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Objective: The objective for this study was to evaluate the effects of short chain fatty acids (SCFAs) on arthritic bone remodeling. Methods: We treated a recently described preclinical murine model of psoriatic arthritis (PsA), R26STAT3Cstopfl/fl CD4Cre mice, with SCFA‐supplemented water. We also performed in vitro osteoclast differentiation assays in the presence of serum‐level SCFAs to evaluate the direct impact of these microbial metabolites on maturation and function of osteoclasts. We further characterized the molecular mechanism of SCFAs by transcriptional analysis. Results: The osteoporosis condition in R26STAT3Cstopfl/fl CD4Cre animals is attributed primarily to robust osteoclast differentiation driven by an expansion of osteoclast progenitor cells (OCPs), accompanied by impaired osteoblast development. We show that SCFA supplementation can rescue the osteoporosis phenotype in this model of PsA. Our in vitro experiments revealed an inhibitory effect of the SCFAs on osteoclast differentiation, even at very low serum concentrations. This suppression of osteoclast differentiation enabled SCFAs to impede osteoporosis development in R26STAT3Cstopfl/fl CD4Cre mice. Further interrogation revealed that bone marrow–derived OCPs from diseased mice expressed a higher level of SCFA receptors than those of control mice and that the progenitor cells in the bone marrow of SCFA‐treated mice presented a modified transcriptomic landscape, suggesting a direct impact of SCFAs on bone marrow progenitors in the context of osteoporosis. Conclusion: We demonstrated how gut microbiota‐derived SCFAs can regulate distal pathology (ie, osteoporosis) and identified a potential therapeutic option for restoring bone density in rheumatic disease, further highlighting the critical role of the gut–bone axis in these disorders. [ABSTRACT FROM AUTHOR]

Objective. To evaluate whether the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) is a responsive instrument in psoriatic arthritis (PsA) and whether it differentiates between axial and peripheral disease activity in PsA. Methods. Individuals with PsA initiating therapy in a longitudinal cohort study based in the United States were included. Axial PsA (axPsA), most often also associated with peripheral disease, was defined as ful- fillment of the Assessment of Spondyloarthritis international Society axial spondyloarthritis classification criteria or presence of axial disease imaging features. Baseline BASDAI, individual BASDAI items, patient global assessment, patient pain, and Routine Assessment of Patient Index Data 3, and score changes following therapy initiation were descriptively reported. Standardized response means (SRMs) were calculated as the mean change divided by the SD of the change. Results. The mean (SD) baseline BASDAI score at the time of therapy initiation was 5.0 (2.2) among those with axPsA (n = 40) and 4.8 (2.0) among those with peripheral-only disease (n = 79). There was no significant difference in patient-reported outcome scores between the groups. The mean change for BASDAI was similar among axial vs peripheral disease (-0.75 vs -0.83). SRMs were similar across axial vs peripheral disease for BASDAI (-0.37 vs -0.44) and the individual BASDAI items. Conclusion. BASDAI has reasonable responsiveness in PsA but does not differentiate between axPsA and peripheral PsA. (ClinicalTrials.gov: NCT03378336) [ABSTRACT FROM AUTHOR]

Objective: To determine the responsiveness to therapy and minimum clinically important improvement (MCII) for patient‐reported outcome measures in psoriatic arthritis (PsA) and to examine the impact of baseline disease activity on the ability to demonstrate change. Methods: A longitudinal cohort study was performed within the PsA Research Consortium. Patients completed several patient‐reported outcomes, including the Routine Assessment of Patient Index Data, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the Psoriatic Arthritis Impact of Disease 12‐item (PsAID12) questionnaire, and others. The mean change in the scores between visits and standardized response means (SRMs) were calculated. The MCII was calculated as the mean change in score among patients who reported minimal improvement. SRMs and MCIIs were compared among subgroups with moderate to highly active PsA and those with lower disease activity. Results: Among 171 patients, 266 therapy courses were included. The mean ± SD age was 51 ± 13.8 years, 53% were female, and the mean swollen and tender joint counts were 3 and 6, respectively, at baseline. SRMs and MCII for all measures were small to moderate, although greater among those with higher baseline disease activity. BASDAI had the best SRM overall and for less active PsA, and the clinical Disease Activity of PsA (cDAPSA) and PsAID12 were best for those with higher disease activity. Conclusion: SRMs and MCII were relatively small in this real‐world population, particularly among those with lower disease activity at baseline. BASDAI, cDAPSA, and PsAID12 had good sensitivity to change, but selection for use in trials should consider the baseline disease activity of patients to be enrolled. [ABSTRACT FROM AUTHOR]

