Lauri A. Laitinen

Effects of Reducing or Discontinuing Inhaled Budesonide in Patients with Mild Asthma

BACKGROUND In a previous study, we found that two years of treatment with an inhaled corticosteroid, budesonide, was more effective than treatment with an inhaled beta 2-agonist, terbutaline, in patients with newly diagnosed, generally mild asthma. We continued this study for a third year to investigate whether the steroid dose could be reduced or discontinued and what effect crossover of patients from beta 2-agonist therapy to corticosteroid therapy would have. METHODS A total of 37 patients treated for two years with inhaled budesonide at a dose of 1200 micrograms per day were randomly assigned to treatment with 400 micrograms of budesonide per day (19 patients) or placebo (18 patients) in a double-blind manner. Another 37 patients, who had received terbutaline during the first two years, were crossed over in an open-label manner to treatment with 1200 micrograms of budesonide per day during the third year. RESULTS Treatment with the reduced dose of budesonide was sufficiently effective in 74 percent of the patients to maintain bronchial responsiveness at a level similar to that achieved with the higher dose. In contrast, improvement was maintained in only 33 percent of the patients receiving placebo, and the differences in pulmonary function between the steroid and placebo groups were significant (for forced expiratory volume in one second, P = 0.007; for bronchial responsiveness to histamine, P = 0.025; and for peak expiratory flow in the morning, P = 0.040). The condition of patients who were crossed over from terbutaline therapy to treatment with 1200 micrograms of budesonide per day improved. However, the degree of improvement in these patients appeared to be less than in those who were treated with budesonide at the beginning of the three-year study. CONCLUSIONS Early treatment with inhaled budesonide results in long-lasting control of mild asthma. Maintenance therapy can usually be given at a reduced dose, but discontinuation of treatment is often accompanied by exacerbation of the disease.

A 10 year asthma programme in Finland: major change for the better

Background: A National Asthma Programme was undertaken in Finland from 1994 to 2004 to improve asthma care and prevent an increase in costs. The main goal was to lessen the burden of asthma to individuals and society. Methods: The action programme focused on implementation of new knowledge, especially for primary care. The main premise underpinning the campaign was that asthma is an inflammatory disease and requires anti-inflammatory treatment from the outset. The key for implementation was an effective network of asthma-responsible professionals and development of a post hoc evaluation strategy. In 1997 Finnish pharmacies were included in the Pharmacy Programme and in 2002 a Childhood Asthma mini-Programme was launched. Results: The incidence of asthma is still increasing, but the burden of asthma has decreased considerably. The number of hospital days has fallen by 54% from 110 000 in 1993 to 51 000 in 2003, 69% in relation to the number of asthmatics (n = 135 363 and 207 757, respectively), with the trend still downwards. In 1993, 7212 patients of working age (9% of 80 133 asthmatics) received a disability pension from the Social Insurance Institution compared with 1741 in 2003 (1.5% of 116 067 asthmatics). The absolute decrease was 76%, and 83% in relation to the number of asthmatics. The increase in the cost of asthma (compensation for disability, drugs, hospital care, and outpatient doctor visits) ended: in 1993 the costs were €218 million which had fallen to €213.5 million in 2003. Costs per patient per year have decreased 36% (from €1611 to €1031). Conclusion: It is possible to reduce the morbidity of asthma and its impact on individuals as well as on society. Improvements would have taken place without the programme, but not of this magnitude.

A susceptibility locus for asthma-related traits on chromosome 7 revealed by genome-wide scan in a founder population

The genetics of asthma and atopy have been difficult to determine because these diseases are genetically heterogeneous and modified by environment. The pedigrees in our study (n=86) originate in eastern central Finland (Kainuu province). According to census records, this region had only 200 households (2,000 inhabitants) in the mid sixteenth to mid seventeenth centuries. The current population of 100,000 represents the expansion of these founders within the past 400 years. Because this population is relatively homogeneous, we hypothesized that the molecular genetic mechanisms underlying asthma might also have reduced heterogeneity and therefore be easier to dissect than in mixed populations. A recent twin family study supported a strong genetic component for asthma in Finland. We carried out a genome-wide scan for susceptibility loci in asthma in the Kainuu subpopulation. We identified two regions of suggestive linkage and studied them further with higher-density mapping. We obtained evidence for linkage in a 20-cM region of chromosome 7p14–p15 for three phenotypes: asthma, a high level of immunoglobulin E (IgE; atopy) and the combination of the phenotypes. The strongest linkage was seen for high serum IgE (non-parametric linkage (NPL) score 3.9, P=0.0001), exceeding the threshold for genome-wide significance based on simulations. We also observed linkage between this locus and asthma or atopy in two independent data sets.

