Faculty Bibliography

Background/Purpose: Symptomatic knee osteoarthritis (SKOA) patients with obesity who undergo bariatric surgery experience knee pain relief, though the reduced mechanical load explains only part of the improvement. A reduction in inflammatory biomarkers from adipose tissue may also impact pain. We previously identified an IL1RN haplotype (TTG; rs419598, rs315952, and rs9005) that associates with OA severity and inflammatory markers. We aimed to determine whether TTG distinguishes patients who lose more weight and have more significant decreases in inflammation with greater knee OA pain relief.
Method(s): From 2013-2019 we enrolled patients >=30 years old with BMI >=30 kg/m 2 and painful knee OA who planned surgical (sleeve gastrectomy, gastric bypass, or laparoscopic band) or medical weight loss (MWL) at Bellevue Hospital or NYU Langone Health. Patients with lupus, rheumatoid arthritis, or psoriatic arthritis were excluded. Weight-bearing knee x-rays assessed OA severity to confirm a Kellgren-Lawrence grade of at least 1 (scale 0-4). Participants completed the Knee Injury and Osteoarthritis Outcomes (KOOS) questionnaire and provided blood at baseline and 1, 3, 6, and 12 months. Patients were genotyped to determine whether they carried 1 or 2 copies of the TTG haplotype (TTG-1/2) or none (TTG-0). Sleeve was the most common weight loss intervention, therefore our analysis is focused on this surgical subset to minimize variable effects on weight and biomarkers.
Result(s): We enrolled 113 patients (95 F, 18 M) with painful knee OA prior to their weight loss intervention. The mean age, BMI, and KOOS pain at baseline were 50.3 +/- 12.0 years, 44.8 +/- 8.9 kg/m 2, and 48.4 +/- 18.2 (0-100, with 100 = no pain). Of 113 patients, 48 underwent sleeve, 20 bypass, 9 laparoscopic banding, 12 did not have the surgery, and 24 pursued medical weight loss. The 77 who completed surgery had a mean % excess weight loss (%EWL) of 51.7 after 6 months, with significant decreases in hsCRP (4.4 mg/L) and leptin (32.8 ng/dL), and mean KOOS pain improvement of 22.4 (MCID= 16.7). The corresponding changes for patients who tried various MWL regimens were modest at best. We obtained the IL1RN haplotype for 45 of the 48 sleeve patients, and found 34 (70.8%) carried the TTG-1 or TTG 2 haplotype while 11 were TTG-0 (with similar baseline age, BMI, and KOOS for the two groups). At each follow-up time point through 6 months (Figure 1), TTG-1/2 patients had more difficulty losing weight than the TTG-0 group (p< 0.005 by ANOVA), with corresponding smaller reductions in hs CRP (p=0.36) and leptin (p=0.006). TTG-1/2 carriers also reported less KOOS pain relief relative to the TTG-0 group (p=0.021), markedly at 1 and 3 months with some improvement later (Table 1). All of these findings held true when only plotting data only from the 23 patients (18 TTG-1/2, 5 TTG-0) who completed each of the followup visits.
Conclusion(s): SKOA patients with obesity achieve marked excess weight loss, reductions in inflammatory mediators, and knee pain relief with bariatric surgery. The subset of patients with the TTG-0 IL1RN haplotype demonstrated more significant and/or rapid improvement in each of these outcomes, suggesting a potential predictor of which OA patients will have a more successful response to bariatric surgery

OBJECTIVE:Predictive biomarkers of progression in knee osteoarthritis are sought to enable clinical trials of structure-modifying drugs. A peripheral blood leukocyte (PBL) inflammatory gene signature, MRI-based bone marrow lesions (BML) and meniscus extrusion scores, meniscal lesions, and osteophytes on X-ray each have been shown separately to predict radiographic joint space narrowing (JSN) in subjects with symptomatic knee osteoarthritis (SKOA). In these studies, we determined whether the combination of the PBL inflammatory gene expression and these imaging findings at baseline enhanced the prognostic value of either alone. METHODS:PBL inflammatory gene expression (increased mRNA for IL-1β, TNFα, and COX-2), routine radiographs, and 3T knee MRI were assessed in two independent populations with SKOA: an NYU cohort and the Osteoarthritis Initiative (OAI). At baseline and 24 months, subjects underwent standardized fixed-flexion knee radiographs and knee MRI. Medial JSN (mJSN) was determined as the change in medial JSW. Progressors were defined by an mJSN cut-point (≥ 0.5 mm/24 months). Models were evaluated by odds ratios (OR) and area under the receiver operating characteristic curve (AUC). RESULTS:We validated our prior finding in these two independent (NYU and OAI) cohorts, individually and combined, that an inflammatory PBL inflammatory gene expression predicted radiographic progression of SKOA after adjustment for age, sex, and BMI. Similarly, the presence of baseline BML and meniscal lesions by MRI or semiquantitative osteophyte score on X-ray each predicted radiographic medial JSN at 24 months. The combination of the PBL inflammatory gene expression and medial BML increased the AUC from 0.66 (p = 0.004) to 0.75 (p < 0.0001) and the odds ratio from 6.31 to 19.10 (p < 0.0001) in the combined cohort of 473 subjects. The addition of osteophyte score to BML and PBL inflammatory gene expression further increased the predictive value of any single biomarker. A causal analysis demonstrated that the PBL inflammatory gene expression and BML independently influenced mJSN. CONCLUSION/CONCLUSIONS:The use of the PBL inflammatory gene expression together with imaging biomarkers as combinatorial predictive biomarkers, markedly enhances the identification of radiographic progressors. The identification of the SKOA population at risk for progression will help in the future design of disease-modifying OA drug trials and personalized medicine strategies.

