Interferon-α-mediated therapeutic resistance in early rheumatoid arthritis implicates epigenetic reprogramming. Issue 9 (9th June 2022)

• Record Type: Journal Article
• Authors: Cooles, Faye A H; Tarn, Jessica; Lendrem, Dennis W; Naamane, Najib; Lin, Chung MA; Millar, Ben; Maney, Nicola J; Anderson, Amy E; Thalayasingam, Nishanthi; Diboll, Julie; Bondet, Vincent; Duffy, Darragh; Barnes, Michael R; Smith, Graham R; Ng, Sandra; Watson, David; Henkin, Rafael; Cope, Andrew P; Reynard, Louise N; Pratt, Arthur G; Isaacs, John D
• Other Names: author non-byline.; Hughes-Morley Adwoa author non-byline.; Walker Alexandra author non-byline.; Cuza Alexandru author non-byline.; Gallagher-Syed Amaya author non-byline.; Anderson Amy author non-byline.; Haynes Andrea author non-byline.; Filer Andrew author non-byline.; Long Andrew author non-byline.; Cope Andrew P author non-byline.; Parke Angela author non-byline.; Rowe Anthony author non-byline.; Didierlaurent Arnaud author non-byline.; Gilmour Ashley author non-byline.; Herath Athula author non-byline.; Wakatsuki Ayako author non-byline.; Aysin Pedersen author non-byline.; Virlan Tulunay author non-byline.; Allen Ben author non-byline.; Fisher Benjamin A author non-byline.; Kola Blerina author non-byline.; Harvey Bohdan author non-byline.; Tom Brian author non-byline.; Goodyear Carl S author non-byline.; Cuff Carolyn author non-byline.; Hilkens Catharien author non-byline.; Lindholm Catharina author non-byline.; Mela Catherine T author non-byline.; Buckley Christopher D author non-byline.; Larminie Chris author non-byline.; Marshall Chris author non-byline.; John Christopher author non-byline.; Mela Christopher M author non-byline.; Carini Claudio author non-byline.; Pitzalis Costantino author non-byline.; Ciurtin Coziana author non-byline.; Baker Dan author non-byline.; Ziemek Daniel author non-byline.; Dastros-Pitei Daniela author non-byline.; Nguyen Dao author non-byline.; Scott David L author non-byline.; Watson David S author non-byline.; Symmons Deborah author non-byline.; Lendrem Dennis author non-byline.; Verbeeck Denny author non-byline.; Padhji Desmond author non-byline.; Finch Donna author non-byline.; Porter Duncan author non-byline.; Vernon Emma author non-byline.; Cooles Faye author non-byline.; Hong Feng author non-byline.; Clarke Fiona author non-byline.; Stirling Fiona author non-byline.; Ibrahim Fowzia author non-byline.; Humby Frances author non-byline.; Capdevila Francisco Bonachela author non-byline.; Geissmann Frederic author non-byline.; Ponchel Frederique author non-byline.; Molyneux Gemma author non-byline.; Simpson Gemma author non-byline.; Thorborn Georgina author non-byline.; Parker Gerry author non-byline.; Altobelli Gioia author non-byline.; Smith Graham R author non-byline.; Edwards Hannah author non-byline.; Tipney Hannah author non-byline.; Zucht Hans-Dieter author non-byline.; Noble Hayley author non-byline.; Lempp Heidi author non-byline.; McInnes Humayara AliIain B author non-byline.; Scott Ian C author non-byline.; Donnelly Ian N BruceIona author non-byline.; Vranic Ivana author non-byline.; Butler James A author non-byline.; Galloway James author non-byline.; Sergeant Jamie C author non-byline.; Worthington Jane author non-byline.; El-Jawhari Jehan author non-byline.; Tarn Jessica author non-byline.; Ellis Joanne author non-byline.; Casement John author non-byline.; Isaacs John author non-byline.; Diboll Julie author non-byline.; Raza Karim author non-byline.; Goldmann Katriona author non-byline.; Hicks Kirsty author non-byline.; Fossati-Jimack Liliane author non-byline.; Rowell Lucy author non-byline.; Levesque Marc author non-byline.; Coles Mark C author non-byline.; Coles Mark author non-byline.; Curran Mark author non-byline.; Hodge Martin author non-byline.; Jenkins Martin author non-byline.; Maciejewski Mateusz author non-byline.; Page Matt author non-byline.; Sleeman Matthew A author non-byline.; Loza Matthew J author non-byline.; Buch Maya author non-byline.; Ho