Background/Purpose: Interstitial lung disease (ILD) affects the majority of patients with systemic sclerosis (SSc). The disease course of ILD varies among SSc patients and no reliable clinical or biological parameters consistently predict outcomes. We investigated whether the presence of a gain-of-function MUC5B promoter polymorphism, previously shown to be strongly associated with idiopathic pulmonary fibrosis and rheumatoid arthritis-related ILD predicted response to immunosuppression with cyclophosphamide (CYC) and mycophenolate (MMF) in SSc-ILD.

Methods: 142 patients in Scleroderma Lung Study (SLS) II (Tashkin et al. Lancet Resp Med 2016) were randomized to receive either MMF for 2 years or oral CYC for 1 year followed by 1 year of placebo. Presence of ground glass opacity was a requirement for enrollment. Genotyping of the MUC5B rs35705950 single nucleotide polymorphism was performed using TaqMan Genotyping Assaysin all patients with an available DNA sample. The forced vital capacity (FVC) and the diffusing capacity for carbon monoxide (DLCO) were measured every 3 months. Quantitaive Lung fibrosis (QLF) and Quantitative ILD (QILD) scores for whole lung (WL) and zone of maximum involvement (ZM) were measured at baseline and 24 months. Linear regression models with the outcomes of change in radiographic fibrosis and ILD scores at 24 months were created to investigate the relationship between the presence of the MUC5B variant and SSc-ILD progression.

Results: Among 128 SLS II participants, 23 (18%) possessed at least one copy of the MUC5B rs35705950 minor allele. There were no significant differences in the baseline characteristics between SSc-ILD patients with and without this variant with respect to age, sex, %diffuse disease, disease duration, FVC, DLCO, radiographic extent of fibrosis, nor the presence of honeycombing on high resolution computed tomography. Similar to available data from the general population, this variant was rare among African Americans (4%) in our cohort. The presence of this MUC5B variant was not significantly associated with the change of QLF-ZM, QLF-WL, QILD-ZM, QILD-WL scores at 24 months, even after adjusting for baseline extent of fibrosis, treatment arm, and race (Table 1). In addition, using a joint model analysis with the covariates of FVC, treatment arm, race and a time trend, the presence of the MUC5B variant did not predict the course of the FVC%-predicted.

Conclusion: Among SSc-ILD patients with ground glass opacity on imaging who received treatment with CYC or MMF in a rigorously-conducted clinical trial, the presence of MUC5B rs35705950 minor allele did not predict ILD disease progression. Future studies are needed to further investigate how the presence of this variant affects outcomes in other SSc populations.

SLS II_MUC5B_ACR_Table 1

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-muc5b-promoter-variant-does-not-predict-outcomes-in-systemic-sclerosis-related-interstitial-lung-disease/