Asthma programme in Finland: a community problem needs community solutions

Finland, like many other western countries, has experienced profound structural changes during the post-war period: urbanisation, increasing education, smaller family size, improved hygiene for food and household water, and prophylaxis and effective care of many potentially dangerous infectious diseases. Many of these factors have been associated with the increased risk for asthma and allergies1 which has also been found in Finland.2 In 1993 the Ministry of Social Affairs and Health in Finland recognised asthma as an important public health issue by appointing a working group to design a national programme for the prevention and alleviation of problems caused by asthma and for reduction of the relevant costs. The group decided to create an action programme emphasising guideline implementation and follow up, which are often neglected in consensus reports on asthma treatment. The 10 year programme was launched in 1994.3 The goals of prevention and treatment were stated as follows: (1) recovery of as many patients as possible with early asthma; (2) asthmatic patients should feel well and their ability for work and functional capacity should correspond with their age; (3) decline in the percentage of patients with severe and moderate asthma from the current 40% to 20%; (4) decrease in the number of bed days of asthmatic patients by 50% by the year 2000 (that is, to 50 000 a year); and (5) reduction in the annual treatment costs per patient by 50% as a result of more effective prevention and treatment of symptoms. The measures towards achieving the goals were as follows: (1) early diagnosis and active treatment; (2) guided self-management as the primary form of treatment; (3) decrease in respiratory irritants such as smoking and tobacco smoke; (4) implementation of rehabilitation on an outpatient basis combined with normal treatment, planned individually and timed appropriately; (5) increase …

DESIPRAMINE IN TREATMENT OF PARKINSON'S DISEASE

Several studies have recently confirmed the finding of Sigwald et al. (1959) that imipramine has a beneficial effect on the Parkinsonian symptoms and signs, alleviating not only the depression but also the tremor, rigor, and akinesia (S t rauss 1959, Blotnberg & Eriksson 1961, D e n m a r k et al. 1961, Gillhespy & Mustard 1963, S f r a n g 1965). In 1965, Pohlmeier and Matussek carried out a pilot study on the effect of desmethylimipramine, desipramine, in Parkinsonism and found that it improved the rigor, akinesia, and psychic activity of the patients. In order to test these findings I performed a double-blind placebo-controlled study on the effect of desipramine in Parkinson’s disease.

BONE MINERAL DENSITY IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE TREATED WITH BUDESONIDE TURBUHALER

There is a need for studying the effects of long-term inhaled corticosteroid therapy on bone mineral density (BMD) and vertebral fracture rates in patients with mild chronic obstructive pulmonary disease (COPD). Patients (n=912, mean age 52 yrs) with mild COPD (mean forced expiratory volume in one second (FEV1) 77% of predicted; mean FEV1/slow vital capacity ratio 62%) were randomized to receive budesonide 400 µg, or placebo twice daily via Turbuhaler®. BMD was measured at the L2–L4 vertebrae and the femoral neck, trochanter and Wards triangle by dual-energy X-ray absorptiometry at baseline and after 6, 12, 24 and 36 months (n=161). Radiographs of the thoracic and lumbar spine were obtained at the beginning and end of treatment (n=653). Previous fractures were present at baseline in 43 budesonide-treated patients (13.4%) and 38 placebo-treated patients (11.5%). New fractures occurred in five budesonide-treated patients, compared with three in the placebo group (p=0.50). There were no significant changes in BMD at any site in budesonide-treated patients, compared with the placebo group, during the course of the study. Budesonide treatment was associated with a slight but statistically significant decrease in the area under the concentration-time curve for serum osteocalcin. In the present study, involving a large group of patients with chronic obstructive pulmonary disease, long-term treatment with budesonide 800 µg·day−1 via Turbuhaler® had no clinically significant effects on bone mineral density or fracture rates.

Placebo-Controlled Study of Inhaled Budesonide on Indices of Airway Inflammation in Bronchoalveolar Lavage Fluid and Bronchial Biopsies in Cross-Country Skiers

Background: Asthma-like symptoms, methacholine hyperresponsiveness, use of inhaled steroids, airway inflammation, and increased tenascin expression in the reticular basement membrane have been reported in competitive cross-country skiers. Objective: To investigate the effect of inhaled budesonide, 400 μg twice daily, on indices of airway inflammation in ‘ski asthma’, defined as asthma-like symptoms within the previous year and bronchial hyperresponsiveness to methacholine. Methods: A randomised double-blind placebo-controlled parallel-group bronchial biopsy and bronchoalveolar lavage (BAL) study of 25 (19 male) competitive cross-country skiers (mean age 18 (16–20) years for a mean (range) treatment period of 22 (10–32) weeks over the competitive season. Results: No changes were seen regarding cellular inflammation in the bronchial mucosa or tenascin expression. In the BAL fluid, both groups had a significant decrease in activated T-suppressor (CD8) lymphocytes and an increase in macrophages, with no differences across the groups. Within the budesonide group, there was a decrease in IL2 receptor-activated T-helper lymphocytes and an improvement in FEV1. Asthma-like symptoms were unchanged in 17 (68%) skiers. Methacholine provocation test was negative in 15 subjects, and remained positive in 5 subjects in each group. The improvement in bronchial responsiveness occurred in both groups and was not accompanied by a decrease in cellular inflammation. Conclusions: We were unable to show any clear beneficial effect of budesonide in ‘ski asthma’. As changes in training intensity probably accounted for the spontaneous improvement in bronchial responsiveness, more attention should be directed at reducing environmental stress to the airways than at attempting pharmacological modulation of induced inflammatory changes.

