Objective Tocilizumab (TCZ) has demonstrated lung function preservation in 2 randomized controlled trials in early systemic sclerosis (SSc) This effect has yet to be characterized in terms of radiographically evident quantitative lung involvement We undertook this study to assess the impact of TCZ on lung function preservation in a post hoc analysis, stratifying treatment arms according to the degree of lung involvement Methods The focuSSced trial was a phase III randomized placebo-controlled trial of TCZ in patients with SSc and progressive skin disease Participants underwent baseline and serial spirometry along with high-resolution chest computed tomography at baseline and at week 48 Quantitative interstitial lung disease (QILD) and fibrosis scores were assessed by computer software We classified QILD into the following categories of lung involvement: mild (>5-10%), moderate (>10-20%), and severe (>20%) Results Of 210 participants recruited for the trial, 136 patients (65%) had ILD The majority of these patients (77%) had moderate-to-severe involvement (defined as >10% lung involvement) The TCZ arm demonstrated preservation of forced vital capacity percent predicted (FVC%) over 48 weeks (least squares mean change in FVC% = -01) compared to placebo (-63%) For mild, moderate, and severe QILD, the mean ± SD change in FVC% in the TCZ arm at 48 weeks were -41 ± 25% (n = 11), 07 ± 19% (n =19), and 21 ± 16% (n = 26), respectively, and in the placebo group were -100 ± 26% (n = 11), -57 ± 16% (n = 26), and -67 ± 20% (n = 16), respectively Similar treatment-related preservation findings were seen independent of fibrosis severity Conclusion TCZ in early SSc-associated ILD with progressive skin disease stabilized FVC% over 48 weeks, independent of the extent of radiographically evident QILD

Tocilizumab Prevents Progression of Early Systemic Sclerosis Associated Interstitial Lung Disease

Summary Background Systemic sclerosis is a connective tissue disease characterised by multiorgan fibrosis with an autoimmune background and poor prognosis. Although a few drugs have shown some efficacy in treating the disease, there remains a great unmet medical need. We aimed to investigate the efficacy and safety of rituximab in patients with systemic sclerosis. Methods We did a double-blind, investigator-initiated, randomised, placebo-controlled trial at four hospitals in Japan. Patients aged 20–79 years, who fulfilled the 2013 American College of Rheumatology and European League Against Rheumatism classification criteria for systemic sclerosis, with a modified Rodnan Skin Score (mRSS) of 10 or greater, and an expected survival of at least 6 months were randomly assigned (1:1) to receive intravenous rituximab (375 mg/m2) or placebo once per week for 4 weeks. Patients and investigators were masked to treatment allocation. The primary endpoint was the absolute change in mRSS 24 weeks after initiation of study treatment, measured in all patients who received at least one dose of study treatment and had one endpoint assessment. This study is registered with ClinicalTrials.gov, NCT04274257, and UMIN-CTR, UMIN000030139. Findings Between Nov 28, 2017, and Nov 6, 2018, 80 individuals were screened and 56 (70%) were enrolled and randomly assigned; 51 (91%) were women and five (9%) were men. 27 (96%) of 28 patients in the rituximab group and 22 (79%) of 28 patients in the placebo group received at least one dose of their allocated treatment and completed 24 weeks of follow-up. The absolute change in mRSS 24 weeks after initiation of study treatment was lower in the rituximab group than in the placebo group (−6·30 in the rituximab group vs 2·14 in the placebo group; difference −8·44 [95% CI −11·00 to −5·88]; p Interpretation Rituximab appears to be an effective and safe treatment for systemic sclerosis. Although this study has some limitations, this is the first clinical trial to show efficacy of rituximab with skin sclerosis as the primary endpoint. Funding Japan Agency for Medical Research and Development (AMED), Zenyaku Kogyo. Translation For the Japanese translation of the abstract see Supplementary Materials section.

Safety and efficacy of rituximab in systemic sclerosis (DESIRES): a double-blind, investigator-initiated, randomised, placebo-controlled trial

Systemic sclerosis (SSc; scleroderma) has the highest individual mortality of all rheumatic diseases and interstitial lung disease (ILD) is among the leading causes of SSc-related death. Two drugs are now approved by the Food and Drug Administration (FDA) and indicated for slowing the rate of decline in pulmonary function in patients with SSc-ILD: nintedanib (a tyrosine kinase inhibitor) and tocilizumab (the first biologic agent targeting the interleukin-6 pathway in SSc). In addition, two generic drugs with cytotoxic and immunoregulatory activity, mycophenolate mofetil and cyclophosphamide, have shown comparable efficacy in a Phase II trial but are not FDA-approved for SSc-ILD. In light of the heterogeneity of the disease, the optimal therapeutic strategy in the management of patients with SSc-ILD is still to be determined. The objectives of this review are two-fold: (1) review the body of research focused on the diagnosis and treatment of SSc-ILD; and (2) propose a practical approach for diagnosis, stratification, management, and therapeutic decision-making in this clinical context. This review presents a practical classification of SSc patients in terms of disease severity (subclinical vs. clinical ILD) and associated risk of progression (low vs. high risk). The pharmacological and non-pharmacological options as first and second-line therapy, as well as potential combination approaches, are discussed in light of the recent approval of tocilizumab for SSc-ILD.

Zaneta Smolenska

Papers

Tocilizumab in systemic sclerosis: a randomised, double-blind, placebo-controlled, phase 3 trial.