Faculty Bibliography

Background/Purpose: The gut microbiome and its metabolites are dysregulated in rheumatoid arthritis. Short chain fatty acids (SCFAs), microbial fermentation byproducts of certain gut microbes, induce regulatory T cells (Treg) that exhibit antiinflammatory properties. Unsurprisingly, SCFA are found at reduced levels in both murine models of RA and patients. The SCFA butyrate has been shown to increase levels of gut and circulating Treg and ameliorate inflammatory arthritis in murine models. Additionally, we previously noted that SCFA supplementation in WT mice led to significant perturbations in gut bacterial composition with a significant increase in SCFA-producing commensals. Similarly, others have shown that a high-fiber diet increases circulating levels of SCFAs and decreases pro-arthritogenic cytokines (Durholz et al. Nutrients. 2020). We therefore hypothesized that butyrate supplementation may promote favorable gut microbial changes and increase tolerogenic adaptive immune response in RA patients.
Method(s): We designed an ongoing, prospective, proof-of-principle study to determine the effects of butyrate supplementation in new-onset RA (NORA) patients. First, we evaluated the effects of butyrate supplementation in healthy subjects (n=7; 1 gm 3 times daily for 14 days). Next, we evaluated the effects of butyrate on new-onset RA (n=5; 1 gm 3 times daily for 30 days) compared to methotrexate (n=20). Clinical history and joint exam were performed at baseline and follow up. Peripheral blood and fecal samples were collected at baseline and follow up for flow cytometric analysis of Treg and 16s rRNA sequencing, respectively. Wilcoxon signed-rank test was used to compare differences in Treg before and after butyrate administration.
Result(s): Although butyrate supplementation in healthy subjects did not lead to significant community changes by 7 days, it did lead to a significant increase in the percentage of circulating CD4+CD25+FoxP3+ Treg (p=0.02) followed by a significant increase in highly activated CD39+ Treg by 14 days (p < 0.0001). Gut bacterial alpha diversity (Shannon index) was significantly lower in NORA patients compared to healthy subjects at baseline (p=0.04; wilcox-test). After butyrate supplementation, NORA alpha diversity increased to levels approaching those of healthy subjects, with a modest increase in abundance of both Firmicutes and Bacteroidetes. LDA Effect Size analysis recapitulated previous studies where healthy subjects had greater abundance of SCFA producing commensals compared to NORA.
Conclusion(s): In both health and new-onset RA, butyrate supplementation is associated with changes in human gut microbiota composition and in peripheral Treg abundance and markers of Treg activation. In preliminary analyses of this ongoing prospective study, butyrate increased gut microbial diversity in NORA, suggesting that gut microbial composition may shift towards a healthier level of diversity. As seen in murine models, butyrate also increased Treg in healthy subjects. We hypothesize that, in patients, butyrate will induce modifications in gut microbial communities that favor a regulatory adaptive immune response that may ultimately lead to better clinical response

Background/Purpose: Psoriatic arthritis (PsA) is a complex immune-mediated disease. Beyond its deleterious effects in the skin and joints, PsA can lead to decreased quality of life, increased psychosocial stress, and is associated with high levels of depression and anxiety. However, little is known about the effects of mental health on disease activity and severity. This may be especially important in PsA where up to half of patients have residual symptoms (i.e., pain, fatigue) despite effective immunomodulatory therapies. The objective of this study was to characterize the prevalence of psychiatric comorbidities and their impact on PsA outcomes in an urban, academic, combined clinic setting.
Method(s): Consecutive adult patients meeting CASPAR criteria (n=537) were prospectively recruited at the NYU Psoriatic Arthritis Center and followed for up to 2 years. All data was obtained from clinical visits using a standardized EPIC template. Depression was defined as patient-reported depression and/or use of anti-depressant medications.