Increasing prevalence of asthma but not of chronic bronchitis in Finland? Report from the FinEsS-Helsinki study

To assess the prevalence of asthma, chronic bronchitis and respiratory symptoms, and to calculate risk factors for them, we performed a postal survey in Helsinki, the capital of Finland. During the spring of 1996, questionnaires were mailed to a random sample of 8000 individuals aged 20-69. The total response rate was 76%, with 6062 complete answers. The prevalence of having ever had asthma was 7.2%, physician-diagnosed asthma was 6.6% and physician-diagnosed chronic bronchitis was 3.7%. Asthma was significantly more common among women than men, but no gender differences existed in prevalence of chronic bronchitis. The most common respiratory symptom was sputum production when coughing, reported by 27%. During the previous 12 months, wheezing had occurred in 20% and attacks of shortness of breath in 13% of subjects. Generally, the prevalence of different respiratory symptoms were significantly higher among smokers. The most important risk factor for asthma was a family history of asthma (Odds ratio:OR 3.3). Multivariate analysis revealed that being a member of the socioeconomic group, manual workers, was associated with a significantly increased risk for chronic productive cough (OR 1.7), and for wheezing during the previous 12 months (OR 1.7). Manual workers of both genders had the highest prevalence of asthma, chronic productive cough and wheezing during the previous 12 months. The prevalence of asthma in Helsinki was higher than previously found in Finland, and was at a similar level to that of other Nordic countries. In contrast, prevalence of chronic bronchitis was lower than previously shown in Finland.

Perinatal risk factors for asthma in Finnish adolescent twins

BACKGROUND Previous studies have suggested that, in addition to genetic liability and environment in early childhood, intrauterine life also influences the risk for asthma beyond childhood. Low birth weight, prematurity, young maternal age, and maternal smoking have all shown an association with asthma. The effect of perinatal factors on the risk for asthma in relation to familial and social risk factors was studied in a nationwide population-based sample of adolescent twins. In addition to a distribution of birth characteristics among twins which differs from that of singletons, data on twins enable a distinction to be made between genetic and environmental sources of variation. METHODS Questionnaires were sent to five consecutive birth cohorts of Finnish 16 year old twins born in 1975–9 and to their parents (3065 families). The outcome measure was life time prevalence of doctor-diagnosed asthma in these adolescents. The association between asthma and potential risk factors was assessed by multiple logistic regression and discordant twin pair analysis. RESULTS Risk for asthma increased with increasing ponderal index (p for trend <0.01) and decreasing maternal age (p for trend <0.05). Among the 25% of twins with the highest ponderal index, the odds ratio for asthma was 1.82 (95% confidence interval 1.18 to 2.79) compared with those in the lowest 25%. Neither birth weight, gestational age, nor Apgar score was associated with asthma. When perinatal risk factors were combined with familial and social risk factors, ponderal index, maternal smoking, parental asthma, and sibship size were all significant independent determinants of asthma in these adolescents. CONCLUSIONS The risk for asthma in adolescent twins increases with increasing ponderal index when adjusted for familial and social factors.

Anchoring complex components laminin-5 and type VII collagen in intestine: association with migrating and differentiating enterocytes.

Anchoring complex component laminin-5 and its subunits laminin (Ln)-alpha3 and Ln-beta3 chains, Type VII collagen, and integrin chains alpha3, alpha6, and beta4 were studied in developing and adult human intestine and compared with findings on Ln-alpha1 and Ln-alpha2 chains. In adult human duodenum, jejunum, and ileum, Ln-5 detected with a polyclonal antiserum and Ln-alpha3 and Ln-beta3 chains, detected with monoclonal antibodies (MAbs), were restricted to the epithelial basement membranes (BMs) of villi, whereas Ln-alpha2 chain was seen only focally in crypt bottoms. In double labeling experiments, the stretch of crypt BM corresponding to the proliferative cell compartment was found to be devoid of both Ln-alpha3 and Ln-alpha2 chains. Double labeling for Ln-5 and proliferating cell nuclear antigen also showed an abrupt onset of Ln-5 expression exactly at the upper edge of the proliferative cell compartment. Type VII collagen was negligible in duodenum and showed a rising duodenal-ileal gradient localizing to villar BMs. Double labeling for Ln-5 and Type VII collagen, however, indicated only partial co-distribution in the intestine. Electron microscopy of ileum revealed both anchoring filaments and anchoring fibrils but no hemidesmosomal plaques. Our results demonstrate the expression of Ln-5 in BMs outside of stratified epithelia and indicate that Ln-5 in the intestine is associated with the compartment of migrating and differentiating enterocytes. Absence of hemidesmosomes and the presence of other anchoring complex components, such as Ln-5, Type VII collagen, and integrin chains alpha3, alpha6, and beta4, suggests unique properties for epithelial cell attachment in the intestine.