Background Systemic sclerosis (SSc) related pulmonary hypertension (PH) carries a high mortality and patients with SSc-PH related to restrictive lung disease (RLD) having an even worse prognosis. Speculation regarding the potential of MMF to exert anti-fibrotic and anti-remodeling effects on parenchymal lung and vascular intimal fibrosis, led us to query the possible differences in outcomes and survival between 4 groups based on forced vital capacity (FVC) and MMF use in SSc PH.
Methods PHAROS is a prospective registry designed to provide substantive data to recognize aspects of PH unique to SSc. For this analysis patients were stratified by an FVC of >70% or ≤70% predicted on spirometry at the time of PH diagnosis by right heart catheterization (RHC) and then by MMF duration of ≥6 months from PH diagnosis. MMF<6 months or cyclophosphamide use was exclusionary to all groups. Calculations are derived from one-way ANOVA with Tukey's post test or Kruskal Wallis with Dunn's post-test. Categorical variables were compared with Chi square. These analyses were followed by Cox and stepwise backward regression analysis to assess baseline characteristics associated with risk of death (variables with p<0.1 included) and Kaplan-Meyer analysis.
Results 256 cases from the PHAROS database matched criteria and had baseline spirometry results coincident with diagnostic RHC, of those 173 had a baseline FVC>70% with 23 on MMF and 150 without; and 83 had a baseline FVC≤70% with 26 on MMF and 57 without.
Across groups, no differences were found in age, disease duration, race nor surprisingly in skin score, 6 minute walk test (6MWD) or NYHA Class. WHO Group I, female sex and lcSSc classification were higher in the FVC>70 MMF- group; with FVC≤70%/RLD groups having significantly more lung fibrosis, lower FVC:DLCO ratio, and more WHO Group III classifications supporting our RLD definition.
There was no significant interval change in baseline FVC and follow-up FVC 6-18 month later.
Of interest, baseline mPAP and PVR were lower in both MMF+ groups regardless of FVC.
Survival was statistically worse with FVC≤70 without MMF at 3 years (p=0.04). Male sex, mPAP, DLCO were significant independent predictors of death in all groups (p=0.001, p<0.0001, p<0.0001) especially when FVC was ≤70% (p=0.007, p=0.003, p=0.005).
Conclusions Statistically significant improved survival in patients with PH with FVC≤70 treated with MMF even in the absence of improvement of FVC is intriguing. MMF effects on pulmonary artery remodeling should be considered. These findings warrant prospective controlled investigations and examination of larger combined international databases of MMF in SScPH particularly in those with restrictive lung disease.
Acknowledgements PHAROS is supported by an investigator initiated grant from Gilead Science.
Disclosure of Interest L. A. Saketkoo Grant/research support from: ACR/EULAR Exchange Awardee; Gilead, M. Lammi: None declared, A. Fischer: None declared, J. Molitor: None declared, V. Steen Grant/research support from: Actelion Pharmaceuticals US Bayer CSL Berhing Intermune Roche Pharmaceuticals Sanofi-Aventis Pharmaceutical UCB United Therapeutics