Anti-IL-5/5Ra biologics improve work productivity and activity in severe asthma: a RAPSODI registry-based cohort study.

INTRODUCTION: Severe asthma is associated with a serious disease burden, partially caused by limitations in activity and work impairment. AIMS AND OBJECTIVES: This study aims to relate treatment with biologics targeting IL-5/5Ra to work productivity and activity in the long term in a real-world context. MATERIAL AND METHODS: This is a registry-based multi-center cohort study evaluating data from adults with severe eosinophilic asthma included in the Dutch Register of Adult Patients with Severe Asthma for Optimal DIsease management (RAPSODI). Patients that started with anti-IL-5/5Ra biologics and completed the work productivity and activity improvement questionnaire, were included. Study and patient characteristics were compared between the employed and unemployed patients. Work productivity and activity impairment are related to accompanying improvements in clinical outcomes. RESULTS: At baseline, 91 of 137 patients (66%) were employed which remained stable throughout the follow-up period. Patients in the working age category were younger and had significantly better asthma control (p = 0.02). Mean overall work impairment due to health decreased significantly from 25.5% (SD2.6) to 17.6% (SD 2.8) during 12 months anti-IL-5/5Ra biologics treatment (P = 0.010). There was a significant association between ACQ6 and overall work improvement after targeted therapy (ß = 8.7, CI 2.1-15.4, P = 0.01). The improvement of asthma control of 0.5 points on the asthma Control Questionnaire was associated with an overall work impairment of -9%. CONCLUSIONS: Work productivity and activity in severe eosinophilic asthma improved after starting anti-IL-5/5Ra biologics. Clinically relevant improvement in asthma control was associated with an overall work impairment score of -9% in this study.

Exhaled nitric oxide predicts lung function decline in difficult-to-treat asthma.

A subset of patients with asthma is known to have progressive loss of lung function despite treatment with corticosteroids. The aim of the present study was to identify risk factors of decline in forced expiratory volume in one second (FEV(1)) in patients with difficult-to-treat asthma. In total, 136 nonsmoking patients with difficult-to-treat asthma were recruited between 1998 and 1999. Follow-up assessment was performed 5-6 yrs later in 98 patients. The predictive effect of clinical characteristics and inflammatory markers were analysed at baseline (asthma onset and duration, atopy, airway hyperresponsiveness, blood and sputum eosinophils, and the fraction of nitric oxide in exhaled air (F(eNO))) on subsequent decline in post-bronchodilator FEV(1). Patients with high F(eNO) (> or =20 ppb) had an excess decline of 40.3 (95% confidence interval (CI) 7.3-73.2) mL.yr(-1) compared to patients with low F(eNO). F(eNO) > or =20 ppb was associated with a relative risk of 1.9 (95% CI, 1.1-2.6) of having an accelerated (> or =25 mL.yr(-1)) decline in FEV(1). In patients with baseline FEV(1) > or =80% of predicted, this relationship was even stronger: 90 versus 29% had accelerated decline in FEV(1) (F(eNO) > or =20 ppb versus F(eNO) <20 ppb respectively; relative risk 3.1 (95% CI, 1.7-3.4). Exhaled nitric oxide is a predictor of accelerated decline in lung function in patients with difficult-to-treat asthma, particularly if forced expiratory volume in one second is still normal.

Chronic bronchitis sub-phenotype within COPD: inflammation in sputum and biopsies.

The presence of chronic bronchitis predicts a more rapid decline of forced expiratory volume in one second (FEV(1)) in patients with chronic obstructive pulmonary disease (COPD). The hallmark of COPD is airway inflammation. It was hypothesised that COPD patients with chronic bronchitis are characterised by a distinct inflammatory cell profile, as measured in bronchial biopsies and sputum. From 114 COPD patients (male/female ratio 99/15, mean+/-sd age 62+/-8 yrs, current smoking 63%, post-bronchodilator FEV(1) 63+/-9% predicted, no steroids), with and without chronic bronchitis, inflammatory cell counts in bronchial biopsies and induced sputum were measured. Analysis was carried out by logistic regression. COPD patients with chronic bronchitis had lower eosinophil counts in biopsies and higher percentages of sputum eosinophils than patients without those symptoms, which remained after adjustment for smoking and sex. Patients with chronic bronchitis also showed higher percentages of macrophages and lower percentages of neutrophils in sputum, which could be explained by differences in smoking and sex. It was concluded that chronic bronchitis reflects an inflammatory sub-phenotype among patients with chronic obstructive pulmonary disease. The present results indicate a preferential distribution of eosinophils towards the airway lumen in patients with chronic bronchitis. This may have implications for anti-inflammatory treatment of chronic obstructive pulmonary disease patients with chronic bronchitis.

[Arthroscopic lavage plus corticosteroids is more effective than joint aspiration plus corticosteroids in patients with arthritis of the knee]. / Artroscopische lavage met toediening van corticosteroïden effectiever dan gewrichtsaspiratie met toediening van corticosteroïden bij artritis van de knie.

