Faculty Bibliography

Background/Purpose : About 30% of patients with skin psoriasis (PsO) develop psoriatic arthritis (PsA). The reasons for why only some progress to synovio-enthesial disease from skin involvement remains unknown. Genetic, environmental and clinical-demographic factors have been implicated, but are yet to be characterized in specialized, combined care centers. We aim to describe clinical phenotypes differentiating patients with PsO from those with PsA at a large, urban tertiary care PsO-PsA clinic. Methods : Consecutive adult patients meeting CASPAR criteria for PsA (n= 448) or with dermatologist diagnosed skin psoriasis only (n=161) were prospectively recruited at the NYU Psoriatic Arthritis Center and the NYU Psoriasis and Psoriatic Arthritis Clinic. All data was collected utilizing clinical visit notes and additional on-site questionnaires. Type of psoriasis and body surface area (BSA) was determined by dermatologists or rheumatologists specializing in psoriatic disease. Data was analyzed using statistical software SPSS using chi squared test with Yates Continuity Correction for dichotomous/categorical variables and t-test for continuous variables. Results : Patients with PsO were more likely to be older (52.7 vs. 48.9, p=.032) and have hypertension, obesity, diabetes, and history of myocardial infarction (Figure 1). Patients with PsO had a statistically higher BSA than those with PsA (5.8% vs 3.1%, p=.003). While the type of psoriasis was similar, the site of psoriasis involvement (specifically the scalp and nail) differentiated the populations (Table 1). In PsA compared to PsO, the odds ratio of scalp involvement was 2.96 (95% Confidence Interval [CI] 2.02, 4.34) and that of nail involvement was 14.66 (95% CI 8.21, 26.16). Inverse psoriasis was not different between groups. Additionally, those with PsA were much more likely to have a first degree relative (FDR) with psoriasis compared to those with cutaneous disease alone (31.9% vs. 12.0%, p=.007) (Figure 1). Conclusion : We report for the first time the comorbidities and psoriasis features of PsA and PsO populations in a large, combined center. We found that scalp involvement and any nail involvement was more prevalent in the PsA as compared to PsO. Only one previous study has identified scalp psoriasis[1] as a possible risk factor for progression, while previous studies looking at nail psoriasis reported much lower odds ratios[1,2]. Patients with PsA also demonstrated a higher number of FDRs with skin psoriasis, reinforcing the notion of strong heritability in PsA. The identification of risk factors for progression is of critical importance to study natural history of psoriatic disease and to inform the adequate design of prevention trials in psoriasis patients who have enriched features associated with future transition to synovio-enthesial disease

Background/Purpose : Although a number of genetic factors, including susceptibility alleles, have been identified in rheumatoid arthritis (RA), the concordance rate in monozygotic (MZ) twins is only 15% (Silman AJ et al, Br J Rheumatol 1993). Given this relatively low rate, environmental factors (including smoking, the microbiome and others) likely play a significant role in disease pathogenesis. Several prior studies have highlighted this relationship. Two examples include oral Porphyromonas gingivalis , which has been implicated in the citrullination of peptides (Hitchon CA et al, J Rheumatol 2010), and intestinal Prevotella copri , which is significantly increased in new-onset RA (Scher JU et al, Elife, 2013). In our study, we sought to further understand this relationship by exploring the microbial, metabolomic and cytokine differences in MZ twins with discordant disease. Methods : Fecal and blood samples were collected from nine pairs of MZ twins where one sibling was diagnosed with RA and the other unaffected. Fecal samples underwent bacterial DNA extraction, amplification and 16S rRNA gene sequencing. Additionally, gas chromatography mass spectrometry (GC-MS) was used to quantify fecal metabolites and multiplex assays were used to quantify fecal and plasma ACPA autoantigens as well as other cytokines (Sokolove J et al, PLoS One, 2012.). Analysis was performed using R, Quantitative Insights into Microbial Ecology (QIIME) and Linear discriminant analysis Effect Size (LEfSe). Results : Microbiome analysis revealed no significant differences in overall bacterial alpha or beta diversity between unaffected and RA twins. On average, RA twins had higher relative abundance of Bacteroidales (RA 56.6% vs Unaffected 47.9%) and lower abundance of Clostridiales (RA 34.5% vs Unaffected 42.8%). LEfSe analysis showed differentially higher abundance of Unclassified Veillonellaceae in unaffected twins (p=0.042). Unaffected twins also demonstrated higher levels of fecal octanoate (p=0.008), a medium-chain fatty acid with beneficial immune effects, as well as significantly increased levels of plasma IL-3 (p=0.039). Conversely, several fecal and plasma citrullinated/ non-citrullinated peptides were significantly higher in RA twins compared to their unaffected siblings (p< 0.05). Conclusion : We characterized differences in the bacterial microbiome, metabolites, cytokines and citrullinated/noncitrullinated peptides in MZ twins discordant for RA. We found changes in the abundance of particular taxa, as well as higher levels of octanoate and IL-3 in unaffected twins, further suggesting the possibility that the initial citrullination and autoimmune events in this disease may occur in the intestinal mucosa. Understanding the immune mechanisms Figure 2 Unaffected twins demonstrate higher levels of octanoate and IL-3, whereas RA twins have significantly higher levels of fecal and plasma citrullinated/non-citrullinated peptides. (A-B) Boxplots of fatty acid metabolites and IL-3 abundance comparing unaffected and RA twins. (C) Tables of plasma and fecal citrullinated/non-citrullinated peptides comparing unaffected and RA twins. Only the top ten peptides by p-value are listed. For all panels, statistical significance calculated using the Wilcoxon signed-rank test. orchestrated by the gut microbiota and their downstream effects may ultimately shed light on the pathogenesis of RA beyond genetic susceptibility and allow us to potentially alter the course of disease development and progression

