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BACKGROUND: Psoriasis is associated with increased cardiovascular risk that is not captured by traditional proinflammatory biomarkers. OBJECTIVE: To investigate the relationship between Psoriasis Area and Severity Index, circulating proinflammatory biomarkers, and vascular health in psoriasis. METHODS: In patients with psoriasis and in age and sex-matched controls, 273 proteins were analyzed with the Proseek Multiplex Cardiovascular disease reagents kit and Inflammatory reagents kit (Olink Bioscience), whereas vascular endothelial inflammation and health were measured via direct transcriptomic analysis of brachial vein endothelial cells. RESULTS: In psoriasis, chemokine ligand 20 (CCL20), interleukin (IL) 6, and IL-17A were the top 3 circulating proinflammatory cytokines. Vascular endothelial inflammation correlated with CCL20 (r = 0.55; P

Spondyloarthritis (SpA) is a group of chronic, immune-mediated, inflammatory diseases affecting the bone, synovium, and enthesis. Microbiome, the community of microorganisms that has co-evolved with human hosts, plays a pivotal role in human health and disease. This invisible "essential organ" supplies the host with a myriad of chemicals and molecules. In turn, microbial metabolites can serve as messengers for microbes to communicate with each other and in the cross-talk with host cells. Gut dysbiosis in SpA is associated with altered microbial metabolites, and an accumulated body of research has contributed to the understanding that changes in intestinal microbiota can modulate disease pathogenesis. We review the novel findings from human and animal studies to provide an overview of the contribution of individual microbial metabolites and antigens to SpA.

Objective To provide guidance about management of psoriatic disease during the COVID-19 pandemic. Study Design A task force (TF) of 18 physician voting members with expertise in dermatology, rheumatology, epidemiology, infectious diseases, and critical care was convened. The TF was supplemented by non-voting members which included fellows and National Psoriasis Foundation (NPF) staff. Clinical questions relevant to the psoriatic disease community were informed by questions received by the NPF. A Delphi process was conducted. Results The TF approved 22 guidance statements. The average of the votes was within the category of agreement for all statements. All guidance statements proposed were recommended, 9 with high consensus, 13 with moderate consensus. Limitations The evidence behind many guidance statements is limited in quality. Conclusion These statements provide guidance for the management of patients with psoriatic disease on topics ranging from how the disease and its treatments impact COVID-19 risk and outcome, how medical care can be optimized during the pandemic, what patients should do to lower their risk of getting infected with SARS-CoV-2 and what they should do if they develop COVID-19. The guidance is intended to be a living document that will be updated by the TF as data emerge., Capsule Summary The NPF COVID-19 Task Force produced 22 guidance statements to promote optimal management of psoriatic disease during the pandemic. Shared decision making is recommended as is adherence to evidence-based recommendations when available. The guidance statements will be updated when necessary in accordance with rapidly evolving science of COVID-19.

Enormous progress has been made in the field of rheumatology in the past several decades, historically led by publicly funded academic innovators but in more recent times with much greater involvement of the pharmaceutical industry. This shift in resources has created a complex new model for reinvestment in the medical community in which the vast majority of private funds are redirected towards influencing the prescription behaviour of practitioners through ‘key opinion leaders’, with the main purpose of enhancing and perpetuating profit rather than innovation and critical thinking, and often at the expense of partnerships with scientists (that is, basic and translational researchers) and academic collaborations. This new episteme brings multiple opportunities to rethink approaches to sustaining long-term critical research in the field, ultimately maximizing the return on investment: scientific knowledge for the benefit of patients and society. Central to such strategies should be the rebalancing of academia–industry partnerships towards academic research and the involvement of ‘innovation and knowledge leaders’, rather than mostly key opinion leaders., In this article, the authors critically appraise the current model of opinion-based academia–industry interactions, and advocate for a realignment towards partnerships that foster innovation and knowledge.

ObjectiveTo evaluate secukinumab (SEC) 300 mg and 150 mg vs placebo in a United States–only population of biologic-naïve patients with psoriatic arthritis (PsA).MethodsCHOICE was a double-blind, randomized controlled trial conducted in the US. Biologic-naïve patients with PsA and psoriasis (PsO) were randomized 2:2:1 to SEC 300 mg (n = 103), SEC 150 mg (n = 103), or placebo (n = 52). The primary objective was to show superiority of SEC 300 mg vs placebo in American College of Rheumatology 20% (ACR20) response at week 16. Additional objectives included the effect of SEC on dactylitis, enthesitis, PsO, and safety.ResultsACR20 response rates at week 16 were higher with SEC 300 mg than with placebo (51.5% vs 23.1%; odds ratio 3.51 [95% CI 1.65-7.45]; P = 0.001). SEC 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 SEC 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.ConclusionSEC 300 mg led to rapid and significant improvements over placebo in symptoms of PsA in this heavier population of US-only, biologic-naïve patients. Findings were consistent with previous studies and suggest that SEC 300 mg is a safe and efficacious first-line biologic treatment for patients with PsA. [ClinicalTrials.gov: NCT02798211]

Psoriatic arthritis (PsA) is part of a group of closely related clinical phenotypes ('psoriatic disease') that is defined by shared molecular pathogenesis resulting in excessive, prolonged inflammation in the various tissues affected, such as the skin, the entheses or the joints. Psoriatic disease comprises a set of specific drivers that promote an aberrant immune response and the consequent development of chronic disease that necessitates therapeutic intervention. These drivers include genetic, biomechanical, metabolic and microbial factors that facilitate a robust and continuous mobilization, trafficking and homing of immune cells into the target tissues. The role of genetic variants involved in the immune response, the contribution of mechanical factors triggering an exaggerated inflammatory response (mechanoinflammation), the impact of adipose tissue and altered lipid metabolism and the influence of intestinal dysbiosis in the disease process are discussed. Furthermore, the role of key cytokines, such as IL-23, IL-17 and TNF, in orchestrating the various phases of the inflammatory disease process and as therapeutic targets in PsA is reviewed. Finally, the nature and the mechanisms of inflammatory tissue responses inherent to PsA are summarized.

OBJECTIVE: To characterize the hospitalization and death rates among patients with inflammatory arthritis (IA) affected by coronavirus disease 2019 (COVID-19) and to analyze the associations of comorbidities and immunomodulatory medications with infection outcomes. METHODS: Data on clinical and demographic features, maintenance treatment, disease course, and outcomes in individuals with IA (rheumatoid arthritis and spondyloarthritis) with symptomatic COVID-19 infection were prospectively assessed via web-based questionnaire followed by individual phone calls and electronic medical record review. Baseline characteristics and medication use were summarized for hospitalized and ambulatory patients, and outcomes with the different medication classes were compared using multivariable logistic regression. RESULTS: A total of 103 patients with IA were included in the study (80 with confirmed COVID-19 and 23 with high suspicion of COVID-19). Hospitalization was required in 26% of the participants, and 4% died. Patients who were hospitalized were significantly more likely to be older (P < 0.001) and have comorbid hypertension (P = 0.001) and chronic obstructive pulmonary disease (P = 0.02). IA patients taking oral glucocorticoids had an increased likelihood of being admitted for COVID-19 (P < 0.001), while those receiving maintenance anticytokine biologic therapies did not. CONCLUSION: Among patients with underlying IA, COVID-19 outcomes were worse in those receiving glucocorticoids but not in patients receiving maintenance anticytokine therapy. Further work is needed to understand whether immunomodulatory therapies affect COVID-19 incidence.

