Specific Factors Identify Patients at Risk for Disease Progression in SSc Clinical Trials

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Researchers identified predictive factors associated with mortality and worsening of organ function in diffuse systemic sclerosis.

The use of predictive factors can help researchers identify patients for clinical trials who are at risk for disease worsening in diffuse systemic sclerosis (SSc), according to research results published in Annals of the Rheumatic Diseases.

Researchers sought to identify possible predictive factors of worsening disease or death in patients with diffuse SSc. Data from the European Scleroderma Trials and Research (EUSTAR) group database were used for analysis.

Data were included for patients with baseline visits in 2009 or later who had either a follow-up visit or died within 12±3 months after baseline. The chosen primary analysis point was 12 months.

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Data were extracted in February 2016. A total of 1451 patients met the inclusion criteria at the time of data extraction; 706 patients had available data relating to the combined end points. No major differences were noted in baseline characteristics between the inclusion and exclusion groups.

Of the patients with available data, 32.3% (n=228) met the predefined criteria for disease worsening within 12±3 months of their baseline visit. The most common methods of disease worsening were deterioration of forced vital capacity and death; renal crisis and worsening of left ventricular ejection fraction were rare.

Based on 100 imputed datasets, all odds ratios were >1 and positively associated with disease worsening. Substantial evidence for a strong association between disease progression and age, active digital ulcers, C-reactive protein (CRP) elevation, lung fibrosis, and muscle weakness was identified. In particular, active digital ulcers, CRP elevation, lung fibrosis, and muscle weakness were associated with a “significantly shorter time to disease progression.”

Investigators calculated outcome probabilities for risk factor combinations within the study cohort. Both lung fibrosis and elevated CRP had high odds ratios; these factors increased the probability of an event occurring during the observation time by 52.0% and 57.9% in patients aged 60 and 70 years, respectively, compared with 32.2% among the general study population. In addition, lung fibrosis, muscle weakness and digital ulcers increased the probability of an event to 74.5% and 78.8% in patients aged 60 and 70 years, respectively.

Researchers evaluated the effect of these predictors on long-term, event-free survival curves for patients with SSc with and without risk factors. The combination of increased CRP and lung fibrosis or digital ulcers showed worse event-free survival with the presence of risk factors. In patients with lung fibrosis and elevated CRP, the median time to an outcome event was 1.53 years, compared with 4.48 years in patients without risk factors.

Investigators used a bootstrap with 10,000 repetitions to validate the final model. The C-index of the model was 0.711 (0.705 at validation), which indicated a good calibration, or agreement between actual and predicted probabilities.

Study limitations included the high incidence of missing data, which can be common with patient registries such as EUSTAR, and the limits associated with the number of potential predictive variables that can be included in statistical models.

“This study provides evidence-based information from the largest SSc database available worldwide regarding which patients are appropriate for inclusion in clinical trials,” the researchers concluded. “This study provides key data to inform a novel study design that could likely be applied in the near future.”

Disclosure: This clinical trial was supported by Bayer AG. Please see the original reference for a full list of authors’ disclosures.


Becker M, Graf N, Sauter R, et al. Predictors of disease worsening defined by progression of organ damage in diffuse systemic sclerosis: a European Scleroderma Trials and Research (EUSTAR) analysis Ann Rheum Dis. 2019;78(9).