Background/Purpose : Prevalence of sacroiliitis (SI) in Crohn's disease (CD) varies widely (range 4% -39%), depending on criteria utilized to define the disease (e.g. inflammatory back pain, plain radiographs or MRI). Sacroiliitis may remain underdiagnosed in CD patients given lack of association with clinical symptoms of back pain and CD activity. However, patients with CD often undergo magnetic resonance enterography (MRE) to assess extent, severity of small bowel CD and radiographic healing, affording clinicians the opportunity to evaluate for the presence of active and/or chronic SI. We sought to identify the prevalence of sacroiliitis in CD patients utilizing MRE and determine its relationship with CD activity, especially with concurrent biologic therapy. Methods : All CD subjects undergoing MRE between years 2014-2018 at a large IBD referral center were identified. A musculoskeletal radiologist, blinded to clinical data, reviewed all MRE exams for the presence of acute bone marrow edema (BME) lesions and chronic lesions suggestive of acute and chronic SI, respectively. A second radiologist, also blinded, assessed MRE for mucosal CD activity using validated measures. Charts were reviewed for demographics, IBD characteristics, presence of back pain, clinical and endoscopic activity of CD, and Crohn's therapies within 3 months of MRE. Comparisons were made between CD subjects with and without SI using chi-square test. Univariate and multivariate logistic regression were used to determine risk factors of SI. Results : 258 subjects with CD underwent MRE during the study period with a mean age of 35 years old, 53% (n=138) were male, and mean duration of CD at the time of MRE was 9 years. Few reported back pain (8%) and 14% had previously seen a rheumatologist. Overall, 17% (n=45) of patients had MR evidence of sacroiliitis (Table 1). Female gender, presence of back pain, and later age of CD diagnosis were associated with signs of sacroiliitis (p=0.05, p< 0.001, p=0.04 respectively; Table 2). Stricturing phenotype was associated with a lower rate of SI (7% vs. 24%; p=0.018), but inflammatory or penetrating phenotypes were not. CD location, activity as noted by clinical scores, endoscopic disease activity, or radiographic disease activity on MRE, were not associated with sacroiliitis (Table 2). On multivariable analysis, back pain was associated with the presence of sacroiliitis on MRE (OR 3.0, 95% CI 1.1-5.6; p=0.04). Concurrent CD therapy with biologics did not lower the risk of sacroiliitis. Conclusion : Although often underdiagnosed, SI is a common comorbid condition in CD. While recent history of back pain was associated with the presence of sacroiliitis visualized on MRE, no correlations were found with other clinical and endoscopic markers of CD activity. Moreover, concurrent CD therapy, especially biologics, was not associated with a lower risk of sacroiliitis on MRE. With limited clinical clues and CD characteristics to suggest sacroiliitis, gastroenterologists can utilize MRE as a screening tool to detect SI and refer CD patients to rheumatologists. Presence of SI on MRE in CD patients with back pain may help identify a subset of individuals likely to benefit from switching to therapies with proven efficacy in axial SpA