OBJECTIVE: To compare the efficacy of arthroscopic lavage plus corticosteroids (ALC), arthroscopic lavage plus placebo (ALP), and joint aspiration plus corticosteroids (JAC) in patients with arthritis of the knee, and to identify clinical or histological factors that predict outcome. DESIGN: Prospective, randomised. METHOD: Patients with arthritis of the knee (not due to gout, osteoarthritis or septic arthritis) were randomised to 1 of 3 treatment arms: ALC, ALP or JAC. The primary endpoint was time to recurrence; recurrence was defined as recurrent or persistent symptomatic knee swelling requiring local treatment, and/or non-improvement in knee joint score. Synovial tissue specimens were collected for histological analysis. RESULTS: Of the 78 patients enrolled, 3 did not receive the intended therapy and 3 were lost to follow-up. The median time to recurrence was 9.6 months in the ALC group, 3.0 months in the JAC group and 1.0 month in the ALP group. Compared with ALC, the relative risk of recurrence of arthritis (RR) was 2.2 for JAC (95% CI: 1.2-4.2; p = 0.02) and 4.7 for ALP (95% CI: 2.3-9.4; p < 0.0001). In the ALC group, extensive synovial fibrosis was associated with a higher risk of recurrence (RR 5-7; 95% CI: 1.6-20.5; p < 0.01). CONCLUSION: Arthroscopic lavage plus corticosteroids was more effective than arthroscopic lavage plus placebo or joint aspiration plus corticosteroids. The absence of synovial fibrosis predicted a beneficial response.

Ozone-induced inflammation assessed in sputum and bronchial lavage fluid from asthmatics: a new noninvasive tool in epidemiologic studies on air pollution and asthma.

We investigated correlations between ozone-induced increases in inflammatory markers in induced sputum and in bronchial lavage fluid. Sixteen volunteers with intermittent asthma participated in a placebo-controlled parallel study with two exposures. Six days before and 16 h after the first exposure to ozone (0.4 ppm during 2 h) sputum was induced with hypertonic saline. This resulted in a significant increase in the sputum levels of eosinophil cationic protein (ECP; 1.8-fold; p = .03), neutrophil elastase (5.0-fold; p = .005) and the total cell number (1.6-fold; p = .02). After 4 weeks, a second exposure was randomized for air or ozone. Six days before and 16 h after the second exposure a bronchial lavage was performed. ECP values in sputum and in bronchial lavage fluid obtained after ozone correlated significantly (Rs = .79; p = .04), as did interleukin-8 (IL-8) values (Rs = .86; p = .01), and the percentage eosinophils (Rs = .89; p = .007). Moreover, the ozone-induced changes in percentage eosinophils observed in sputum and lavage fluid were highly correlated (Rs = .93; p = .003). In conclusion, changes in eosinophils, IL-8, and ECP markers induced by ozone and measured in sputum reflect the inflammatory responses in the lower airways of asthmatics, and may provide a noninvasive tool in epidemiologic studies on air pollution and asthma.

Role of neutral endopeptidase in exercise-induced bronchoconstriction in asthmatic subjects.

The membrane-bound metalloproteinase, neutral endopeptidase (NEP), is a degrading enzyme of both bronchoconstrictor and bronchodilator peptides within the airways. To examine the role of NEP in exercise-induced bronchoconstriction (EIB) in asthmatic subjects, we used inhaled thiorphan, a NEP inhibitor, as pretreatment to a 6-min standardized exercise challenge. Thirteen clinically stable asthmatic subjects participated in this double-blind, placebo-controlled, crossover study that was performed on 2 days separated by 48 h. Thiorphan was administered by two inhalations of 0.5 ml containing 1.25 mg/ml. Subsequently, exercise was performed on a bicycle ergometer at 40-50% of predicted maximal voluntary ventilation while inhaling dry air (20 degrees C, relative humidity 6%). The airway response to exercise was measured by forced expiratory volume in 1 s (FEV1) every 3 min, up to 30 min postexercise challenge, and was expressed both as the maximal percent fall in FEV1 from baseline and as the area under the time-response curve (AUC) (0-30 min). The acute effects of both pretreatments on baseline FEV1 were not different (P > 0.2), neither was there any difference in maximal percent fall in FEV1 between thiorphan and placebo (P > 0.7). However, compared with placebo, thiorphan reduced the AUC by, on average, 26% [AUC (0-30 min, +/-SE): 213.6 +/- 47.7 (thiorphan) and 288.6 +/- 46.0%fall.h (placebo); P = 0.047]. These data indicate that NEP inhibition by thiorphan reduces EIB during the recovery period. This suggests that bronchodilator NEP substrates, such as vasoactive intestinal polypeptide or atrial natriuretic peptide, modulate EIB in patients with asthma.

Nutrient supplementation with polyunsaturated fatty acids and micronutrients in rheumatoid arthritis: clinical and biochemical effects.

