Background Interstitial lung disease (ILD) is a common manifestation of systemic sclerosis and a leading cause of systemic sclerosis-related death. Nintedanib, a tyrosine kinase inhibitor, has been shown to have antifibrotic and antiinflammatory effects in preclinical models of systemic sclerosis and ILD. Methods We conducted a randomized, double-blind, placebo-controlled trial to investigate the efficacy and safety of nintedanib in patients with ILD associated with systemic sclerosis. Patients who had systemic sclerosis with an onset of the first non-Raynaud's symptom within the past 7 years and a high-resolution computed tomographic scan that showed fibrosis affecting at least 10% of the lungs were randomly assigned, in a 1:1 ratio, to receive 150 mg of nintedanib, administered orally twice daily, or placebo. The primary end point was the annual rate of decline in forced vital capacity (FVC), assessed over a 52-week period. Key secondary end points were absolute changes from baseline in the modified Rodnan skin score and in the total score on the St. George's Respiratory Questionnaire (SGRQ) at week 52. Results A total of 576 patients received at least one dose of nintedanib or placebo; 51.9% had diffuse cutaneous systemic sclerosis, and 48.4% were receiving mycophenolate at baseline. In the primary end-point analysis, the adjusted annual rate of change in FVC was -52.4 ml per year in the nintedanib group and -93.3 ml per year in the placebo group (difference, 41.0 ml per year; 95% confidence interval [CI], 2.9 to 79.0; P = 0.04). Sensitivity analyses based on multiple imputation for missing data yielded P values for the primary end point ranging from 0.06 to 0.10. The change from baseline in the modified Rodnan skin score and the total score on the SGRQ at week 52 did not differ significantly between the trial groups, with differences of -0.21 (95% CI, -0.94 to 0.53; P = 0.58) and 1.69 (95% CI, -0.73 to 4.12 [not adjusted for multiple comparisons]), respectively. Diarrhea, the most common adverse event, was reported in 75.7% of the patients in the nintedanib group and in 31.6% of those in the placebo group. Conclusions Among patients with ILD associated with systemic sclerosis, the annual rate of decline in FVC was lower with nintedanib than with placebo; no clinical benefit of nintedanib was observed for other manifestations of systemic sclerosis. The adverse-event profile of nintedanib observed in this trial was similar to that observed in patients with idiopathic pulmonary fibrosis; gastrointestinal adverse events, including diarrhea, were more common with nintedanib than with placebo. (Funded by Boehringer Ingelheim; SENSCIS ClinicalTrials.gov number, NCT02597933.).

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Nintedanib for Systemic Sclerosis-Associated Interstitial Lung Disease.

Objective

To assess survival and incidence of organ-based complications in a large single-center cohort of unselected systemic sclerosis (SSc) patients, and to explore predictors of survival and clinically significant pulmonary fibrosis (PF) and pulmonary hypertension (PH).



Methods

The study cohort consisted of 398 consecutive SSc patients, followed up for up to 15 years. Cox proportional hazards analysis with demographic, clinical, and laboratory characteristics as predictor variables was used to develop prediction models for pulmonary complications and survival.



Results

The overall survival estimate at the end of followup was 57% among patients with limited cutaneous SSc (lcSSc) and 50% among patients with diffuse cutaneous SSc (dcSSc) (P = 0.017). We found that greater age at disease onset, dcSSc, lower diffusing capacity for carbon monoxide (DLco), lower hemoglobin levels, higher serum creatinine levels, and the presence of PH or cardiac involvement were independent predictors of worse survival. Over the entire followup period, 42% of dcSSc patients and 22% of lcSSc patients developed clinically significant PF (P < 0.001). The variables that predicted clinically significant PF development were dcSSc, greater age at onset, lower forced vital capacity and DLco, and the presence of anti–topoisomerase I antibody, while the presence of anticentromere antibody was protective. There was no difference in cumulative incidence of PH between the 2 subsets—24% in lcSSc and 18% in dcSSc (P = 0.558). Incidence rates were 1–2% per year. The PH prediction model demonstrated that greater age at onset, increase in serum creatinine levels, lower DLco, and the presence of anti–RNA polymerase III or anti–U3 RNP antibodies were associated with increased risk of PH, while anti–topoisomerase I antibody positivity reduced the hazard.



Conclusion

Our study provides data on long-term outcome of SSc and the timing and frequency of major organ complications. The predictive models we present could be used as clinical tools for patient risk stratification and could facilitate cohort enrichment for event-driven studies.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.38390

Prediction of pulmonary complications and long-term survival in systemic sclerosis.

There is little literature about the mortality associated with bronchiectasis. The aim of the present study was to investigate factors affecting mortality in patients with bronchiectasis. In total, 91 patients were examined for aetiology, pulmonary function tests, high-resolution computed tomography, sputum microbiology and quality of life scores and were then followed over 13 yrs. Overall, 29.7% of the patients died. On multivariate analysis, age, St George's Respiratory Questionnaire activity score, Pseudomonas aeruginosa infection, total lung capacity (TLC), residual volume/TLC and the transfer factor coefficient were all independently associated with mortality. In patients with moderate to severe bronchiectasis, mortality is associated with a degree of restrictive and obstructive disease, poor gas transfer and chronic pseudomonas infection. These features should guide future research into disease progression, and identify those patients needing intensive treatment.

https://erj.ersjournals.com/content/erj/34/4/843.full.pdf

Mortality in bronchiectasis: a long-term study assessing the factors influencing survival

Interstitial lung disease in connective tissue disorders.

Diagnosis and treatment of connective tissue disease-associated interstitial lung disease

Rationale: In interstitial lung disease complicating systemic sclerosis (SSc-ILD), the optimal prognostic use of baseline pulmonary function tests (PFTs) and high-resolution computed tomography (HRCT) is uncertain.Objectives: To construct a readily applicable prognostic algorithm in SSc-ILD, integrating PFTs and HRCT.Methods: The prognostic value of baseline PFT and HRCT variables was quantified in patients with SSc-ILD (n = 215) against survival and serial PFT data.Measurements and Main Results: Increasingly extensive disease on HRCT was a powerful predictor of mortality (P < 0.0005), with an optimal extent threshold of 20%. In patients with HRCT extent of 10–30% (termed indeterminate disease), an FVC threshold of 70% was an adequate prognostic substitute. On the basis of these observations, SSc-ILD was staged as limited disease (minimal disease on HRCT or, in indeterminate cases, FVC ⩾ 70%) or extensive disease (severe disease on HRCT or, in indeterminate cases, FVC < 70%). This system (hazards ratio [H...

Jonathan Ratoff

Papers

Interstitial lung disease in systemic sclerosis: a simple staging system.