Meilien author non-byline.; Binks Michael author non-byline.; McDermott Michael F author non-byline.; Macoritto Michael author non-byline.; Barnes Michael R author non-byline.; Ehrenstein Michael R author non-byline.; Bombardieri Michele author non-byline.; Lewis Myles author non-byline.; Gozzard Neil author non-byline.; Payne Neil author non-byline.; Ward Neil author non-byline.; Joseph Nina author non-byline.; Emery Paul author non-byline.; Taylor Peter C author non-byline.; Schulz-Knappe Peter author non-byline.; Budde Petra author non-byline.; Jones Philip author non-byline.; Stocks Philip author non-byline.; Harry Rachel author non-byline.; Henkin Rafael author non-byline.; Rao Ravi author non-byline.; Harris Ray author non-byline.; Parmar Rekha author non-byline.; Toward Ruth author non-byline.; Hollis Sally author non-byline.; Schwank Samana author non-byline.; Lipsky Samantha author non-byline.; Hasan Samiul author non-byline.; Martins Sandra author non-byline.; Ng Sandra author non-byline.; Brockbank Sarah author non-byline.; Keidel Sarah author non-byline.; Jelinsky Scott author non-byline.; Rana Sharmila author non-byline.; Read Simon author non-byline.; Kelly Stephen author non-byline.; Wright Stephen author non-byline.; Young Steve P author non-byline.; Kaymakcalan Sukru author non-byline.; Talbot Susan author non-byline.; Verstappen Suzanne MM author non-byline.; Lazarov Tomi author non-byline.; Sabin Tony author non-byline.; Ludbrook Valerie author non-byline.; Farewell Vernon author non-byline.; Tsuji Wayne author non-byline.; Wu Wing author non-byline.; Burny Wivine author non-byline.; Zhong Yujie author non-byline.; Liu Zheng author non-byline.; Jia Zhilong author non-byline.;
• Is Part Of: Annals of the rheumatic diseases. Volume 81:Issue 9(2022)
• Page Start: 1214
• Page End: 1223
• Publication Date: 2022-06-09
• Subjects: inflammation -- arthritis, rheumatoid -- antirheumatic agents -- immune system diseases; Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2022-222370
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Objectives: An interferon (IFN) gene signature (IGS) is present in approximately 50% of early, treatment naive rheumatoid arthritis (eRA) patients where it has been shown to negatively impact initial response to treatment. We wished to validate this effect and explore potential mechanisms of action. Methods: In a multicentre inception cohort of eRA patients (n=191), we examined the whole blood IGS ( MxA, IFI44L, OAS1, IFI6, ISG15 ) with reference to circulating IFN proteins, clinical outcomes and epigenetic influences on circulating CD19+ B and CD4+ T lymphocytes. Results: We reproduced our previous findings demonstrating a raised baseline IGS. We additionally showed, for the first time, that the IGS in eRA reflects circulating IFN-α protein. Paired longitudinal analysis demonstrated a significant reduction between baseline and 6-month IGS and IFN-α levels (p<0.0001 for both). Despite this fall, a raised baseline IGS predicted worse 6-month clinical outcomes such as increased disease activity score (DAS-28, p=0.025) and lower likelihood of a good EULAR clinical response (p=0.034), which was independent of other conventional predictors of disease activity and clinical response. Molecular analysis of CD4+ T cells and CD19+ B cells demonstrated differentially methylated CPG sites and dysregulated expression of disease relevant genes, including PARP9, STAT1, and EPSTI1, associated with baseline IGS/IFNα levels. Differentially methylated CPG sites implicated altered transcription factor binding in B cells (GATA3, ETSI, NFATC2, EZH2) and T cells (p300, HIF1α). Conclusions: Our data suggest that, in eRA, IFN-α can cause a sustained, epigenetically mediated, pathogenic increase in lymphocyte activation and proliferation, and that the IGS is, therefore, a robust prognostic biomarker. Its persistent harmful effects provide a rationale for the initial therapeutic targeting of IFN-α in selected patients with eRA.