Result(s): The cohort was 53% male, mostly Caucasian (79.7%) and had an average age of 49 years. Within our population, 23% had depression, 18% anxiety, and 4% ADHD (Table 1). At the initial visit, patients with depression were more likely to be female, older, and have concomitant anxiety compared to those without depression. Moreover, compared to their nondepressed counterparts, patients with depression had similar swollen joint counts (SJCs), tender joint counts (TJCs) and RAPID3 scores, as well as a lower percent body surface area (BSA). However, at the subsequent timepoints, while other outcomes remained similar between the groups, patients with depression had a higher TJC (Figure 1). When adjusting for age, sex, race, medication use, and comorbidities, the rate ratio (RR) of TJC in patients with depression vs. without depression was 1.23 (95%CI 0.78, 1.94, p=0.79) at baseline (Figure 2). This ratio was even higher at year 1 (RR 1.47, 95%CI 0.91, 2.35, p=0.19) and year 2 (RR 1.75, 95%CI 0.97, 3.14, p=0.07), nearing significance. In the adjusted models for SJC, BSA, and RAPID3, this pattern was not seen.
Conclusion(s): High rates of depression and anxiety in this cohort expand upon previously reported data. While most patients improve over time, TJC is significantly higher in those who carry a diagnosis of depression whereas SJC and BSA are similar in patients with and without depression. This may reflect differences in how patients with depression perceive their disease and may lead to difficulty in achieving low disease activity/remission by composite score measures. Therefore, addressing depression, along with inflammatory symptoms, should be considered, especially in those with residual pain. Further work is needed to understand if intervening on depression could help improve PsA outcomes

Background/Purpose: The skin is recognized as a window into the immunopathogenic mechanisms driving the vast phenotypic spectrum of psoriatic disease.
Method(s): To better decipher the cellular landscape of both healthy and psoriatic skin, we employed spatial transcriptomics (ST), a ground-breaking technology that precisely maps gene expression from histologically-intact tissue sections (Fig. 1A).
Result(s): Findings gleaned from computationally integrating our 23 matched lesional and non-lesional psoriatic and 7 healthy control samples with publicly-available single-cell ribonucleic acid (RNA) sequencing datasets established the ability of ST to recapitulate the tissue architecture of both healthy and inflamed skin (Fig. 1B) and highlighted topographic shifts in the immune cell milieu, from a predominantly perifollicular distribution in steady-state skin to the papillary and upper reticular dermis in psoriatic lesional skin. We also incidentally discovered that ST's ability to ascertain gene expression patterns from intact tissue rendered it particularly conducive to studying the transcriptome of lipid-laden cells such as dermal adipose tissue and sebaceous glands (Fig. 1C), whose expression profiles are typically lost in the process of tissue handling and dissociation for bulk and single-cell RNA seq. Unbiased clustering of pooled healthy and psoriatic samples identified two epidermal clusters and one dermal cluster that were differentially expanded in psoriatic lesional skin (p values <=0.05) (Fig. 1D); pathway analysis of these clusters revealed enrichment of known psoriatic inflammatory pathways (Fig. 1E). Unsupervised classification of skin-limited psoriasis and psoriatic arthritis samples revealed stratification by cutaneous disease severity or Psoriasis Area and Severity Index (PASI) score and not by presence or absence of concomitant systemic/synovial disease (Fig. 1F). Remarkably, this PASI-dependent segregation was also evident in distal, non-lesional samples and was driven by the dermal macrophage and fibroblast cluster and the lymphatic endothelium (Fig. 2A). Inquiry into the mechanistic drivers of this observed stratification yielded enrichment of pathways associated with key T cell and innate immune cell activation, B cells, and metabolic dysfunction (Fig. 2B). Finally, tissue scale computational cartography of gene expression revealed differences in regional enrichment of specific cell types across phenotypic groups, most notably upward extension of fibroblasts to the upper dermis in both lesional and non-lesional samples from mild psoriasis and restriction to the lower dermis in the moderate-to-severe psoriasis samples (Fig. 2C), suggesting that disease severity stratification may be driven by emergent cellular ecosystems in the upper dermis. Fig. 1. (A) Schematic of spatial transcriptomics study workflow. Four mm skin punch biopsies were obtained from healthy volunteers (n=3) and lesional and non-lesional skin from patients with psoriatic disease (n=11). Ten micron-thick