Faculty Bibliography

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.

OBJECTIVE:=0.02). CONCLUSIONS:In patients with psoriasis, platelets are activated and induce endothelial cell inflammation. Low-dose aspirin improved endothelial cell health in psoriasis via platelet COX-1 inhibition. These data demonstrate a previously unappreciated role of platelets in psoriasis and endothelial cell inflammation, which suggests that aspirin may be effective in improving vascular health in patients with psoriasis. Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT03228017.

BACKGROUND:Dual neutralisation of interleukin 17A (IL17A) and interleukin 17F (IL17F) is a potential novel therapeutic approach in psoriatic arthritis. We assessed bimekizumab, a monoclonal antibody that selectively neutralises IL17A and IL17F, in patients with active psoriatic arthritis. METHODS:BE ACTIVE was a randomised, double-blind, placebo-controlled, dose-ranging phase 2b study done at 41 sites in the Czech Republic, Germany, Hungary, Poland, Russia, and the USA. Eligible patients aged 18 years or older with active adult-onset psoriatic arthritis and symptoms for at least 6 months were randomly assigned (1:1:1:1:1) to placebo, 16 mg bimekizumab, 160 mg bimekizumab, 160 mg bimekizumab with a one-off 320 mg loading dose, or 320 mg bimekizumab, which were administered as subcutaneous injections every 4 weeks for 12 weeks. After 12 weeks, patients assigned to the placebo and 16 mg bimekizumab groups were randomly reassigned (1:1) to either 160 mg or 320 mg bimekizumab, and all other patients remained on their originally assigned initial dose up to 48 weeks. Both participants and researchers were blinded to treatment allocation in the first 12 weeks, and blinded to the dose of bimekizumab thereafter. The primary endpoint was the proportion of patients with at least 50% improvement in the American College of Rheumatology response criteria at week 12, which was assessed in all patients who received at least one dose of study treatment and had a valid measurement of the primary efficacy endpoint at baseline. The trial, including all follow-up, has been completed. This trial is registered with ClinicalTrials.gov, NCT02969525. FINDINGS:Between Oct 27, 2016, and July 16, 2018, 308 patients were screened, and 206 were randomly assigned: 42 to the placebo group, and 41 each to the four bimekizumab groups. At 12 weeks, compared with the placebo group, significantly more patients in the 16 mg bimekizumab (odds ratio [OR] 4·2 [95% CI 1·1-15·2]; p=0·032), 160 mg bimekizumab (8·1 [2·3-28·7]; p=0·0012), and 160 mg (loading dose) bimekizumab (9·7 [2·7-34·3]; p=0·0004) groups achieved an ACR50 response. At 12 weeks, 24 (57%) of 42 patients in the placebo group and 68 (41%) of the 164 patients in the bimekizumab groups reported treatment-emergent adverse events. Most of these adverse events were mild or moderate. Serious treatment-emergent adverse events occurred in nine patients, eight of whom were receiving bimekizumab. No deaths or cases of inflammatory bowel disease were reported. INTERPRETATION:Bimekizumab doses of 16 mg and 160 mg (with or without a 320 mg loading dose) were associated with significant improvements in ACR50 compared with placebo, with an acceptable safety profile. Our results support phase 3 investigation of bimekizumab as a treatment for psoriatic arthritis. FUNDING:UCB Pharma.

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.

