MUC5B Promoter Variant and Rheumatoid Arthritis with Interstitial Lung Disease.

BACKGROUND: Given the phenotypic similarities between rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) (hereafter, RA-ILD) and idiopathic pulmonary fibrosis, we hypothesized that the strongest risk factor for the development of idiopathic pulmonary fibrosis, the gain-of-function MUC5B promoter variant rs35705950, would also contribute to the risk of ILD among patients with RA. METHODS: Using a discovery population and multiple validation populations, we tested the association of the MUC5B promoter variant rs35705950 in 620 patients with RA-ILD, 614 patients with RA without ILD, and 5448 unaffected controls. RESULTS: Analysis of the discovery population revealed an association of the minor allele of the MUC5B promoter variant with RA-ILD when patients with RA-ILD were compared with unaffected controls (adjusted odds ratio, 3.8; 95% confidence interval [CI], 2.8 to 5.2; P=9.7×10-17). The MUC5B promoter variant was also significantly overrepresented among patients with RA-ILD, as compared with unaffected controls, in an analysis of the multiethnic case series (adjusted odds ratio, 5.5; 95% CI, 4.2 to 7.3; P=4.7×10-35) and in a combined analysis of the discovery population and the multiethnic case series (adjusted odds ratio, 4.7; 95% CI, 3.9 to 5.8; P=1.3×10-49). In addition, the MUC5B promoter variant was associated with an increased risk of ILD among patients with RA (adjusted odds ratio in combined analysis, 3.1; 95% CI, 1.8 to 5.4; P=7.4×10-5), particularly among those with evidence of usual interstitial pneumonia on high-resolution computed tomography (adjusted odds ratio in combined analysis, 6.1; 95% CI, 2.9 to 13.1; P=2.5×10-6). However, no significant association with the MUC5B promoter variant was observed for the diagnosis of RA alone. CONCLUSIONS: We found that the MUC5B promoter variant was associated with RA-ILD and more specifically associated with evidence of usual interstitial pneumonia on imaging. (Funded by Société Française de Rhumatologie and others.).

Characterization of SLC26A9 in patients with CF-like lung disease.

Diffuse bronchiectasis is a common problem in respiratory clinics. We hypothesized that mutations in the solute carrier 26A9 (SLC26A9) gene, encoding for a chloride (Cl(-)) transporter mainly expressed in lungs, may lead to defects in mucociliary clearance. We describe two missense variants in the SLC26A9 gene in heterozygote patients presenting with diffuse idiopathic bronchiectasis : p.Arg575Trp, identified in a patient also heterozygote for p.Phe508del in the CFTR gene; and p.Val486Ile. Expression of both mutants in Xenopus laevis oocytes abolished SLC26A9-mediated Cl(-) conductance without decreasing protein membrane expression. Coexpression of CFTR with SLC26A9-p.Val486Ile resulted in a significant increase in the Cl(-) current induced by PKA stimulation, similar to that obtained in oocytes expressing CFTR and SLC26A9-WT. In contrast, coexpression of CFTR with SLC26A9-p.Arg575Trp inhibited SLC26A9-enhanced CFTR activation upon PKA. Further structure-function analyses led us to propose a site encompassing Arg575 in the SLC26A9-STAS domain for CFTR-SLC26A9 interaction. We hypothesize that SLC26A9-p.Arg575Trp prevented SLC26A9-mediated functional activation of CFTR by altering SLC26A9-CFTR interaction. Although we cannot confirm that these mutations by themselves are deleterious, we propose that they trigger the pathogenic role of a single CFTR mutation and provide insight into a novel mechanism of Cl(-) transport alteration across the respiratory mucosa, based on functional inhibition of CFTR.

Role for interferon-gamma release assays in latent tuberculosis screening before TNF-α antagonist therapy.

TNF-α antagonist therapy is associated with a risk of severe, extrapulmonary, disseminated tuberculosis, which is fatal in 10% of cases. The risk of tuberculosis is increased four-fold in patients on TNF-α antagonist therapy. The main risk factors are a history of untreated or inadequately treated primary tuberculosis, recent contact with a tuberculosis patient, and residence in or travel to a high-endemicity region. Infection surveillance agencies throughout the world have issued recommendations to ensure the detection and treatment of latent tuberculosis before TNF-α antagonist initiation. These recommendations have returned the incidence of tuberculosis to the level seen before the introduction of TNF-α antagonists. Nevertheless, there is still room for improvement. Recommendations about latent tuberculosis screening include the use of tuberculin skin tests. However, these tests are positive in individuals vaccinated with the BCG vaccine, which leads to overuse of tuberculosis chemoprophylaxis and, therefore, to unnecessary patient exposure to hepatotoxic effects. Furthermore, tuberculin skin tests may be falsely negative in immunosuppressed patients, leading to underuse of tuberculosis prophylaxis. These shortcomings of tuberculin skin tests have generated interest in interferon-gamma release assays (IGRAs). In patients with overt tuberculosis, IGRAs are more sensitive and more specific than tuberculin skin tests. However, the accuracy of IGRAs for diagnosing latent tuberculosis remains unknown, because no reference standard is available. In addition, patients taking immunosuppressant agents to treat systemic disease may exhibit anergia, which complicates the interpretation of IGRAs. Until additional data become available, caution requires that IGRAs be used only when a positive or negative result, as assessed on a case-by-case basis, will help to decide whether tuberculosis chemoprophylaxis is in order.