sections were then placed on capture areas on the ST microarray slide, each containing molecularly barcoded, spatially encoded spots with a diameter of 50 microns and a center-to-center distance of 100 microns. (B) Side-by-side comparison of a hematoxylin-eosin (H&E) stained section of representative healthy, lesional, and non-lesional skin samples and the corresponding ST plots showed concordance of unbiased gene expression-based clustering with histologic tissue architecture. (C) Pathway analysis of the adipose cluster in healthy skin (cluster 2) confirmed upregulation of lipid-associated processes. Inset: Spots corresponding to the adipose cluster highlighted in yellow. (D) Wilcoxon rank sum test (results displayed as box plots) yielded statistically significant expansion of three clusters in lesional skin compared to both non-lesional and healthy skin-inflamed suprabasal epidermis (cluster 4), epidermis 2 (cluster 7), and inflamed dermis (cluster 10). HC=healthy control, L=lesional psoriatic skin, NL=non-lesional psoriatic skin. (E) Pathways enriched in clusters 4, 7, and 10. (F) Principal component analysis (PCA) plots demonstrating segregation of samples by severity of cutaneous disease in both lesional and non-lesional samples along the first principal component (right) that was not seen in the samples categorized according to presence or absence of arthritis (left). PsA=psoriatic arthritis, PsO=skin-limited psoriasis. Fig. 2. (A) PCA of lesional and non-lesional samples colored by disease severity in spatial clusters 1 (left) and 12 (right) revealed more discrete clustering. (B) Pathways significantly enriched in clusters 1 (left) and 12 (right) showed enrichment of pathways associated with key T cell and innate immune cell activation, B cells, and metabolic dysfunction (highlighted in red). (C) SpaceFold one dimension projection of cell distribution from an independently-generated single-cell RNA seq data set on aggregated ST lesional and non-lesional samples from mild (PASI-low) and moderate-severe (PASI-high) samples. Y-axis represents tissue position, starting with the lower dermis marked as position 0 to suprabasal epidermis marked as position 1. Dashed line represents epidermal-dermal junction, discerned by cell types in the basal epidermal layer (melanocytes and Langerhans cells). Fibroblast signatures (red arrows) were largely relegated to the lower dermis in the PASI-high group, but extended to the upper dermis in the PASI-low group. This striking difference in fibroblast localization was also noted in non-lesional PASI-high vs. PASI-low groups. In addition to fibroblasts, lymphatic, endothelial, myeloid, and T cells signatures (black arrows) were also observed in the upper dermis of lesional PASI-low samples, but were much lower in the dermis of PASI-low non-lesional and all samples in the PASI-high group. Interfollicular epidermis (IFE), hair follicle and infundibulum (HF/IFN), n= number of individual biopsies.
Conclusion(s): Thus, we have been able to successfully leverage ST integrated with independently-generated single-cell RNA seq data to spatially define the emergent cellular ecosystems of healthy and matched psoriatic lesional and non-lesional skin and in so doing, demonstrated the value of ST in unearthing the genetic groundwork at both the site of inflammation and in distal, clinically-uninvolved skin

Background/Purpose: Patients with systemic lupus erythematosus (SLE) are at high risk for severe disease from COVID-19 and decreased vaccine efficacy, due to inherent immune perturbations and frequent immunosuppressant use. The impact of vaccine responses was "pressure" tested in New York City (NYC) from December 2021-February 2022, due to the highly infectious omicron BA.1 variant which resulted in a significant increase in COVID-19 cases and hospitalizations. This study was performed to assess clinical efficacy and seroreactivity in SLE patients with and without an additional vaccination dose after initial vaccine series, particularly during the omicron BA.1 surge in NYC.
Method(s): COVID-19 infections after vaccination were evaluated during patient encounters and chart review in subjects from the NYU Lupus Cohort who received an initial SARS-CoV-2 vaccine series with follow-up for at least 6 months or until breakthrough infection. Clinical follow-up was required after February 4, 2022 (when NYC COVID-19 cases returned to their preomicron BA.1 baseline), with last patient follow-up recorded April 24, 2022. Positive PCR or antigen-based testing was required, performed at the clinical site or self-reported. Fifty-seven patients receiving additional vaccine doses were evaluated longitudinally for recombinant SARS-CoV-2 spike receptor binding domain antibodies (#BT10500; R&D Systems). Low post-vaccine antibody response was defined as <=100 units/ml.
