Predicting treatment outcomes and responder subsets in scleroderma-related interstitial lung disease

Abstract

Objective: To identify baseline characteristics of patients with scleroderma-related interstitial lung disease (SSc-ILD) that could serve as predictors of the most favorable response to 12-month treatment with oral cyclophosphamide (CYC).

Methods: Regression analyses were retrospectively applied to the Scleroderma Lung Study data in order to identify baseline characteristics that correlated with the absolute change in forced vital capacity (FVC) (% predicted values) and the placebo-adjusted change in % predicted FVC over time (the CYC treatment effect).

Results: Completion of the CYC arm of the Scleroderma Lung Study was associated with a placebo-adjusted improvement in the % predicted FVC of 2.11% at 12 months, which increased to 4.16% when patients were followed up for another 6 months (P=0.014). Multivariate regression analyses identified the maximal severity of reticular infiltrates (assessed as maximum fibrosis scores) on high-resolution computed tomography (HRCT) at baseline, the modified Rodnan skin thickness score (MRSS) at baseline, and the Mahler baseline dyspnea index as independent correlates of treatment response. When patients were stratified on the basis of whether 50% or more of any lung zone was involved by reticular infiltrates on HRCT and/or whether patients exhibited an MRSS of at least 23, a subgroup of patients emerged in whom there was an average CYC treatment effect of 9.81% at 18 months (P<0.001). Conversely, there was no treatment effect (a -0.58% difference) in patients with less severe HRCT findings and a lower MRSS at baseline.

Conclusion: A retrospective analysis of the Scleroderma Lung Study data identified the severity of reticular infiltrates on baseline HRCT and the baseline MRSS as patient features that might be predictive of responsiveness to CYC therapy.

Trial registration: ClinicalTrials.gov NCT00004563.

Figure 1. Predictors of the CYC treatment effect at 18 months

Baseline values for the (A) maximal severity of reticular changes on HRCT (MaxFIB score), (B) modified Rodnan skin score (mRSS) and (C) Mahler's baseline dyspnea index (BDI) were divided into clinically-relevant groups and plotted against the placebo (Plac)-adjusted treatment effect at 18 months (the change in %-predicted FVC from baseline to 18 months in the CYC arm minus the change observed in the same subset in the placebo arm). All of these baseline characteristics demonstrated a significant correlation with FVC outcome (p<0.05).

Figure 2. Multivariate tree regression analysis

In Step 1, the study population was dichotomized into those assigned to the CYC versus placebo arms. The mean change in %-predicted FVC from 0 to 18 months is indicated, as are the applicable subjects numbers (N) and histograms demonstrating the number of subjects with different ranges of change in %-predicted FVC. The difference between groups and the resulting p-value are also shown. In Step 2, each group was further subdivided into two subsets based on the MaxFIB score. In Step 3, subjects were again subdivided based on their mRSS score. Rather than dividing each treatment arm into 4 different subsets, subjects with a MaxFIB score ≥3 and/or a mRSS ≥23 were pooled into one group and subjects with a MaxFIB score <3 and a mRSS <23 were left as the alternative grouping. When the resulting populations were compared, a CYC responsive group was identified with an average treatment effect of 9.81%. Conversely, the subset with a low MaxFIB score and a low mRSS demonstrated no significant CYC treatment effect.

Figure 3. Time-trend curves

The changes in %-predicted FVC from baseline to 18 months (adjusted for baseline FVC) are plotted for the cyclophosphamide (CYC) and placebo (Plac) arms (mean ±SEM). The number of subjects (N) at each time-point and the p-value comparing groups is presented. (A) There was a small but significant difference between the treatment arms at 18 months when results were plotted for all patients. (B) Dividing the study population into Responder and Non-responder subsets resulted in two distinct plots with a highly-significant treatment effect from 9 to 18 months occurring only in the Responder population.