OBJECTIVE: The objective of this study is to evaluate whether adding oral glucocorticoids to immunosuppressive therapy improves skin scores and ensures safety in patients with early diffuse cutaneous systemic sclerosis (dcSSc). METHODS: We performed an emulated randomized trial comparing the changes from baseline to 12 ± 3 months of the modified Rodnan skin score (mRSS: primary outcome) in patients with early dcSSc receiving either oral glucocorticoids (≤20 mg/day prednisone equivalent) combined with immunosuppression (treated) or immunosuppression alone (controls), using data from the European Scleroderma Trials and Research Group. Secondary end points were the difference occurrence of progressive skin or lung fibrosis and scleroderma renal crisis. Matching propensity score was used to adjust for baseline imbalance between groups. RESULTS: We matched 208 patients (mean age 49 years; 33% male; 59% anti-Scl70), 104 in each treatment group, obtaining comparable characteristics at baseline. In the treated group, patients received a median prednisone dose of 5 mg/day. Mean mRSS change at 12 ± 3 months was similar in the two groups (decrease of 2.7 [95% confidence interval {95% CI} 1.4-4.0] in treated vs 3.1 [95% CI 1.9-4.4] in control, P = 0.64). Similar results were observed in patients with shorter disease duration (≤ 24 months) or with mRSS ≤22. There was no between-group difference for all prespecified secondary outcomes. A case of scleroderma renal crisis occurred in both groups. CONCLUSION: We did not find any significant benefit of adding low-dose oral glucocorticoids to immunosuppression for skin fibrosis, and at this dosage, glucocorticoid did not increase the risk of scleroderma renal crisis.
- MeSH
- Administration, Oral MeSH
- Databases, Factual MeSH
- Scleroderma, Diffuse * drug therapy pathology diagnosis MeSH
- Adult MeSH
- Fibrosis MeSH
- Glucocorticoids * administration & dosage adverse effects MeSH
- Immunosuppressive Agents * administration & dosage adverse effects MeSH
- Drug Therapy, Combination MeSH
- Skin * pathology drug effects MeSH
- Middle Aged MeSH
- Humans MeSH
- Prednisone * administration & dosage adverse effects MeSH
- Treatment Outcome MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Randomized Controlled Trial MeSH
- Geographicals
- Europe MeSH
OBJECTIVE: To examine disease and target engagement biomarkers in the RISE-SSc trial of riociguat in early diffuse cutaneous systemic sclerosis and their potential to predict the response to treatment. METHODS: Patients were randomized to riociguat (n = 60) or placebo (n = 61) for 52 weeks. Skin biopsies and plasma/serum samples were obtained at baseline and week 14. Plasma cyclic guanosine monophosphate (cGMP) was assessed using radio-immunoassay. α-Smooth muscle actin (αSMA) and skin thickness were determined by immunohistochemistry, mRNA markers of fibrosis by qRT-PCR in skin biopsies, and serum CXC motif chemokine ligand 4 (CXCL-4) and soluble platelet endothelial cell adhesion molecule-1 (sPECAM-1) by enzyme-linked immunosorbent assay. RESULTS: By week 14, cGMP increased by 94 (78)% with riociguat and 10 (39)% with placebo (P < 0.001, riociguat vs placebo). Serum sPECAM-1 and CXCL-4 decreased with riociguat vs placebo (P = 0.004 and P = 0.008, respectively). There were no differences in skin collagen markers between the two groups. Higher baseline serum sPECAM-1 or the detection of αSMA-positive cells in baseline skin biopsies was associated with a larger reduction of modified Rodnan skin score from baseline at week 52 with riociguat vs placebo (interaction P-values 0.004 and 0.02, respectively). CONCLUSION: Plasma cGMP increased with riociguat, suggesting engagement with the nitric oxide-soluble guanylate cyclase-cGMP pathway. Riociguat was associated with a significant reduction in sPECAM-1 (an angiogenic biomarker) vs placebo. Elevated sPECAM-1 and the presence of αSMA-positive skin cells may help to identify patients who could benefit from riociguat in terms of skin fibrosis. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02283762.
- MeSH
- Biomarkers * blood MeSH
- Biopsy MeSH
- Scleroderma, Diffuse * drug therapy pathology MeSH
- Adult MeSH
- Double-Blind Method MeSH
- Fibrosis drug therapy MeSH
- Cyclic GMP blood metabolism MeSH
- Skin * pathology drug effects metabolism MeSH
- Middle Aged MeSH
- Humans MeSH
- Pyrazoles * therapeutic use MeSH
- Pyrimidines * therapeutic use MeSH
- Treatment Outcome MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase II MeSH
- Randomized Controlled Trial MeSH
OBJECTIVES: Riociguat is approved for pulmonary arterial hypertension and has antiproliferative, anti-inflammatory and antifibrotic effects in animal models of tissue fibrosis. We evaluated the efficacy and safety of riociguat in patients with early diffuse cutaneous systemic sclerosis (dcSSc) at high risk of skin fibrosis progression. METHODS: In this randomised, double-blind, placebo-controlled, phase IIb trial, adults with dcSSc of <18 months' duration and a modified Rodnan skin score (mRSS) 10-22 units received riociguat 0.5 mg to 2.5 mg orally three times daily (n=60) or placebo (n=61). The primary endpoint was change in mRSS from baseline to week 52. RESULTS: At week 52, change from baseline in mRSS units was -2.09±5.66 (n=57) with riociguat and -0.77±8.24 (n=52) with placebo (difference of least squares means -2.34 (95% CI -4.99 to 0.30; p=0.08)). In patients with interstitial lung disease, forced vital capacity declined by 2.7% with riociguat and 7.6% with placebo. At week 14, average Raynaud's condition score had improved ≥50% in 19 (41.3%)/46 patients with riociguat and 13 (26.0%)/50 patients with placebo. Safety assessments showed no new signals with riociguat and no treatment-related deaths. CONCLUSIONS: Riociguat did not significantly benefit mRSS versus placebo at the predefined p<0.05. Secondary and exploratory analyses showed potential efficacy signals that should be tested in further trials. Riociguat was well tolerated.
- MeSH
- Enzyme Activators administration & dosage MeSH
- Scleroderma, Diffuse drug therapy pathology MeSH
- Adult MeSH
- Double-Blind Method MeSH
- Risk Assessment MeSH
- Immunohistochemistry MeSH
- Internationality MeSH
- Biopsy, Needle MeSH
- Middle Aged MeSH
- Humans MeSH
- Follow-Up Studies MeSH
- Treatment Failure MeSH
- Pyrazoles administration & dosage MeSH
- Pyrimidines administration & dosage MeSH
- Respiratory Function Tests MeSH
- Drug Administration Schedule MeSH
- Severity of Illness Index MeSH
- Dose-Response Relationship, Drug MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase II MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
- Randomized Controlled Trial MeSH