Result(s): Among the 163 subjects evaluated, 125 (76.7%) received an additional COVID-19 vaccination after the initial series. Demographics and medication usage were similar in patients who did and did not receive the additional vaccination dose, with 50% on at least one immunosuppressant and 16% on more than one at the time of the initial vaccine. Twentyeight (63.6%) of the 44 patients with a breakthrough infection had received an additional vaccination compared to 97 (81.5%) of the 119 without breakthrough infection (p=0.022) (Table 1). Of the 44 COVID-19 cases, only 2 occurred prior to the omicron wave, both in patients who did not receive the additional dose. There were no COVID-19 related deaths and two patients were hospitalized. Among the 57 patients with serologic evaluation, the median antibody level after initial vaccination series was 397 u/mL (IQR 57-753), and 1036 (IQR 517-1338.5) after the additional dose. After initial vaccination, 21 (37%) had low ELISA responses, but only 4 (7%) continued to have low responses after the additional dose. There was no association between the level of antibody after the additional dose and COVID-19 breakthrough.
Conclusion(s): SLE patients from a cohort of patients in NYC who received an additional SARS-CoV-2 vaccine dose were significantly less likely to have a subsequent COVID-19 infection compared to those who only completed their initial vaccine series. SLE patients demonstrated an improvement in serologic response after an additional dose of SARS-CoV-2 vaccine. The mild disease in all vaccinated patients is reassuring given the risks inherent and frequent immunosuppressant use in this patient population

Background/Purpose: Despite significant heterogeneity in psoriatic arthritis (PsA), randomized controlled trials (RCTs) generally enroll a homogenous subgroup of PsA patients (polyarticular similar to rheumatoid arthritis). In clinical practice, however, majority of patients have oligoarticular disease, often making it difficult to observe meaningful changes. To improve our understanding of how therapies work in the "real world" and among understudied patient subgroups, trials in real world environments are crucial. Before conducting pragmatic studies in PsA, however, it is necessary to define the appropriate outcome measures including patient-reported outcomes (PROs). The objectives of this study were to determine the responsiveness to therapy and minimally clinically important improvement (MCII) for PROs in PsA and to examine the impact of baseline disease activity on the ability to demonstrate change.
Method(s): A longitudinal cohort study was performed within the PsA Research Consortium (PARC). Patients completed PROs including the Routine Assessment of Patient Index Data, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the PsA Impact of Disease questionnaire, and three PRO Measure Information System (PROMIS) instruments (global 10a, depression 8a, and fatigue 8a). Mean change in the scores between visits and standardized response means (SRMs) were calculated. The MCII was calculated as the mean change in score among patients who reported minimal improvement. SRMs and MCIIs were compared among subgroups with moderate to highly active PsA (>=3 swollen and >=3 tender joint counts based on 66-and 68-joint counts respectively) and those with less active PsA (< 3 swollen and < 3 tender joint counts). This cut-off is used as an inclusion criterion in most PsA RCTs.
Result(s): Among 171 patients, 266 therapy courses were included. Mean age was 51 (SD 13.8), 53% were female, and mean body mass index (BMI) was 29.9 (SD 6.5). At baseline, the mean swollen and tender joint counts were 3 and 6, respectively. Therapies initiated included a tumor necrosis factor inhibitor (N=145), interleukin 17 inhibitor (N=55), other biologic or JAK inhibitor (N=14), or an oral small molecule (N=96). SRMs (Figure 1) and MCII for all measures (Table 1 & 2) were small to moderate though greater among those with higher baseline disease activity. BASDAI had the best SRM overall and for less active PsA. cDAPSA and PsAID performed better and comparable to BASDAI respectively in the moderate to highly active PsA subgroup. SRMs were similar among those initiating a biologic therapy compared to those initiating any therapy.