Objectives Autoantibody seroconversion has been extensively studied in the context of COVID-19 infection but data regarding post-vaccination autoantibody production is lacking. Here we aimed to determine the incidence of common autoantibody formation following mRNA COVID-19 vaccines in patients with inflammatory arthritis (IA) and in healthy controls. Methods Autoantibody seroconversion was measured by serum ELISA in a longitudinal cohort of IA participants and healthy controls before and after COVID-19 mRNA-based immunization. Results Overall, there was a significantly lower incidence of ANA seroconversion in participants who did not contract COVID-19 prior to vaccination compared with those who been previously infected (7.4% vs 24.1%, P  = 0.014). Incidence of de novo anti-CCP seroconversion in all participants was low at 4.9%. Autoantibody levels were typically of low titre, transient, and not associated with increase in IA flares. Conclusions In both health and inflammatory arthritis, the risk of autoantibody seroconversion is lower following mRNA-based immunization than following natural SARS-CoV-2 infection. Importantly, seroconversion does not correlate with self-reported IA disease flare risk, further supporting the encouragement of mRNA-based COVID-19 immunization in the IA population. [ABSTRACT FROM AUTHOR]

Objective: To evaluate secukinumab (SEC) 300 mg and 150 mg vs placebo in a United States-only population of biologic-naïve patients with psoriatic arthritis (PsA).Methods: CHOICE 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.Results: ACR20 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.Conclusion: SEC 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]. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 multicenter 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: To evaluate seroreactivity and disease flares after COVID‐19 vaccination in a multiethnic/multiracial cohort of patients with systemic lupus erythematosus (SLE). Methods: 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. Results: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Objective: To examine the association of biologic therapy use for psoriasis with incident psoriatic arthritis (PsA) diagnosis.Methods: A 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.Results: Among 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).Conclusions: In 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. [ABSTRACT FROM AUTHOR]

The article discusses developments in the treatment of psoriatic arthritis (PsA), particularly the adoption of combination immunomodulatory therapies. Also cited are the use of tumor necrosis factor inhibitors (TNFi) to identify the signs and symptoms of PsA, rheumatoid arthritis (RA), and psoriasis, and some TNFis like etanercept, adalimumab, and infliximab.

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. [ABSTRACT FROM AUTHOR]

At the 2020 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA)-Collaborative Research Network (CRN) annual meeting, the GRAPPA-CRN group presented a pilot investigator-initiated study protocol to test electronic case report forms (eCRFs) and proposed Standardized Operating Procedures (SOPs) to evaluate biomarkers of psoriatic arthritis (PsA) associated with axial disease. The progress on 3 studies was also presented: BioDAM PsA (Biomarkers as Predictors of structural DAMage in PsA; to validate soluble biomarkers as predictors of structural damage in PsA), PreventPsA (examining the development of PsA and risk factors among patients with psoriasis and no arthritis), and PredictORPsA (Predicting Treatment respOnse in patients with eaRly PsA; in collaboration with Pfizer using samples from the Oral Psoriatic Arthritis TriaL [OPAL], to identify biomarkers of treatment response). GRAPPA-CRN funding partnerships and applications are also underway with both the Innovative Medicines Initiative (IMI) in Europe and Accelerating Medicines Partnerships (AMP) 2.0 in the USA, and the progress of these applications and associated objectives were presented. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The authors discuss a study by C. S. E. Lim which reported a single-center study assessing the utility of computed tomography (CT) scans in identifying sacroiliitis in patients with established inflammatory bowel disease (IBD). Topics include attempts made to improve the assessment of spondyloarthritis (SpA) in IBD populations, the need to develop a broader and more systematic approach to expand screening strategies for SpA in patients with IBD, and the challenge in the diagnosis of SpA.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: To 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).Methods: Patients 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.Results: Among 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.Conclusion: RAPID3 and PsAID12 have excellent construct validity in PsA and are strongly correlated despite differing items. Contextual factors (i.e., the presence of depression and obesity) should be considered when interpreting raw scores of the RAPID3 and PsAID12. [ABSTRACT FROM AUTHOR]

From birth, humans coexist and coevolve with trillions of micro-organisms inhabiting most body surfaces and cavities, referred to as the human microbiome. Advances in sequencing technologies and computational methods have propelled the exploration of the microbiome's contribution to human health and disease, spearheaded by massive efforts such as the Human Microbiome Project and the Europe-based MetaHit Consortium. Yet, despite the accumulated body of literature and a growing awareness among patients, microbiome research in rheumatology has not had a key impact on clinical practice. Herein, we describe some of the landmark microbiome studies in autoimmunity and rheumatology, the challenges and opportunities of microbiome research and how to navigate them, advances in related fields that have overcome these pitfalls, and future directions of harnessing the microbiome for diagnostic and therapeutic purposes. [ABSTRACT FROM AUTHOR]

Objective: In 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).Methods: Over 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.Results: Carriage 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)).Conclusion: Carriage 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. [ABSTRACT FROM AUTHOR]

Purpose of Review: 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. Recent Findings: 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. Summary: 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. [ABSTRACT FROM AUTHOR]

Objective: Intestinal microbiota are associated with the development of inflammatory arthritis. The aim of this study was to dissect intestinal mucosal immune responses in the preclinical phase of arthritis and determine whether the presence of Th17 cells, beyond involvement of the cytokine interleukin‐17 (IL‐17), is required for arthritis development, and whether the involvement of Th17 cells in arthritis depends on the composition of the host microbiota. Methods: Mucosal T cell production of IL‐17, interferon‐γ, tumor necrosis factor α (TNFα), IL‐22, and granulocyte–macrophage colony‐stimulating factor (GM‐CSF) was analyzed by flow cytometry and Luminex assay before arthritis onset in mice immunized to develop collagen‐induced arthritis (CIA). Pathogenic features of arthritis in mice with CIA and mice with antigen‐induced arthritis were compared between Th17 cell–deficient (CD4‐Cre+Rorcflox/flox) and Th17 cell–sufficient (CD4‐Cre−Rorcflox/flox) mice. In addition, the impact of intestinal microbiota on the Th17 cell dependence of CIA was assessed. Results: Lamina propria CD4 T cells were activated before the onset of arthritis in mice with CIA, with marked up‐regulation of several cytokines, including IL‐17A, TNFα, and GM‐CSF. CD4‐Cre+Rorcflox/flox mice showed a specific reduction in intestinal mucosal levels of Th17 cells and partially reduced levels of IL‐17–producing CD8 T cells. However, total levels of IL‐17A, mostly produced by γδ T cells and neutrophils, were unaffected. The severity of arthritis was significantly reduced in Th17 cell–deficient mice, suggesting that Th17 cells have additional, IL‐17A–independent roles in inflammatory arthritis. Accordingly, antigen‐stimulated T cells from Th17 cell–deficient mice produced less IL‐17A, IL‐17F, and GM‐CSF. Importantly, the dependence of CIA on the involvement of Th17 cells was mitigated in the presence of an alternative microbiome. Conclusion: These data from murine models suggest that activation of mucosal immunity precedes the development of arthritis, and also that Th17 cells have a microbiota‐dependent role in arthritis. Therefore, a microbiome‐guided stratification of patients might improve the efficacy of Th17‐targeted therapies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: Reactive arthritis (ReA) is an inflammatory disorder occurring several weeks after gastrointestinal or genitourinary tract infections. HLA–B27 positivity is considered a risk factor, although it is not necessarily predictive of disease incidence. Among nongenetic 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 postinfectious spondyloarthritis. Methods: Adult subjects with peripheral spondyloarthritis and control subjects with preceding infections who did not develop arthritis were prospectively recruited from a geographic region with a high prevalence of ReA. Clinical variables, HLA status, and 16S ribosomal RNA gene sequencing of intestinal microbiota were analyzed. Results: Subjects with ReA showed no significant differences from controls in gut bacterial richness or diversity. However, there was a significantly higher abundance of Erwinia and Pseudomonas and an 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 enriched in Erwinia and unclassified Ruminococcaceae, respectively; both were enriched in Dialister. Host genetics, particularly HLA–A24, were associated with differences in gut microbiota diversity irrespective of disease status. We identified several co‐occurring taxa that were also predictive of HLA–A24 status. Conclusion: This is the first culture‐independent study characterizing the gut microbial community in postinfectious 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 postinfectious spondyloarthritides. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Oral vancomycin remains the mainstay of therapy for severe infections produced by Clostridium difficile, the most prevalent cause of healthcare-associated infectious diarrhoea in developed countries. However, its short- and long-term effects on the human intestinal microbiota remain largely unknown.Methods: We utilized high-throughput sequencing to analyse the effects of vancomycin on the faecal human microbiota up to 22 weeks post-antibiotic cessation. The clinical relevance of the observed microbiota perturbations was studied in mice.Results: During vancomycin therapy, most intestinal microbiota genera and operational taxonomic units (OTUs) were depleted in all analysed subjects, including all baseline OTUs from the phylum Bacteroidetes. This was accompanied by a vast expansion of genera associated with infections, including Klebsiella and Escherichia/Shigella. Following antibiotic cessation, marked differences in microbiota resilience were observed among subjects. While some individuals recovered a microbiota close to baseline composition, in others, up to 89% of abundant OTUs could no longer be detected. The clinical relevance of the observed microbiota changes was further demonstrated in mice, which developed analogous microbiota alterations. During vancomycin treatment, mice were highly susceptible to intestinal colonization by an antibiotic-resistant pathogen and, upon antibiotic cessation, a less-resilient microbiota allowed higher levels of pathogen colonization.Conclusions: Oral vancomycin induces drastic and consistent changes in the human intestinal microbiota. Upon vancomycin cessation, the microbiota recovery rate varied considerably among subjects, which could influence, as validated in mice, the level of susceptibility to pathogen intestinal colonization. Our results demonstrate the negative long-term effects of vancomycin, which should be considered as a fundamental aspect of the cost-benefit equation for antibiotic prescription. [ABSTRACT FROM AUTHOR]

