Publisher Correction: A genome-wide association analysis reveals new pathogenic pathways in gout.Nature genetics • November 05, 2024
Tanya Major, Riku Takei, Hirotaka Matsuo, Megan Leask, Nicholas Sumpter, Ruth Topless, Yuya Shirai, Wei Wang, Murray Cadzow, Amanda Phipps Green, Zhiqiang Li, Aichang Ji, Marilyn Merriman, Emily Morice, Eric Kelley, Wen-hua Wei, Sally P Mccormick, Matthew Bixley, Richard Reynolds, Kenneth Saag, Tayaza Fadason, Evgenia Golovina, Justin O'sullivan, Lisa Stamp, Nicola Dalbeth, Abhishek Abhishek, Michael Doherty, Edward Roddy, Lennart T Jacobsson, Meliha Kapetanovic, Olle Melander, Mariano Andrés, Fernando Pérez Ruiz, Rosa Torres, Timothy Radstake, Timothy Jansen, Matthijs Janssen, Leo A Joosten, Ruiqi Liu, Orsolya Gaal, Tania Crişan, Simona Rednic, Fina Kurreeman, Tom W Huizinga, René Toes, Frédéric Lioté, Pascal Richette, Thomas Bardin, Hang Ea, Tristan Pascart, Geraldine Mccarthy, Laura Helbert, Blanka Stibůrková, Anne-k Tausche, Till Uhlig, Véronique Vitart, Thibaud Boutin, Caroline Hayward, Philip Riches, Stuart Ralston, Archie Campbell, Thomas Macdonald, Tappei Takada, Masahiro Nakatochi, Seiko Shimizu, Yusuke Kawamura, Yu Toyoda, Hirofumi Nakaoka, Ken Yamamoto, Keitaro Matsuo, Nariyoshi Shinomiya, Kimiyoshi Ichida, Chaeyoung Lee, Matthew Brown, Russell R Buchanan, Catherine Hill, Susan Lester, Malcolm Smith, Maureen Rischmueller, Hyon Choi, Eli Stahl, Jeff Miner, Daniel Solomon, Jing Cui, Kathleen Giacomini, Deanna Brackman, Eric Jorgenson, Hongbo Liu, Katalin Susztak, Suyash Shringarpure, Yukinori Okada, Changgui Li, Tony Merriman
Gout is a chronic disease that is caused by an innate immune response to deposited monosodium urate crystals in the setting of hyperuricemia. Here, we provide insights into the molecular mechanism of the poorly understood inflammatory component of gout from a genome-wide association study (GWAS) of 2.6 million people, including 120,295 people with prevalent gout. We detected 377 loci and 410 genetically independent signals (149 previously unreported loci in urate and gout). An additional 65 loci with signals in urate (from a GWAS of 630,117 individuals) but not gout were identified. A prioritization scheme identified candidate genes in the inflammatory process of gout, including genes involved in epigenetic remodeling, cell osmolarity and regulation of NOD-like receptor protein 3 (NLRP3) inflammasome activity. Mendelian randomization analysis provided evidence for a causal role of clonal hematopoiesis of indeterminate potential in gout. Our study identifies candidate genes and molecular processes in the inflammatory pathogenesis of gout suitable for follow-up studies.
Novel therapies in Sjögren's disease: A systematic review of the literature.Best Practice & Research. Clinical Rheumatology • May 30, 2025
Cristina Pelkas, Kyle Franke, Fabien Vincent, Maureen Rischmueller
Sjögren's disease (SjD) is a chronic systemic autoimmune disorder that primarily involves lymphocytic infiltration of exocrine glands, with frequent extra-glandular manifestations. Historically, treatment options for SjD have been limited to alleviating symptoms, rather than treating the underlying cause or preventing disease progression. Furthermore, past clinical trials of therapies such as rituximab failed to demonstrate improvement in symptoms or disease activity. Recently, novel therapeutic strategies targeting underlying disease pathogenesis - including transcription factors, circulating RNA, and B and T cell activity - herald a paradigm shift. Given the complexities of diagnosis, clinical assessment and treatment in SjD, improved clinical trial design with enhanced patient stratification, greater inclusivity and better outcome measures are paramount in evaluating new therapeutics. This systematic review aims to provide a comprehensive overview of recent SjD therapeutic advances, assess trial inclusivity with respect to sex/gender and ethnicity, critically examine negative pivotal trials and highlight promising directions for future research.
