Objective

To investigate the prevalence of the MUC5B promoter variant rs35705950 in patients with systemic sclerosis-interstitial lung disease (SSc-ILD) and whether its presence predicts response to immunosuppression with cyclophosphamide (CYC) and mycophenolate (MMF).

Methods

SSc-ILD patients who participated in Scleroderma Lung Study (SLS) II (MMF versus CYC) were included in this study (N = 142). TaqMan Genotyping Assays were used to determine the MUC5B rs35705950 single nucleotide polymorphism. Joint models were created to examine how the presence of this variant affected the course of the forced vital capacity (FVC) over 2 years. Linear regression models were used to investigate the relationship between the presence of this variant and the change in quantitative radiographic fibrosis.

Results

Among 128 participants who were tested for this variant, 18% possessed at least one copy of the MUC5B minor allele. Patients with at least one copy of this allele were similar to those without the allele with respect to age, sex, SSc subtype, ILD disease severity; however, this variant was rare among African Americans (3.7%). The presence of the MUC5B variant did not affect the course of the FVC, nor the change in quantitative radiographic fibrosis, ground glass or ILD scores in either treatment arm.

Conclusion

In the context of a randomized controlled trial for SSc-ILD, the presence of the MUC5B variant did not predict disease severity, nor affect treatment response to MMF or CYC. Future studies are needed to determine whether this variant affects ILD progression in other SSc cohorts and in patients receiving anti-fibrotic therapy.

Background

Increased circulatory levels of the chemokine CXCL4 have been associated with the presence of interstitial lung disease (ILD) in an observational study of patients with systemic sclerosis (SSc). The purpose of the present study was to evaluate the relationship between baseline CXCL4 level and extent of ILD in the context of a randomized controlled trial and to determine whether changes in CXCL4 levels in response to immunosuppression are associated with future progression of SSc-ILD.

Methods

A total of 142 SSc-ILD patients from Scleroderma Lung Study (SLS) II were randomized in a double-blind, parallel-arm trial, to receive mycophenolate (MMF) for 2 years or oral cyclophosphamide (CYC) for 1 year followed by 1 year of placebo. Plasma CXCL4 levels were measured at baseline, 12 months, and 24 months in SLS II participants (N = 136) and at a single time point in healthy controls (N = 67). A mixed-effects model evaluated the relationship between change in CXCL4 levels and SSc-ILD progression. The primary outcome was the course of the forced vital capacity.

Results

Baseline CXCL4 levels were significantly higher in SSc-ILD patients compared with healthy controls (2699 ± 1489 ng/ml vs 2233 ± 1351 ng/ml (mean ± SD); P = 0.019). However, no significant correlations were identified between CXCL4 levels and extent of ILD at baseline, as measured by the forced vital capacity, diffusing capacity of carbon monoxide, or radiographic extent of ILD. Plasma CXCL4 decreased significantly from baseline to 12 months in all patients (CYC: P < 0.001; MMF: P = 0.006) with no between-treatment differences (CYC vs MMF). Patients with the largest decline in CXCL4 levels during the first 12 months had an improved course of forced vital capacity %-predicted from 12 to 24 months (P = 0.040), even after adjusting for baseline disease severity and treatment arm assignment.

Conclusions

Levels of CXCL4 were higher in patients with SSc-ILD compared with controls and decreased in all patients treated with immunosuppressive therapy. While CXCL4 levels were not correlated with extent of ILD at baseline, changes in CXCL4 at 12 months predicted future progression of SSc-ILD from 12 to 24 months. These findings suggest that intermediate-term changes in CXCL4 may have predictive significance for long-term progression of SSc-ILD in patients receiving immunosuppressive therapy.

Trial registration

ClinicalTrials.gov NCT00883129 . Registered 16 April 2009.

Objective

To investigate the relationship between Krebs von den Lungen 6 (KL-6) and CCL18 levels and the severity and progression of systemic sclerosis (SSc)-related interstitial lung disease (ILD).

Methods

Patients enrolled in the Scleroderma Lung Study II (cyclophosphamide [CYC] versus mycophenolate mofetil [MMF]) were included. Baseline and 12-month plasma samples were analyzed by enzyme-linked immunosorbent assay to assess CCL18 and KL-6 levels. The forced vital capacity (FVC) and the diffusing capacity for carbon monoxide (DLco) were measured every 3 months. Joint models were created to investigate the relationship between baseline CCL18 and KL-6 levels and the course of the FVC and DLco over 1 year according to treatment arm.

Results

Baseline KL-6 and CCL18 levels each correlated with the extent of radiographic fibrosis. Levels of both CCL18 and KL-6 declined significantly at 1 year. In both treatment arms (n = 71 for CYC, n = 62 for MMF), a higher baseline KL-6 level predicted progression of ILD based on the course of FVC (P = 0.024 for CYC; P = 0.005 for MMF) and DLco (P < 0.001 for CYC; P = 0.004 for MMF) over 1 year. A higher baseline CCL18 level predicted progression of ILD based on the course of the FVC (P < 0.001 for CYC; P = 0.007 for MMF) and DLco (P = 0.001 for CYC; P < 0.001 for MMF) over 1 year, as well as mortality (P = 0.0008 for CYC arm only).

Conclusion

In a rigorously conducted clinical trial for SSc-related ILD, KL-6 and CCL18 levels correlated with ILD severity and declined with immunosuppression. Patients with higher baseline KL-6 and CCL18 levels were more likely to experience disease progression despite treatment. KL-6 and CCL18 levels could be used to identify patients with a progressive ILD phenotype who may benefit from a more aggressive initial treatment approach.