Faculty Bibliography

OBJECTIVE:The intestinal microbiota has been associated with the development of inflammatory arthritis. The aim of this study was to dissect intestinal mucosal immune responses in the preclinical phase of arthritis and determine the requirement of Th17 cells, beyond the cytokine interleukin-17 (IL-17), for arthritis development. We further examined whether the involvement of Th17 cells in arthritis depends on the host microbiota. METHODS:) mice, and assessed the impact of microbiota on the Th17-dependence of CIA. RESULTS: mice showed a specific reduction of mucosal Th17 and partially reduced IL-17-producing CD8 T cells. However, total levels of IL-17A, mostly produced by γδ T cells and neutrophils, were unaffected. Arthritis was significantly reduced in Th17-deficient mice, suggesting additional IL-17A-independent roles for Th17 cells. Accordingly, antigen-stimulated T cells from Th17-deficient mice produced less IL-17A, IL-17F and GM-CSF. Importantly, Th17-dependence of arthritis was lost upon substitution of intestinal microbiota. CONCLUSION/CONCLUSIONS:These data suggest that activation of mucosal immunity precedes arthritis development, and support a microbiota-dependent role for Th17 cells in arthritis. Therefore, a microbiome-guided stratification of patients might improve the efficacy of Th17-targeted therapies.

PURPOSE OF REVIEW/OBJECTIVE:Despite a robust therapeutic landscape, significant gaps exist in the quality of care of psoriatic disease. Thus, an improved understanding of the challenges in providing quality care and the implementation of effective strategies to overcome them is needed. In this review, we summarize the burden of psoriatic disease, discuss the challenges in the care of psoriatic patients, and outline how combined dermatology-rheumatology clinics bridge many of these gaps. RECENT FINDINGS/RESULTS:Multiple challenges are faced in providing high-quality care to patients with psoriasis and psoriatic arthritis from the pre-diagnosis phase of disease to the follow-up period. Challenges are mainly driven by lack of education of patients and healthcare providers, inefficient communication between specialists, lack of a holistic approach to patients, and limitations of available therapies. The Psoriasis and Psoriatic Arthritis Clinics Multicenter Advancement Network (PPACMAN) is working on demonstrating the effectiveness of combined dermatology-rheumatology clinics in addressing some of these challenges. Recent findings show that combined clinic models may improve quality of care by raising awareness of psoriatic disease, fostering educational activities for both patients and physicians, and allowing for comprehensive evaluation and management of patients through improved communications between disciplines. Psoriasis and psoriatic arthritis are complex diseases that often require an interdisciplinary approach. Thus, combined dermatology-rheumatology clinics and local-regional partnerships are potentially effective in improving quality of care in psoriatic disease.

Background/Purpose: Psoriatic Arthritis (PsA) affects up to 30% patients with psoriasis and is characterized by wide spread synovio-entheseal inflammation. Physiologically, the human gut microbiota metabolizes dietary fiber into shortchain fatty acids (FA)- which exert anti-inflammatory effects by increasing activity of regulatory T cells (Tregs).Moreover, we have previously shown decreased abundance of Akkermansia and Ruminococcus and concomitant decrease in mediumchain FA (MCFA) levels in stool of PsA patients. We therefore hypothesized that FA supplementation may have favorable effects on gut microbiome and lead to increase in tolerance, potentially serving as therapeutic target in psoriatic disease.
Method(s): Wild type (WT)animals were fed SCFA-rich diet for 14 days followed by 16S rRNA sequencing and microbiota analysis of pellet specimens.We then evaluated effects ofMCFA-rich diet in healthy subjects. Peripheral blood and stool samples were collected at days 0, 7 and 14 for 16s rRNA sequencing and FACS. Finally, we conducted a small, prospective, proof-ofprinciple study in new-onset, drug-naive psoriatic disease patients (with or without PsA). Each participant received MCFA (1 gm 4 times a day for 6 weeks). Clinical history was obtained at baseline. Skin and joint exam were performed at baseline and follow up. Serum and stool samples were collected at baseline, weeks 3, and 6 for 16S rRNA sequencing and FACS, respectively. Wilcoxon signed-rank test was used to compare differences in Tregs before and after MCFA-rich administration.
Result(s): SCFA rich diet in WT mice led to statistically significant perturbations in gut bacterial composition 14 days into intervention, with a dramatic increase in commensals (Fig 1A; p<0.001), most notably in Akkermansia(Fig 1B). MCFA administration to healthy subjects (n=7) also led to significant changes in community structure (Fig 2A; p=0.03) and associated increases in circulating Treg cells (Fig 2B; p<0.001). These findings were also observed in psoriatic disease patients (n=4) showing a significant alteration in specific taxa, including Actinobacteria (Fig 2 C; p<0.05) and Mollicutes (p=0.09) and concomitant increase in circulatory Treg cells (Fig 2D)
Conclusion(s): In both health and psoriatic disease, MCFA supplementation is associated with distinct changes in human gut microbiota composition and peripheral Treg cells. These findings rationalize the need for a larger placebo controlled, prospective trial to study the effects of MCFA in patients with psoriasis and PsA as a potential therapy alone or in combination with DMARDs. (Figure Presented)