Background/Purpose : The trillions of microorganisms (microbiota) found within the human gut play a critical role in shaping the immune system, yet these complex microbial communities are also highly sensitive to numerous environmental factors. While much of the focus to date has been on dietary intake, emerging data has begun to suggest that the use of pharmaceutical drugs, even those that are not considered to be antibiotics, can alter the human gut microbiota with unknown consequences for treatment outcomes. Here, we examine the effect of methotrexate (MTX), which is first-line therapy for rheumatoid arthritis (RA), on microbiota composition and physiology as well as downstream consequences on the host ' s immune system. Methods : To examine the effect of MTX on human gut microbiota composition in vivo , gnotobiotic mice were colonized with microbiota from either healthy or RA patient donors and treated with oral MTX at varying doses. We performed high-throughput sequencing of the 16S rRNA gene to examine changes in taxonomic composition. We looked at the effects of varying the route of administration or co-administration with folic acid. To determine the direct effects of MTX on bacterial growth, we treated monocultures of 42 different human gut isolates with MTX and monitored growth using optical density. To identify MTX-induced transcriptional changes, we performed RNA-Seq on 4 isolates treated with MTX. To determine the effects of MTX on bacterial taxonomy in vivo , fecal samples from RA patients (100% fulfilling ACR criteria) starting MTX were profiled longitudinally using 16S sequencing. To determine if MTX-induced shifts reduce the inflammatory potential of the RA microbiome, microbiota from RA patient donors either before or after MTX initiation were transplanted into germ-free mice. These mice were challenged with an inflammatory trigger with dextran-sodium sulfate (DSS), and immune profiling was done to assess inflammation. Results : MTX altered community composition in vivo in humanized mice, leading to reduced Bacteroidetes and increased Firmicutes. Varying the route of drug administration or co-administration with folic acid produced similar, reproducible shifts. MTX directly altered growth of many human gut isolates. At the phylum level, Bacteroidetes tended to be more sensitive than Firmicutes, recapitulating the trends observed in gnotobiotic mice in vivo . RNA-Seq revealed that MTX alters transcriptional pathways involved in purine and pyrimidine metabolism. Furthermore, longitudinal analyses of the in vivo gut microbiotas of RA patients showed that MTX-induced shifts in bacterial relative abundance are associated with improved drug response. Transplant experiments revealed that mice harboring MTXaltered microbiota exhibited a reduced Th17 and Th1 response to DSS compared to mice harboring pre-treatment microbiota, suggesting that MTX alters the inflammatory potential of the RA patient microbiome. Conclusion : Together, these results suggest that the mechanism-of-action of non-antibiotic drugs may be due in part to off-target effects on the gut microbiota, while providing a critical first step towards explaining long-standing differences in drug response between patients

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

PURPOSE OF REVIEW/OBJECTIVE:The therapeutic response to biologic agents in psoriasis is significantly higher than observed in psoriatic arthritis (PsA). In this review, specific actions to improve treatment outcomes in PsA are discussed. RECENT FINDINGS/RESULTS:Increased understanding of disease pathogenesis derived from improved preclinical models and advances in cell-based and molecular technologies provide new tools to identify therapeutic targets. In addition to the important contributions of metabolic comorbidities, chronic pain and the lack of a diagnostic biomarker signal the need for new strategies to improve outcomes. Potential strategies include the following: (1) discover a novel pathway or cellular subset, (2) apply stratification biomarkers to individualize therapy, (3) preclinical intervention, (4) combination therapy, (5) lifestyle modification, (6) address chronic pain and fatigue, and (7) multidisciplinary care. The future holds great promise for enhanced treatment responses in PsA based on improved understanding of individual variation in disease pathophysiology coupled with comprehensive and integrated treatment programs.

Gut-dwelling Prevotella copri (P. copri), the most prevalent Prevotella species in the human gut, have been associated with diet and disease. However, our understanding of their diversity and function remains rudimentary because studies have been limited to 16S and metagenomic surveys and experiments using a single type strain. Here, we describe the genomic diversity of 83 P. copri isolates from 11 human donors. We demonstrate that genomically distinct isolates, which can be categorized into different P. copri complex clades, utilize defined sets of polysaccharides. These differences are exemplified by variations in susC genes involved in polysaccharide transport as well as polysaccharide utilization loci (PULs) that were predicted in part from genomic and metagenomic data. Functional validation of these PULs showed that P. copri isolates utilize distinct sets of polysaccharides from dietary plant, but not animal, sources. These findings reveal both genomic and functional differences in polysaccharide utilization across human intestinal P. copri strains.