OBJECTIVE:To characterize the ecological effects of biologic therapies on the gut bacterial and fungal microbiome of psoriatic arthritis (PsA)/spondyloarthritis (SpA) patients. METHODS:Fecal samples from PsA/SpA patients pre- and post-treatment with tumor necrosis factor inhibitors (TNFi; n=15) or an anti-interleukin (IL)-17A monoclonal antibody inhibitor (IL-17i; n=14) underwent sequencing (16S, ITS and shotgun metagenomics) and computational microbiome analysis. Fecal levels of fatty acid metabolites and cytokines/proteins implicated in PsA/SpA pathogenesis or intestinal inflammation were correlated with sequence data. Additionally, ileal biopsies obtained from SpA patients who developed clinically overt Crohn's disease (CD) after treatment with IL-17i (n=5) were analyzed for expression of IL-23/Th-17 related cytokines, IL-25/IL-17E-producing cells and type-2 innate lymphoid cells (ILC2s). RESULTS:There were significant shifts in abundance of specific taxa after treatment with IL-17i compared to TNFi, particularly Clostridiales (p=0.016) and Candida albicans (p=0.041). These subclinical alterations correlated with changes in bacterial community co-occurrence, metabolic pathways, IL-23/Th17-related cytokines and various fatty acids. Ileal biopsies showed that clinically overt CD was associated with expansion of IL-25/IL-17E-producing tuft cells and ILC2s (p<0.05) compared to pre-IL-17i treatment levels. CONCLUSION/CONCLUSIONS:In a subgroup of SpA patients, the initiation of IL-17A blockade correlated with features of subclinical gut inflammation and intestinal dysbiosis of certain bacterial and fungal taxa, most notably C. albicans. Further, IL-17i-related CD was associated with overexpression of IL-25/IL-17E-producing tuft cells and ILC2s. These results may help to explain the potential link between inhibition of a specific IL-17 pathway and the (sub)clinical gut inflammation observed in SpA.

OBJECTIVE:To examine the construct validity of Routine Assessment of Patient Index Data (RAPID3) and Psoriatic Arthritis Impact of Disease (PSAID) in patients with psoriatic arthritis (PsA). In examining construct validity, we also addressed scores among subgroups with severe psoriasis, polyarticular disease, enthesitis and dactylitis and evaluated influences of sociodemographic factors and comorbidities (contextual factors) on these patient-reported outcomes (PROs). METHODS:Patients with PsA were enrolled in the Psoriatic Arthritis Research Consortium (PARC) between 2014-2016. PARC is a longitudinal observational cohort study conducted at four United States institutions. In this cross-sectional study, construct validity was assessed by examining Spearman's correlation coefficients for RAPID3 and PSAID with physician-reported disease activity measures and other PROs (e.g., Short Form 12 (SF12-PCS/-MCS), Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue). Contextual factors and disease subgroups were assessed in multivariable linear regression models with RAPID3 or PSAID12 as outcomes of interest and the hypothesized contextual factors as covariates. RESULTS:Among 401 patients enrolled in PARC, 347 completed RAPID3 or PSAID12. Of these, most were Caucasian females with a mean age of 51.74 (SD 14.02). RAPID3 and PSAID were highly correlated (r=0.90). These measures were also correlated with the SF12-PCS (r=-0.67) and FACIT-Fatigue (r=-0.77). Important contextual factors and disease subgroups included enthesitis, joint counts, education, insurance type, and depression. CONCLUSION/CONCLUSIONS:RAPID3 and PSAID12 have excellent construct validity in PsA and are strongly correlated despite differing items. Contextual factors (i.e., the presence of depression and obesity) should be considered when interpreting raw scores of the RAPID3 and PSAID12.