ObjectiveIn these studies, we examined the association of single nucleotide polymorphisms (SNPs) of the IL1RN 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).MethodsOver 1000 subjects who met American College of Rheumatology criteria for tibiofemoral OA were selected from three independent, National Institute of Health (NIH)-funded cohorts. CTA and TTG haplotypes formed from three SNPs of the IL1RN gene (rs419598, rs315952, rs9005) were assessed for association with radiographic severity, and risk for incident radiographic OA (rOA) in a nested case–control cohort. These IL1RN haplotypes were also assessed for association with disease activity (DAS28) and plasma inflammatory markers in patients with RA.ResultsCarriage of the IL1RN TTG haplotype was associated with increased odds of more severe rOA compared with age-matched, sex-matched and body mass index-matched individuals. Examination of the osteoarthritis initiative Incidence Subcohort 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)).ConclusionCarriage of the IL1RN TTG haplotype is associated with more severe rOA, increased risk for incident OA, and increased evidence of inflammation in RA. These data suggest that the IL1RN TTG risk haplotype, associated with decreased IL-1Ra plasma levels, impairs endogenous ‘anti-inflammatory’ mechanisms.

At the 2021 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) annual meeting, a summary of the research conducted by the recipients of the 2020 GRAPPA Research Awards was presented by the awardees. The summary of the 4 presentations is provided here.

IntroductionPsoriatic arthritis (PsA) is a complex, immune-mediated disease associated with skin psoriasis that, if left untreated, can lead to joint destruction. Up to 30% of patients with psoriasis progress to PsA. In most cases, psoriasis precedes synovio-entheseal inflammation by an average of 5–7 years, providing a unique opportunity for early and potentially preventive intervention in a susceptible and identifiable population. Guselkumab is an effective IL-23p19 inhibitor Food and Drug Administration (FDA)-approved for treatment of moderate-to-severe psoriasis and PsA. The Preventing Arthritis in a Multicentre Psoriasis At-Risk cohort (PAMPA) study aims to evaluate the efficacy of guselkumab in preventing PsA and decreasing musculoskeletal power Doppler ultrasound (PDUS) abnormalities in a population of patients with psoriasis who are at-increased risk for PsA progression.Methods and analysisThe PAMPA study is a multicentre, randomised, double-blind, placebo-controlled, interventional, preventive trial comparing PDUS involvement and conversion to PsA in patients with psoriasis at-increased risk for progression treated with guselkumab compared with non-biological standard of care. The study includes a screening period, a double-blind treatment period (24 weeks) and an open-label follow-up period (72 weeks). At baseline, 200 subjects will be randomised (1:1) to receive either guselkumab 100 mg (arm 1) or placebo switching to guselkumab 100 mg starting at week 24 (arm 2). Arm 3 will follow 150 at-risk psoriasis patients who decline biological therapy and randomisation. Changes from baseline in the PDUS score at week 24 and the difference in proportion of patients transitioning to PsA at 96 weeks will be examined as the coprimary endpoints.Ethics and disseminationEthics approval for this study was granted by the coordinating centre’s (NYU School of Medicine) Institutional Review Board (IRB). Each participating site received approval through their own IRBs. The findings will be shared in peer-reviewed articles and scientific conference presentations.Trial registration numberNCT05004727.

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.

To evaluate seroreactivity and disease flares after COVID-19 vaccination in a multiethnic/multiracial cohort of patients with systemic lupus erythematosus (SLE).Ninety SLE patients and 20 healthy controls receiving a complete COVID-19 vaccine regimen were included. IgG seroreactivity to the SARS-CoV-2 spike receptor-binding domain (RBD) and SARS-CoV-2 microneutralization were used to evaluate B cell responses; interferon-γ (IFNγ) production was measured by enzyme-linked immunospot (ELISpot) assay in order to assess T cell responses. Disease activity was measured by the hybrid SLE Disease Activity Index (SLEDAI), and flares were identified according to the Safety of Estrogens in Lupus Erythematosus National Assessment-SLEDAI flare index.Overall, fully vaccinated SLE patients produced significantly lower IgG antibodies against SARS-CoV-2 spike RBD compared to fully vaccinated controls. Twenty-six SLE patients (28.8%) generated an IgG response below that of the lowest control (100 units/ml). In logistic regression analyses, the use of any immunosuppressant or prednisone and a normal anti-double-stranded DNA antibody level prior to vaccination were associated with decreased vaccine responses. IgG seroreactivity to the SARS-CoV-2 spike RBD strongly correlated with the SARS-CoV-2 microneutralization titers and correlated with antigen-specific IFNγ production determined by ELISpot. In a subset of patients with poor antibody responses, IFNγ production was similarly diminished. Pre- and postvaccination SLEDAI scores were similar in both groups. Postvaccination flares occurred in 11.4% of patients; 1.3% of these were severe.In a multiethnic/multiracial study of SLE patients, 29% had a low response to the COVID-19 vaccine which was associated with receiving immunosuppressive therapy. Reassuringly, severe disease flares were rare. While minimal protective levels remain unknown, these data suggest that protocol development is needed to assess the efficacy of booster vaccination.

Psoriatic arthritis (PsA) is a complex inflammatory disease with heterogeneous clinical features, which complicates psoriasis in 30% of patients. There are no diagnostic criteria or tests available. Diagnosis is most commonly made by identifying inflammatory musculoskeletal features in joints, entheses or the spine in the presence of skin and/or nail psoriasis and in the usual absence of rheumatoid factor and anti-cyclic citrullinated peptide. The evolution of psoriasis to PsA may occur in stages, although the mechanisms are unclear. In many patients, there may be little or no relationship between severity of musculoskeletal inflammation and severity of skin or nail psoriasis. The reason for this disease heterogeneity may be explained by differences in genotype, especially in the HLA region. New targeted therapies for PsA have been approved with additional therapies in development. These developments have substantially improved both short-term and long-term outcomes including a reduction in musculoskeletal and skin manifestations and in radiographic damage. With efforts underway aimed at improving our understanding of the molecular basis for the heterogeneity of PsA, a personalized approach to treating PsA may become possible.

ObjectiveTo examine the association of biologic therapy use for psoriasis with incident psoriatic arthritis (PsA) diagnosis.MethodsA retrospective cohort study was conducted in the OptumInsights Electronic Health Record Database between 2006 and 2017 among patients with psoriasis between the ages of 16 and 90 initiating a therapy for psoriasis (oral, biologic or phototherapy). The incidence of PsA was calculated within each therapy group. Multivariable Cox models were used to calculate the HR for biologic versus oral or phototherapy using biologics as a time-varying exposure and next in a propensity score-matched cohort.ResultsAmong 1 93 709 patients with psoriasis without PsA, 14 569 biologic and 20 321 cumulative oral therapy and phototherapy initiations were identified. Mean age was lower among biologic initiators compared with oral/phototherapy initiators (45.9 vs 49.8). The incidence of PsA regardless of therapy exposure was 9.75 per 1000 person-years compared with 77.26 among biologic users, 61.99 among oral therapy users, 26.11 among phototherapy users and 5.85 among those without a prescription for one of the target therapies. Using a multivariable adjustment approach with time-varying exposure, adjusted HR (95% CI) for biologic users was 4.48 (4.23 to 4.75) compared with oral or phototherapy users. After propensity score matching, the HR (95% CI) was 2.14 (2.00 to 2.28).ConclusionsIn this retrospective cohort study, biologic use was associated with the development of PsA among patients with psoriasis. This may be related to confounding by indication and protopathic bias. Prospective studies are needed to address this important question.

