Predicting the risk of subsequent progression in patients with systemic sclerosis-associated interstitial lung disease with progression: a multicentre observational cohort study

Background: In patients with systemic sclerosis, it is common practice to treat interstitial lung disease (ILD) in patients in whom progression has already occurred. We sought to clarify whether observed progression of systemic sclerosis-associated ILD confers risk for subsequent progression.

Methods: In this multicentre observational cohort study, based on an analysis of prospectively collected data, we included patients with systemic sclerosis-associated ILD aged 18 years or older at diagnosis, who fulfilled the 2013 American College of Rheumatology-European Association of Alliances in Rheumatology systemic sclerosis classification criteria. The main cohort (diagnosed between January 2001 and December 2019) was consecutively followed up annually over 4 years at the Department of Rheumatology at the Oslo University Hospital, Norway, and the Department of Rheumatology at the University Hospital Zurich, Switzerland. We applied four definitions of ILD progression: the primary definition was forced vital capacity (FVC) decline of 5% or more, and secondary definitions included FVC decline of 10% or more, progressive pulmonary fibrosis (PPF), and progressive fibrosing ILD (PF-ILD). We applied these definitions at each annual visit after the first (visit 1). We validated our findings in an enriched cohort that included patients from the main cohort with systemic sclerosis-associated ILD and short disease duration of less than 3 years along with patients diagnosed between January 2003 and September 2019 from the Division of Rheumatology, University of Michigan, Ann Arbor, MI, USA. Multivariable logistic regression analyses were applied to predict ILD progression and its effect on mortality. There was no involvement of people with lived experience in this study.

Findings: Of 231 patients with systemic sclerosis-associated ILD from the main cohort (mean age 48·0 years [SD 14·6], 176 [76%] female and 55 [24%] male), 71 (31%) had ILD progression as defined by an FVC decline of 5% or more between visit 1 and visit 2, 38 (16%) as defined by an FVC decline of 10% or more, 39 (17%) as defined by PPF, and 89 (39%) defined by PF-ILD. In multivariable logistic regression analyses, adjusted for risk factors for progressive systemic sclerosis-associated ILD and immunosuppressive treatment, we found that ILD progression, defined by FVC decline of 5% or more, from visit 1 to visit 2 reduced the risk for further progression from visit 2 to visit 3 (odds ratio [OR] 0·28 [95% CI 0·12-0·63]; p=0·002) and that there was no risk for subsequent progression using the other definitions (FVC decline of ≥10%: 0·57 [0·16-1·99; p=0·38]; PPF: 0·93 [0·39-2·22; p=0·88]; and PF-ILD: 0·69 [0·35-1·36]; p=0·28]). Using the primary definition of progression, we found the same results in the enriched systemic sclerosis-associated ILD cohort, wherein 41 (34%) of 121 patients had progression defined by an FVC decline of 5% or more (OR 0·22 [95% CI 0·06-0·87]; p=0·031). FVC decline of 5% or more was significantly associated with mortality (hazard ratio 1·66 [95% CI 1·05-2·62]; p=0·030) adjusted for other risk factors.

Interpretation: Systemic sclerosis-associated ILD progression does not predict further ILD progression at the next annual follow-up visit, even in an enriched population, but progression was associated with mortality. These results have implications for clinical practice because they support a paradigm shift in treatment strategy, advocating for initiating therapy in patients at risk of progression. Further research is needed to confirm these findings.

Funding: None.

Translations: For the German and Norwegian translations of the abstract see Supplementary Materials section.