Background/Purpose : Patient-reported outcomes (PROs) are an important part of clinical decision making and are frequently used in combination with objective measures of disease activity and physicians' clinical assessment to help guide treatment decisions. Discrepancies between PROs and clinical measures of disease activity can lead to over-treated or under-treated disease and patient dissatisfaction. We sought to examine the correlation between minimal disease activity (MDA) with PROs as measured by the NIH Patient-Reported Outcomes Measurement Information System (PROMIS) Global Health (GH) questionnaire, and assess the effect of demographics, psoriatic arthritis related comorbidities, and number of comorbidities on PROMIS GH and MDA status. Methods : A cross-sectional study was performed within Psoriatic Arthritis Research Consortium (PARC), a cohort of adult psoriatic arthritis patients meeting CASPAR criteria enrolled between 2016-2019. PARC is a longitudinal observational cohort study conducted at four institutions in the United States. The mean differences of PROMIS Physical, Mental and Fatigue T-scores between patients in MDA compared to those not in MDA were compared using the two sample t-tests. Correlations between MDA scores (0-7 criteria met) and PROMIS Physical, Mental and Fatigue T-scores were calculated using Spearman rank correlation. Higher T-scores on PROMIS measures mean 'more' of that concept for PROMIS Physical and Mental domains. Logistic regression model was used to evaluate contribution of additional covariates on MDA, including age, gender, hypertension, dyslipidemia, BMI, diabetes, smoking and number of comorbidities (Table 2). The odds ratios and 95% confidence intervals were presented. Multiple imputation was performed to impute missing data points. Data analysis was performed in SAS software (Version 9.4; Cary, NC). Results : 235 patients (50% female, mean age 51+/-13.9) were included. 129 were in MDA and 106 were not in MDA. Patients in MDA had significantly higher PROMIS Physical, Mental and improved Fatigue T-scores compared to non-MDA patients (Table 1; p< 0.001). There was a positive correlation between MDA scores and PROMIS scores in Physical and Mental domains; correlation was strongest for PROMIS Physical T-score (Figure 1; r=0.65, p< 0.001). There was a moderate correlation between MDA and PROMIS Fatigue T-score (Figure 1; r=-0.51, p< 0.001). In the univariate analysis, there was a statistically significant association between hypertension and number of comorbidities with MDA status (Table 2). However, this effect was not observed in the multivariate analysis. Conclusion : Achieving MDA was associated with a positive effect on patients' physical, mental and fatigue domains, irrespective of their demographics or PsA comorbidities. However, patients with a greater number of comorbidities were less likely to be in MDA. In this study, the PROMIS Physical domain had a higher correlation with MDA scores compared to the Mental domain and PROMIS Fatigue. PROMIS measures may be a useful tool in assessing disease activity from the patient's perspective. (Table Presented)

Background/Purpose : The multi-dimensional health assessment questionnaire (MDHAQ) is a patient-reported outcome that is commonly used in clinical practice in the US and comprises of 10 items. Although the validated Health Assessment Questionnaire Disability Index (HAQDI) measures similar constructs as the MDHAQ, is less commonly used and has 16 items. Therefore, the objective of this study is to assess if the MDHAQ (divided by 3.33 to transform to the same scale as HAQDI) can substitute for the HAQDI in ACR20 assessment and cohort studies. Methods : Between 2016-2019, patients with PsA were enrolled in the Psoriatic Arthritis Research Consortium (PARC), a longitudinal observational cohort at four United States institutions: University of Pennsylvania, Cleveland Clinic, New York University, and University of Utah. Baseline patient characteristics were descriptively reported. A priori we hypothesized that the MDHAQ and HAQDI would have high correlation at baseline ( >0.8) and among the change scores ( >0.8) and that responsiveness would be similar. Correlations were calculated among the total scores using Spearman's correlation coefficients at baseline and follow-up visit. Change scores (e.g., score at visit 1 minus score at visit 2) and standardized mean responses were calculated. Sensitivity analyses excluding patients with low disease activity were calculated. We additionally examined agreement with the 20% improvement cut-offto determine the potential effect of using MDHAQ in the ACR20 criteria in place of HAQDI. Results : HAQDI and MDHAQ data were available in 438 visits in which both questionnaires were completed and 161 patients with HAQDI and MDHAQ at two time points. The mean age was 51.5 +/- 14.6 years old, 53% were male, and most had low disease activity with mean swollen (66) and tender (68) joint counts 2.3 +/- 4.4 and 4.3 +/- 6.4, respectively. At baseline, the mean HAQDI was 0.64 +/- 0.62 (range 0-3) and the mean MDHAQ was 1.9 +/- 1.7 (range 0-10; Table 1). Dividing the MDHAQ by 3.33 to transform it to the same scale as the HAQDI resulted in a transformed MDHAQ mean of 0.56 +/- 0.48 with a mean excursion from the HAQDI score of 0.07 +/- 0.35 (Figure 1). Among all time points, the Spearman's correlation coefficient between the two instruments was 0.84 and among the first visit only, the coefficient was 0.83. The mean change over two visits in the HAQDI was -0.07 +/- 0.4, with a standardized response mean (SRM) of 0.19 and mean change in the MDHAQ was -0.16 +/- 1.1 with an SRM of 0.14. The Spearman's correlation coefficient among the two change variables was 0.55 (Table 2). Using the 20% criteria for the ACR20, the agreement among use of HAQ-DI and MDHAQ is 74%. When excluding patients with a clinical Disease Activity index for Psoriatic Arthritis (c-DAPSA) score < 14 (i.e., low disease activity), the correlation coefficients were similar. Conclusion : Although the HAQDI consists of more questions than the MDHAQ, the total scores correlated well when analyzed cross-sectionally. However, the correlation was moderate between the change over time. Using the 20% improvement cut-off, most were correctly classified with MDHAQ but MDHAQ cannot directly replace HAQDI for the ACR20 criteria. (Figure Presented )