Objective To update guidance regarding the management of psoriatic disease during the COVID-19 pandemic. Study Design The task force (TF) includes 18 physician voting members with expertise in dermatology, rheumatology, epidemiology, infectious diseases, and critical care. The TF was supplemented by non-voting members, which included fellows and National Psoriasis Foundation (NPF) staff. Clinical questions relevant to the psoriatic disease community were informed by inquiries received by the NPF. A Delphi process was conducted. Results The TF updated evidence for the original 22 statements and added 5 new recommendations. The average of the votes was within the category of agreement for all statements, 13 with high consensus, 14 with moderate consensus. Limitations The evidence behind many guidance statements is variable in quality and/or quantity. Conclusion These statements provide guidance for the management of patients with psoriatic disease on topics ranging from how the disease and its treatments impact COVID-19 risk, how medical care can be optimized during the pandemic, what patients should do to lower their risk of getting infected with SARS-CoV-2 (including novel vaccination), and what they should do if they develop COVID-19. The guidance is a living document that is continuously updated by the TF as data emerge., Capsule Summary:• The NPF COVID-19 TF produced 27 guidance statements to promote optimal management of psoriatic disease during the pandemic. • Shared decision making, adherence to evidence-based treatment, and the urgent use of novel COVID-19 vaccination are recommended. The guidance statements will be updated in accordance with the rapidly evolving science of COVID-19.

Objective— Psoriasis is an inflammatory skin disease which heightens the risk of cardiovascular disease. This study directly investigated vascular endothelial health and systemically altered pathways in psoriasis and matched controls. Approach and Results— Twenty patients (mean age, 40 years; 50% male) with active psoriasis and 10 age-, sex-matched controls were recruited. To investigate systemically alerted pathways, a deep sequencing omics approach was applied, including unbiased blood transcriptomic and targeted proteomic analysis. Vascular endothelial health was assessed by transcriptomic profiling of endothelial cells obtained from the brachial veins of recruited participants. Blood transcriptomic profiling identified inflammasome signaling as the highest differentially expressed canonical pathway ( Z score 1.6; P =1×10 -7 ) including upregulation of CASP5 and interleukin ( IL ) -1β . Proteomic panels revealed IL-6 as a top differentially expressed cytokine in psoriasis with pathway analysis highlighting IL-1β ( Z score 3.7; P =1.02×10 -23 ) as an upstream activator of the observed upregulated proteins. Direct profiling of harvested brachial vein endothelial cells demonstrated inflammatory transcript (eg, IL-1β, CXCL10, VCAM-1, IL-8, CXCL1 , Lymphotoxin beta , ICAM-1 , COX-2 , and CCL3 ) upregulation between psoriasis versus controls. A linear relationship was seen between differentially expressed endothelial inflammatory transcripts and psoriasis disease severity. IL-6 levels correlated with inflammatory endothelial cell transcripts and whole blood inflammasome-associated transcripts, including CASP5 and IL-1β . Conclusions— An unbiased sequencing approach demonstrated the inflammasome as the most differentially altered pathway in psoriasis versus controls. Inflammasome signaling correlated with psoriasis disease severity, circulating IL-6, and proinflammatory endothelial transcripts. These findings help better explain the heightened risk of cardiovascular disease in psoriasis. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT03228017.

Psoriasis is one of the most common chronic inflammatory skin diseases, affecting 3% of the world's population, and approximately one-third of patients with psoriasis will eventually transition to having psoriatic arthritis (PsA). The evolution from cutaneous to synovio-entheseal inflammation in these patients presents an opportunity to investigate the critical events linked to arthritis development. The events responsible for progression to PsA are currently unclear. Genetic and clinical-demographic risk factors (most notably familial aggregation and psoriasis sub-phenotypes) provide relevant insights into the variables that promote transition. The specific underlying molecular and cellular mechanisms, however, remain poorly defined. Intriguingly, although targeting the IL-23-IL-17 axis substantially improves psoriasis outcomes, this strategy is not more effective than TNF inhibitors in improving musculoskeletal symptoms in PsA. Major unmet needs in the field of PsA include defining those patients with psoriasis at increased risk of developing arthritis, improving our understanding of the natural history of disease and characterizing the immune, environmental and molecular subclinical events preceding PsA onset. Improving our knowledge of this transition is essential for designing clinical trials with treatments that can delay, attenuate or even prevent the development of PsA in patients with psoriasis.

The coronavirus disease 2019 (COVID-19; caused by SARS-CoV-2) pandemic has affected the healthcare system on a global scale, and we utilized the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) 2020 annual meeting to examine how COVID-19 might affect patients with psoriatic disease (PsD) and the clinicians who care for them. Pressing issues and concerns identified included whether having psoriasis increased the risk of acquiring COVID-19, vaccine safety, and the acceptability of telehealth. The general message from rheumatologists, dermatologists, infectious disease specialists, and patient research partners was that data did not suggest that having PsD or its treatment significantly increased risk of infection or more severe disease course, and that the telehealth experience was a success overall.

The concept of psoriatic arthritis (PsA) prevention is gaining increased interest owing to the physical limitation, poor quality of life and low remission rates that are achieved with current therapies for PsA. The psoriasis-to-PsA transition offers a unique opportunity to identify individuals at increased risk of developing PsA and to implement preventive strategies. However, identifying individuals at increased risk of developing PsA is challenging as there is no consensus on how this population should be defined. This Consensus Statement puts forward recommended terminology from the Psoriasis and Psoriatic Arthritis Clinics Multicenter Advancement Network (PPACMAN) for defining specific subgroups of individuals during the preclinical and early clinical phases of PsA to be used in research studies. Following a three-round Delphi process, consensus was reached for three terms and definitions: ‘increased risk for PsA’, ‘psoriasis with asymptomatic synovio-entheseal imaging abnormalities’ and ‘psoriasis with musculoskeletal symptoms not explained by other diagnosis’. These terms and their definitions will enable improved identification and standardization of study populations in clinical research. In the future, as increasing evidence emerges regarding the molecular and clinical features of the psoriasis-to-PsA continuum, these terms and definitions will be further refined and updated., In this Consensus Statement, an expert panel from the Psoriasis and Psoriatic Arthritis Clinics Multicenter Advancement Network (PPACMAN) recommends terminology for defining specific subgroups of individuals during the preclinical and early clinical phases of psoriatic arthritis to be used in research studies.