Conclusion(s): SRMs and MCII were relatively small in this real-world population, particularly among those with lower disease activity at baseline. The PsAID and cDAPSA measures performed better in those with higher disease activity compared to Figure 1. Standard Response Means of different measures tested in PARC. Abbreviations: PARC: Psoriatic Arthritis Research Consortium; TNFi: tumor necrosis factor inhibitor; IL17i: interleukin-17 inhibitor; HAQDI: Health Assessment Questionnaire Disability Index; MD global: physician's global assessment; Pt: patient; SJC: swollen joint count; TJC: tender joint count; BASDAI: Bath Ankylosing Spondylitis Disease Activity Index; PSAID: Psoriatic Arthritis Impact of Disease; cDAPSA: clinical Disease Activity of Psoriatic Arthritis; MDHAQ: Multidimensional Health Assessment Questionnaire; PROMIS: Patient-Reported Outcomes Measurement Information System Global Short Form; PROMIS10 MH: Patient-Reported Outcomes Measurement Information System Global Short Form Mental Health; PROMIS10 PH: Patient-Reported Outcomes Measurement Information System Global Short Form Physical Health; RAPID3: Routine Assessment of Patient Index Data. those with lower disease activity. In future pragmatic trials, selection of measures should take into account the projected baseline disease activity of patients enrolled

Rheumatoid arthritis is a chronic systemic immune-mediated disease caused by genetic and environmental factors. It is often characterized by the generation of autoantibodies that lead to synovial inflammation and eventual multi-joint destruction. A growing number of studies have shown significant differences in the gut microbiota composition of rheumatoid arthritis (RA) patients compared to healthy controls. Environmental factors, and changes in diet and nutrition are thought to play a role in developing this dysbiosis. This review aims to summarize the current knowledge of intestinal dysbiosis, the role of nutritional factors, and its implications in the pathogenesis of rheumatoid arthritis and autoimmunity. The future direction focuses on developing microbiome manipulation therapeutics for RA disease management.

OBJECTIVE:To evaluate secukinumab 300 mg and 150 mg vs placebo in a US-only population of biologic-naive patients with psoriatic arthritis (PsA). METHODS:CHOICE was a randomized, double-blind, controlled trial conducted in the United States. Biologic-naive patients with PsA and psoriasis were randomized 2:2:1 to secukinumab 300 mg (n = 103), secukinumab 150 mg (n = 103), or placebo (n = 52). The primary objective was to show superiority of secukinumab 300 mg vs placebo in ACR20 response at week 16. Additional objectives included the effect of secukinumab on dactylitis, enthesitis, psoriasis, and safety. RESULTS:= .0011). Secukinumab 300 mg also led to greater ACR50/70 responses and improvements in other variables vs placebo. Responses were generally sustained over time. Patients with inadequate response to secukinumab 150 mg at weeks 16, 28, or 40 who received dose escalation to 300 mg experienced improved clinical response after uptitration. The most common adverse events were upper respiratory tract infections and diarrhea. No inflammatory bowel disease was reported or new safety signals observed. CONCLUSION/CONCLUSIONS:Secukinumab 300 mg led to rapid and significant improvements over placebo in symptoms of PsA in this heavier population of US-only biologic-naive patients. Findings were consistent with previous studies and suggest that secukinumab 300 mg is a safe and efficacious first-line biologic treatment for patients with PsA.

At the 2021 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA)- Collaborative Research Network (CRN) annual meeting, the GRAPPA-CRN group presented a number of project updates, including a pilot investigator-initiated study to evaluate liquid and tissue biomarkers associated with axial involvement in psoriatic arthritis (PsA). The GRAPPA-CRN session updated progress made with 3 parallel international research initiatives based on 3 previously defined unmet needs in PsA. The Health Initiatives in Psoriasis and PsOriatic arthritis ConsoRTium European States (HIPPOCRATES) is a European research consortium formed to address unmet clinical needs in PsA. The Preventing Arthritis in a Multi-Center Psoriasis At-Risk Population (PAMPA) is a US-based organization that has defined consensus terminology for preclinical phases of PsA and is interested in the transition process from psoriasis to PsA. An overview of the Accelerating Medicines Partnership Autoimmune and Immune-Mediated Diseases (AMP AIM) program 2.0, a consortium including GRAPPA-CRN members that addressed these 3 unmet needs in PsA, was also presented.