Background/Purpose : Psoriatic arthritis (PsA) is a heterogenous inflammatory disease affecting skin, joints, and other domains. While psychiatric diseases (i.e., depression and anxiety) are known comorbidities, little is known about their impact on disease severity and patient reported outcomes (PROs). The objective of this study was to characterize the prevalence of psychiatric comorbidities in an academic combined psoriasis-psoriatic arthritis center and determine their impact on PsA clinical and patient derived outcomes. Methods : Consecutive adult patients meeting CASPAR criteria for PsA (n=436) were prospectively recruited at the NYU Psoriatic Arthritis Center. All data was collected from clinical visits utilizing a standardized EPIC template. Depression was defined by established diagnosis and/or use of anti-depressant medications. Objective measures of disease severity included swollen and tender joint counts (SJC/TJC) and PROs including RAPID3 scores. Data was analyzed using statistical software R. Results : Our cohort was comprised of 436 patients: 54% male, mean age of 47 years, and mostly Caucasians (74.1%). Within our population, 19.5% had depression, 15.6% had anxiety, and 4.8% had ADHD (Table 1). Of those with depression, 71% were on anti-depressive medication. At the initial visit, patients with PsA and depression were more likely to be on medication(s) for PsA (80% vs 65%, p=.01) and had a trend towards higher rates of biologic use (47.5% vs 40.4%, p=.126). Those with depression had a similar TJC to their non-depressed counterparts, but had a trend towards fewer swollen joints and concomitant higher RAPID3 scores (Table 2). When analyzing repeated outcome measures over subsequent visits, individuals with depression were similarly more likely to have a higher TJC, a lower SJC, and a higher RAPID3 score (although only RAPID3 was found to be statistically significant, p=.004). Importantly, these findings persisted when analyzing participants that were matched with propensity scores to adjust for age, sex, comorbidities, and medication use. In addition to joint activity, psoriasis activity measured by body surface area (BSA) was lower in those who were depressed (1.4% vs 3.03%, p=.001) and these differences were maintained over subsequent visits. Conclusion : Our results expand on prior reports of significantly elevated rates of depression in PsA. Notably, individuals with depression were more likely to be on medication(s) for their PsA, had fewer swollen joints, and a lower BSA but, paradoxically reported higher RAPID3 scores. This discrepancy is likely a manifestation of how depression could affect the way patients experience their PsA despite apparent improvement in skin and joint symptoms. Depression should, therefore, be considered a critical comorbidity when addressing PsA care in routine visits. Further work is needed to understand whether modulation of psychiatric comorbidities can lead to improved PsA outcomes