Combining Clinical and Biological Data to Predict Progressive Pulmonary Fibrosis in Patients With Systemic Sclerosis Despite Immunomodulatory Therapy

Abstract

ObjectiveProgressive pulmonary fibrosis (PPF) is the leading cause of death in systemic sclerosis (SSc). This study aimed to develop a clinical prediction nomogram using clinical and biological data to assess risk of PPF among patients receiving treatment of SSc‐related interstitial lung disease (SSc‐ILD).MethodsPatients with SSc‐ILD who participated in the Scleroderma Lung Study II (SLS II) were randomized to treatment with either mycophenolate mofetil (MMF) or cyclophosphamide (CYC). Clinical and biological parameters were analyzed using univariable and multivariable logistic regression, and a nomogram was created to assess the risk of PPF and validated by bootstrap resampling.ResultsAmong 112 participants with follow‐up data, 22 (19.6%) met criteria for PPF between 12 and 24 months. An equal proportion of patients randomized to CYC (n = 11 of 56) and mycophenolate mofetil (n = 11 of 56) developed PPF. The baseline severity of ILD was similar for patients who did, compared to those who did not, experience PPF in terms of their baseline forced vital capacity percent predicted, diffusing capacity for carbon monoxide percent predicted, and quantitative radiological extent of ILD. Predictors in the nomogram included sex, baseline CXCL4 level, and baseline gastrointestinal reflux score. The nomogram demonstrated moderate discrimination in estimating the risk of PPF, with a C‐index of 0.72 (95% confidence interval 0.60‐0.84).ConclusionThe SLS II data set provided a unique opportunity to investigate predictors of PPF and develop a nomogram to help clinicians identify patients with SSc‐ILD who require closer monitoring while on therapy and potentially an alternative treatment approach. This nomogram warrants external validation in other SSc‐ILD cohorts to confirm its predictive power.

Biomarkers in Systemic Sclerosis: An Overview

“…However, the initial trigger event has not yet been identified. Recent studies supported the role of a genetic predisposition and both endogenous and/or exogenous environmental triggers may be promoter for epigenetic mechanisms in genetically predisposed population [1][2][3][4][5][6][7][8][9][10][68][69][70][71][72][73][74][75]. Interestingly, a recent study supported the role of infectious triggers in SSc pathogenesis; in particular, the authors reported a possible role of Parvovirus B19 in this disease [15].…”

“…Moreover, the presence of ANA, NVC abnormalities and recurrent Raynaud's phenomenon are predictive factors for progression to definitive SSc. In particular, anti-topoisomerase I antibodies are predictive, in the first 3 years of disease of the development of diffused skin involvement and digital ulcers (DU), as well as severe interstitial lung disease (ILD) [65][66][67][68][69][70][71][72][73][74][76][77][78][79][80][81][82][83][84][85][86][87][119][120][121][122][123][124][125][126][127]. The anti-centromere autoantibodies (ACA) are associated with PAH and anti-topoisomerase I autoantibodies with ILD.…”

“…Interstitial lung disease (ILD) is one of the most common manifestations of SSc (SSc-ILD), affecting approximately 40-60% of patients, and pulmonary hypertension (PH) is the leading cause of both mortality and disability in SSc [69][70][71][72][73][74][75]. Pulmonary involvement is responsible for approximately 35% of all SSc-related deaths [70][71][72][73][74][75][76][77].…”

“…Indeed, the presence of capillaroscopic abnormalities of the nail fold, together with the presence of ANA and recurrent Raynaud's phenomenon, are predictive factors for progression to definitive SSc. Anti-topoisomerase I antibodies are also predictive, in the first 3 years of disease of the development of diffused skin involvement and digital ulcers (DU), as well as severe interstitial lung disease (ILD) [66][67][68][69][70][71][72][73][74][75][76][77].…”

Enrichment Strategies for Systemic Sclerosis–Interstitial Lung Disease Trials

“…Although the prevalence of ILD is higher in patients with diffuse cutaneous disease than in those with limited cutaneous disease, in SLS II, there was no difference in the course of the FVC% predicted between patients with limited versus diffuse cutaneous disease ( 4 ). Neither cutaneous subtype was associated with the development of PPF in patients receiving treatment with MMF or cyclophosphamide in this trial ( 7 ).…”