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of mature T-cell neoplasms characterized by the accumulation of clonal malignant CD4+ T cells in the skin. The most common variant of CTCL, mycosis fungoides (MF ), is confined to the skin in early stages but can be accompanied by extracutaneous dissemination of malignant T cells to the blood and lymph nodes in advanced stages of disease. Sézary syndrome (SS), a leukemic form of disease, is characterized by significant blood involvement. Little is known about the transcriptional and genomic relationship between skin- and blood-residing malignant T cells in CTCL. To identify and interrogate malignant clones in matched skin and blood from patients with leukemic MF and SS, we combine T-cell receptor clonotyping with quantification of gene expression and cell surface markers at the single cell level. Our data reveal clonal evolution at a transcriptional and genetic level within the malignant populations of individual patients. We highlight highly consistent transcriptional signatures delineating skin- and blood-derived malignant T cells. Analysis of these 2 populations suggests that environmental cues, along with genetic aberrations, contribute to transcriptional profiles of malignant T cells. Our findings indicate that the skin microenvironment in CTCL promotes a transcriptional response supporting rapid malignant expansion, as opposed to the quiescent state observed in the blood, potentially influencing efficacy of therapies. These results provide insight into tissue-specific characteristics of cancerous cells and underscore the need to address the patients’ individual malignant profiles at the time of therapy to eliminate all subclones.

Following the pivotal manuscript that outlined unique disease features half a century ago, investigators in the field of psoriatic arthritis (PsA) have extrapolated clinical trial data and molecular insights from the more expansive experience in rheumatoid arthritis (RA). As a result, many of the diagnostic approaches, imaging modalities, therapeutics and outcome measures paralleled (and at times became identical to) those developed for RA.

OBJECTIVE Although oral methotrexate (MTX) remains the anchor drug for rheumatoid arthritis (RA), up to 50% of patients do not achieve a clinically adequate outcome. In addition, there is a lack of prognostic tools for treatment response prior to drug initiation. This study was undertaken to investigate whether interindividual differences in the human gut microbiome can aid in the prediction of MTX efficacy in new-onset RA. METHODS We performed 16S ribosomal RNA gene and shotgun metagenomic sequencing on the baseline gut microbiomes of drug-naive patients with new-onset RA (n = 26). Results were validated in an additional independent cohort (n = 21). To gain insight into potential microbial mechanisms, we conducted ex vivo experiments coupled with metabolomics analysis to evaluate the association between microbiome-driven MTX depletion and clinical response. RESULTS Our analysis revealed significant associations of the abundance of gut bacterial taxa and their genes with future clinical response (q < 0.05), including orthologs related to purine and MTX metabolism. Machine learning techniques were applied to the metagenomic data, resulting in a microbiome-based model that predicted lack of response to MTX in an independent group of patients. Finally, MTX levels remaining after ex vivo incubation with distal gut samples from pretreatment RA patients significantly correlated with the magnitude of future clinical response, suggesting a possible direct effect of the gut microbiome on MTX metabolism and treatment outcomes. CONCLUSION Taken together, these findings are the first step toward predicting lack of response to oral MTX in patients with new-onset RA and support the value of the gut microbiome as a possible prognostic tool and as a potential target in RA therapeutics.

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.

The second basic science session at the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) annual meeting focused on 2 recent publications that have increased our understanding of the pathogenesis of psoriatic arthritis (PsA). Data from the first publication, presented by Prof. Erik Lubberts, showed that interleukin (IL)-17A is produced by CD4+ and not CD8+ T cells in PsA synovial fluid following T cell receptor activation. These findings contrast with previously published data, which had suggested that CD8+ T cells are a prominent source of IL-17A. In further experiments, they showed that when CD8+ T cells were stimulated with paramethoxyamphetamine/ionomycin, relatively high levels of IL-17A were detected. Prof. Jose Scher presented work on the role of the microbiome in PsA and more specifically, on pharmacomicrobiomics. He demonstrated the baseline collection of genomes and genes from the microbiota community (the metagenome) can be used as predictor for future treatment response in early rheumatoid arthritis and also likely in PsA.

Objective To characterize patients with systemic lupus erythematosus (SLE) affected by coronavirus disease 2019 (COVID-19) and to analyze associations of comorbidities and medications on infection outcomes. Methods Patients with SLE and reverse transcriptase-polymerase chain reaction-confirmed COVID-19 were identified through an established New York University lupus cohort, query of 2 hospital systems, and referrals from rheumatologists. Data were prospectively collected via a web-based questionnaire and review of medical records. Data on baseline characteristics were obtained for all patients with COVID-19 to analyze risk factors for hospitalization. Data were also collected on asymptomatic patients and those with COVID-19-like symptoms who tested negative or were not tested. Statistical analyses were limited to confirmed COVID-19-positive patients. Results A total of 226 SLE patients were included: 41 with confirmed COVID-19, 19 who tested negative for COVID-19, 42 with COVID-19-like symptoms who did not get tested, and 124 who remained asymptomatic without testing. Of the SLE patients with confirmed COVID-19, hospitalization was required in 24 (59%) and intensive care unit-level of care in 4, and 4 died. Hospitalized patients tended to be older, nonwhite, Hispanic, have higher body mas index (BMI), history of nephritis, and at least 1 comorbidity. An exploratory (due to limited sample size) logistic regression analysis identified race, presence of at least 1 comorbidity, and BMI as independent predictors of hospitalization. Conclusion In general, the variables predictive of hospitalization in our SLE patients were similar to those identified in the general population. Further studies are needed to understand additional risk factors for poor COVID-19 outcomes in patients with SLE.

To provide a general overview of the organizations dedicated to advance clinical and translational research in the field of psoriatic disease and to describe the current and future opportunities for team science approaches to overcome unmet needs in the field. Descriptions of initiatives from the NPF, PPACMAN, and GRAPPA are summarized. Program projects have recently identified areas of knowledge gaps in diagnosis, treatment, and prevention of psoriasis and psoriatic arthritis (PsA). NPF’s Psoriasis Prevention Initiative aims to identify interventions that can prevent the onset and relapse of psoriatic disease or related comorbidities. The Psorcast Study is a joint venture between PPACMAN and Sage Bionetworks based on patient-generated smartphone measurements of psoriatic disease. Similarly, GRAPPA is involved in a number of projects related to axial PsA, enthesitis prevalence, and biomarker discoveries. As important initiatives bring new targets for diagnosis and therapeutics in psoriatic disease, supra-endeavors such as the NIH-Accelerating Medicines Partnership (AMP) and the European Innovative Medicines Initiative (IMI) are promising public-private partnerships that can significantly catapult the field forward.

