Resumen
BackgroundToday, there are still no DMARDs licensed for primary Sjögren Syndrome (pSS) patients. Among the explanations, are the limitations of current outcome measures used as primary endpoints: e.g; high placebo response rate, evaluation of either symptoms or systemic activity, and important features not being assessed. The NECESSITY consortium (https://www.necessity-h2020.eu/), including pSS experts from academia, pharmaceutical industry and patient groups formed to develop a new composite responder index, the Sjögren’s Tool for Assessing Response (STAR) that solve the issues of current outcome measures in pSS and is intended for use in clinical trials as an efficacy endpoint.ObjectivesTo develop a composite responder index in primary Sjögren’s syndrome (pSS): the STAR.MethodsTo develop the STAR, the NECESSITY consortium used data-driven methods, based on 9 randomized controlled trials (RCTs), and consensus techniques, involving 78 experts and 20 patients. Based on reanalysis of rituximab trials (TRACTISS and TEARS) and literature review, the Delphi panel identified a core set of domains to include in the STAR, with their respective outcome measures. STAR options combining these domains were designed and proposed to the panel to select and improve them. For each STAR option, sensitivity to change was estimated by the C-index (derived from Effect size) in all 9 RCTs. Delphi rounds were run for selecting STAR among these options. The Delphi panel also voted to classify trials as positive, negative or “in between” in regards to primary but also key secondary endpoints. For the options remaining before the final vote, meta-analyses of the RCTs were performed separately for positive and “in between” trials together, and for negative trials.ResultsThe Delphi panel identified 5 core domains (systemic activity, patient symptoms, lachrymal gland function, salivary gland function and biological parameters), and 227 STAR options, combining these domains, were selected to be tested for sensitivity to change. After two Delphi rounds, meta-analyses of the 20 remaining options were performed. The candidate STAR was selected by a final vote based on metrological properties and clinical relevance. In positive/in between trials, candidate STAR detected a difference between arms (OR 3.29, 95%-CI [2.07;5.22], whereas it did not in negative trials (OR 1.53, 95%-CI [0.81;2.91]).ConclusionThe candidate STAR is a composite responder index, including in a single tool all main disease features, and is designed for use as a primary endpoint in pSS RCTs. Its rigorous and consensual development process ensures its face and content validity. The candidate STAR showed good sensitivity and specificity to change. The candidate STAR will be prospectively validated in a dedicated three arms RCT of the NECESSITY consortium that will evaluate combination of synthetic DMARDs (hydroxychloroquine + lefunomide or hydroxychloroquine + mycophenolate vs placebo). We encourage the use of STAR in any ongoing and future trials.Table 1.Candidate STARDomainPointDefinition of responseSystemic activity3Decrease of clinESSDAI ≥ 3Patient reported outcome3Decrease of ESSPRI ≥ 1 point or ≥ 15%Lachrymal gland function1Schirmer:If abnormal score at baseline: increase ≥ 5 mm from baselineIf normal score at baseline: no change to abnormalOrOcular Staining Score:If abnormal score at baseline: decrease ≥ 2 points from baselineIf normal score at baseline: no change to abnormalSalivary gland function1Unstimulated Whole Salivary Flow:If score > 0 at baseline: increase ≥ 25% from baselineIf score is 0 at baseline: any increase from baselineorUltrasound:Decrease ≥ 25% in total Hocevar score from baselineBiological1Serum IgG levels: decrease ≥ 10%orRheumatoid Factor levels: decrease ≥ 25%Candidate STAR responder≥ 5 pointsESSDAI: EULAR Sjögren syndrome disease activity index; ESSPRI: EULAR Sjögren syndrome patient reported index; IgG: Immunoglobulin G;AcknowledgementsNECESSITY WP5 STAR development participants: Suzanne Arends (University Medical Center Groningen, Department of Rheumatology and Clinical Immunology, Groningen 9700 RB, Netherlands), Francesca Barone (Centre for Translational Inflammation Research, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK), Albin Björk (Division of Rheumatology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden), Coralie Bouillot (Association Française du Gougerot Sjögren et des Syndromes Secs, France), Guillermo Carvajal Alegria (University of Brest, Inserm, CHU de Brest, LBAI, UMR1227, Brest, France; Service de Rhumatologie, Centre de Référence Maladies Autoimmunes Rares CERAINO, CHU Cavale Blanche, Brest, France), Wen-Hung Chen (GlaxoSmithKline, Research Triangle Park, North Carolina, USA), Kenneth Clark (GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom), Konstantina Delli (Department of Oral and Maxillofacial Surgery, University Medical Center Groningen (UMCG), University of Groningen, The Netherlands), Salvatore de Vita (Rheumatology Clinic, University Hospital of Udine, Italy), Liseth de Wolff (University Medical Center Groningen, Department of Rheumatology and Clinical Immunology, Groningen 9700 RB, Netherlands), Jennifer Evans (Novartis Pharmaceuticals corporation USA), Stéphanie Galtier (Institut de Recherches Internationales Servier (IRIS), Suresnes Cedex, France), Saviana Gandolfo (Rheumatology Clinic, Department of Medical area, University of Udine, ASUFC, 33100 Udine, Italy), Mickael Guedj (Institut de Recherches Internationales Servier (IRIS), Suresnes Cedex, France), Dewi Guellec (CHU de Brest, Service de Rhumatologie, Inserm, CIC 1412, Brest, France), Safae Hamkour (Center of Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht 3584 GA, Netherlands), Dominik Hartl (Novartis Institutes for BioMedical Research, Basel, Switzerland), Malin Jonsson (Section for Oral and Maxillofacial Radiology, Department of Clinical Dentistry, Faculty of Medicine and Dentistry, University of Bergen, Norway), Roland Jonsson (Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Department of Rheumatology, Haukeland University Hospital, Bergen, Norway), Frans Kroese (University Medical Center Groningen, Department of Rheumatology and Clinical Immunology, Groningen 9700 RB, Netherlands), Aike Albert Kruize (University Medical Center Utrecht, Department Rheumatology and Clinical Immunology, Utrecht, Netherlands), Laurence Laigle (Institut de Recherches Internationales Servier (IRIS), Suresnes Cedex, France), Véronique Le Guern (AP-HP, Hôpital Cochin, Centre de référence maladies auto-immunes et systémiques rares, service de médecine interne, Paris, France), Wen-Lin Luo (Department of Biometrics and Statistical Science, Novartis Pharmaceuticals, East Hanover, New Jersey), Esther Mossel (University Medical Center Groningen, Department of Rheumatology and Clinical Immunology, Groningen 9700 RB, Netherlands), Wan-Fai Ng (Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK), Gaëtane Nocturne (Department of Rheumatology, Université Paris-Saclay, INSERM U1184: Centre for Immunology of Viral Infections and Autoimmune Diseases, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin Bicêtre, Paris, France), Marleen Nys (Global Biometric Sciences, Bristol Myers Squibb, Braine L’Alleud, Belgium), Roald Omdal (Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, PO Box 8100, 4068, Stavanger, Norway), Jacques-Olivier Pers (LBAI, UMR1227, University of Brest, Inserm, Brest, France and CHU de Brest, Brest, France), Maggy Pincemin (Association Française du Gougerot Sjögren et des Syndromes Secs, France), Manel Ramos-Casals (Department of Autoimmune Diseases, Hospital Clinic de Barcelona Institut Clinic de Medicinai Dermatologia, Barcelona, Catalunya, Spain), Philippe Ravaud (Centre d’Epidémiologie Clinique, Hôpital Hôtel-Dieu, Assistance Publique-Hôpitaux de Paris, Paris, France), Neelanjana Ray (Global Drug Development - Immunology, Bristol Myers Squibb Company, Princeton, New Jersey, USA), Alain Saraux (HU de Brest, Service de Rhumatologie, Univ Brest, Inserm, UMR1227, Lymphocytes B et Autoimmunité, Univ Brest, Inserm, LabEx IGO, Brest, France), Athanasios Tzioufas (Rheumatology Clinic, Department of Medical area, University of Udine, ASUFC, 33100 Udine, Italy), Gwenny Verstappen (University Medical Center Groningen, Department of Rheumatology and Clinical Immunology, Groningen 9700 RB, Netherlands), Arjan Vissink, Marie Wahren-Herlenius (Division of Rheumatology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden). We thank the following experts: Esen Karamursel Akpek, Alan Baer, Chiara Baldini, Elena Bartoloni, Marí-Alfonso Begona, Johan Brun, Vatinee Bunya, Laurent Chiche, Troy Daniels, Paul Emery, Robert Fox, Roberto Giacomelli, John Gonzales, John Greenspan, Robert Moots, Susumu Nishiyama, Elizabeth Price, Christophe Richez, Caroline Shiboski, Roser Solans Laque, Muthiah Srinivasan, Peter Olsson, Tsutomu Takeuchi, Frederick Vivino, Paraskevi Voulgari, Daniel Wallace, Ava Wu, Wen Zhang. We thank the anonymous patients from the NECESSITY Patient Advisory Group and the Sjögren Foundation for their valuable contribution to the Delphi process. We thank EW StClair and AN Baer who generated the baminercept data and made them publicly available.Disclosure of InterestsRaphaèle Seror Consultant of: GlaxoSmithKline, Boehringer, Janssen and Novartis, Grant/research support from: GlaxoSmithKline and Amgen, Gabriel Baron: None declared, Marine Camus: None declared, Divi Cornec Consultant of: GlaxoSmithKline, Bristol Myers Squibb, Janssen, Amgen, Pfizer and Roche, Elodie Perrodeau: None declared, Simon J. Bowman Consultant of: Abbvie, Astra Zeneca, Galapagos and Novartis Pharmaceuticals, Michele Bombardieri Consultant of: UCB, Amgen/Medimmune, Janssen, and GlaxoSmithKline, Grant/research support from: Amgen/Medimmune, Janssen, and GlaxoSmithKline, Hendrika Bootsma: None declared, Jacques-Eric Gottenberg Consultant of: AbbVie, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, Pfizer, Roche, Sanofi, Novartis, MSD, CSL-Behring and Genzyme, Grant/research support from: Bristol Myers Squibb, Benjamin Fisher Speakers bureau: Bristol Myers Squibb and Novartis, Consultant of: Novartis, Bristol Myers Squibb, Janssen and Servier, Grant/research support from: Servier, Galapagos and Janssen, Wolfgang Hueber Shareholder of: Novartis Pharma, Employee of: Novartis Pharma, Joel van Roon: None declared, Valerie Devauchelle-Pensec: None declared, Peter Gergely Shareholder of: Novartis Pharma, Employee of: Novartis Pharma, Xavier Mariette Consultant of: Bristol Myers Squibb, Galapagos, GlaxoSmithKline, Janssen, Novartis, Pfizer and UCB, Grant/research support from: Ose Pharmaceuticals, Raphaël Porcher: None declared
