Rituximab versus cyclophosphamide for the treatment of connective tissue disease associated interstitial lung disease (RECITAL): a multi-centre randomised controlled trial

Maher, T.M., Tudor, V., Saunders, P., Gibbons, M., Fletcher, S., Parfrey, H., Denton, C.P., Renzoni, E., Kokosi, M., Wells, A.U., Ashby, D., Szigeti, M. and Molyneaux, P.L. (2022) Rituximab versus cyclophosphamide for the treatment of connective tissue disease associated interstitial lung disease (RECITAL): a multi-centre randomised controlled trial. American Journal of Respiratory and Critical Care Medicine, 205, [A4779]. (doi:10.1164/ajrccm-conference.2022.205.1_MeetingAbstracts.A4779).

Abstract

Rationale: interstitial lung disease (ILD) is frequently a life shortening complication of connective tissue disease (CTD). Rituximab,a chimeric anti-CD20 monoclonal antibody which depletes B-cells is widely used as a treatment for systemic manifestations ofCTD. Open-label and cohort studies suggest that rituximab is an effective therapy for CTD-ILD but this has never been tested in a randomized placebo controlled trial. The current trial (NCT01862926) compared rituximab to cyclophosphamide as first line therapy for CTD-ILD.

Methods: individuals with ILD related to scleroderma, idiopathic inflammatory myositis or mixed connectivetissue disease for whom their caring physician had recommended treatment with cyclophosphamide were enrolled. Subjects were randomised 1:1 to receive cyclophosphamide 600mg/m2 body surface area administered every 4 weeks for 6 doses orrituximab 1g given at baseline and repeated at 2 weeks. A double dummy design ensured blinding of subjects and trial staff throughout the study. The primary endpoint was rate of change in forced vital capacity (FVC) at 24 weeks. Secondary end points included safety and tolerability, corticosteroid exposure, FVC change at 48 weeks and patient reported quality of life.

Results: a total of 101 subjects were randomised: 51 to rituximab, 50 to cyclophosphamide (Table 1). At 24 weeks, both rituximab and cyclophosphamide resulted in an improvement in FVC (97±234mL and 99±329mL respectively). In a linear mixed effects model the difference between arms was 38mL (95% CI 155 - -78 mL, p=0.493) in favour of cyclophosphamide. At week 48 improvement in FVC was preserved in subjects receiving both rituximab (112±249mL) and cyclophosphamide (138±440mL). Treatment in both arms improved QoL parameters; K-BILD at 24 weeks improved by 8.8±17.0 and 9.4±20.8 units in the rituximab and cyclophosphamide arms respectively with no statistically significantly difference between groups. Five deaths occurred during the first 24 weeks of the study with 3 in subjects receiving rituximab. Numerically fewer adverse events were reported by subjects receiving rituximab (445 compared to 646 in subjects receiving cyclophosphamide). Corticosteroid exposure over the 48 weeksof the trial was less in the rituximab arm compared to cyclophosphamide.

Conclusions: rituximab improved FVC and patientreported quality of life at 24 weeks, but was not superior to cyclophosphamide as first line treatment for CTD-ILD. Rituximabcaused fewer adverse events and was associated with a reduction in corticosteroid exposure compared to cyclophosphamide. Rituximab should be considered as a therapeutic alternative to cyclophosphamide in individuals with CTD-ILD requiringintravenous therapy.

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