Faculty Bibliography

Background/Purpose: Psoriasis (PsO) is a chronic immune-mediated skin condition affecting ~3% of adults worldwide. Up to a third of PsO patients go on to develop psoriatic arthritis (PsA), a heterogeneous inflammatory arthritis characterized by concomitant bone erosion and osteoproliferation. Although multiple advances have been made in the pathogenesis and therapeutics of these disorders, it is currently not possible to predict which individuals will progress from PsO to PsA. The role of the microbiome as a potential trigger for autoimmunity and rheumatic disease has recently been implicated. The goal of this study was to characterize the cutaneous microbiota of patients with PsO and PsA (in both psoriatic plaques and unaffected skin) to determine if there are characteristic features related to disease phenotype. Methods: Skin swabs from subjects with PsO (n=29) and PsA (n=62) were collected from both psoriatic plaque lesions and contralateral unaffected skin. 16S rDNA was extracted per protocol (MoBio, USA) and amplicons targeting the hypervariable V4 region were sequenced using MiSeq (Illumina) to define the microbiota composition. The obtained 16S rRNA sequences were analyzed using the Quantitative Insights into Microbial Ecology (QIIME) pipeline. Taxonomic relative abundance was determined to compare their prevalence among different phenotypes using Kruskal-Wallis statistical analysis. Alpha diversity plots and weighted Unifrac analysis (beta diversity) of cutaneous bacterial communities were generated. False discovery rate analysis was applied to identify unique differentiating taxa. Results: Baseline characteristics were comparable in both groups. PsO samples had, on average, a similar number of operational taxonomic units as compared to PsA samples. Beta diversity plots did not demonstrate statistically distinct clustering of microbial communities between PsO and PsA subjects, PsO and PsA nonlesional skin, or PsO and PsA lesional skin. Staphylococcus and Corynebacterium were the most abundant genera across all samples. However, several genera were statistically more abundant in PsO compared to PsA lesions, including unclassified Bradyrhizobiaceae (p<0.0006), Rahnella (p<0.0006), unclassified Prevotellaceae (p<0.001), and Parvibaculum (p<0.002). Rothia was more abundant in PsA (p<0.02). Conclusion: Our results characterize, for the first time, the cutaneous microbial composition of individuals with PsO compared to those with PsA both in psoriatic lesions and unaffected skin. Although we did not find overall community differences among the various phenotypes, our preliminary observations point towards differences in specific genera, which are characteristically more abundant in PsO. Further in-depth analysis is required to better understand the significance of this dysbiotic process in PsA and whether it contributes to the pathogenesis of the psoriatic disease spectrum. Current efforts are devoted to incorporating healthy controls into our analysis, and analyzing the cutaneous microbiome (and metagenome) across multiple body sites, multiple visits, as well as pre- and post-immunosuppressive/biologic therapy

