Tocilizumab In Systemic Sclerosis Research Articles

Biomarkers of fibrosis, inflammation, and extracellular matrix in the phase 3 trial of tocilizumab in systemic sclerosis

Drug development for systemic sclerosis (SSc) benefits from understanding the relationship between disease and circulating biomarkers to enable activities such as patient stratification and evaluation of therapeutic response. We measured biomarkers in serum from SSc patients from a phase 3 trial of tocilizumab (focuSSced) and compared baseline levels with healthy controls (HCs). Several baseline biomarkers appeared elevated in SSc patients compared to HCs, suggesting activation of epithelial damage, inflammation, fibrosis, and extracellular matrix (ECM) remodeling. Baseline correlations among both periostin/COMP and ECM biomarker subsets implicated their participation in fibroblast activation. Tocilizumab treatment modulated serum biomarkers of macrophage activation, inflammation, and ECM turnover, including collagen formation and degradation neoepitopes. Baseline CRP, periostin, and SP-D showed prognostic trends for worsening lung function, and IL-6, COMP, periostin, and Pro-C3 showed prognostic trends for worsening skin thickness. These prognostic results warrant confirmation in additional patient cohorts to verify their utility.

Real-world experience of tocilizumab in systemic sclerosis: potential benefit on lung function for anti-topoisomerase-positive patients.

Real-world experience of tocilizumab in systemic sclerosis: potential benefit on lung function for anti-topoisomerase-positive patients.

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

A phase 2 trial of tocilizumab showed preliminary evidence of efficacy in systemic sclerosis. We assessed skin fibrosis and systemic sclerosis-associated interstitial lung disease (SSc-ILD) in a phase 3 trial to investigate the safety and efficacy of tocilizumab, an anti-interleukin-6 receptor antibody, in the treatment of systemic sclerosis. In this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial, participants were recruited from 75 sites in 20 countries across Europe, North America, Latin America, and Japan. Adults with diffuse cutaneous systemic sclerosis for 60 months or less and a modified Rodnan skin score (mRSS) of 10-35 at screening were randomly assigned (1:1) with a voice-web-response system to receive subcutaneous tocilizumab 162 mg or placebo weekly for 48 weeks, stratified by IL-6 levels; participants and investigators were masked to treatment group. The primary endpoint was the difference in change from baseline to week 48 in mRSS. Percentage of predicted forced vital capacity (FVC% predicted) at week 48, time to treatment failure, and patient-reported and physician-reported outcomes were secondary endpoints. This trial is registered with ClinicalTrials.gov (number NCT02453256) and is closed to accrual. Between Nov 20, 2015, and Feb 14, 2017, 210 individuals were randomly assigned to receive tocilizumab (n=104) or placebo (n=106). In the intention-to-treat population, least squares mean [LSM] change from baseline to week 48 in mRSS was -6·14 for tocilizumab and -4·41 for placebo (adjusted difference -1·73 [95% CI -3·78 to 0·32]; p=0·10). The shift in distribution of change from baseline in FVC% predicted at week 48 favoured tocilizumab (van Elteren nominal p=0·002 vs placebo), with a difference in LSM of 4·2 (95% CI 2·0-6·4; nominal p=0·0002), as did time to treatment failure (hazard ratio 0·63 [95% CI 0·37-1·06]; nominal p=0·08). Change in LSM from baseline to week 48 in Health Assessment Questionnaire-Disability Index and in patient-global and physician-global visual analogue scale assessments did not differ between tocilizumab and placebo. In the safety set, infections were the most common adverse events (54 [52%] of 104 participants in the tocilizumab group, 53 [50%] of 106 in the placebo group). Serious adverse events were reported in 13 participants treated with tocilizumab and 18 with placebo, primarily infections (three events, eight events) and cardiac events (two events, seven events). The primary skin fibrosis endpoint was not met. Findings for the secondary endpoint of FVC% predicted indicate that tocilizumab might preserve lung function in people with early SSc-ILD and elevated acute-phase reactants. Safety was consistent with the known profile of tocilizumab. F Hoffmann-La Roche Ltd.

P153 Tocilizumab in systemic sclerosis: real world experience from a single centre cohort supports potential benefit on lung function for anti-topoisomerase (Scl-70) positive subgroup

