Progression of skin fibrosis within 1 year was associated with deteriorating lung function and overall mortality in patients with diffuse cutaneous systemic sclerosis (SSc), a large European study determined.
In a multivariable analysis from the European Scleroderma Trials and Research (EUSTAR) database, skin progression was independently associated with a decline in forced vital capacity (FVC) of 10% or more within a year, with a hazard ratio of 1.79 (95% CI 1.20-2.65, P=0.004), according to Oliver Distler, MD, of University Hospital Zurich in Switzerland, and colleagues.
In addition, skin progression was independently associated with all-cause death, with a hazard ratio of 2.58 (95% CI 1.31-5.09, P=0.006), the researchers reported online in Annals of the Rheumatic Diseases.
While skin fibrosis is the hallmark of SSc, the major morbidities and mortality associated with this connective tissue disorder result from complications in visceral organs, with manifestations such as interstitial lung disease, pulmonary arterial hypertension, and renal crisis.
"A major challenge for physicians is to identify patients at high risk of future complications before irreversible visceral involvement occurs. With several new disease-modifying agents in late-stage development, improved identification of at-risk patients will become even more important to inform early treatment intervention," Distler and colleagues wrote.
A previous study by this group identified disease duration of 15 months or less and low baseline modified Rodnan skin scores (≤22 units) as predictors of skin progression in patients with diffuse cutaneous SSc. Skin fibrosis progression was defined as an increase of more than five units in the skin score and by at least 25% at 1 year.
Earlier studies had suggested that a change in Rodnan skin score might be a useful surrogate marker for disease progression, but those studies were conducted almost 20 years ago. In addition, spontaneous regression of skin fibrosis can occur, and patients vary widely in their disease course. More recent, comprehensive data are therefore required to determine whether skin progression reflects organ damage and risks for mortality and should be considered a possible marker for progression in daily practice and clinical trials, the investigators stated.
Accordingly, they analyzed data on 1,021 patients with diffuse cutaneous SSc enrolled in EUSTAR from 2009 to 2017. Patients' mean age was 52, mean duration of disease was 7.7 years, and mean modified Rodnan skin score at baseline was 16.9. Whereas in the overall cohort, 13.4% had disease duration of 15 months or less, 27.9% of skin progressors were classified as having early disease compared with 12.2% of non-progressors (P<0.001).
A total of 35.8% of patients experienced a decrease in FVC of 10% or more during a median follow-up of 3.7 years.
Among patients whose baseline Rodnan skin score was 22 or lower and whose disease duration was less than 15 months (which are the criteria for recruitment into clinical trials in recent years), those identified as skin progressors had a significantly greater risk for decline in FVC. A total of 57.4% of patients with low baseline skin scores had declines in FVC compared with 33.9% of those with higher baseline skin scores (P<0.001), and FVC declines were seen in 58.3% of patients with short disease duration compared with 29.2% of those with longer disease duration (P=0.019).
With regard to other organ involvement, the investigators found no association between skin progression in systolic heart dysfunction and scleroderma renal crisis when stratified by baseline Rodnan skin score or disease duration.
There also was no significant difference between skin progressors and non-progressors in the development of pulmonary hypertension, with the exception of a lower probability of this outcome among skin progressors with disease duration over 15 months.
During 3.4 years of follow-up, 7.9% of patients died, including 15.4% of skin progressors and 7.3% of non-progressors. In the subgroup of patients with low baseline Rodnan skin scores, skin progressors had a significantly higher rate of all-cause mortality (13.4% vs 7.2%, P=0.017). Mortality was also higher among skin progressors with short disease duration (21.% vs 2.8%, P=0.009).
"Our findings indicate that patients with diffuse cutaneous SSc and skin progression within 1 year have a higher probability of lung progression and worse survival during follow-up. These findings suggest that such patients should be monitored very carefully in clinical practice," the investigators wrote.
"In subgroup analyses, we confirmed that disease course is worse in patients with diffuse cutaneous SSc with early disease," they stated, but noted that organ progression also was observed in patients with later-stage disease. "This underlines the heterogeneity of the disease course, and clinicians should therefore pay attention to all patients with progression of skin fibrosis, even those with longer disease duration," they advised.
A limitation of the study was the lack of information in the EUSTAR database on specific causes of death, the researchers said.
The study was supported by Bayer AG.
The authors reported financial relationships with multiple companies including Bayer, Sanofi-Aventis, Boehringer Ingelheim, Actelion, Pfizer, Biogen Idec, Bristol-Myers Squibb, Genentech/Roche, GlaxoSmithKline, Medimmune, Eli Lilly, Corbus, UCB, CSL Behring, Merck-Serono, Biogen IDEC, Inventiva, and Servier.
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