The Fibrosis Burden of Systemic Sclerosis

Interstitial lung disease (ILD) tends to occur early in systemic sclerosis (SSc), places a significant burden on the patient, and is a leading cause of death (1–4). Although there is a well-recognized association between SSc and ILD, it is still not clear who will develop ILD, and if ILD does indeed develop, which patients will experience significant progression and over what period that progression might occur. Our current understanding of the incidence and progression of this disease comes from several well-designed clinical trials, including SLS I (Scleroderma Lung Study I) and SLS II (3–5).

SLS I included 158 patients from 13 centers with symptomatic lung disease and either BAL evidence of alveolitis or any ground-glass opacities on computed tomography (CT), and with FVC between 45% and 85% predicted (3). Approximately 90% of the patients had some ground-glass opacity and 89% had evidence of fibrosis on high-resolution CT of the chest; 73% of the placebo group had worsening of FVC over a 12-month period. In that study, treatment with cyclophosphamide was found to have a modest effect on lung function decline. In the follow-on SLS II study, there was an 11% mortality at 1 year, which was due to progressive ILD, even in patients receiving cyclophosphamide (4).

The study by Hoffmann-Vold and colleagues (pp. 1258–1266) in the current issue of the Journal provides further insight into the natural history of SSc-associated ILD (6). The authors assessed ILD using data from the Norwegian SSc cohort, which included all 815 SSc patients who resided in Norway between 2000 and 2012. This also included all incident cases that occurred during that period and some prevalence cases that occurred before 2000. Because all patients with SSc in Norway are followed in the public system, the dataset likely represents a nearly complete cohort of patients with SSc in the country during this period. This provides a very rich data source that is reflective of a real-world population, as opposed to the more selected cohorts that are recruited into clinical trials. The value of well-characterized population cohorts in understanding the natural history of ILD has been previously documented in the Journal (7, 8).

One of the strengths of the study is the robust assessment for ILD at baseline: 80% of the patients had a baseline CT and 86% had a baseline pulmonary function test (PFT). In contrast, a potential weakness is the variable follow-up of these two parameters: 56% of the patients had a follow-up CT after a mean of 3.7 years and 48% had a follow-up PFT after a mean of 6.2 years. Notwithstanding these limitations, the follow-up findings provide significant insight into the behavior of ILD in SSc. Fibrosis was defined as a reticular pattern with a superimposed ground-glass change, and 50% of the patients had radiological evidence of ILD at baseline. The presence of fibrosis on baseline CT correlated with 5- and 10-year survival rates of 69% and 56%, respectively, even with normal baseline FVC, and the extent of fibrosis correlated with the standardized mortality rate. Interestingly, the degree of fibrosis that was present at baseline (either <10% or >10%) was equally associated with decreased overall survival (63% and 62%, compared with 82% if no fibrosis was present at baseline). Therefore, although the extent of fibrosis correlated with the standardized mortality rate, the mere presence of any fibrosis on a baseline CT scan is predictive of decreased survival regardless of any other measurements. Interestingly, the proportion of patients with fibrosis was lower than that reported in previous studies of SSc, and the proportion with ground-glass opacity was very low compared with that observed in the SLS (3). This may be because superimposed ground-glass opacity was defined as being equivalent to fibrosis and therefore may have been underestimated. Alternatively, it may reflect the unselected nature of the cohort as opposed to the randomized controlled trial cohort of SLS I, which was enriched for patients with symptomatic lung disease (3).

The finding that baseline fibrosis is predictive of a decline in lung function is similar to previous observations in a study of patients with idiopathic interstitial pneumonia (IP), where a honeycomb change on CT was shown to be a good surrogate for usual IP (UIP) on biopsy and was associated with a poor prognosis (9). In a similar study, the degree of fibrosis was greater in patients with concordant UIP on CT than in those with either discordant UIP or concordant nonspecific IP findings on biopsy (10). Furthermore, the degree of fibrosis also correlated with survival. Taken together, these findings suggest that a baseline CT that demonstrates fibrosis is a significant predictor of a subsequent decline and poor prognosis. Further support for this comes from the recently published SENSCIS (Safety and Efficacy of Nintedanib in Systemic Sclerosis) trial, which included 576 patients with SSc and >10% fibrosis. In this trial, the annual rate of decline in the placebo group was 93 ml/yr, again indicating that the presence of fibrosis predicts a subsequent decline (11).

There is an interesting twist to the findings in the current study: although the presence of any fibrosis at baseline predicted decreased survival, this was not the case for progression of fibrosis on serial CT imaging. Intuitively, one would think that radiological evidence of fibrosis progression would predict further progression. The mean change in extent of lung fibrosis was 3%, whereas previous studies have suggested that the minimal clinically important difference between scans in ILD is about 3.4%, as quantified by a data-driven texture analysis (12). In contrast, evidence of a decline in FVC over serial testing was associated with increased mortality. This may be because the interval was shorter for CT follow-up than for PFT follow-up (3.7 vs. 6.2 yr), or the extent of change in CT fibrosis was at the borderline of the minimal clinically important difference. This suggests that once a baseline CT detects fibrosis, the best follow-up is achieved by means of serial PFTs.

Interestingly, although baseline fibrosis is associated with decreased mortality, not all patients with fibrosis progressed, and a significant proportion were alive at 10 years. In the era of personalized medicine, the challenge therefore is to pick out the patients with fibrosis at baseline who will go on to develop progressive disease. Until we can do so, the search for the holy grail of biomarkers will continue. Furthermore, the current study does not answer the question as to how frequently we should image the patients who have no evidence of fibrosis on baseline CT imaging, despite their good prognosis.

How can the current study influence our practice? From the Norwegian experience, there is now good evidence to recommend a baseline CT in all patients with SSc. Patients who show any evidence of fibrosis on imaging should have close follow-up and serial PFTs, as even mild disease at baseline can have severe disease progression. Remaining questions are, how do we predict which subgroup of patients will have a significant decline, how should we follow patients with no fibrosis at baseline, and who and when do we treat?