Background/Purpose: The microbiome serves a number of important functions, including modulation of the immune system and protection from pathogenic microorganisms1. Many autoimmune diseases have been associated with intestinal microbial dysbiosis1. Recent studies have also demonstrated that microbiota can affect the lifetime, bioavailability and efficacy of drugs2. Conversely, even drugs designed to specifically target human cells have been associated with changes in microbial composition3. To date, most research has focused on bacterial microorganisms and little is known about the role that fungal microorganisms (the mycobiome) play, including their interactions with bacteria. In this study, we characterized the ecological effects of biologic therapies on the intestinal mycobiome.
Method(s): Fecal samples were collected from SpA patients pre- and post-treatment with either tumor necrosis factor inhibitors (TNFi; n=15) or secukinumab (n=14), an anti-IL-17A monoclonal antibody (IL-17i). Subjects treated with TNFi were naive to biologic therapy, whereas those treated with secukinumab previously failed or had incomplete response to TNFi. Samples underwent DNA extraction, amplification, and gene sequencing of the ITS1 region conserved in fungi. In parallel, gene sequencing of the 16S rRNA gene region conserved in bacteria was also performed. Sequences were analyzed with R and Quantitative Insights into Microbial Ecology (QIIME).
Result(s): ITS fungal data reveled that, on average, subjects treated with TNFi and IL-17i did not have major differences in overall microbial alpha or beta diversity pre- and post-treatment. However, there were dramatic shifts in the relative abundance of specific taxa, such as Candida albicans, which were more prominent in the IL-17i cohort compared to the TNFi cohort (p=0.04). The IL-17i cohort also demonstrated similar changes in certain 16S bacterial taxa, including Clostridia (p=0.02) and Clostridiales (p=0.02).
Conclusion(s): We characterized, for the first time, the effects of two biologic therapies on human intestinal fungal and bacterial microbiota composition. Treatment with biologics, particularly IL-17i, leads to a gut microbial dysbiosis characterized by significant changes in abundance of C. albicans and Clostridia in a subgroup of SpA patients. This is in line with the known increased risk of candidiasis seen with IL-17i, and may at least partially explain the potential link between IL-17 blockade, intestinal dysbiosis, and the subclinical and clinical gut inflammation observed in some patients treated with these molecules. Further studies to understand the downstream effects of these perturbations may allow for the development of precision medicine approaches in PsA and SpA

Background/Purpose: The Psoriatic Arthritis Impact of Disease (PsAID) questionnaire is a patient reported measure of disease impact. The 12-item questionnaire has many advantages including demonstrated validity, reliability, responsiveness and discrimination. However, few studies have examined the use of individual items as surrogates for important patient reported outcomes. For example, we were interested in whether the single PsAID fatigue item could be used in place of the 13 item FACIT-F instrument. Likewise, the pain, function, depression, and anxiety items could be used in place of additional questionnaires if the items correlated well with validated instruments both in cross-sectional and longitudinal settings. The objective of this study was to examine the longitudinal construct validity of the individual PSAID items for pain, fatigue, function, depression and anxiety.
Method(s): Patients with PsA were enrolled in the Psoriatic Arthritis Research Consortium (PARC) between 2015- 2017. PARC is a longitudinal observational cohort at four institutions: University of Pennsylvania, Cleveland Clinic, New York University, and University of Utah. Two of these institutions (Utah and Penn) administered the PSAID. Patient characteristics at the first/baseline visit were descriptively reported. The correlations were calculated among individual PSAID items with similar constructs (e.g., 'tired' item with FACIT-F, BASDAI tired item, etc.) at baseline using Spearman's correlation coefficients. The change scores (e.g., score at visit 1 - score at visit 0) and the correlation among change scores between the individual items and related constructs were also calculated.
Result(s): PSAID data were available from 862 visits; 302 patients completed at least one PSAID and 208 patients completed PSAIDs at >=2 visits. Most patients were in low disease activity (mean 66/68 swollen and tender joint counts were 2.6 and 5.3, respectively). At baseline, the mean PsAID9 and PsAID12 scores were 3.39 (SD2.45) and 3.22 (2.40) respectively. The individual PsAID items were moderately correlated (rho= 0.5-0.8) with similar constructs at baseline. However, aside from the moderate to strong correlation between the PsAID pain question with the RAPID3 pain question (rho=0.71), change scores were only slightly correlated with like instruments (rho = 0.2-0.45, Table).
Conclusion(s): The individual PsAID items did not correlate well with change in similar constructs over time. This may be due to the attribution of each symptom to PsA in the PSAID questionnaire. The assessed PsAID items cannot be used as close substitutes for the validated questionnaires with which they were compared