Background/Purpose: Previous studies have established the value of measuring complement activation products (C4d) bound to platelets (PC4d) for the diagnosis and monitoring of Systemic Lupus Erythematosus (SLE). Separately, Antiphospholipid (APL) antibodies have been associated with complement activation and PC4d expression. In this study, we sought to validate the performance characteristics of PC4d, stratified by the presence or absence of APL antibodies. Methods: This multi-centered validation cross sectional study (16 sites in the US) enrolled 402 SLE subjects fulfilling the 1982 American College of Rheumatology Criteria revised in 1997 (mean age 41 years; 91% female), 411 subjects with rheumatic and autoimmune diseases other than SLE (mean age 55, 86% female consisting of 181 rheumatoid arthritis, 90 primary fibromyalgia, 92 other rheumatic diseases, and 48 autoimmune thyroiditis or hepatitis) and 198 healthy volunteers (mean age 41 years; 66% female). PC4d densities were determined using flow cytometry (expressed as mean fluorescence intensity [MFI]). Positive PC4d consisted of PC4d levels greater than 20 net MFI. Anticardiolipin IgG, anti-Beta-2-glycoprotein 1 IgG, or anti-Phosphatidylserine/Prothrombin (PSPT) complex IgG antibodies were determined using ELISA (INOVA diagnostics, San Diego, CA). Presence of APL antibodies consisted of any of these antibodies above manufacturer cutoff. SLE Disease activity was assessed using the non-serological SLE Disease Activity Index SELENA modification (ns-SELENA-SLEDAI, without the complement and anti-dsDNA). Performance characteristics were established using sensitivity, specificity, and ROC Curve Area Under the Curve (AUC). Statistical evaluation was by t-test (for disease activity), by chi-squared test for equality of proportions (for sensitivities and specificities) and by the method of DeLong (for ROC Curve AUC). Results: PC4d was highly specific in distinguishing SLE from other rheumatic diseases (Table) and normals. Among SLE subjects, 47% (n=187) presented with at least one APL antibody as compared to 21% (n=86) of subjects with other diseases and 15% of normals. PC4d sensitivity for SLE was higher among APL positive subjects by comparison to APL negative subjects (p=0.003). Specificity was not significantly different between APL positive and negative subjects (p>0.372). ROC AUC was significantly higher among the APL positive compared to negative subjects (p=0.002). The incidence of APL antibodies among all PC4d positive subjects was 60% compared to 27% among PC4d negative subjects (p<0.001). SLE subjects presenting with positive PC4d had higher disease activity (4.1+/-0.5) than those presenting with negative PC4d (3.0+/-0.2) (p=0.03). Conclusion: We confirm that PC4d is highly specific for SLE, and is associated with disease activity. (Table Presented)

Anti-tumor necrosis factors (Anti-TNFs) are a class of biologic disease-modifying anti-rheumatic drugs indicated for the treatment of moderate-to-severe psoriatic arthritis (PsA). Refractory patients are commonly managed by switching from one anti-TNF to another. To assess the evidence on the effectiveness of anti-TNF cycling in PsA patients, a systematic review of the literature was conducted. MEDLINE- and Embase-indexed English-language publications were systematically searched from 1995 to 2015 for studies assessing real-world effectiveness outcomes of anti-TNF cycling in PsA patients. Of 1086 citations identified, 18 studies were included; most conducted in Europe. Six of seven studies testing between lines found significant differences in effectiveness between earlier and subsequent lines of anti-TNF therapy. First-line therapy yielded better results compared with second-line therapy, and significant differences were observed between second- and third-line anti-TNF treatments. In the only study with multivariate regression testing for predictors of response, Danish registry patients were less likely to respond (American College of Rheumatology 20 % or 50 % response) to a second anti-TNF course if safety, rather than lack of effect, caused them to switch (odds ratio [OR] 0.04; p = 0.003 and OR 0.05; p = 0.03, respectively). Effectiveness of anti-TNFs at second line and later is reported in a small number of real-world studies of PsA patients. Subsequent treatment lines may be associated with less response in some measures. More research is needed to quantify the effectiveness of sequential anti-TNF lines in this progressive population' and to compare these effects with responses to drugs with different mechanisms of action.