2023 International Rome consensus for the nomenclature of Sjögren disease.Nature Reviews. Rheumatology • May 08, 2025
Manuel Ramos Casals, Alan Baer, María Del Brito Zerón, Katherine Hammitt, Coralie Bouillot, Soledad Retamozo, Alison Mackey, David Yarowsky, Breck Turner, Jaime Blanck, Benjamin Fisher, Esen Akpek, Chiara Baldini, Hendrika Bootsma, Simon Bowman, Thomas Dörner, Leslie Laing, Scott Lieberman, Xavier Mariette, Stephen Pflugfelder, Vidya Sankar, Antoni Sisó Almirall, Athanasios Tzioufas, Juan-manuel Anaya, Berkan Armağan, Michele Bombardieri, Steven Carsons, Salvatore De Vita, Robert Fox, Roberto Gerli, Roberto Giacomelli, Jacques Gottenberg, Gabriela Hernández Molina, Roland Jonsson, Aike Kruize, Seung-ki Kwok, Xiaomei Li, Sara Mccoy, Wan-fai Ng, Peter Olsson, Maureen Rischmueller, Alain Saraux, R Scofield, Valéria Valim, Claudio Vitali, Frederick Vivino, Marie Wahren Herlenius, Haralampos Moutsopoulos
Nomenclature for the disease widely known as Sjögren syndrome has proven unsatisfactory. Patients have perceived 'syndrome' as indicative of a vague collection of symptoms, prompting the Sjögren's Foundation to abandon the term. Furthermore, the traditional distinction between 'primary' and 'secondary' forms fails to account for the complex interplay between overlapping autoimmune diseases. Following a bibliometric analysis, systematic literature review and a Delphi consensus process with equal involvement of professional and patient representatives, five recommendations are now issued. First, the term 'Sjögren disease' should replace 'Sjögren syndrome'. Second, the acronym 'SjD' should be used as an abbreviation for 'Sjögren disease'. Third, the descriptor 'associated' should be used in lieu of 'secondary' for Sjögren disease occurring in association with a second systemic autoimmune disease for which classification criteria are fulfilled. Fourth, Sjögren disease is the preferred terminology in common parlance and in clinical diagnosis, without differentiation as to primary and associated forms. Fifth, the differentiation between primary and associated Sjögren is recommended for scientific studies to define a homogeneous population. In conclusion, the consensus endorses 'Sjögren disease' as the official nomenclature to acknowledge the distinct pathogenesis of this disorder and to improve clarity in both clinical practice and research.
Variants in the DDX6-CXCR5 autoimmune disease risk locus influence the regulatory network in immune cells and salivary gland.Annals Of The Rheumatic Diseases • March 04, 2025
Mandi Wiley, Marcin Radziszewski, Bhuwan Khatri, Michelle Joachims, Kandice Tessneer, Anna Stolarczyk, Songyuan Yao, James Li, Cherilyn Pritchett Frazee, Audrey Johnston, Astrid Rasmussen, Juan-manuel Anaya, Lara Aqrawi, Sang-cheol Bae, Eva Baecklund, Albin Björk, Johan Brun, Sara Bucher, Nick Dand, Maija-leena Eloranta, Fiona Engelke, Helena Forsblad D'elia, Cecilia Fugmann, Stuart Glenn, Chen Gong, Jacques-eric Gottenberg, Daniel Hammenfors, Juliana Imgenberg Kreuz, Janicke Jensen, Svein Joar Johnsen, Malin Jonsson, Jennifer Kelly, Sharmily Khanam, Kwangwoo Kim, Marika Kvarnström, Thomas Mandl, Javier Martín, David Morris, Gaetane Nocturne, Katrine Norheim, Peter Olsson, Øyvind Palm, Jacques-olivier Pers, Nelson Rhodus, Christopher Sjöwall, Kathrine Skarstein, Kimberly Taylor, Phil Tombleson, Gudny Thorlacius, Swamy Venuturupalli, Edward Vital, Daniel Wallace, Lida Radfar, Michael Brennan, Judith James, R Scofield, Patrick Gaffney, Lindsey Criswell, Roland Jonsson, Silke Appel, Per Eriksson, Simon Bowman, Roald Omdal, Lars Rönnblom, Blake Warner, Maureen Rischmueller, Torsten Witte, A Farris, Xavier Mariette, Caroline Shiboski, Marta Alarcón Riquelme, Wan-fai Ng, Joel Guthridge, Timothy Vyse, Betty Tsao, Gunnel Nordmark, Christopher Lessard
Objective: Sjögren's disease (SjD) and systemic lupus erythematosus (SLE) share genetic risk at the DDX6-CXCR5 locus (11q23.3). Identifying and functionally characterising shared SNPs spanning this locus can provide new insights into common genetic mechanisms of autoimmunity.
