Sclerotic Graft-Versus-Host Disease of the Torso As a Determinant of Pulmonary Function and Clinical Outcomes

Introduction Reduced parameters of pulmonary function tests (PFTs) are a hallmark manifestation of pulmonary chronic graft-versus-host disease (cGVHD). Skin sclerosis, one of the most severe manifestations of cGVHD, could adversely impact lung volumes due to chest wall mobility restriction and complicate accurate diagnosis of lung disease. Objectives The objective of this analysis was to evaluate if sclerotic skin GVHD (ScGVHD) of the torso is associated with lung function and overall survival (OS). Methods Patients (n=312) were enrolled on the cross-sectional NIH cGVHD natural history study (NCT00092235) and evaluated for percent body surface area (%BSA) affected by ScGVHD. Dermal and subcutaneous sclerosis %BSA measurements were summed for the anterior, posterior and total torso affected by ScGVHD. Measures of lung function (fraction predicted normal), NIH cGVHD lung score, and OS were compared between groups, defined using %BSA affected by ScGVHD (0% vs. 1-74% vs. 75-100%; <75% vs. 75-100%; 0% vs. 1-100%) separately for anterior, posterior, and total torso. Results Over half of patients (57%) had ScGVHD involvement on the torso, including 54% on anterior and 49% on posterior torso. Among patients with involvement, median (interquartile range) %BSA involved was 40% (15, 70) for anterior torso, 33% (10, 65) for posterior torso, and 35% (11, 61) for total torso. The extent of %BSA affected by ScGVHD showed a weak correlation with obstruction on PFTs and a moderately strong correlation with restriction (total torso %BSA and total lung capacity [TLC]: ρ −0.367, p<0.001). All three groups defined by %BSA ScGVHD were significantly associated with reduced TLC (p<0.001). None of the groups were associated with the NIH cGVHD lung score. Analyses found that 75% BSA ScGVHD of posterior and total torso was the most effective discriminator of OS between patients (adjusted p=0.003 and p=0.006, respectively). The median OS was not reached for patients with <75% BSA ScGVHD but was 83.8 months (95% confidence interval [CI]: 17.9 to not estimable) for patients with ≥75% BSA posterior (n=35) or total torso (n=25) ScGVHD. The multivariable Cox regression analysis with stepwise elimination resulted in a model in which posterior torso ≥75% BSA involvement was independently associated with worse OS (hazard ratio = 1.91 [95% CI: 1.16 - 3.14]; P=0.011) adjusted for NIH cGVHD lung score, Karnofsky performance status, renal function, and absolute lymphocyte count, all of which have previously been associated with OS in this study cohort. Conclusion Sclerotic involvement of the torso did not show a significant association with the NIH cGVHD lung scoring. However, a higher degree of posterior torso sclerotic skin cGVHD was independently associated with inferior OS, likely not via effects on lung function. These data are consistent with the hypothesis that lung and sclerotic skin cGVHD are two separate disease processes.