Background:Potential efficacy and favorable safety profiles of tocilizumab (TCZ) have been demonstrated in patients with diffuse cutaneous systemic sclerosis (dcSSc) [1, 2]. However, clinical outcomes after dose-reduction or discontinuation of TCZ due to an improvement of skin thickness remain unclear.Objectives:To investigate the clinical outcomes after dose-reduction or discontinuation of TCZ in patients with dcSSc in a real-world setting.Methods:This is a single-center, retrospective, observational study using a database of consecutive SSc patients who visited our center between April 2014 and October 2020. For this study, we selected eligible patients from the database based on the following criteria: patients who (i) fulfilled the ACR/EULAR classification criteria, (ii) were classified as having dcSSc, (iii) had been treated with TCZ for at least 6 months, and (iv) were follow-up >6 months after TCZ introduction. Clinical information including demographic and clinical characteristics at TCZ introduction; dosing, administration route, and adherence of TCZ; and serial clinical parameters (modified Rondan total skin thickness score [mRSS], and percent predicted forced vital capacity [%FVC]), safety profiles, and outcomes after TCZ introduction regardless of TCZ continuation were extracted from the database.Results:Of 404 patients enrolled in the database, 13 dcSSc patients were eligible for this study. Baseline characteristics included a mean age of 51 ± 9 years, 85% female, disease duration of 27 ± 24 months, and mRSS of 19.5 ± 10.6. Seven patients (54%) had HRCT-confirmed ILD at baseline, and 9 (69%) were positive for anti-topoisomerase I antibody. Two (14%) and 11 (85%) were on mycophenolate mofetil and low-dose prednisolone (7.2 ± 6.0 mg/day), respectively. Seven patients (54%) each had active skin disease and elevated inflammatory markers defined in the phase III clinical trial [2], while only 4 (31%) fulfilled the inclusion criteria. TCZ was initially administered intravenously (8 mg/kg every 4 weeks) in 8 patients and subcutaneously in 5 (162 mg every 2 weeks in 4 and every week in one). At one year, mRSS was improved from 20.9 ± 11.4 to 10.7 ± 8.9 in 11 patients (p = 0.007), and %FVC was stable in 7 patients with ILD (76.8 ± 15.0 to 78.6 ± 16.1). During the observation period of 60.4 ± 26.7 months, 4 patients were treated with a stable dose of TCZ, while TCZ dose was reduced and/or discontinued in 9. Four of them discontinued TCZ due to adverse events (n = 2; acute lung injury and phlegmon) or prominent improvement of skin thickening (n = 2). Of 9 patients with dose reduction/discontinuation of TCZ, 4 patients who discontinued TCZ (n = 3) or received dose reduction of TCZ (n = 1) experienced a recurrence of progressive skin thickening together with inflammatory complications, including edematous induration of the skin, progression of ILD, polyarthritis, and/or pericarditis with increased inflammatory markers. The interval between dose-reduction/discontinuation of TCZ and clinical worsening ranged from 2 to 11 months. These manifestations were promptly improved by dose-escalation or resumption of TCZ in all patients except one who experienced progressive ILD and died of respiratory failure 27 months later.Conclusion:In dcSSc patients who experienced improvement of skin thickness during treatment with TCZ, dose-reduction or discontinuation of TCZ may result in a recurrence of the disease. Randomized comparative studies are necessary to examine optimal timing for dose-reduction or discontinuation of TCZ in dcSSc patients after improvement of skin thickness.References:[1]Khanna, D., et al., Safety and efficacy of subcutaneous tocilizumab in systemic sclerosis: results from the open-label period of a phase II randomised controlled trial (faSScinate). Ann Rheum Dis, 2018. 77(2):212-220.[2]Khanna, D., et al., Tocilizumab in systemic sclerosis: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med, 2020; 8(10): 963-974.Disclosure of Interests:Yohei Isomura: None declared, Yoshioki Yamasaki Speakers bureau: Boehringer-Ingelheim, Nippon Shinyaku, Bristol Myers, Yuichiro Shirai Speakers bureau: Janssen, Grant/research support from: Janssen, Masataka Kuwana Speakers bureau: Abbie, Astellas, Asahi Kasei Parma, Boehringer-Ingelheim, Chugai, Eisai, Janssen, MBL, Mochida, Nippon Shinyaku, Ono Pharmaceuticals, Pfizer, Tanabe-Mitsubishi, Consultant of: Boehringer-Ingelheim, Chugai, Corbus, MBL, Mochida, Grant/research support from: Boehringer-Ingelheim, Chugai, Eisai, MBL, Ono Pharmaceuticals, Tanabe-Mitsubishi
Correlations between changes in cytokines and clinical outcomes for early phase (proof of concept) trials in active diffuse systemic sclerosis using data from an imatinib study