Methods: Transdisease meta-analyses, fine-mapping, and bioinformatic analyses prioritised shared likely functional single nucleotide polymorphisms (SNPs) for allele-specific and cell type-specific functional interrogation using electromobility shift, luciferase reporter, and quantitative chromatin conformation capture assays and clustered regularly interspaced short palindromic repeat (CRISPR) gene regulation.
Results: Five shared SNPs were identified as likely functional in primary human immune cells, salivary gland and kidney tissues: rs57494551, rs4936443, rs4938572, rs7117261, and rs4938573. All 5 SNPs exhibited cell type-specific and allele-specific effects on nuclear protein binding affinity and enhancer/promoter regulatory activity in immune, salivary gland epithelial, and kidney epithelial cell models. Mapping of chromatin-chromatin interactions revealed a chromatin regulatory network that expanded beyond DDX6 and CXCR5 to include PHLDB1, lnc-PHLDB1-1, BCL9L, TRAPPC4, among others. Coalescence of functional assays and multiomic data analyses indicated that these SNPs likely modulate the activity of 3 regulatory regions: intronic rs57494551 regulatory region, intergenic SNP haplotype (rs4938572, rs4936443, and rs7117261) regulatory region, and rs4938573 regulatory region upstream of the CXCR5 promoter.
Conclusions: Shared genetic susceptibly at the DDX6-CXCR5 locus in SjD and SLE likely alters common mechanisms of autoimmunity, including interferon signalling (DDX6), autophagy (TRAPPC4), and lymphocytic infiltration of disease-target tissues (CXCR5). Further, using multiomic data from patients with SjD, combined with bioinformatic and in vitro functional studies, can provide mechanistic insights into how genetic risk influences the biological pathways that drive complex autoimmunity.
Safety and Efficacy of Upadacitinib in Patients with Rheumatoid Arthritis Refractory to Biologic DMARDs: Results Through Week 216 from the SELECT-CHOICE Study.Rheumatology And Therapy • February 21, 2024
Andrea Rubbert Roth, Koji Kato, Boulos Haraoui, Maureen Rischmueller, Yanxi Liu, Nasser Khan, Heidi Camp, Ricardo Xavier
Background: The safety and efficacy of upadacitinib 15 mg (UPA15) through week 216 was evaluated in patients with rheumatoid arthritis (RA) from the long-term extension (LTE) of the phase 3 SELECT-CHOICE study.
Methods: Patients with RA refractory to biologic disease-modifying antirheumatic drugs (bDMARDs) were randomized to UPA15 or abatacept (ABA) for 24 weeks. During the open-label LTE, patients on ABA switched to UPA15 at week 24, and those on UPA15 continued treatment. The safety and efficacy of continuous UPA15, and ABA to UPA15, are summarized through week 216.
Results: The LTE was comprised of 91.4% (n = 277/303) of patients that initially received UPA15, and 89.6% (n = 277/309) that initially received ABA. Of patients on UPA15 in the LTE (n = 547), 28.3% (n = 155/547) discontinued the study drug by week 216. Relative to other adverse events of special interest, and largely consistent with previous findings at week 24, higher rates of serious infection, COVID-19, herpes zoster, and elevated creatine phosphokinase were reported, while rates of malignancy excluding nonmelanoma skin cancer (NMSC), NMSC, major adverse cardiovascular event (MACE), and venous thromboembolism (VTE) were low. Long-term safety data with UPA through week 216 aligned with previous observations and no new safety risks were identified, including in patients who switched from ABA to UPA15. Proportions of patients achieving 28-joint disease activity score based on C-reactive protein (DAS28[CRP]) < 2.6/ ≤ 3.2, clinical disease activity index (CDAI) and simple disease activity index (SDAI) low disease activity/remission, ≥ 20%/50%/70% improvement in the American College of Rheumatology (ACR20/50/70) response criteria, and Boolean remission were maintained or improved with UPA15 through week 216. Improvements in the Health Assessment Questionnaire-Disability Index (HAQ-DI), patient's assessment of pain, and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) were also maintained or improved with UPA15 through week 216. Across all efficacy endpoints, similar results were observed in patients who switched from ABA to UPA15 versus continuous UPA15. Patients with an inadequate response to ≥ 1 prior tumor necrosis factor (TNF) inhibitor (UPA15: n = 263/303, 86.8%; ABA to UPA15: n = 273/309, 88.3%) showed similar responses to the total population.
Conclusions: The long-term safety profile of UPA was consistent with previous findings and the broader RA clinical program. Compared to the primary analyses at week 24, efficacy responses were maintained or further improved with UPA15 through week 216 in patients with RA. Trial registration, ClinicalTrials.gov identifier: NCT03086343.