Background/Purpose: Psoriatic arthritis (PsA) and Psoriasis (PsO) are chronic inflammatory diseases associated with vascular inflammation and increased CVD risk. Few studies have examined vascular inflammatory differences between PsO and PsA and how these differences may impart a different CVD risk profile. We directly investigated the vascular endothelium of patients with PsA, PsO and compared to controls to better understand the inflammatory mechanism(s) that predispose psoriatic patients to CVD risk.
Method(s): Twenty patients with psoriatic disease (PD) (mean age 45 years, 55% male, 11.2 +/- 19% body surface area (BSA) involvement) were first compared to 10 matched controls. Next, comparisons were made between PsO (n = 14, average age 50 years, 57% male, 11 +/- 22% BSA) and active PsA (n = 6, average age 36 years, 50% male, 11 +/- 10% BSA, average 2 - 3 tender/swollen joints per individual). To measure vascular endothelial health, venous endothelial cells were collected from the brachial vein using guidewires inserted through an angiocatheter and isolated with CD146-conjugated magnetic beads. Following collection, endothelial mRNA was isolated, converted to cDNA and inflammatory gene profiling performed by RT-qPCR with Taqman probes and primers. Transcripts were chosen based on in vitro gene arrays of human aortic endothelial cells co-stimulated with IL-17 and TNF-alpha.
Result(s): PD patients compared to controls showed a trend towards higher levels of hs-CRP (2.4 +/- 4 mg/dl vs. 0.8 +/- 2 mg/ dl, p = 0.08) with no overall difference noted between PsA and PsO patients (2.8 +/- 2 mg/dl vs. 2.7 +/- 4 mg/dl, p = 0.24). Transcriptomic profiling of venous endothelial cells comparing PD (PsO and PsA) to controls revealed upregulation of inflammatory cytokine- and chemokine- associated transcripts (lymphotoxin beta [4 - fold], CCL3 [11 - fold], CXCL10 [16 - fold], IL-8 [10 - fold] and IL-1beta [4 - fold], P < 0.05 for all) and transcripts related to intracellular adhesion (ICAM1 [2.4 - fold] and inflammation COX-2 [3 - fold], P < 0.05). Increased expression of the chemokine fractalkine (CX3CL1 [2.8 - fold], p < 0.05) and lymphotoxin beta [2 - fold, p = 0.10] were found in patients with active PsA compared to PsO. No differences in CCL3, CXCL10, IL-8, IL-1B, ICAM1 and COX-2 where seen between PsA and PsO patients.
Conclusion(s): Endothelial cell pro-inflammatory transcripts are upregulated in patients with active PD compared with controls. Levels of lymphotoxin beta and fractalkine, a chemokine present in inflamed arthritic synovial tissue, are greater in endothelial cells of patients with PsA than PsO. These findings may underlie increased CVD risk in patients with PD and highlight the inflammatory vascular differences between PsO and PsA

OBJECTIVE:CD4Cre mice, and investigate the role of Th17 cytokines in the disease pathogenesis. METHODS:CD4Cre mice onto an IL-22 knockout background or treating them with a neutralizing antibody against IL-17, we interrogated how these Th17 cytokines contribute to disease pathogenesis. RESULTS:CD4Cre mice, revealing a central role of Th17 cells in the regulation of OCP numbers and RANKL expression on stromal cells. CONCLUSION/CONCLUSIONS:CD4Cre mice, leading to cutaneous and synovio-entheseal inflammation, and bone pathology highly reminiscent of psoriatic arthritis. Both IL-17A and IL-22 produced by Th17 cells play critical roles in promoting the cutaneous and musculoskeletal inflammation that characterizes psoriatic arthritis..

The microbiome is a known and established immunomodulator of many inflammatory disorders, including psoriasis and psoriatic arthritis. Microbes co-evolved with their human hosts and provide them with nutritional, metabolic, and immunologic support. An accumulating body of evidence has revealed that psoriatic diseases are characterized by a state of intestinal dysbiosis, which has been linked to a decrease in beneficial commensals and fatty acids. This has been shown in both animal models and human samples, and multiple studies have addressed the physiological and potentially pathogenic role of intestinal and cutaneous microbes in human health and disease. In this review, we discuss state-of-the-art literature in the field of the microbiome in psoriatic diseases that was presented during the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) 2017 annual meeting, with a special emphasis on synovio-entheseal inflammation. A better understanding of these microbe-host interactions can lead to novel diagnostic and therapeutic targets.