Introduction: Several studies have shown that obesity is more common among patients with psoriasis and psoriatic arthritis, and this correlation may be related to the systemic inflammation associated with obesity. Although bariatric surgery has been shown to improve several obesity-related comorbidities, the effects of surgical weight loss on psoriasis and psoriatic arthritis have not been adequately studied. Our objective was to investigate the effects of weight loss from bariatric surgery on psoriasis and psoriatic arthritis. Methods: A retrospective database of 9,073 bariatric surgeries performed at a single center between 2002 and 2013 was queried. Patients with a diagnosis of psoriasis prior to bariatric surgery were identified. Preoperative demographic, anthropometric, and comorbidity data were collected. Patients were contacted about their history of psoriasis, changes in symptoms after surgery, diagnosis of psoriatic arthritis, and treatment modalities for psoriasis and psoriatic arthritis pre- and postoperatively. The primary outcome was the percentage of patients who reported improvement in psoriasis after surgery. Secondary analyses were performed to define factors associated with improvement in psoriasis. Results: We identified 128 patients with a preoperative diagnosis of psoriasis. Seventy-four (58%) patients completed the study. Baseline patient characteristics are listed in Table 1. The mean time from surgery was 6.2 years, with a mean excess weight loss (EWL) of 46.5%. At the time of contact, forty-one (55%) patients reported improvement in their psoriasis, 24.3% reported improvement with subsequent relapse, 6.8% had no change, and 12.6% reported that their psoriasis progressively worsened. Sixteen (22%) patients also had a preoperative diagnosis of psoriatic arthritis; 62.5% reported improvement in their psoriatic arthritis, whereas 19% had no change and 19% worsened. In secondary analyses, lower preoperative BMI (43.7kg/m² vs. 48.4 kg/m², p=0.004) was found to be independently associated with postoperative improvement in psoriasis. Patients with severe psoriasis at the time of surgery and significant postoperative improvement, excluding those whose improvement may have been due to escalation in medication class, demonstrated greater weight loss (101.4 lb vs. 66.0 lb, p=0.025) and EWL (63.7% vs. 44.7% EWL, p=0.028). Similarly, improvement in psoriatic arthritis was associated with greater EWL, but this did not reach statistical significance (51.4 vs. 48.3, p=0.815). Conclusion: Although the natural history of psoriasis and psoriatic arthritis is typically chronic, a majority of patients experience improvement after bariatric surgery. Based on our results, there is an association between excess weight loss and symptomatic improvement in severe cases of psoriasis. Factors such as lower preoperative BMI may be used to identify those patients with a greater likelihood of remission. Additionally, ours is the first study to show an improvement in psoriatic arthritis after bariatric surgery and a possible association between surgical EWL and improvement in psoriatic arthritis. Larger prospective studies are needed to further define the true effect of surgical weight loss on psoriasis and psoriatic arthritis

OBJECTIVE: To characterize the diversity and taxonomic relative abundance of the gut microbiota in patients with never-treated, recent-onset psoriatic arthritis (PsA). METHODS: High-throughput 16S ribosomal RNA pyrosequencing was utilized to compare the community composition of gut microbiota in patients with PsA (n = 16), patients with psoriasis of the skin (n = 15), and healthy, matched control subjects (n = 17). Samples were further assessed for the presence and levels of fecal and serum secretory IgA (sIgA), proinflammatory proteins, and fatty acids. RESULTS: The gut microbiota observed in patients with PsA and patients with skin psoriasis was less diverse when compared to that in healthy controls. This could be attributed to the reduced presence of several taxa. Samples from both patient groups showed a relative decrease in abundance of Coprococcus species, while samples from PsA patients were also characterized by a significant reduction in Akkermansia, Ruminococcus, and Pseudobutyrivibrio. Supernatants of fecal samples from PsA patients revealed an increase in sIgA levels and decrease in RANKL levels. Analysis of fatty acids revealed low fecal quantities of hexanoate and heptanoate in both patients with PsA and patients with psoriasis. CONCLUSION: Patients with PsA and patients with skin psoriasis had a lower relative abundance of multiple intestinal bacteria. Although some genera were concomitantly decreased in both conditions, PsA samples had a lower abundance of reportedly beneficial taxa. This gut microbiota profile in PsA was similar to that previously described in patients with inflammatory bowel disease and was associated with changes in specific inflammatory proteins unique to this group, and distinct from that in patients with skin psoriasis and healthy controls. Thus, the role of the gut microbiome in the continuum of psoriasis-PsA pathogenesis and the associated immune response merits further study.

Psoriatic arthritis (PsA) is an inflammatory arthritis associated with psoriasis that can lead to decreased health-related quality of life and permanent joint damage leading to functional decline. In addition to joint and skin manifestations, both psoriasis and PsA are associated with numerous comorbidities and extraarticular/cutaneous manifestations, which may influence the physician's choice of therapy. The objectives of this review are (1) to identify comorbidities in patients with PsA based on the available evidence; (2) to examine the effects of these comorbidities or extraarticular/cutaneous manifestation on the management of patients with PsA as well as the selection of therapy; and (3) to highlight research needs around comorbidities and treatment paradigms. This review is part of a treatment recommendations update initiated by the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA).