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The Pre-treatment Gut Microbiome is Associated with Lack of Response to Methotrexate in New Onset Rheumatoid Arthritis

Artacho, Alejandro; Isaac, Sandrine; Nayak, Renuka; Flor-Duro, Alejandra; Alexander, Margaret; Koo, Imhoi; Manasson, Julia; Smith, Philip B; Rosenthal, Pamela; Homsi, Yamen; Gulko, Percio; Pons, Javier; Puchades-Carrasco, Leonor; Izmirly, Peter; Patterson, Andrew; Abramson, Steven B; Pineda-Lucena, Antonio; Turnbaugh, Peter J; Ubeda, Carles; Scher, Jose U
OBJECTIVES/OBJECTIVE:Although oral methotrexate (MTX) remains the anchor drug for RA, up to 50% of patients do not achieve a clinically adequate outcome. Concomitantly, there is a lack of prognostic tools for treatment response prior to drug initiation. Here we study whether inter-individual differences in the human gut microbiome can aid in the prediction of MTX efficacy in new-onset RA (NORA). METHODS:16S rRNA gene and shotgun metagenomic sequencing were performed on the baseline gut microbiomes of drug-naïve, NORA patients (n=26). Results were validated in an additional independent cohort (n=21). To gain insight into potential microbial mechanisms, ex vivo experiments coupled with metabolomics analysis evaluated the association between microbiome-driven MTX depletion and clinical response. RESULTS:Our analysis revealed significant associations between the abundance of gut bacterial taxa and their genes with future clinical response, including orthologs related to purine and methotrexate metabolism. Machine learning techniques were applied to the metagenomic data, resulting in a microbiome-based model that predicts lack of response to MTX in an independent group of patients. Finally, MTX levels remaining after ex vivo incubation with distal gut samples from pre-treatment 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. CONCLUSIONS:Together, these results provide the first step towards predicting lack of response to oral MTX in NORA patients and support the value of the gut microbiome as a possible prognostic tool and as a potential target in RA therapeutics.
PMID: 33314800
ISSN: 2326-5205
CID: 4717542

Prevalence, Predictors, and Disease Activity of Sacroiliitis Among Patients with Crohn's Disease

Levine, Irving; Malik, Fardina; Castillo, Gabriel; Jaros, Brian; Alaia, Erin; Ream, Justin; Scher, Jose U; Hudesman, David; Axelrad, Jordan
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/CONCLUSIONS: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.
PMID: 32793977
ISSN: 1536-4844
CID: 4557222

A comparison of physical function instruments in psoriatic arthritis: HAQ-DI vs MDHAQ vs PROMIS10 global physical health

Wan, Marilyn T; Walsh, Jessica A; Craig, Ethan T; Husni, M Elaine; Scher, Jose U; Reddy, Soumya M; Leung, Ying-Ying; Ogdie, Alexis
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.
PMID: 33313838
ISSN: 1462-0332
CID: 4905652

Methotrexate Hampers Immunogenicity to BNT162b2 mRNA COVID-19 Vaccine in Immune-Mediated Inflammatory Disease

Haberman, Rebecca H; Herati, Ramin Sedaghat; Simon, David; Samanovic, Marie; Blank, Rebecca B; Tuen, Michael; Koralov, Sergei B; Atreya, Raja; Tascilar, Koray; Allen, Joseph R; Castillo, Rochelle; Cornelius, Amber R; Rackoff, Paula; Solomon, Gary; Adhikari, Samrachana; Azar, Natalie; Rosenthal, Pamela; Izmirly, Peter; Samuels, Jonathan; Golden, Brian; Reddy, Soumya; Neurath, Markus; Abramson, Steven B; Schett, Georg; Mulligan, Mark J; Scher, Jose U
Objective/UNASSIGNED:To investigate the humoral and cellular immune response to mRNA COVID-19 vaccines in patients with immune-mediated inflammatory diseases (IMIDs) on immunomodulatory treatment. Methods/UNASSIGNED:Established patients at NYU Langone Health with IMID (n=51) receiving the BNT162b2 mRNA vaccination were assessed at baseline and after second immunization. Healthy subjects served as controls (n=26). IgG antibody responses to the spike protein were analyzed for humoral response. Cellular immune response to SARS-CoV-2 was further analyzed using high-parameter spectral flow cytometry. A second independent, validation cohort of controls (n=182) and patients with IMID (n=31) from Erlangen, Germany were also analyzed for humoral immune response. Results/UNASSIGNED:Although healthy subjects (n=208) and IMID patients on biologic treatments (mostly on TNF blockers, n=37) demonstrate robust antibody responses (over 90%), those patients with IMID on background methotrexate (n=45) achieve an adequate response in only 62.2% of cases. Similarly, IMID patients do not demonstrate an increase in CD8+ T cell activation after vaccination. Conclusions/UNASSIGNED:In two independent cohorts of IMID patients, methotrexate, a widely used immunomodulator for the treatment of several IMIDs, adversely affected humoral and cellular immune response to COVID-19 mRNA vaccines. Although precise cut offs for immunogenicity that correlate with vaccine efficacy are yet to be established, our findings suggest that different strategies may need to be explored in patients with IMID taking methotrexate to increase the chances of immunization efficacy against SARS-CoV-2 as has been demonstrated for augmenting immunogenicity to other viral vaccines. KEY MESSAGES/UNASSIGNED:These results suggest that patients on methotrexate may need alternate vaccination strategies such as additional doses of vaccine, dose modification of methotrexate, or even a temporary discontinuation of this drug. Further studies will be required to explore the effect of these approaches on mRNA vaccine immunogenicity.
PMCID:8132259
PMID: 34013285
ISSN: n/a
CID: 4877422