We engineered a machine learning approach, MSHub, to enable auto-deconvolution of gas chromatography–mass spectrometry (GC–MS) data. We then designed workflows to enable the community to store, process, share, annotate, compare and perform molecular networking of GC–MS data within the Global Natural Product Social (GNPS) Molecular Networking analysis platform. MSHub/GNPS performs auto-deconvolution of compound fragmentation patterns via unsupervised non-negative matrix factorization and quantifies the reproducibility of fragmentation patterns across samples., Fil: Aksenov, Alexander A. University of California. Skaggs School of Pharmacy and Pharmaceutical Sciences; Estados Unidos, Fil: Aksenov, Alexander A. University of California. Skaggs School of Pharmacy and Pharmaceutical Sciences. Collaborative Mass Spectrometry Innovation Center; Estados Unidos, Fil: Laponogov, Ivan. South Kensington Campus. Imperial College London. Department of Surgery and Cancer; Reino Unido, Fil: Zhang, Zheng. University of California. Skaggs School of Pharmacy and Pharmaceutical Sciences; Estados Unidos, Fil: Doran, Sophie L. F. South Kensington Campus. Imperial College London. Department of Surgery and Cancer; Reino Unido, Fil: Belluomo, Ilaria. South Kensington Campus. Imperial College London. Department of Surgery and Cancer; Reino Unido, Fil: Veselkov, Dennis. Intelligify Limited. Reino Unido. South Kensington Campus. Imperial College. Department of Computing; Reino Unido, Fil: Bittremieux, Wout. University of California. Skaggs School of Pharmacy and Pharmaceutical Sciences; Estados Unidos, Fil: Bittremieux, Wout. University of California. Skaggs School of Pharmacy and Pharmaceutical Sciences. Collaborative Mass Spectrometry Innovation Center; Estados Unidos, Fil: Bittremieux, Wout. University of Antwerp. Department of Computer Science; Belgica, Fil: Nothias, Louis Felix. University of California. Skaggs School of Pharmacy and Pharmaceutical Sciences; Estados Unidos, Fil: Nothias, Louis Felix. University of California. Skaggs School of Pharmacy and Pharmaceutical Sciences. Collaborative Mass Spectrometry Innovation Center; Estados Unidos, Fil: Nothias-Esposito, Mélissa. University of California. Skaggs School of Pharmacy and Pharmaceutical Sciences; Estados Unidos, Fil: Nothias-Esposito, Mélissa. University of California. Skaggs School of Pharmacy and Pharmaceutical Sciences. Collaborative Mass Spectrometry Innovation Center; Estados Unidos, Fil: Maloney, Katherine N. University of California. Skaggs School of Pharmacy and Pharmaceutical Sciences; Estados Unidos, Fil: Maloney, Katherine N. Point Loma Nazarene University. Department of Chemistry; Estados Unidos, Fil: Misra, Biswapriya B. Wake Forest School of Medicine. Section of Molecular Medicine. Department of Internal Medicine. Center for Precision Medicine; Estados Unidos, Fil: Melnik, Alexey V. University of California. Skaggs School of Pharmacy and Pharmaceutical Sciences; Estados Unidos, Fil: Smirnov, Aleksandr. University of North Carolina at Charlotte. Department of Bioinformatics and Genomics; Estados Unidos, Fil: Du, Xiuxia. University of North Carolina at Charlotte. Department of Bioinformatics and Genomics; Estados Unidos, Fil: Jones, Kenneth L. University of North Carolina at Charlotte. Department of Bioinformatics and Genomics; Estados Unidos, Fil: Dorrestein, Kathleen. University of California. Skaggs School of Pharmacy and Pharmaceutical Sciences; Estados Unidos, Fil: Dorrestein, Kathleen. University of California. Skaggs School of Pharmacy and Pharmaceutical Sciences. Collaborative Mass Spectrometry Innovation Center; Estados Unidos, Fil: Panitchpakdi, Morgan. University of California. Skaggs School of Pharmacy and Pharmaceutical Sciences; Estados Unidos, Fil: Ernst, Madeleine. University of California. Skaggs School of Pharmacy and Pharmaceutical Sciences; Estados Unidos, Fil: Ernst, Madeleine. Statens Serum Institut. Danish Center for Neonatal Screening. Department of Congenital Disorders. Section for Clinical Mass Spectrometry; Dinamarca, Fil: van der Hooft, Justin J. J. University of California. Skaggs School of Pharmacy and Pharmaceutical Sciences; Estados Unidos, Fil: van der Hooft, Justin J. J. Wageningen University. Bioinformatics Group; Países Bajos, Fil: Gonzalez, Mabel. Universidad de los Andes. Department of Chemistry; Colombia, Fil: Carazzone, Chiara. Universidad de los Andes. Department of Chemistry; Colombia, Fil: Amézquita, Adolfo. Universidad de los Andes. Department of Biological Sciences; Colombia, Fil: Callewaert, Chris. Center for Microbial Ecology and Technology; Belgica, Fil: Callewaert, Chris. University of California. Department of Pediatrics; Estados Unidos, Fil: Morton, James T. University of California. Department of Pediatrics; Estados Unidos, Fil: Morton, James T. Simons Foundation. Flatiron Institute. Center for Computational Biology; Estados Unidos, Fil: Quinn, Robert A. Michigan State University. Department of Biochemistry and Molecular Biology; Estados Unidos, Fil: Bouslimani, Amina. University of California. Skaggs School of Pharmacy and Pharmaceutical Sciences; Estados Unidos, Fil: Bouslimani, Amina. University of California. Skaggs School of Pharmacy and Pharmaceutical Sciences. Collaborative Mass Spectrometry Innovation Center; Estados Unidos, Fil: Orio, Andrea Albarracín. Universidad Católica de Córdoba. IRNASUS. CONICET. Facultad de Ciencias Agropecuarias; Argentina, Fil: Petras, Daniel. University of California. Skaggs School of Pharmacy and Pharmaceutical Sciences; Estados Unidos, Fil: Petras, Daniel. University of California. Skaggs School of Pharmacy and Pharmaceutical Sciences. Collaborative Mass Spectrometry Innovation Center; Estados Unidos, Fil: Smania, Andrea M. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Química Biológica Ranwel Caputto; Argentina, Fil: Smania, Andrea M. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. CONICET; Argentina, Fil: Couvillion, Sneha P. Pacific Northwest National Laboratory. Biological Sciences Division; Estados Unidos, Fil: Burnet, Meagan C. Pacific Northwest National Laboratory. Biological Sciences Division; Estados Unidos, Fil: Nicora, Carrie D. Pacific Northwest National Laboratory. Biological Sciences Division; Estados Unidos, Fil: Zink, Erika. Pacific Northwest National Laboratory. Biological Sciences Division; Estados Unidos, Fil: Metz, Thomas O. Pacific Northwest National Laboratory. Biological Sciences Division; Estados Unidos, Fil: Artaev, Viatcheslav. LECO Corporation; Estados Unidos, Fil: Humston-Fulmer, Elizabeth. LECO Corporation; Estados Unidos, Fil: Gregor, Rachel. Ben-Gurion University of the Negev. Department of Chemistry and the National Institute for Biotechnology in the Negev; Israel, Fil: Meijler, Michael M. Ben-Gurion University of the Negev. Department of Chemistry and the National Institute for Biotechnology in the Negev; Israel, Fil: Mizrahi, Itzhak. Ben-Gurion University of the Negev. Department of Life Sciences and the National Institute for Biotechnology in the Negev; Israel, Fil: Eyal, Stav. Ben-Gurion University of the Negev. Department of Life Sciences and the National Institute for Biotechnology in the Negev; Israel, Fil: Anderson, Brooke. University of California. Division of Biological Sciences; Estados Unidos, Fil: Dutton, Rachel. University of California. Division of Biological Sciences; Estados Unidos, Fil: Lugan, Raphaël. Université d’Avignon et des Pays du Vaucluse, Agrosciences. UMR Qualisud; Francia, Fil: Boulch, Pauline Le. Université d’Avignon et des Pays du Vaucluse, Agrosciences. UMR Qualisud; Francia, Fil: Guitton, Yann. INRAe. Oniris. Laboratoire d’Etude des Résidus et Contaminants dans les Aliments (LABERCA); Francia, Fil: Prevost, Stephanie. INRAe. Oniris. Laboratoire d’Etude des Résidus et Contaminants dans les Aliments (LABERCA); Francia, Fil: Poirier, Audrey. INRAe. Oniris. Laboratoire d’Etude des Résidus et Contaminants dans les Aliments (LABERCA); Francia, Fil: Dervilly, Gaud. INRAe. Oniris. Laboratoire d’Etude des Résidus et Contaminants dans les Aliments (LABERCA); Francia, Fil: Le Bizec, Bruno. Oniris. Laboratoire d’Etude des Résidus et Contaminants dans les Aliments (LABERCA); Francia, Fil: Fait, Aaron. Ben Gurion University of the Negev. Sede Boqer Campus. The Jacob Blaustein Institutes for Desert Research. The French Associates Institute for Agriculture and Biotechnology of Dryland; Israel, Fil: Persi, Noga Sikron. Ben Gurion University of the Negev. Sede Boqer Campus. The Jacob Blaustein Institutes for Desert Research. The French Associates Institute for Agriculture and Biotechnology of Dryland; Israel, Fil: Song, Chao. Ben Gurion University of the Negev. Sede Boqer Campus. The Jacob Blaustein Institutes for Desert Research. The French Associates Institute for Agriculture and Biotechnology of Dryland; Israel, Fil: Gashu, Kelem. Ben Gurion University of the Negev. Sede Boqer Campus. The Jacob Blaustein Institutes for Desert Research. The French Associates Institute for Agriculture and Biotechnology of Dryland; Israel, Fil: Coras, Roxana. University of California. Department of Medicine. Division of Rheumatology; Estados Unidos, Fil: Guma, Monica. University of California. Department of Medicine. Division of Rheumatology; Estados Unidos, Fil: Manasson, Julia. New York University School of Medicine. Department of Medicine. Division of Rheumatology; Estados Unidos, Fil: Scher, Jose U. New York University School of Medicine. Department of Medicine. Division of Rheumatology; Estados Unidos, Fil: Barupal, Dinesh Kumar. Icahn School of Medicine at Mount Sinai. Department of Environmental Medicine and Public Health; Estados Unidos, Fil: Alseekh, Saleh. Max Planck Institute for Molecular Plant Physiology; Alemania, Fil: Alseekh, Saleh. Center of Plant Systems Biology and Biotechnology (CPSBB); Bulgaria, Fil: Fernie, Alisdair R. Max Planck Institute for Molecular Plant Physiology; Alemania, Fil: Fernie, Alisdair R. Center of Plant Systems Biology and Biotechnology (CPSBB); Bulgaria, Fil: Mirnezami, Reza. Royal Free Hospital NHS Foundation Trust. Department of Colorectal Surgery; Reino Unido, Fil: Vasiliou, Vasilis. Yale University. Yale School of Public Health. Department of Environmental Health Sciences; Estados Unidos, Fil: Schmid, Robin. University of Münster. Institute of Inorganic and Analytical Chemistry; Alemania, Fil: Borisov, Roman S. A.V. Topchiev Institute of Petrochemical Synthesis RAS; Rusia, Fil: Kulikova, Larisa N. Рeoples’ Friendship University of Russia (RUDN University); Rusia, Fil: Knight, Rob. University of California. Department of Pediatrics; Estados Unidos, Fil: Knight, Rob. University of California. UCSD Center for Microbiome Innovation; Estados Unidos, Fil: Knight, Rob. University of California. Department of Bioengineering; Estados Unidos, Fil: Wang, Mingxun. University of California. Skaggs School of Pharmacy and Pharmaceutical Sciences; Estados Unidos, Fil: Wang, Mingxun. University of California. Skaggs School of Pharmacy and Pharmaceutical Sciences. Collaborative Mass Spectrometry Innovation Center; Estados Unidos, Fil: Hanna, George B. South Kensington Campus. Imperial College London. Department of Surgery and Cancer; Reino Unido, Fil: Dorrestein, Pieter C. University of California. Skaggs School of Pharmacy and Pharmaceutical Sciences; Estados Unidos, Fil: Dorrestein, Pieter C. University of California. Skaggs School of Pharmacy and Pharmaceutical Sciences. Collaborative Mass Spectrometry Innovation Center; Estados Unidos, Fil: Dorrestein, Pieter C. University of California. Department of Pediatrics; Estados Unidos, Fil: Veselkov, Kirill. South Kensington Campus. Imperial College London. Department of Surgery and Cancer; Reino Unido

