1461 Secchiero,etal:TRAILandDMARDinERA Personal non-commercial use only. The Journal of Rheumatology Copyright © 2010. All rights reserved. Baseline Serum Concentrations of TRAIL in Early Rheumatoid Arthritis: Relationship with Response to Disease-modifying Antirheumatic Drugs PAOLA SECCHIERO, FEDERICA CORALLINI, GABRIELLA CASTELLINO, ALESSANDRA BORTOLUZZI, LORENZO CARUSO, SERENABUGATTI, RAFFAELLABOSCO, MAURIZIO MONTECUCCO, and FRANCESCO TROTTA ABSTRACT. Objective. To assess the relationship between serum concentrations of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and osteoprotegerin (OPG) and the therapeutic response to disease-modifying antirheumatic drugs (DMARD) in patients with early rheumatoid arthritis (RA). Methods. Circulating levels of TRAIL and its soluble receptor OPG were measured by ELISA in paired serum samples obtained from 66 patients with early RA at their first visit (baseline) and after 1 year of therapy. Levels of TRAIL and OPG were analyzed in relation to the clinical response, defined by the 28-joint count Disease Activity Score (DAS28). Results. Both serum TRAIL and OPG increased after DMARD therapy. Baseline levels of TRAIL, but not OPG, were significantly higher (p < 0.05) in the patients that achieved a clinical response by DAS28 after 1 year of therapy, versus patients without clinical response to DMARD. Baseline serum levels of TRAIL were higher (p < 0.01) in rheumatoid factor-negative patients. Conclusion. Our data suggest that the basal level of circulating TRAIL is an important determinant in the therapeutic response to DMARD in patients with early RA. (First Release May 15 2010; J Rheumatol 2010;37:1461–6; doi:10.3899/jrheum.091363) KeyIndexingTerms: EARLYRHEUMATOIDARTHRITIS DISEASE MODIFYINGANTIRHEUMATIC DRUGS TUMOR NECROSIS FACTOR RELATEDAPOPTOSIS INDUCING LIGAND FromtheDepartmentofMorphologyandEmbryology,andthe RheumatologySection,DepartmentofClinicalandExperimental Medicine,UniversityofFerrara,Ferrara,Italy;andtheDepartmentof Rheumatology,IRCCSPoliclinicoS.Matteo,UniversityofPavia,Pavia, Italy. SupportedbygrantsfromtheFondoRegioneEmiliaRomagna(PG08 23943/2008/P18A4)andCariFeFoundation. P.Secchiero,PhD;F.Corallini,PhD,DepartmentofMorphologyand Embryology;G.Castellino,MD;A.Bortoluzzi,MD,Rheumatology Section,DepartmentofClinicalandExperimentalMedicine;L.Caruso, PhD,DepartmentofMorphologyandEmbryology,UniversityofFerrara; S.Bugatti,MD,DepartmentofRheumatology,IRCCSPoliclinicoS. Matteo,UniversityofPavia;R.Bosco,PhD,DepartmentofMorphology andEmbryology,UniversityofFerrara;M.Montecucco,MD,Department ofRheumatology,IRCCSPoliclinicoS.Matteo,UniversityofPavia; F.Trotta,MD,RheumatologySection,DepartmentofClinicaland ExperimentalMedicine,UniversityofFerrara. Dr.SecchieroandDr.Corallinicontributedequallytothisreport. AddresscorrespondencetoDr.F.Corallini,DepartmentofMorphology andEmbryology,UniversityofFerrara,ViaFossatodiMortara70, 44100Ferrara,Italy.E-mail:federica.corallini@unife.it AcceptedforpublicationFebruary16,2010. Early diagnosis of rheumatoid arthritis (RA) is crucial to prevent unfavorable disease outcome 1 . RA treatment includes early use of disease-modifying antirheumatic drugs (DMARD) such as methotrexate (MTX), leflunomide, sul- fasalazine (SSZ), and hydroxychloroquine, and, for the most aggressive disease subsets, biologic agents initiated as soon as the diagnosis is confirmed. To achieve remission, optimal management of RA is needed within 3–6 months after onset of disease 2 . Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), also known as Apo-2 ligand, is a member of the structurally related TNF family of cytokines, and exists as either a type II membrane protein or as a soluble protein 3 . Four transmembrane TRAIL receptors belonging to the apoptosis-inducing TNF-receptor (R) family have been described. While TRAIL-R1 (DR4) and TRAIL-R2 (DR5) transduce apoptotic signals upon binding of TRAIL, TRAIL-R3 (DcR1) and TRAIL-R4 (DcR2) are homologous to DR4 and DR5 in their cysteine-rich extracellular domain, but lack intracellular death domain and apoptosis-inducing capability 3 . In addition, it has recently been shown that the soluble receptor osteoprotegerin (OPG) interacts with and neutralizes the biological activity of TRAIL with affinity comparable to that of RANKL, another member of the TNF family of cytokines 4 . Various invitro and invivo studies in animal models have shown that TRAIL might have a thera- peutic role in ameliorating experimental osteoarthritis, as well as in promoting apoptosis of synovial fibroblasts obtained from patients with RA 5-10 .Todate,limiteddataare available on the levels of circulating TRAIL in RA patients. Moreover, although it has been shown that TRAIL is able to www.jrheum.org Downloaded on July 28, 2022 from