OBJECTIVE: To investigate in a double-blind placebo-controlled, parallel group study, the effects of a nutrient supplement, containing, among other ingredients, the omega-3 fatty acids eicosapentaenoic acid (1.4 g EPA), docosahexaenoic acid (0.211 g DHA), omega-6 fatty acid gamma-linolenic acid (0.5 g GLA) and micronutrients in patients with active rheumatoid arthritis (RA). DESIGN, SUBJECTS AND INTERVENTION: RA patients were randomized to receive either daily liquid nutrient supplementation or placebo for 4 months. The primary end point was the change in tender joint count at 2 and 4 months. Other clinical variables included swollen joint count, visual analogue scales for pain and disease activity, grip strength, functionality score and morning stiffness. Biochemical parameters included plasma concentrations of PUFA and vitamins C and E. SETTING: Outpatient university clinic. RESULTS: In all, 66 patients enrolled, 55 completed the study. No significant change from baseline in tender joint count or any of the other clinical parameters was detected in either group. Patients receiving nutrient supplementation, but not those receiving placebo, had significant increases in plasma concentrations of vitamin E (P=0.015), and EPA, DHA and docosapentaenoic acid concomitant with decreases of arachidonic acid (P=0.01). Intergroup differences for PUFA and vitamin E were significantly different (P=0.01 and 0.03, respectively). CONCLUSIONS: This double-blind, placebo-controlled study in RA patients did not show superior clinical benefit of daily nutrient supplementation with EPA, GLA and micronutrients at the doses tested as compared to placebo. The study adds information regarding doses of omega-3 fatty acids, below which anti-inflammatory effects in RA are not seen.

Internet-based self-management compared with usual care in adolescents with asthma: a randomized controlled trial.

INTRODUCTION: Asthma control often is poor in adolescents and this causes considerable morbidity. Internet-based self-management (IBSM) improves asthma-related quality of life in adults. We hypothesized that IBSM improves asthma-related quality of life in adolescents. METHODS: Adolescents (12-18 years) with persistent and not well-controlled asthma participated in a randomized controlled trial with 1 year follow-up and were allocated to IBSM (n = 46) or usual care (UC, n = 44). IBSM consisted of weekly asthma control monitoring with treatment advice by a web-based algorithm. Outcomes included asthma-related quality of life (Pediatric Asthma Quality of Life Questionnaire, PAQLQ) and asthma control (Asthma Control Questionnaire, ACQ) and were analyzed by a linear mixed-effects model. RESULTS: At 3 months, PAQLQ improved with 0.40 points (95% CI: 0.17-0.62, P < 0.01), by IBSM compared to 0.0 points for UC (P = 0.02 for the difference). At 12 months the between-group difference was -0.05 (95% CI: -0.50 to 0.41, P = 0.85). At 3 months ACQ improved more in IBSM than in UC (difference: -0.32 points; 95% CI: -0.56 to -0.079, P < 0.01). At 12 months the difference was -0.05 (95% CI: -0.35 to 0.25, P = 0.75). CONCLUSION: IBSM improved asthma-related quality of life and asthma control in adolescents with not well-controlled asthma after 3 months, but not after 12 months.

Comparison of efficacy of arthroscopic lavage plus administration of corticosteroids, arthroscopic lavage plus administration of placebo, and joint aspiration plus administration of corticosteroids in arthritis of the knee: A randomized controlled trial.

OBJECTIVE: To compare the efficacy of arthroscopic lavage plus administration of corticosteroids (ALC), arthroscopic lavage plus administration of placebo (ALP), and joint aspiration plus administration of corticosteroids (JAC) in knee arthritis, and to evaluate whether clinical or histologic characteristics determine outcome. METHODS: Patients with knee arthritis (not due to gout, osteoarthritis, or septic arthritis) were randomized over 3 treatment arms: ALC, ALP, and JAC. The primary end point was event-free survival, with events defined as 1) recurrence or persistence of symptomatic knee swelling necessitating local re-treatment, or 2) nonimprovement of the knee joint score. Synovial tissue specimens were collected and analyzed histologically to identify predictive factors of responsiveness. RESULTS: A total of 78 patients were enrolled; 3 patients did not receive their allocated therapy and 3 were lost to followup. The median time until recurrence was 9.6 months after ALC, 3.0 months after JAC, and 1.0 month after ALP, corresponding to a relative risk (RR) of arthritis recurrence of 2.2 for JAC (95% confidence interval [95% CI] 1.2-4.2, P = 0.02) and 4.7 for ALP (95% CI 2.3-9.4, P < 0.0001) compared with ALC. A high versus low synovial extent of fibrosis conferred an RR for recurrence of 5.7 (95% CI 1.6-20.5, P < 0.01) after ALC. CONCLUSION: Arthroscopic lavage plus administration of corticosteroids was more effective than arthroscopic lavage plus administration of placebo or joint aspiration plus injection of corticosteroids. The absence of fibrosis was a histologic predictor of a beneficial response.