Psoriasis is a chronic inflammatory condition characterized by systemic immune dysregulation. Over the past several years, advances in genetics, microbiology, immunology, and mouse models have revealed the complex interplay between the heritable and microenvironmental factors that drive the development of psoriatic inflammation. In the first of this two-part review series, the authors will discuss the newest insights into the pathogenesis of psoriatic disease and highlight how the evolution of these scientific fields has paved the way for a more personalized approach to psoriatic disease treatment.

Objectives Physical function is a core outcome in PsA. We examined the construct validity and responsiveness of three commonly used instruments to assess physical function in PsA: HAQ disability index (HAQ-DI), MultiDimensional HAQ (MDHAQ) and the Patient-Reported Outcomes Measurement Information System (PROMIS®) Global-10. Methods Between 2016 and 2019, patients with PsA were enrolled in the Psoriatic Arthritis Research Consortium longitudinal cohort study in the USA. Correlations were calculated at baseline and among change scores using Spearman’s correlation coefficient. Standardized response means were calculated. Agreement with the 20% improvement cut-off was used to determine the potential effect of using MDHAQ or the PROMIS Global-10 physical health (GPH) subscore in place of HAQ-DI when assessing the ACR20. Results A total of 274 patients were included in the analysis. The mean age of patients was 49 years and 51% were male. At baseline, the mean HAQ-DI was 0.6 (s.d. 0.6; range 0–3), the mean MDHAQ was 1.8 (s.d. 1.6; range 0–10) and the mean GPH T-score was 43.4 (s.d. 9.3; range 0–100). All three instruments were strongly correlated at baseline (rho 0.75–0.85). Change scores were moderately correlated (rho 0.42–0.71). Among therapy initiators, the mean change between two visits in HAQ-DI, MDHAQ and GPH was −0.1 (s.d. 0.4), −0.2 (s.d. 1.2) and 2.5 (s.d. 6.1), respectively. The standardized response means were 0.18, 0.16 and 0.41, respectively. Conclusion The three instruments tested are not directly interchangeable but have overall similar levels of responsiveness.