National Psoriasis Foundation COVID-19 Task Force guidance for management of psoriatic disease during the pandemic: Version 2-Advances in psoriatic disease management, COVID-19 vaccines, and COVID-19 treatments

Gelfand, Joel M; Armstrong, April W; Bell, Stacie; Anesi, George L; Blauvelt, Andrew; Calabrese, Cassandra; Dommasch, Erica D; Feldman, Steven R; Gladman, Dafna; Kircik, Leon; Lebwohl, Mark; Lo Re, Vincent; Martin, George; Merola, Joseph F; Scher, Jose U; Schwartzman, Sergio; Treat, James R; Van Voorhees, Abby S; Ellebrecht, Christoph T; Fenner, Justine; Ocon, Anthony; Syed, Maha N; Weinstein, Erica J; Gondo, George; Heydon, Sue; Koons, Samantha; Ritchlin, Christopher T
OBJECTIVE:To update guidance regarding the management of psoriatic disease during the COVID-19 pandemic. STUDY DESIGN/METHODS: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 nonvoting members, which included fellows and National Psoriasis Foundation staff. Clinical questions relevant to the psoriatic disease community were informed by inquiries received by the National Psoriasis Foundation. 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 and 14 with moderate consensus. LIMITATIONS/CONCLUSIONS:The evidence behind many guidance statements is variable in quality and/or quantity. CONCLUSIONS:These statements provide guidance for the treatment of patients with psoriatic disease on topics including how the disease and its treatments affect COVID-19 risk, how medical care can be optimized during the pandemic, what patients should do to lower their risk of getting infected with severe acute respiratory syndrome coronavirus 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.
PMCID:7788316
PMID: 33422626
ISSN: 1097-6787
CID: 4838062

CCL20 in Psoriasis: A Potential Biomarker of Disease Severity, Inflammation, and Impaired Vascular Health

Elnabawi, Youssef A; Garshick, Michael S; Tawil, Michael; Barrett, Tessa J; Fisher, Edward A; Lo Sicco, Kristen; Neimann, Andrea L; Scher, Jose U; Krueger, James; Berger, Jeffrey S
BACKGROUND:Psoriasis is associated with increased cardiovascular risk that is not captured by traditional pro-inflammatory biomarkers. OBJECTIVE:To investigate the relationship between psoriasis area and severity index (PASI), circulating pro-inflammatory biomarkers, and vascular health in psoriasis. METHODS:In psoriasis and age, sex-matched controls, 273 proteins were analyzed utilizing the OLINK platform, while vascular endothelial inflammation and health was measured via direct transcriptomic analysis of brachial vein endothelial cells. RESULTS:= 48.18, p<0.001) in predicting vascular endothelial inflammation. LIMITATIONS/CONCLUSIONS:Our study was observational and does not allow for causal inference in the relationship between CCL20 and cardiovascular risk. CONCLUSION/CONCLUSIONS:We demonstrate that CCL20 expression has a strong association with vascular endothelial inflammation, reflects systemic inflammation, and may serve as a potential biomarker of impaired vascular health in psoriasis.
PMID: 33259876
ISSN: 1097-6787
CID: 4694102

Microbial-derived antigens and metabolites in spondyloarthritis

Yang, Katharine Lu; Lejeune, Alannah; Chang, Gregory; Scher, Jose U; Koralov, Sergei B
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.
PMID: 33569635
ISSN: 1863-2300
CID: 4779892

Consensus terminology for preclinical phases of psoriatic arthritis for use in research studies: results from a Delphi consensus study

Perez-Chada, Lourdes M; Haberman, Rebecca H; Chandran, Vinod; Rosen, Cheryl F; Ritchlin, Christopher; Eder, Lihi; Mease, Philip; Reddy, Soumya; Ogdie, Alexis; Merola, Joseph F; Scher, Jose U
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.
PMID: 33589818
ISSN: 1759-4804
CID: 4788332

Psoriasis and Psoriatic Arthritis in the Context of the COVID-19 Pandemic: A Plenary Session From the GRAPPA 2020 Annual Meeting

Mease, Philip J; Calabrese, Leonard H; Callis Duffin, Kristina; Haberman, Rebecca H; Firmino, Rodrigo; Scher, Jose U; Schick, Lori; Winthrop, Kevin; Merola, Joseph F
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.
PMID: 33722951
ISSN: 0315-162x
CID: 4950152

Proceedings of the 2020 GRAPPA Collaborative Research Network (CRN) Meeting

Stober, Carmel; Jadon, Deepak R; Armstrong, April W; Chandran, Vinod; de Wit, Maarten; Helliwell, Philip S; Mease, Philip; Ogdie, Alexis; O'Sullivan, Denis; Pennington, Stephen R; Löve, Thorvardur; Cauli, Alberto; van Mens, Leonieke; Waxman, Robin; Scher, Jose U; Barton, Anne; Ritchlin, Christopher T; FitzGerald, Oliver
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.
PMID: 33589562
ISSN: 0315-162x
CID: 4947552