Abstract Background The FaSScinate and FocuSSced trials of tocilizumab versus placebo in early diffuse systemic sclerosis (SSc) highlighted the potential impact of tocilizumab on lung function with preservation of lung function in those treated with tocilizumab versus placebo, despite only a trend of benefit for skin fibrosis. Our centre have been using tocilizumab to treat SSc patients and overlap inflammatory arthritis, in line with NICE guidance treatment for inflammatory arthritis. We report here our experience of tocilizumab in SSc and the impact on lung function. Methods A retrospective medical chart review of patients attending our centre with SSc and having ever been on tocilizumab were identified, mostly with overlap inflammatory arthritis. Patients included in the FaSScinate trial were excluded, however patients receiving compassionate use of tocilizumab following the phase 3 FocuSSced trial were included. Mann-Whitney-U test was used for statistical analysis. Results In total 32 patients were identified. 68.8% (n = 22) of patients had a diagnosis of dcSSc. 75% (n = 24) patients were female. The most common autoantibodies were ATA (anti-topoisomerase antibody) (34.3%) and ARA (anti-RNA polymerase-III antibody) (18.8%). 46.9% (n = 17) patients had known interstitial lung disease. 6 patients received tocilizumab on a compassionate basis following completion of the open label phase of the focuSSced clinical trial, the remainder had overlap inflammatory arthritis. Mean age of disease onset was 38.6 years, and the median disease duration to tocilizumab initiation was 7.9 years. 11 patients discontinued tocilizumab: 6 due to cessation of the compassionate use access, 2 due to side effects, 3 due to lack of benefit. 75% (n = 24) patients had serial lung function data to compare FVC and DLCO before and after initiation of treatment. Baseline FVC prior to tocilizumab was 3.09L (sd = 0.98). To standardise results, the yearly change rate in FVC and DLCO was calculated. Median change in % predicted FVC was -1.5% (IQR=0.107) and median change in % predicted DLCO was -0.5% (IQR=0.061). Subgroup analysis revealed a significant difference between autoantibody groups and change in FVC while on tocilizumab. It was notable that there was an increase in median change in FVC in patients with ATA antibody (3.27%, IQR=0.1355) whereas there was a decrease in median change in FVC in all other autoantibody groups (-4.7%, IQR=0.111, p = 0.0019). There was a near significant difference in change in DLCO between these antibodies at 12 months (p = 0.056) in favour of improvement in ATA subgroup. Conclusion We report our experience of the impact of tocilizumab on lung function in SSc. Consistent with trial results, there is a signal of potential benefit for lung function among those with ATA autoantibody irrespective of disease subset. As this autoantibody confers high risk of extensive lung fibrosis in SSc it may help in future case selection. Disclosures K.E.N. Clark None. Y. Suleman None. S.I. Nihtyanova None. V.H. Ong None. C.P. Denton Grants/research support; Actelion, GlaxoSmithKline, Bayer, Sanofi, lnventiva, Boehringer Ingelheim, Roche, Bristol Myers Squibb, CSL Behring, UCB, Leadiant Biosciences.

Skin Gene Expression Is Prognostic for the Trajectory of Skin Disease in Patients With Diffuse Cutaneous Systemic Sclerosis.

At present, there are no clinical or laboratory measures that accurately forecast the progression of skin fibrosis and organ involvement in patients with systemic sclerosis (SSc). The goal of this study was to identify skin biomarkers that could be prognostic for the progression of skin fibrosis in patients with early diffuse cutaneous SSc (dcSSc). We analyzed clinical data and gene expression in skin biopsy samples from 38 placebo-treated patients, part of the Roche Safety and Efficacy of Subcutaneous Tocilizumab in Adults with Systemic Sclerosis (FASSCINATE) phase II study of tocilizumab in SSc. RNA samples were analyzed using nCounter. Atrajectory model based on a modified Rodnan skin thickness score was used to describe 3 skin disease trajectories over time. We examined the association of skin gene expression with skin score trajectory groups, by chi-square test. Logistic regression was used to examine the prognostic power of each gene identified. We found that placebo-treated patients with high expression of messenger RNA for CD14, SERPINE1, IL13RA1, CTGF, and OSMR at baseline were more likely to have progressive skin score trajectories. We also found that those genes were prognostic for the risk ofskin progression and that IL13RA1, OSMR, and SERPINE1 performed the best. Skin gene expression of biomarkers associated with macrophages (CD14, IL13RA1) and transforming growth factor β activation (SERPINE1, CTGF, OSMR) are prognostic for progressive skin disease in patients with dcSSc. These biomarkers may provide guidance in decision-making about which patients should be considered for aggressive therapies and/or for clinical trials.

Use of tocilizumab in systemic sclerosis: A brief literature review

The available treatments for systemic sclerosis (SS) have limited effectiveness. Treatment with tocilizumab (TCZ), a biological drug that inhibits interleukin 6 (IL-6), has recently been proposed. In this study, we conducted a literature review to assess the safety and efficacy of TCZ in SS. We found 52 articles, 10 of which we selected after evaluating the articles. In a randomized clinical trial, TCZ showed a nonsignificant improvement in the degree of skin induration, while another observational study showed neutral results. In this same clinical trial, the functional respiratory parameters showed a certain degree of stabilization. The safety profile of TCZ is acceptable; however, the current evidence regarding treatment of SS with TCZ is highly limited, although the drug could have a beneficial effect in skin disorder. New clinical trials are needed to determine the usefulness of TCZ in SS.

Utilización de tocilizumab en la esclerosis sistémica: breve revisión de la literatura

The available treatments for systemic sclerosis (SS) have limited effectiveness. Treatment with tocilizumab (TCZ), a biological drug that inhibits interleukin 6 (IL-6), has recently been proposed. In this study, we conducted a literature review to assess the safety and efficacy of TCZ in SS. We found 52 articles, 10 of which we selected after evaluating the articles. In a randomised clinical trial, TCZ showed a nonsignificant improvement in the degree of skin induration, while another observational study showed neutral results. In this same clinical trial, the functional respiratory parameters showed a certain degree of stabilization. The safety profile of TCZ is acceptable; however, the current evidence regarding treatment of SS with TCZ is highly limited, although the drug could have a beneficial effect in skin disorder. New clinical trials are needed to determine the usefulness of TCZ in SS.

Safety and efficacy of subcutaneous tocilizumab in systemic sclerosis: results from the open-label period of a phase II randomised controlled trial (faSScinate)

ObjectivesAssess the efficacy and safety of tocilizumab in patients with systemic sclerosis (SSc) in a phase II study.MethodsPatients with SSc were treated for 48 weeks in an open-label extension phase...