Background Sacroiliitis is an inflammatory arthritis of the sacroiliac joints and is associated with inflammatory bowel disease (IBD). Yet, sacroiliitis often goes undiagnosed in IBD, and the clinical association between IBD disease activity and sacroiliitis is not well established. Patients with Crohn’s disease (CD) often receive magnetic resonance enterography (MRE) to assess disease activity, affording clinicians the opportunity to evaluate for the presence of sacroiliitis. We aimed to identify the prevalence and disease characteristics associated with sacroiliitis in CD patients undergoing MRE. Methods All CD patients undergoing MRE for any indication between 2014 and 2018 at an IBD referral center were identified. The MREs were reviewed for the presence of sacroiliitis based on bone marrow edema (BME) and structural lesions. We analyzed demographics, IBD characteristics, clinical and endoscopic disease activity, and management between CD patients with and without sacroiliitis. Results Two hundred fifty-eight patients with CD underwent MRE during the study period. Overall, 17% of patients had MR evidence of sacroiliitis, of whom 73% demonstrated bone marrow edema. Female gender, back pain, and later age of CD diagnosis were associated with sacroiliitis (P = 0.05, P < 0.001, P = 0.04, respectively). Disease location and CD therapy were not associated with sacroiliitis on MRE. Clinical, endoscopic, and radiographic disease activity were not associated with sacroiliitis on MRE. Conclusion Sacroiliitis is a common comorbid condition in CD. With limited clinical clues and disease characteristics to suggest sacroiliitis, physicians may utilize MRE to identify sacroiliitis, especially in CD patients with back pain.

Objective: Patients with psoriasis have impaired vascular health and increased cardiovascular disease (CVD). Platelets are key players in the pathogenesis of vascular dysfunction in cardiovascular disease and represent therapeutic targets in cardiovascular prevention. The object of this study was to define the platelet phenotype and effector cell properties on vascular health in psoriasis and evaluate whether aspirin modulates the platelet-induced phenotype. Approach and Results: Platelets from psoriasis patients (n=45) exhibited increased platelet activation (relative to age- and gender-matched controls, n=18), which correlated with psoriasis skin severity. Isolated platelets from psoriasis patients demonstrated a 2- to 3-fold ( P IL 8 (interleukin 8), IL1β , and Cox (cyclooxygenase)-2 Platelet RNA sequencing revealed an interferon signature and elevated expression of COX-1 , which correlated with psoriasis disease severity ( r =0.83, P =0.01). In a randomized trial of patients with psoriasis, 2 weeks of 81 mg low-dose aspirin, a COX-1 inhibitor, reduced serum thromboxane (Tx) B 2 and reduced brachial vein endothelial proinflammatory transcript expression >70% compared with the no-treatment group ( P 2 ( r =0.48, P =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 and suggests that aspirin may be effective in improving vascular health in patients with psoriasis. Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT03228017.

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 To characterize the ecological effects of biologic therapies on the gut bacterial and fungal microbiome in psoriatic arthritis (PsA)/spondyloarthritis (SpA) patients. Methods Fecal samples from PsA/SpA patients pre- and posttreatment with tumor necrosis factor inhibitors (TNFi; n = 15) or an anti-interleukin-17A monoclonal antibody inhibitor (IL-17i; n = 14) underwent sequencing (16S ribosomal RNA, internal transcribed spacer 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/Th17-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 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.

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. 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.

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 Reactive arthritis (ReA) is an inflammatory disorder occurring several weeks after gastrointestinal or genitourinary infections. HLA-B27 positivity is considered a risk factor, though not necessarily predictive of disease incidence. Among non-genetic factors, the intestinal microbiome may play a role in disease susceptibility. The objective of this study was to characterize the gut microbiota and host gene interactions in ReA and post-infectious spondyloarthritis. Methods Adult peripheral spondyloarthritis and control subjects with preceding infections that did not develop arthritis were prospectively recruited from a highly prevalent geographic region. Clinical variables, HLA status, and 16S rRNA gene sequencing of intestinal microbiota were analyzed. Results ReA subjects showed no significant differences from controls in gut bacterial richness or diversity. However, there was a significantly higher abundance of Erwinia and Pseudomonas, and increased prevalence of typical enteropathogens associated with ReA. Subjects with ultrasound evidence of enthesitis were enriched in Campylobacter, while subjects with uveitis and radiographic sacroiliitis were respectively enriched in Erwinia and unclassified Ruminococcaceae, and both enriched in Dialister. Host genetics, particularly HLA-A24, were associated with differences in gut microbiota diversity irrespective of disease status. We determined several co-occurring taxa that were also predictive of HLA-A24 status. Conclusion This is the first culture-independent study characterizing the gut microbial community of post-infectious arthritis. 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 post-infectious spondyloarthropathies. This article is protected by copyright. All rights reserved.

The objective of the study is to determine the risk factors for the development of reactive arthritis (ReA) and examine the factors associated with the persistence of symptoms. Patients with a new diagnosis of ReA and controls with a gastrointestinal (GI), urogenital, or sexually transmitted infection in the 3-6 months prior to study entry were prospectively enrolled in Guatemala City. ReA patients fulfilled the Assessment in Spondyloarthritis International Society criteria for peripheral spondyloarthropathy (SpA). Patients underwent history, examination, Achilles tendon ultrasound, and blood draw. Human leukocyte antigen (HLA) type and serum biomarkers were measured. t tests and nonparametric equivalents were used to examine the association of clinical, laboratory, and imaging factors with ReA. Patients were contacted 2 years later to assess for persistence of symptoms. Study subjects included patients with ReA (N = 32) and controls (N = 32). ReA patients were most frequently infected in April whereas controls were most frequently infected in August. Two ReA patients and two controls were HLA-B27-positive. Serum cathepsin K and C-reactive protein were higher in ReA patients compared to controls (p = 0.03 for both), while total cholesterol and low-density lipoprotein were lower (p = 0.008 and 0.045, respectively). Among those with ReA, 15 (47%) patients had continued symptoms at 2 years. These patients had a lower matrix metalloproteinase-3 level at diagnosis than patients for whom ReA resolved (p = 0.004). HLA-B27 was not associated with development of ReA in Guatemala; however, the month of infection was associated with ReA. The most striking finding was the persistence of arthritis at 2 years in nearly half of the patients.

ObjectiveTo examine the construct validity of Routine Assessment of Patient Index Data 3 (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, poly articular disease, enthesitis, and dactylitis, and evaluated influences of sociodemographic factors and comorbidities (contextual factors) on these patient-reported outcomes (PRO).MethodsPatients with PsA were enrolled in the Psoriatic Arthritis Research Consortium (PARC) between 2014 and 2016. PARC is a longitudinal observational cohort study conducted at 4 US institutions. In this cross-sectional study, construct validity was assessed by examining Spearman correlation coefficients for RAPID3 and PsAID with physician-reported disease activity measures and other PRO [e.g., Medical Outcomes Study Short Form-12 physical component summary/mental component summary (SF-12 PCS/MCS), Functional Assessment of Chronic Illness Therapy–Fatigue scale (FACIT-F)]. 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.ResultsAmong 401 patients enrolled in PARC, 347 completed RAPID3 or PsAID12. Of these, most were white females with a mean age of 51.7 years (SD 14.02). RAPID3 and PsAID were highly correlated (r = 0.90). These measures were also correlated with the SF-12 PCS (r = −0.67) and FACIT-F (r = −0.77). Important contextual factors and disease subgroups included enthesitis, joint counts, education, insurance type, and depression.ConclusionRAPID3 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.

Summary 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.

