Immune checkpoints in rheumatoid arthritis: progress and promise

Rheumatoid arthritis (RA) is one of the most prevalent autoimmune inflammatory conditions, and while the mechanisms driving pathogenesis are yet to be completely elucidated, self-reactive T cells and immune checkpoint pathways have a clear role. In this review, we provide an overview of the importance of checkpoint pathways in the T cell response and describe the involvement of these in RA development and progression. We discuss the relationship between immune checkpoint therapy in cancer and autoimmune adverse events, draw parallels with the involvement of immune checkpoints in RA pathobiology, summarise emerging research into some of the lesser-known pathways, and the potential of targeting checkpoint-related pathways in future treatment approaches to RA management

Editorial: Synovial tissue biopsy research

No abstract available

Personal non-commercial use only

ABSTRACT. Objective. To investigate the association between adherence to treat-to-target (T2T) protocol and disease activity, functional outcomes, and radiographic outcomes in early rheumatoid arthritis (RA). Methods. Data from a longitudinal cohort of patients with early RA were used. Adherence was determined at each followup visit over 3 years according to predefined criteria. The primary endpoint was remission according to Disease Activity Score in 28 joints (DAS28) and Simplified Disease Activity Index (SDAI) criteria. Functional and radiographic outcomes measured by modified Health Assessment Questionnaire and modified total Sharp score, respectively, were secondary endpoints. Results. A total of 198 patients with 3078 clinic visits over 3 years were included in this analysis. After adjusting for relevant variables, although there was no significant association between adherence to T2T and remission rate after 1 year, the associations reached significance after 3 years for both DAS28 (OR 1.71, 95% CI 1.16-2.50; p = 0.006) and SDAI criteria (OR 1.94, 95% CI 1.06-3.56; p = 0.033). After 3 years, adherence was also associated with improvement in physical function (β = 0.12, 95% CI 0.06-0.18; p < 0.0001). None of the radiographic outcomes were associated with adherence after either 1 or 3 years, although there was a trend for higher adherence to be associated with less radiographic progression at the end of the study (p = 0.061). Conclusion. Increased adherence to T2T was associated with better longterm disease activity and functional outcomes, which suggests that the benefit of a T2T protocol may be enhanced by ensuring adequate adherence. (J Rheumatol First Release July 15 2016; doi:10.3899/jrheum.151392

Personal non-commercial use only

ABSTRACT. Objective. To investigate the association between adherence to treat-to-target (T2T) protocol and disease activity, functional outcomes, and radiographic outcomes in early rheumatoid arthritis (RA). Methods. Data from a longitudinal cohort of patients with early RA were used. Adherence was determined at each followup visit over 3 years according to predefined criteria. The primary endpoint was remission according to Disease Activity Score in 28 joints (DAS28) and Simplified Disease Activity Index (SDAI) criteria. Functional and radiographic outcomes measured by modified Health Assessment Questionnaire and modified total Sharp score, respectively, were secondary endpoints. Results. A total of 198 patients with 3078 clinic visits over 3 years were included in this analysis. After adjusting for relevant variables, although there was no significant association between adherence to T2T and remission rate after 1 year, the associations reached significance after 3 years for both DAS28 (OR 1.71, 95% CI 1.16-2.50; p = 0.006) and SDAI criteria (OR 1.94, 95% CI 1.06-3.56; p = 0.033). After 3 years, adherence was also associated with improvement in physical function (β = 0.12, 95% CI 0.06-0.18; p < 0.0001). None of the radiographic outcomes were associated with adherence after either 1 or 3 years, although there was a trend for higher adherence to be associated with less radiographic progression at the end of the study (p = 0.061). Conclusion. Increased adherence to T2T was associated with better longterm disease activity and functional outcomes, which suggests that the benefit of a T2T protocol may be enhanced by ensuring adequate adherence

Multinational evidence-based recommendations for the diagnosis and management of gout: integrating systematic literature review and expert opinion of a broad panel of rheumatologists in the 3e initiative

