Poor survival in rheumatoid arthritis associated with bronchiectasis: a family-based cohort study.

BACKGROUND: Diffuse bronchiectasis (DB) may occur in rheumatoid arthritis (RA). CFTR (cystic fibrosis transmembrane conductance regulator) mutations predispose RA patients to DB, but the prognosis of RA-associated DB (RA-DB) is unclear. METHODS: We report long-term mortality data from a nationwide family-based association study of patients with RA only, DB only or RA-DB. We assessed mortality as a function of clinical characteristics and CF/CFTR-RD (CFTR-related disorders) mutations in 137 subjects from 24 kindreds. Potential risk factors were investigated by Cox proportional-hazard analysis with shared Gaussian random effects to account for within-family correlations. RESULTS: During a median follow-up of 11 years after inclusion, 18 patients died, mostly from cardiorespiratory causes. Survival was significantly lower for RA-DB patients than for unaffected relatives and for patients with RA or DB only. RA patients with DB had also a poorer prognosis in terms of survival after RA diagnosis (HR, 8.6; 95% CI, 1.5-48.2; P = 0.014) and from birth (HR, 9.6; 95% CI, 1.1-81.7; P = 0.039). Early onset of DB (HR, 15.4; 95% CI, 2.1-113.2; P = 0.007) and CF/CFTR-RD mutation (HR, 7.2; 95% CI, 1.4-37.1; P = 0.018) were associated with poorer survival in patients with RA-DB. Thus, CF/CFTR-RD mutations in RA patients with early-onset DB defined a subgroup of high-risk patients with higher mortality rates (log-rank test P = 1.28×10(-5)). CONCLUSION: DB is associated with poorer survival in patients with RA. Early-onset DB and CFTR mutations are two markers that identify RA patients at a high risk of death, for whom future therapeutic interventions should be designed and evaluated

Perception of bronchial obstruction in asthmatic patients. Relationship with bronchial eosinophilic inflammation and epithelial damage and effect of corticosteriod treatment

Abstract We studied the perception of bronchoconstriction in asthmatic subjects who were randomly treated with inhaled 12 agonist given either alone (n = 9) or associated with inhaled corticosteroids (n = 9). Methacholine and bradykinin challenges, bronchoalveolar lavage, and bronchial biopsies were performed in all subjects. After each dose of agonist, breathlessness was assessed using a visual analog scale (VAS) and the forced expiratory volume in 1 s (FEV1) was measured. The relationship between VAS scores and FEVY and the slope of the regression line of VAS scores on the corresponding FEV1 (VAS/FEV1 slope) were analyzed for each agonist. Subjects without corticosteroids had good perception of methacholine but poor perception of bradykinin-induced bronchoconstriction. In subjects with corticosteroids, bronchoconstriction was well perceived whatever the agonist. VAS/FEV1 slopes for bradykinin but not for methacholine correlated negatively with the magnitude of eosinophilic inflammation in airway mucosa. VAS/FEV1 slopes for each agonist correlated positively with the percentage of basement membrane covered by airway epithelium. We conclude that in asthmatic patients perception of bronchoconstriction is related to eosinophilic inflammation and to epithelial damage in airways and that corticosteroid treatment is associated with improved perception of bronchoconstriction induced by bradykinin, a mediator endogenously produced in asthma. (J. Clin. Invest. 1995. 96:12-21.

Analysis of survival from birth of 30 patients with both RA and DB.

<p>RA: rheumatoid arthritis; DB: diffuse bronchiectasis.</p><p>Early-onset DB: respiratory symptoms preceding RA by >10 years (mostly childhood DB).</p><p><i>CFTR</i>: cystic fibrosis transmembrane conductance regulator gene.</p><p>A mixed effect Cox model was used, with shared random effects, depending on the kinship coefficient of individuals.</p><p>The variance of the random effect was 4×10⁻⁴.</p><p>Analysis of survival from birth of 30 patients with both RA and DB.</p

Kaplan-Meier probability of survival from inclusion of the various participants in the study cohort, according to their phenotype.

<p><b>Panel A.</b> Kaplan-Meier survival curves from inclusion in the study for the various groups of individuals. <b>Panel B.</b> Hazard ratios (95% CI) of death after inclusion for the various disease groups, compared with unaffected relatives as the reference group. A mixed effect Cox model was fitted, taking inclusion as the starting point and adjusting for age at inclusion. Individual random effects were assumed to be correlated as a function of the corresponding kinship coefficients. The variance of the random effect was 1.48. RA: rheumatoid arthritis; DB: diffuse bronchiectasis.</p

Kaplan-Meier probability of survival from birth of patients with both RA and DB according to risk of death categories.

<p>The analysis classified RA patients with DB into categories of low or high risk of death. Patients with early onset of DB and CF/<i>CFTR</i>-related disorders mutations were classified in the high group as compared with the other patients with both RA and DB who were classified into the low risk. RA: rheumatoid arthritis; DB: diffuse bronchiectasis. Early-onset DB: respiratory symptoms preceding RA by >10 years (mostly childhood DB). Late-onset DB: respiratory symptoms occurring at the same time or <10 years before RA onset (adulthood DB). Mutations: cystic fibrosis (CF) and cystic fibrosis transmembrane conductance regulator (<i>CFTR</i>)-related disorder mutations. See Patients and Methods for additional information.</p

Kaplan-Meier probability of survival after RA diagnosis in patients, as a function of the presence or absence of associated DB.

<p><b>Panel A</b>. Kaplan-Meier curves of survival after RA diagnosis, as a function of the presence or absence of associated DB. <b>Panel B</b>. Hazard ratios (95% CI) for death after RA diagnosis associated with the presence of DB. A mixed effect Cox model was fitted, taking RA diagnosis as the starting point. Individual random effects were assumed to be correlated as a function of the corresponding kinship coefficients. The variance of the random effect was 4 10⁻⁴. RA: rheumatoid arthritis; DB: diffuse bronchiectasis.</p

Characteristics and outcome of the 137 participants in the family-based cohort study.

<p>RA: rheumatoid arthritis; DB: diffuse bronchiectasis. <i>CFTR</i>: cystic fibrosis transmembrane conductance regulator gene.</p><p>Plus-minus values are means+SD.</p>a<p> <i>P</i>-values of Fisher exact tests.</p>b<p> <i>P</i>-values of Kruskal-Wallis tests.</p><p>* Causes of death included CVA, Hodgkin lymphoma, cancer, and refractory RA, in one patient each.</p>†<p> Cause of death was CVA.</p>‡<p> Cause of death was cancer.</p>¥<p> Causes of death included cancer in 4 patients and degenerative neurological disease in one patient.</p><p>Characteristics and outcome of the 137 participants in the family-based cohort study.</p

Comparative analysis of amino acid patterns at the P450 signature motif CXG in fungal P450s.

<p>In total 4304 P450s from the fungal phyla ascomycota (1336 P450s), basidiomycota (2859 P450s), zygomycota (102 P450s) and chytridiomycota (seven P450s) were used for the analysis. As shown in the figures, 32 amino acid patterns were identified in fungal P450 for the CXG motif. The numbers on the bars represent the number of amino acids representing the pattern. The overall percentage of that pattern is shown in parenthesis.</p