In the past three decades, extraordinary advances have been made in the understanding of the pathogenesis of, and treatment options for, inflammatory arthritides, including rheumatoid arthritis and spondyloarthritis. The use of methotrexate and subsequently biologic therapies (such as TNF inhibitors, among others) and oral small molecules have substantially improved clinical outcomes for many patients with inflammatory arthritis; for others, however, these agents do not substantially improve their symptoms. The emerging field of pharmacomicrobiomics, which investigates the effect of variations within the human gut microbiome on drugs, has already provided important insights into these therapeutics. Pharmacomicrobiomic studies have demonstrated that human gut microorganisms and their enzymatic products can affect the bioavailability, clinical efficacy and toxicity of a wide array of drugs through direct and indirect mechanisms. This discipline promises to facilitate the advent of microbiome-based precision medicine approaches in inflammatory arthritis, including strategies for predicting response to treatment and for modulating the microbiome to improve response to therapy or reduce drug toxicity.

The revision of the curriculum at New York University School of Medicine in 2010, with a reduction of the preclerkship curriculum to 18 months, made it possible to offer an accelerated 3-year pathway in 2013 for students who know their career path. The goals of the program include individualizing education, reducing student debt, and integrating undergraduate and graduate medical education. This accelerated 3-year doctor of medicine (3YMD) pathway is the first program of its kind in the United States to offer conditional acceptance to residency programs in all specialties through the National Resident Matching Program. Since inception of the pathway 6 years ago, 81 students have graduated. Critical components to successfully launch and implement the program are described.Unwavering commitment to the program as a high institutional priority by the dean and vice dean for education facilitated the support required by department chairs and residency program directors and the flexibility needed for success. Alignment between the 3- and 4-year pathways has made it possible to add points of entry into the 3-year pathway during the second and third years and to shift back into the 4-year pathway, as warranted. Modifications to how 3YMD students are mentored included changing the role of the departmental advisor and adding a dedicated 3YMD pathway advisor who serves as an advocate for both the students and the program. Having a relatively large number of 3YMD students has contributed to the success of the program and facilitated acceptance by the residencies.

OBJECTIVE:gene with radiographic severity of symptomatic knee osteoarthritis (SKOA) and the risk of incident OA. We also explored these genetic polymorphisms in patients with new onset rheumatoid arthritis (RA). METHODS:haplotypes were also assessed for association with disease activity (DAS28) and plasma inflammatory markers in patients with RA. RESULTS:demonstrated that carriage of the TTG haplotype was associated with 4.1-fold (p=0.001) increased odds of incident rOA. Plasma IL-1Ra levels were lower in TTG carriers, while chondrocytes from TTG carriers exhibited decreased secretion of IL-1Ra. In patients with RA, the TTG haplotype was associated with increased DAS28, decreased plasma IL-1Ra and elevations of plasma inflammatory markers (hsCRP, interleukin 6 (IL-6)). CONCLUSION/CONCLUSIONS:TTG risk haplotype, associated with decreased IL-1Ra plasma levels, impairs endogenous 'anti-inflammatory' mechanisms.

Osteoarthritis (OA) is characterized by progressive loss of articular cartilage accompanied by the new bone formation and, often, a synovial proliferation that culminates in pain, loss of joint function, and disability. However, the cellular and molecular mechanisms of OA progression and the relative contributions of cartilage, bone, and synovium remain unclear. We recently found that the extracellular matrix (ECM) protein periostin (Postn, or osteoblast-specific factor, OSF-2) is expressed at high levels in human OA cartilage. Multiple groups have also reported elevated expression of Postn in several rodent models of OA. We have previously reported that in vitro Postn promotes collagen and proteoglycan degradation in human chondrocytes through AKT/β-catenin signaling and downstream activation of MMP-13 and ADAMTS4 expression. Here we show that Postn induces collagen and proteoglycan degradation in cartilage by signaling through discoidin domain receptor-1 (DDR1), a receptor tyrosine kinase. The genetic deficiency or pharmacological inhibition of DDR1 in mouse chondrocytes blocks Postn-induced MMP-13 expression. These data show that Postn is signaling though DDR1 is mechanistically involved in OA pathophysiology. Specific inhibitors of DDR1 may provide therapeutic opportunities to treat OA.

