Performance of respiratory patient reported outcome instruments in systemic sclerosis associated interstitial lung disease trials: Are we falling at the first hurdle?

Interstitial lung disease (ILD) affects up to half of individuals with systemic sclerosis (SSc), within which it is a major cause of disease-related morbidity and a leading cause of mortality. Forced vital capacity (FVC) has been endorsed as a primary outcome measure for randomised controlled trials (RCT) assessing the efficacy of novel treatments for SSc-ILD. The FVC is considered a suitable surrogate biomarker, although does not directly capture information on how patients 'feel' and 'function', which regulators consider essential for marketing authorisation. Only patient-reported outcome (PRO) instruments can provide this insight. This review aims to systematically examine the inclusion, validity and performance of respiratory-specific PRO instruments used in SSc-ILD RCTs, using the COnsensus based Standards for the selection of health Measurement INstruments (COSMIN) framework and regulatory guidance. Our search identified 10 respiratory-specific PRO instruments used in SSc-ILD RCTs. Of these, 4 are single-item instruments and 2 were developed with any ILD patient input. Seventeen studies assessing the measurement properties of respiratory-specific PRO instruments within an SSc-ILD population were identified, with varying methodologies. The findings of this review highlight the lack of consensus for the use of respiratory-specific PRO instrument use in SSc-ILD RCTs. Identified instruments have unproven content validity within this population and limited evidence for other measurement properties, primarily derived from post hoc analyses of RCT data or cross-sectional studies. Future work should prioritise assessing the content validity and measurement properties of existing ILD specific instruments according to COSMIN guidance.