P169 A validated two-score system for interferon is a predictor of response to rituximab in SLE
Authors: Carter Lucy M , Alase Adewonuola , Wigston Zoe , Burska Agata , Psarras Antony , Yusof Yuzaiful , Reynolds John ,   The Masterplans Consortium, Wittmann Miriam , Bruce Ian , Vital Edward M 
Published: April 2021

Background/Aims 

We developed two interferon-stimulated gene (ISG) expression scores (IFN-Score-A and IFN-Score-B) that predict clinical outcomes in SLE better than a conventional “interferon signature”. IFN-Score-A includes the ISGs usually present in an interferon signature. IFN-Score-B includes additional ISGs responsive to multiple IFN subtypes and was better at predicting development of SLE among ANA-positive individuals, development of RA among CCP-positive individuals, and subclinical synovitis in SLE. Here, we investigate whether IFN-Score-A and IFN-Score-B predict response to Rituximab (RTX) therapy. The British Isles Lupus Assessment Group Biologics Register (BILAG-BR) is a UK wide study enrolling patients undergoing treatment with RTX for active SLE despite previous treatment with cyclophosphamide or mycophenolate mofetil. MASTERPLANS is a consortium aimed at identifying therapeutic biomarkers in SLE.

Methods 

We studied all BILAG-BR subjects undergoing their first cycle of RTX in whom a pre-treatment RNA sample was available. Disease activity was measured blind to biomarker status, using BILAG-2004. Response was defined as improvement in BILAG-2004 disease activity by at least one grade, with a maximum of one domain showing persistent BILAG-2004 grade B activity, and no new BILAG grade A or B disease flares at 6 months. Whole blood was collected into TEMPUS tubes and RNA extracted for measurement of IFN-Scores using a custom Taqman array as previously described. Multivariable logistic regression was used to test IFN-Scores and key baseline clinical covariates as predictors of response at 6 months.

Results 

147 patients were recruited, of whom there were 6 month BILAG data in 90. 59/90 (65.6%) were responders. In univariable and multivariable analysis, higher IFN-Score-B expression was significantly associated with clinical response (Table 1). Other characteristics typically associated with more severe SLE (younger age, African ancestry, and autoantibody repertoire) also independently predicted response.

Conclusion 

High expression of interferon scores predicts better response to RTX. The novel IFN score-B was more predictive than a typical interferon signature. Future work will validate this biomarker in a replication cohort and integrate other with data on IFN biomarkers in other contexts. P169 Table 1:Baseline VariableNon respondersRespondersUnivariable OR (95% CI)P valueMultivariable OR (95% CI)P valueInterferon Score-A, median (IQR)-1.75 (-4.7,-1.0)-1.1 (-2.24,-0.1)1.21 (0.98,1.48)0.070.94 (0.58,1.53)0.81Interferon Score-B, median (IQR)-2.4 (-3.2,-1.6)-1.6 (-2.6,-1.11.56 (1.04,2.33)0.033.27 (1.39,7.68)0.007Age years, median (IQR)44 (38,52)38 (30,50)0.97 (0.94,1.00)0.060.92 (0.86,0.97)0.005African ancestry, n/N (%)8/31 (26)4/59 (7)0.21 (0.06,0.76)0.020.005 (0.000,0.22)0.006Numerical BILAG-2004, median (IQR)21 (20,25)18 (13,24)0.91 (0.86,0.93)0.010.80 (0.67,0.94)0.010Count of ANA subtypes, median (IQR)1 (1,3)2 (1,3)1.28 (0.84,1.95)0.252.38 (1.06,5.31)0.034Count of ANA subtypes is sum of positive Ro, La, Sm, RNP & dsDNA by local laboratories.

Disclosure 

L.M. Carter: None. A. Alase: None. Z. Wigston: None. A. Burska: None. A. Psarras: None. Y. Yusof: None. J. Reynolds: None. M. Wittmann: Honoraria; Abbvie, Celgene, Janssen, L’Oreal, Novartis and Pfizer. I. Bruce: Consultancies; AstraZeneca, Eli Lilly, GlaxoSmithKline, ILTOO Pharma, MedImmune, Merck Serono. Member of speakers’ bureau; GlaxoSmithKline, UCB Pharma. Grants/research support; Genzyme Sanofi & GlaxoSmithKline. E.M. Vital: Honoraria; Roche, GSK and AstraZeneca. Grants/research support; Roche, GSK and AstraZeneca.