patient has developed signs or symptoms of TB reactivation. CONCLUSION: The use of INH for LTB was well tolerated in RA patients on a background regimen of MTX. While the risks and benefits of all therapy must always be considered, in our experience the additive risk of INH to MTX in terms of hepatotoxicity was low. Nonetheless it is prudent to follow LFT closely on patients taking this combination

Over the past decade, significant advances have been made regarding the pathogenesis, clinical implications, and treatment of hyperuricemia. While physicians have understood for at least a century that uric acid causes gout, we are now beginning to address the question of why hyperuricemia exists and the mechanisms by which uric acid acts to stimulate inflammation. This review focuses on (1) previously unknown biological roles of uric acid; (2) why the loss of the uricase gene and resultant hyperuricemia may have provided an evolutionary advantage to primates and, in particular, to humans; (3) the molecular effects of uric acid on inflammatory cells; and (4) novel antihyperuricemic agents currently under study

OBJECTIVE: Serial measurements of anti-double-stranded DNA (anti-dsDNA) and complement are routine in the management of systemic lupus erythematosus (SLE), but their utility as biomarkers in preemptive treatment to prevent flares remains a subject of controversy. We hypothesized that concomitant elevation of anti-dsDNA and C3a can predict SLE activity in patients with stable or inactive disease and that short-term treatment with corticosteroids can avert flares. METHODS: In this prospective, randomized, double-blind, placebo-controlled trial, 154 patients were evaluated monthly for up to 18 months, with measurements of C3a, C3, C4, CH50, and anti-dsDNA levels. Patients who remained clinically stable but showed serologic evidence of an SLE flare (elevation of both the anti-dsDNA level by 25% and the C3a level by 50% over the previous 1-2 monthly visits) were randomized to receive either prednisone or placebo therapy at a dosage of 30 mg/day for 2 weeks, 20 mg/day for 1 week, and 10 mg/day for 1 week. RESULTS: Forty-one patients (21 randomized to prednisone and 20 randomized to placebo) experienced a serologic flare. Analysis of severe flares occurring </=90 days from randomization revealed that 6 occurred in patients taking placebo and none occurred in patients taking prednisone (P = 0.007). Severe flares resulted in an increase in the prednisone dosage to >40 mg/day and/or the addition of an immunosuppressive agent. Furthermore, improvement in scores on the Systemic Lupus Erythematosus Disease Activity Index, decreased levels of anti-dsDNA antibodies, and increased levels of C4 occurred 1 month after initiation of prednisone treatment. CONCLUSION: These preliminary data support our hypothesis that in a subset of clinically stable SLE patients with a combination of elevated C3a and anti-dsDNA levels, short-term corticosteroid therapy may avert a severe flare