MUC5B promoter variant rs35705950 and rheumatoid arthritis associated interstitial lung disease survival and progression.

BACKGROUND: The major risk factor for idiopathic pulmonary fibrosis (IPF), MUC5B rs35705950, was found to be associated with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Whilst the MUC5B rs35705950 T risk allele has been associated with better survival in IPF, its impact on RA-ILD prognosis remains to be determined. Our objective was to explore the influence of MUC5B rs35705950 on survival and progression in RA-ILD. METHODS: Through an international retrospective observational study, patients with RA-ILD were genotyped for the MUC5B rs35705950 variant and consecutive pulmonary function tests (PFTs) findings were collected. Longitudinal data up to a 10-year follow-up were considered and analyzed using mixed regression models. Proportional hazards and joint proportional hazards models were used to analyze the association of baseline and longitudinal variables with lung transplant-free survival. Significant progression of RA-ILD was defined as at least an absolute or relative 10% decline of forced vital capacity at 2 years from baseline. RESULTS: Out of 321 registered patients, 261 were included in the study: 139 women (53.3%), median age at RA-ILD diagnosis 65 years (interquartile range [IQR] 57 to 71), 151 ever smokers (59.2%). Median follow-up was 3.5 years (IQR 1.3 to 6.6). Mortality rate was 32% (95%CI 19 to 42) at 10 years. The MUC5B rs35705950 variant did not impact lung transplant-free survival (HR for the T risk allele carriers=1.26; 95%CI 0.61 to 2.62; P=0.53). Decline in pulmonary function at 2 years was not influenced by MUC5B rs35705950 (OR=0.95; 95%CI 0.44 to 2.05; P=0.89), irrespective of the HRCT pattern. CONCLUSION: In this study, the MUC5B rs35705950 promoter variant did not influence transplant- free survival or decline in pulmonary function in patients with RA-ILD.

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.).

Fatigue in Primary Sjögren's Syndrome: Clinical, Laboratory, Psychometric, and Biologic Associations.

OBJECTIVE: To identify independent contributors of fatigue in primary Sjögren's syndrome (SS) patients, taking into account clinical, laboratory, and psychological features, and to explore the potential role of interferon (IFN)-induced gene indoleamine 2,3-dioxygenase (IDO-1), anti-21-hydroxylase (anti-21[OH]) antibodies, and soluble BAFF. METHODS: Detailed clinical and laboratory characteristics were recorded for 106 primary SS patients. The Functional Assessment of Chronic Illness Therapy-Fatigue, Zung Depression Scale, State-Trait Anxiety Inventory, Eysenck Personality Questionnaire Scale, and Athens Insomnia Scale were adopted to assess fatigue, depression, anxiety, and sleep disturbances, respectively. Peripheral whole blood expression levels of IDO-1, as well as type I and II IFN-induced genes were calculated using quantitative reverse transcriptase-polymerase chain reaction. Serum anti-21(OH) antibodies and soluble BAFF levels were determined by a radioimmunoassay and an enzyme-linked immunosorbent assay, respectively. Univariate and multivariate models were performed to identify determinants of fatigue. RESULTS: Fatigue was detected in 32 of 106 (30.2%) primary SS patients. In univariate analysis, fatigue was associated with arthralgias/myalgias, fibromyalgia hydroxychloroquine therapy, both state and trait anxiety scores, depression, and neuroticism, as well as impaired sleep patterns. Multivariate analysis revealed neuroticism (odds ratio [OR] 6.9, [95% confidence interval (95% CI) 1.7-28.0]), depression (OR 3.0 [95% CI 0.8-11.0]), and fibromyalgia (OR 5.5 [95% CI 1.1-27.7]) as independent fatigue contributors. Soluble BAFF levels, anti-21(OH) autoantibodies, and IDO-1 messenger RNA expression did not significantly differ between fatigued and nonfatigued primary SS patients. CONCLUSION: Depression, neuroticism, and fibromyalgia play a major role in primary SS-associated fatigue and should be addressed in clinical practice, with active collaboration between rheumatologists and mental health professionals. Further studies are warranted in order to explore underlying pathophysiologic pathways that might explain fatigue in the setting of primary SS.