We aimed to develop evidence-based multinational recommendations for the diagnosis and management of gout. Using a formal voting process, a panel of 78 international rheumatologists developed 10 key clinical questions pertinent to the diagnosis and management of gout. Each question was investigated with a systematic literature review. Medline, Embase, Cochrane CENTRAL and abstracts from 2010-2011 European League Against Rheumatism and American College of Rheumatology meetings were searched in each review. Relevant studies were independently reviewed by two individuals for data extraction and synthesis and risk of bias assessment. Using this evidence, rheumatologists from 14 countries (Europe, South America and Australasia) developed national recommendations. After rounds of discussion and voting, multinational recommendations were formulated. Each recommendation was graded according to the level of evidence. Agreement and potential impact on clinical practice were assessed. Combining evidence and clinical expertise, 10 recommendations were produced. One recommendation referred to the diagnosis of gout, two referred to cardiovascular and renal comorbidities, six focused on different aspects of the management of gout (including drug treatment and monitoring), and the last recommendation referred to the management of asymptomatic hyperuricaemia. the level of agreement with the recommendations ranged from 8.1 to 9.2 (mean 8.7) on a 1-10 scale, with 10 representing full agreement. Ten recommendations on the diagnosis and management of gout were established. They are evidence-based and supported by a large panel of rheumatologists from 14 countries, enhancing their utility in clinical practice.AbbVieAustralian National Health and Medical Research Council (NHMRC)Hosp Gen Univ Elda, Dept Reumatol, Elda 03600, SpainHosp Gen Univ Alicante, Dept Reumatol, Alicante, SpainUniv Camilo Jose Cela, Fac Ciencias Salud, Madrid, SpainUniv British Columbia, Div Rheumatol, Vancouver, BC V5Z 1M9, CanadaRoyal Melbourne Hosp, Parkville, Vic 3050, AustraliaUniv Hosp Southampton NHS Fdn Trust, Southampton, Hants, EnglandNIHR Wellcome Trust Clin Res Facil, Southampton, Hants, EnglandCtr Hosp Univ Liege, Liege, BelgiumMaastricht Univ, Med Ctr, Dept Internal Med Rheumatol, Maastricht, NetherlandsAtrium Med Ctr, Heerlen, NetherlandsUniv Toronto, Div Rheumatol, Toronto, ON, CanadaRepatriat Gen Hosp, Rheumatol Res Unit, Adelaide, SA, AustraliaFlinders Univ S Australia, Adelaide, SA 5001, AustraliaMed Univ Vienna, Dept Internal Med 3, Div Rheumatol, Vienna, AustriaUniv Toronto, Dept Hlth Policy Management & Evaluat, Toronto, ON, CanadaMt Sinai Hosp, Univ Hlth Network, Toronto Gen Res Inst, Div Clin Decis Making & Hlth Care, Toronto, ON M5G 1X5, CanadaCabrini Hosp, Monash Dept Clin Epidemiol, Malvern, Vic, AustraliaMonash Univ, Dept Epidemiol & Prevent Med, Malvern, Vic, AustraliaUniv Amsterdam, Acad Med Ctr, Dept Clin Immunol & Rheumatol, NL-1105 AZ Amsterdam, NetherlandsUniv Med Ctr Utrecht, Dept Rheumatol & Clin Immunol, Utrecht, NetherlandsUniv Nova Lisboa, Fac Ciencias Med, CEDOC, P-1200 Lisbon, PortugalEPE Hosp Egas Moniz, CHLO, Dept Rheumatol, Lisbon, PortugalHosp Gen Mexico City, Rheumatol Unit, Mexico City, DF, MexicoKarolinska Univ Hosp, Dept Rheumatol, Stockholm, SwedenKarolinska Inst, Stockholm, SwedenGhent Univ Hosp, Dept Rheumatol, Ghent, BelgiumUniversidade Federal de São Paulo, Div Rheumatol, São Paulo, BrazilSt Georges Healthcare NHS Trust, Dept Rheumatol, London, EnglandState Hosp Stockerau, Ctr Rheumatol, Lower Austria, Stockerau, AustriaUniv Pavia, IRCCS Policlin S Matteo, Cattedra Reumatol, I-27100 Pavia, ItalyUniv Giessen, Kerckhoff Klin, Dept Rheumatol & Clin Immunol, Bad Nauheim, GermanyCopenhagen Univ Hosp, Ctr Rheumatol & Spine Dis, Copenhagen Ctr Arthrit Res, Glostrup, DenmarkMenzies Res Inst Tasmania, Hobart, Tas, AustraliaColumbia Univ, Med Ctr, New York, NY USALeiden Univ, Med Ctr, Leiden, NetherlandsUniversidade Federal de São Paulo, Div Rheumatol, São Paulo, BrazilWeb of Scienc

Immune checkpoint inhibitor PD-1 pathway is down-regulated in synovium at various stages of rheumatoid arthritis disease progression.