The acceptance of students to a medical school places a considerable emphasis on performance in standardized tests and undergraduate grade point average (uGPA). Traditionally, applicants may be judged as a homogeneous population according to simple quantitative thresholds that implicitly assume a linear relationship between scores and academic success. This 'one-size-fits-all' approach ignores the notion that individuals may show distinct patterns of achievement and follow diverse paths to success. In this study, we examined a dataset composed of 53 variables extracted from the admissions application records of 1,088 students matriculating to NYU School of Medicine between the years 2006-2014. We defined training and test groups and applied K-means clustering to search for distinct groups of applicants. Building an optimized logistic regression model, we then tested the predictive value of this clustering for estimating the success of applicants in medical school, aggregating eight performance measures during the subsequent medical school training as a success factor. We found evidence for four distinct clusters of students-we termed 'signatures'-which differ most substantially according to the absolute level of the applicant's uGPA and its trajectory over the course of undergraduate education. The 'risers' signature showed a relatively higher uGPA and also steeper trajectory; the other signatures showed each remaining combination of these two main factors: 'improvers' relatively lower uGPA, steeper trajectory; 'solids' higher uGPA, flatter trajectory; 'statics' both lower uGPA and flatter trajectory. Examining the success index across signatures, we found that the risers and the statics have significantly higher and lower likelihood of quantifiable success in medical school, respectively. We also found that each signature has a unique set of features that correlate with its success in medical school. The big data approach presented here can more sensitively uncover success potential since it takes into account the inherent heterogeneity within the student population.

Background/Purpose : Early treatment initiation in rheumatoid arthritis (RA) is fundamental to avoid chronic joint destruction and disability. Despite remarkable advances in RA therapeutics, oral methotrexate (MTX) remains the anchor drug and mainstay of treatment worldwide. However, MTX bioavailability has a wide inter-individual variability and >50% of patients with moderate or severe RA show no or suboptimal improvement in their symptoms in response to MTX. The reasons for these disparities in treatment response remain unclear. Prior studies have shown that the biotransformation of MTX is altered in germ-free and microbiome-depleted mice, prompting us to hypothesize that inter-individual differences in the human gut microbiome could impact drug bioavailability and thus clinical efficacy. We sought to determine differences in the microbiome of drug-naive, new onset RA (NORA) patients that could predict response to MTX therapy. Methods : We enrolled 27 drug-naive, NORA patients priori to MTX initiation (test cohort), and classified them as either MTX-responders (MTX-R; 39% of the cohort) or non-responders (MTX-NR; 61%) based on a stringent definition of clinical response (delta improvement of DAS28 >1.8 by month 4). We performed 16S rRNA gene and Shotgun Metagenomic sequencing on the baseline gut microbiomes of these NORA patients and confirmed the results in an independent validation cohort (n=31). NMR and LC-MS were performed in ex vivo incubations to measure the capacity of each NORA microbiome to metabolize MTX. Results : Our analysis revealed significant associations between the abundance of gut bacterial taxa and future MTX response. Patients that responded to therapy had significantly lower microbial diversity (p< 0.05). A significant difference in overall gut microbial community structure was also observed between groups (Bray-Curtis distance; PERMANOVA < 0.05). At the class level, we observed statistically higher abundance of Clostridia and lower abundance of Bacteroidia in MTX-NR (p< 0.05; q< 0.2). Furthermore, the baseline metagenome separated most MTX-R from MTX-NR (PCoA; PERMANOVA p< 0.05). We identified 8 microbial modules and 23 pathways, whose abundance significantly differed between groups (p< 0.05, q< 0.2), including genes related with purine and MTX metabolism, indicating a major difference in metabolic and biosynthetic potential between the microbiome of MTX-R and MTX-NR patients. Machine learning techniques were applied to this metagenomic data, resulting in a robust model based on bacterial gene abundance that accurately predicted response to MTX in an independent cohort. Finally, MTX available levels remaining after ex vivo incubation with distal gut samples from pre-treatment RA patients significantly correlated with the magnitude of future clinical response, suggesting a direct effect of the gut microbiome on MTX bioavailability and response to therapy. Conclusion : Together, these results provide the first step towards predicting response to oral MTX in NORA patients and support the utility of the gut microbiome as a prognostic tool and perhaps even as a target for manipulation in the treatment of rheumatic and autoimmune disease