Incidences and Risk Factors of Organ Manifestations in the Early Course of Systemic Sclerosis: A Longitudinal EUSTAR Study

Abstract

Objective: Systemic sclerosis (SSc) is a rare and clinically heterogeneous autoimmune disorder characterised by fibrosis and microvascular obliteration of the skin and internal organs. Organ involvement mostly manifests after a variable period of the onset of Raynaud's phenomenon (RP). We aimed to map the incidence and predictors of pulmonary, cardiac, gastrointestinal (GI) and renal involvement in the early course of SSc.

Methods: In the EUSTAR cohort, patients with early SSc were identified as those who had a visit within the first year after RP onset. Incident SSc organ manifestations and their risk factors were assessed using Kaplan-Meier methods and Cox regression analysis.

Results: Of the 695 SSc patients who had a baseline visit within 1 year after RP onset, the incident non-RP manifestations (in order of frequency) were: skin sclerosis (75%) GI symptoms (71%), impaired diffusing capacity for monoxide<80% predicted (65%), DU (34%), cardiac involvement (32%), FVC<80% predicted (31%), increased PAPsys>40mmHg (14%), and renal crisis (3%). In the heart, incidence rates were highest for diastolic dysfunction, followed by conduction blocks and pericardial effusion. While the main baseline risk factor for a short timespan to develop FVC impairment was diffuse skin involvement, for PAPsys>40mmHg it was higher patient age. The main risk factors for incident cardiac manifestations were anti-topoisomerase autoantibody positivity and older age. Male sex, anti-RNA-polymerase-III positivity, and older age were risk factors associated with incident renal crisis.

Conclusion: In SSc patients presenting early after RP onset, approximately half of all incident organ manifestations occur within 2 years and have a simultaneous rather than a sequential onset. These findings have implications for the design of new diagnostic and therapeutic strategies aimed to 'widen' the still very narrow 'window of opportunity'. They may also enable physicians to counsel and manage patients presenting early in the course of SSc more accurately.

Fig 1. Flow chart of patients included and excluded in the analysis.

Fig 2

Kaplan-Meier curves with 95% CI of the manifestation of any first non-RP feature after RP onset in all SSc patients in the entire EUSTAR cohort (A) and stratified by sex (B), the median age at RP onset (C) and the autoantibody status (D). CI, confidence interval; RP, Raynaud’s phenomenon; Pts, patients; ACA, anti-centromere autoantibodies; anti-TOPO, anti-topoisomerase-I autoantibodies; anti-RNAP-III, anti-RNA-polymerase-III autoantibodies; hash marks represent censored observations.

Fig 3. Kaplan-Meier curves of incident organ involvement in SSc patients of the study population after RP onset.

RP, Raynaud’s phenomenon; Pts, patients; DLCO, single breath diffusing capacity for monoxide; GI symptoms, gastrointestinal symptoms, defined as a history of either dysphagia, reflux, early satiety, vomiting, diarrhoea, bloating or constipation; Skin involvement, defined as a modified Rodnan skin score of ≥2 at any part of the body; Cardiac involvement, defined as either the presence of diastolic dysfunction, conduction blocks, a left ventricular ejection fraction (LVEF) < 50%, or a pericardial effusion; FVC, forced vital capacity; PAPsys, systolic pulmonary artery pressure as estimated by echocardiography.

Fig 4

Kaplan-Meier curves with 95% CI of incident pulmonary restriction (FVC<80% of predicted; (A-D)), suspected pulmonary hypertension (PAPsys>40 mmHg; (E-H)), cardiac involvement (I-L) and renal crisis (M-P) after RP onset in SSc patients of the study population; stratified by sex (A/E/I/M), the median age at RP onset (B/F/J/N), autoantibody status (C/G/K/O) and extent of skin involvement within the first year after RP onset (D/H/L/P). CI, confidence interval; FVC, forced vital capacity; PAPsys, systolic pulmonary artery pressure as estimated by echocardiography; cardiac involvement, defined as either the presence of diastolic dysfunction, conduction blocks, a left ventricular ejection fraction (LVEF)<50%, or a pericardial effusion; RP, Raynaud’s phenomenon; yrs, years; ACA, anti-centromere autoantibodies; Anti-TOPO, Anti-topoisomerase-I autoantibodies; Anti-RNAP-III, anti-RNA-polymerase-III autoantibodies; hash marks represent censored observations.

Fig 5. Kaplan-Meier curves of incident cardiac manifestations after RP onset in SSc in the study population.

RP, Raynaud’s phenomenon; Pts, patients; LVEF, left ventricular ejection fraction; hash marks represent censored observations.