Objective: To characterize the gut microbiota and host gene interactions in Reactive Arthritis (ReA) and postinfectious SpA. Methods: 32 patients with ReA and 32 controls with preceding Gastrointestinal (GI) and/or Genitourinary (GU) infections that did not develop arthritiswere prospectively recruited in Guatemala, a highly prevalent geographic region for this disease. Clinical variables, HLA status and 16S ribosomal RNA gene sequencing of intestinal microbiota were analysed. Results: Subjects with ReA showed no significant differences from controls in gut bacterial richness, alpha or beta diversity. However there was a higher abundance of Erwinia and Pseudomonas, and increased prevalence of typical enteropathogens associated with ReA. In Fact, at least one enteropathogen was present in 71.9% of ReA subjects vs 46.8% of controls (p<0.05). Subjects with ultrasound evidence of enthesitiswere enriched with Campylobacter,while subjects with Uveitis and radiographic sacroiliitis were enriched with Erwinia and unclassified Ruminococcaceae, respectively. Both were enriched in Dialister (log LDA>2). Host genetics, particularly HLA-A24 were associated with differences in gut microbiota diversity irrespective of disease status. We identified several co-occurring taxa that were also predictive of HLA-A24 status, including Ruminococcaceae-Rikenellaceae-Coriobacteriacea and Prevotellaceaeunclassified Sphingobacteriales-Elusimicrobiaceae. Conclusion: This is the first culture-independent study characterizing the gut microbial community of ReA. Although bacterial factors correlated with disease presence and clinical features of ReA, host genetics also appeared to be a major independent driver of intestinal community composition. Understanding of these gut microbiota host-genetic relationships may further clarify the pathogenesis of ReA and related Spondyloarthritis

Objective: To identify potential risk factors for the development of Reactive Arthritis (ReA) among Guatemalan patients with a known history of being infected with gastrointestinal (GI), genitourinary (GU), or sexually transmitted pathogens. A prospective study was performed to examine clinical, environmental, and genetic risk factors for the development of ReA. Methods: Patients were enrolled from July to October 2014. Cases and controls were recruited in the same time window. Cases were ascertained from 2 rheumatology clinics in Guatemala City: Asociacion Guatemalteca Anti Enfermedades Reumaticas (AGAR) and AGK: Private Clinic. ReAwas defined as inflammatory arthritis following a gastrointestinal (GI) or genitourinary infection (GU) and meeting the ASAS peripheral SpA criteria. Subjects had a preceding GI or GU infection 3-6 months before enrolment. A standardized questionnaire ascertained infection details, family history, medication, medical comorbidities, smoking status and literacy. Subjects completed a standardized joint and enthesis examination, radiographs of the Sacroiliac (SI) joints interpreted by a trained radiologist and ultrasound (USG) of the Achilles tendons. Results: 32 patients with ReA and 32 controls were enrolled.Mean age was 39 and 36 respectively. The majority of patients were female (81% and 63% (Figure presented) respectively). None of the controls had swollen or tender joints or entheses. History of Uveitis was present in 60%. The most frequent tender joint: right SI joint (81%). (see figure 1). The most common finding on SI joint Xray: bilateral sacroiliitis 45%. Enthesitis was noted on Achilles tendon ultrasound in 44% cases. All ReA patients had peripheral arthritis and 91% had back pain. Only 2 subjects from each group were found to carry an HLA-B27 allele. The most frequent HLA-A allele was HLA-A2 in both patients 44% and controls 63%. Serum Cathepsin K(ng/mL) levels were elevated in patients with ReA compared to controls (2.70 vs 2.17 p=0.028). All patients completed a follow up survey at 2 years (in person or by phone). 47% of patients had continued symptoms. Uveitis resolved in all but one of the patients. Conclusion: We report the results of a study examining the epidemiology of ReA in Guatemala. As expected, SpA characteristics were common: Achilles Enthesitis (67% on exam, 44% on USG). Strengths of this study: First, 81% were female, previous studies have reported ReA as a male-predominant disease, but as in Ankylosing Spondylitis (AS) women comprise a larger proportion of patients than previously recognized when newer definitions are used. This is the first study to examine potential risk factors for ReA, including serum biomarkers. Finally, this is one of the few studies to follow patients for persistence or resolution of symptoms at 2 years