Immune checkpoint blockade with therapeutic anti-cytotoxic T lymphocyte-associated antigen (CTLA)-4 (Ipilimumab) and anti-programmed death (PD)-1 (Nivolumab and Pembrolizumab) antibodies alone or in combination has shown remarkable efficacy in multiple cancer types, concomitant with immune-related adverse events, including arthralgia and inflammatory arthritis (IA) in some patients. Herein, using Nivolumab (anti-PD-1 antagonist)-responsive genes along with transcriptomics of synovial tissue from multiple stages of rheumatoid arthritis (RA) disease progression, we have interrogated the activity status of PD-1 pathway during RA development. We demonstrate that the expression of PD-1 was increased in early and established RA synovial tissue compared to normal and OA synovium, whereas that of its ligands, programmed death ligand-1 (PD-L1) and PD-L2, was increased at all the stages of RA disease progression, namely arthralgia, IA/undifferentiated arthritis, early RA and established RA. Further, we show that RA patients expressed PD-1 on a majority of synovial tissue infiltrating CD4+ and CD8+ T cells. Moreover, enrichment of Nivolumab gene signature was observed in IA and RA, indicating that the PD-1 pathway was downregulated during RA disease progression. Furthermore, serum soluble (s) PD-1 levels were increased in autoantibody positive early RA patients. Interestingly, most of the early RA synovium tissue sections showed negative PD-L1 staining by immunohistochemistry. Therefore, downregulation in PD-1 inhibitory signaling in RA could be attributed to increased serum sPD-1 and decreased synovial tissue PD-L1 levels. Taken together, these data suggest that agonistic PD1 antibody-based therapeutics may show efficacy in RA treatment and interception

Standardisation of synovial biopsy analyses in rheumatic diseases: a consensus of the EULAR Synovitis and OMERACT Synovial Tissue Biopsy Groups

Following publication of the original article [1], the authors reported an error in the spelling of the ninth author’s name. Incorrect spelling: Soeren Andreas Just. Correct spelling: Søren Andreas Just. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background: The aim of this global collaboration was to develop a consensual set of items for the analysis of synovial biopsies in clinical practice and translational research through the EULAR Synovitis Study Group (ESSG) and OMERACT Synovial Tissue Biopsy Group. Methods: Participants were consulted through a modified Delphi method. Three sequential rounds occurred over 12 months. Members were sent a written questionnaire containing items divided into two parts. Items were identified and formulated based on a scoping review. The first part of the questionnaire referred to synovial biopsies in clinical practice including five subsections, and the second part to translational research with six subsections. Every participant was asked to score each item on a 5-point Likert scale. Items with a median score above 3.5 and a >70% agreement were selected for the next round. The last round was conducted orally at EULAR in June 2017. Results: Twenty-seven participants from 19 centers were contacted by email. Twenty participants from 17 centers answered. Response rates for next rounds were 100%. For the first part relating to clinical practice, 20/44 items (45.5%) were selected. For the second part relating to translational research, 18/43 items (41.9%) were selected for the final set. Conclusions: We herein propose a consensual set of analysis items to be used for synovial biopsies conducted in clinical practice and translational research. Correction: Following publication of the original article [1], the authors reported an error in the spelling of the ninth author's name

Nonsteroidal anti-inflammatory drugs for treatment of acute gout

Are nonsteroidal anti-inflammatory drugs (NSAIDs) associated with better outcomes than cyclooxygenase inhibitors, glucocorticoids, IL-1 inhibitors or placebo in the treatment of acute gout? NSAIDs are not significantly associated with a difference in pain reduction compared with cyclooxygenase inhibitors and glucocorticoids for treating acute gout. However, NSAIDs are associated with higher rates of adverse events and higher rates of withdrawal due to adverse events compared with cyclooxygenase inhibitor