Kallikrein-related peptidase 6 (KLK6) is a secreted serine protease hypothesized to promote inflammation via cleavage of protease-activated receptor 1 (PAR1) and PAR2. KLK6 levels are elevated in multiple inflammatory and autoimmune conditions, but no definitive role in pathogenesis has been established. Here, we show that skin-targeted overexpression of KLK6 causes generalized, severe psoriasiform dermatitis with spontaneous development of debilitating psoriatic arthritis-like joint disease. The psoriatic skin and joint phenotypes are reversed by normalization of skin KLK6 levels and attenuated following genetic elimination of PAR1 but not PAR2. Conservation of this regulatory pathway was confirmed in human psoriasis using vorapaxar, an FDA-approved PAR1 antagonist, on explanted lesional skin from patients with psoriasis. Beyond defining a critical role for KLK6/PAR1 signaling in promoting psoriasis, our results demonstrate that KLK6/PAR1-mediated inflammation in the skin alone is sufficient to drive inflammatory joint disease. Further, we identify PAR1 as a promising cytokine-independent target in therapy of psoriasis and psoriatic arthritis.

Summary 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.

Objective:To develop an evidence-based guideline for the pharmacologic and nonpharmacologic treatment of psoriatic arthritis (PsA), as a collaboration between the American College of Rheumatology (ACR) and the National Psoriasis Foundation (NPF).Methods:We identified critical outcomes in PsA and clinically relevant PICO (population/intervention/comparator/outcomes) questions. A Literature Review Team performed a systematic literature review to summarize evidence supporting the benefits and harms of available pharmacologic and nonpharmacologic therapies for PsA. GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology was used to rate the quality of the evidence. A voting panel, including rheumatologists, dermatologists, other health professionals, and patients, achieved consensus on the direction and the strength of the recommendations.Results:The guideline covers the management of active PsA in patients who are treatment-naive and those who continue to have active PsA despite treatment, and addresses the use of oral small molecules, tumor necrosis factor inhibitors, interleukin-12/23 inhibitors (IL-12/23i), IL-17 inhibitors, CTLA4-Ig (abatacept), and a JAK inhibitor (tofacitinib). We also developed recommendations for psoriatic spondylitis, predominant enthesitis, and treatment in the presence of concomitant inflammatory bowel disease, diabetes, or serious infections. We formulated recommendations for a treat-to-target strategy, vaccinations, and nonpharmacologic therapies. Six percent of the recommendations were strong and 94% conditional, indicating the importance of active discussion between the health care provider and the patient to choose the optimal treatment.Conclusion:The 2018 ACR/NPF PsA guideline serves as a tool for health care providers and patients in the selection of appropriate therapy in common clinical scenarios. Best treatment decisions consider each individual patient situation. The guideline is not meant to be proscriptive and should not be used to limit treatment options for patients with PsA.

Immunomodulatory drugs can inhibit bacterial growth, yet their mechanism of action, spectrum, and clinical relevance remain unknown. Methotrexate (MTX), a first-line rheumatoid arthritis (RA) treatment, inhibits mammalian dihydrofolate reductase (DHFR), but whether it directly impacts gut bacteria is unclear. We show that MTX broadly alters the human gut microbiota. Drug sensitivity varied across strains, but the mechanism of action against DHFR appears conserved between mammalian and bacterial cells. RA patient microbiotas were sensitive to MTX, and changes in gut bacterial taxa and gene family abundance were distinct between responders and non-responders. Transplantation of post-treatment samples into germ-free mice given an inflammatory trigger led to reduced immune activation relative to pre-treatment controls, enabling identification of MTX-modulated bacterial taxa associated with intestinal and splenic immune cells. Thus, conservation in cellular pathways across domains of life can result in broad off-target drug effects on the human gut microbiota with consequences for immune function.

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. 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.

Objective To introduce a novel preclinical animal model of psoriatic arthritis (PsA) in R26Stat3Cstopfl/fl CD4Cre mice, and to investigate the role of Th17 cytokines in the disease pathogenesis. Methods We characterized a novel murine model of Th17-driven cutaneous and synovio-entheseal disease directed by T cell-specific expression of a hyperactive Stat3 allele. By crossing R26Stat3Cstopfl/fl CD4Cre mice onto an interleukin-22 (IL-22)-knockout background or treating the mice with a neutralizing antibody against IL-17, we interrogated how these Th17 cytokines could contribute to the pathogenesis of PsA. Results R26Stat3Cstopfl/fl CD4Cre mice developed acanthosis, hyperkeratosis, and parakeratosis of the skin, as well as enthesitis/tendinitis and periarticular bone erosion in different joints, accompanied by osteopenia. T cell-specific expression of a hyperactive Stat3C allele was found to drive the augmented Th17 response in these animals. Careful characterization of the mouse bone marrow revealed an increase in osteoclast progenitor (OCP) and RANKL-producing cells, which contributed to the osteopenia phenotype observed in the mutant animals. Abrogation of the Th17 cytokines IL-17 or IL-22 improved both the skin and bone phenotype in R26Stat3Cstopfl/fl CD4Cre mice, revealing a central role of Th17 cells in the regulation of OCP and RANKL expression on stromal cells. Conclusion Perturbation of the IL-23/Th17 axis instigates Th17-mediated inflammation in R26Stat3Cstopfl/fl CD4Cre mice, leading to cutaneous and synovio-entheseal inflammation and bone pathologic features highly reminiscent of human PsA. Both IL-17A and IL-22 produced by Th17 cells appear to play critical roles in promoting the cutaneous and musculoskeletal inflammation that characterizes PsA.

The role of the gut microbiome in models of inflammatory and autoimmune disease is now well characterized. Renewed interest in the human microbiome and its metabolites, as well as notable advances in host mucosal immunology, has opened multiple avenues of research to potentially modulate inflammatory responses. The complexity and interdependence of these diet-microbe-metabolite-host interactions are rapidly being unraveled. Importantly, most of the progress in the field comes from new knowledge about the functional properties of these microorganisms in physiology and their effect in mucosal immunity and distal inflammation. This review summarizes the preclinical and clinical evidence on how dietary, probiotic, prebiotic, and microbiome based therapeutics affect our understanding of wellness and disease, particularly in autoimmunity.

Programmed death-1 (PD-1) is an inhibitory co-receptor that is highly expressed in T lymphocytes that has been shown to downregulate inflammatory responses in several inflammatory diseases including systemic lupus erythematosus and rheumatoid arthritis. Yet, the role of PD-1 in psoriatic arthritis (PsA) has not been studied. In order to fill this gap, we measured the expression levels of PD-1 in peripheral T cells from patients with active disease. Twenty patients and fifteen age-matched healthy control subjects were recruited. The percentage of CD3(+)PD-1(+) T cells was measured by flow cytometry. Despite normal concentration of peripheral T cells, the expression levels of PD-1 were significantly higher in patients compared to healthy controls. Interestingly, among the patients, the expression levels inversely correlated with disease activity measured by disease activity scores (DAS28). PD-1 expression levels strongly correlated with the number of tender and swollen joints, but not with C-reactive protein (CRP) levels or psoriasis area and severity index (PASI). Functionally, in vitro ligation of PD-1 receptor in PsA T cells inhibited interleukin-2 (IL-2) secretion, Akt phosphorylation, and Rap1 activation. These findings suggest that PD-1 might serve as a biomarker for disease activity in PsA and highlight the need for additional studies in order to establish the role of PD-1 in PsA pathogenesis.