RA is a complex multifactorial chronic disease that transitions through several stages. Multiple studies now support that there is a prolonged phase in early RA development during which there is serum elevation of RA-related autoantibodies including RF and ACPAs in the absence of clinically evident synovitis. This suggests that RA pathogenesis might originate in an extra-articular location, which we hypothesize is a mucosal site. In discussing this hypothesis, we will present herein the current understanding of mucosal immunology, including a discussion about the generation of autoimmune responses at these surfaces. We will also examine how other factors such as genes, microbes and other environmental toxins (including tobacco smoke) could influence the triggering of autoimmunity at mucosal sites and eventually systemic organ disease. We will also propose a research agenda to improve our understanding of the role of mucosal inflammation in the development of RA. [ABSTRACT FROM AUTHOR]

The article reviews various studies regarding intestinal microbiome and its role in prosiatic arthritis (PsA), rheumatoid arthritis (RA) and spondyloarthritides (SpA). Topics covered include the composition and function of microbiome, its prokaryotic nature, the hypothesis on toxemic factor and jejunoileal bypass surgery triggering arthritis syndrome. Conclusions indicated the need to explore microbiome aspects as to the dysbiotic process, microbial perturbation and immunosuppressive drugs.

In the article, the authors present a case of a 27-year-old woman with a history of psoriasis and psoriatic arthritis (PsA) who was presented to a centre due to active skin, joint and enthesial disease to discuss the induction of remission in biologic-naive, severe psoriasis and PsA with dual anti-cytokine combination. She also has bilateral sacroiliitis and was treated with adalimumab.

A response from the authors of the article "Decreased bacterial diversity characterizes the altered gut microbiota in patients with psoriatic arthritis, resembling dysbiosis in inflammatory bowel disease," published in the 2015 issue is presented.

The human microbiome, which represents the total collection of microorganisms (and their genes) inhabiting the human body, has increasingly been recognized as a potential key factor in the development of autoimmune disease. Multiple studies suggest that the microbiome has significant influence on immune homeostasis, while disruptions in local microbiome composition can result in a heightened systemic inflammatory response. The intestinal microbiome, in particular, harbors the densest assembly of bacteria and appears to influence the immune system in the context of inflammatory arthropathies. Although studies are still sparse, this review will examine the role of the microbiome in the pathogenesis of spondyloarthritis (SpA), particularly in enteropathic arthritis (EA), reactive arthritis (ReA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]