Disease marker combination enhances patient characterization in the Finnish sarcoidosis patients.

Sarcoidosis is an inflammatory disease of unknown etiology and multiple clinical phenotypes. Clinical manifestations range from asymptomatic disease to severe loss-of-function leading to the hypothesis that sarcoidosis might not be just one disease, but consists of several distinct disease entities each with potentially distinct genetic associations. We have previously demonstrated that in our series HLADRB1* 03:01 and haplotype HLA-DRB1*04:01-DPB1*04:01 are associated with good prognosis sarcoidosis. In our recent work, we found a novel SNP (rs9905945) in the 5'upstream region of the ACE gene to be associated with favorable disease prognosis as well. The main objective of this study was to expand the previous results and analyse combined influence of the found ACE SNP rs9905945 with the protective HLA markers HLADRB1* 03:01 and HLA-DRB1*04:01-DPB1*04:01 in 188 Finnish sarcoidosis patients (resolved disease, n = 90; persistent disease, n = 98). When combining the frequencies of the rs9905945 and of the HLA markers, the strongest association was found for a combination of either/or both HLA markers and rs9905945 for good disease prognosis (37.1% in resolved vs. 11.3% in persistent, p < 0.001, OR = 4.61, (95%CI 2.15-9.86)). In conclusion, we discovered that a combination of the ACE SNP rs9905945 and HLA markers enhance the accuracy for predicting disease course in Finnish sarcoidosis patients further characterizing genetic differences between Finnish sarcoidosis patients with different prognosis.

Linkage between smoking and asthma.

Smoking is one of the most important preventable public health problems. Prevalence of smoking is decreasing in the Western world but lot of work is left. We reviewed the most important papers related to smoking and asthma. Despite of decreasing smoking figures in Finland, about 15-20 per cent of pregnant women smokes. Children's exposure to harmful effects of environmental tobacco smoke (ETS) still continues. Exposure to tobacco smoke during pregnancy and in early childhood both deteriorates permanently children's lungs and increases their asthma risk. The exposure of adults to ETS also increases their asthma risk. Both passive exposure to ETS and active smoking worsen asthma. In addition, smoking asthmatics run a higher risk of developing COPD compared to non-smokers. Smoking prevalence among the population can be regulated through legislation, but the health care personnel have a central role in encouraging smoking cessation among smoking patients.

Scientific rationale for the Finnish Allergy Programme 2008-2018: emphasis on prevention and endorsing tolerance.

In similarity to many other western countries, the burden of allergic diseases in Finland is high. Studies worldwide have shown that an environment rich in microbes in early life reduces the subsequent risk of developing allergic diseases. Along with urbanization, such exposure has dramatically reduced, both in terms of diversity and quantity. Continuous stimulation of the immune system by environmental saprophytes via the skin, respiratory tract and gut appears to be necessary for activation of the regulatory network including regulatory T-cells and dendritic cells. Substantial evidence now shows that the balance between allergy and tolerance is dependent on regulatory T-cells. Tolerance induced by allergen-specific regulatory T-cells appears to be the normal immunological response to allergens in non atopic healthy individuals. Healthy subjects have an intact functional allergen-specific regulatory T-cell response, which in allergic subjects is impaired. Evidence on this exists with respect to atopic dermatitis, contact dermatitis, allergic rhinitis and asthma. Restoration of impaired allergen-specific regulatory T-cell response and tolerance induction has furthermore been demonstrated during allergen-specific subcutaneous and sublingual immunotherapy and is crucial for good therapeutic outcome. However, tolerance can also be strengthened unspecifically by simple means, e.g. by consuming farm milk and spending time in nature. Results so far obtained from animal models indicate that it is possible to restore tolerance by administering the allergen in certain circumstances both locally and systemically. It has become increasingly clear that continuous exposure to microbial antigens as well as allergens in foodstuffs and the environment is decisive, and excessive antigen avoidance can be harmful and weaken or even prevent the development of regulatory mechanisms. Success in the Finnish Asthma Programme was an encouraging example of how it is possible to reduce both the costs and morbidity of asthma. The time, in the wake of the Asthma Programme, is now opportune for a national allergy programme, particularly as in the past few years, fundamentally more essential data on tolerance and its mechanisms have been published. In this review, the scientific rationale for the Finnish Allergy Programme 2008-2018 is outlined. The focus is on tolerance and how to endorse tolerance at the population level.

Chronic bronchitis and chronic obstructive pulmonary disease. The Finnish Action Programme, interim report.

The Finnish National Prevention and Treatment Programme for Chronic Bronchitis and COPD, launched in 1998, has, to date, been running for 6 years (2003). The goals of this action programme were to reduce the incidence of COPD and the number of moderate and severe cases of the disease, and to reduce both the number of days of hospitalisation and treatment costs. A prevalent implementation of over 250 information and training events started. Health centres and pharmacies appointed a person in charge of COPD patients. In order to improve the cooperation between primary and specialised care, two thirds of hospital districts created local COPD treatment chains. The early diagnosis of COPD by spirometric examination was activated during the programme. Number of health centres with available spirometric services increased to 95%. Before the start of the programme, approximately 5-9% of the adult population had COPD. During the whole programme, the proportion of male and female smokers decreased from 30% to 26% and from 20% to 19%, respectively. The total number of hospitalisation periods and days due to COPD decreased by 15% and 18%, respectively. Both the number of pensioners and daily sickness days due to COPD also decreased by 18%. Registered COPD induced deaths remained at their previous levels during the monitoring period, i.e. around 1000 deaths out of 5.2 millions annually. The measures recommended by the programme have been widely introduced but they need to be still more effective.

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 euro which had fallen to 213.5 million euro in 2003. Costs per patient per year have decreased 36% (from 1611 euro to 1031 euro). 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.

Asthma control and steroid doses 5 years after early or delayed introduction of inhaled corticosteroids in asthma: a real-life study.

UNLABELLED: We evaluated asthma control and medication use 5 years after introduction of an inhaled corticosteroid (budesonide via Turbuhaler) in 462 patients with persistent asthma and symptoms of different duration. An early treatment group with symptoms for <2 years (group A) was compared with a delayed treatment group (group B) (median duration 5 years and 3 months). Most patients received budesonide 400 microg twice daily as initial dose. We report 5-year follow-up data on 404 patients (group A n = 253; group B n = 151) and on a few more patients after treatment for 6 months, 1 year and 3 years. At 5 years the mean maintenance doses of budesonide were 412 microg (A) and 825 microg (B), respectively (P<0.001). Nevertheless, treatment goals (normal lung function, normal exercise tolerance, minimal use of reliever medication, no asthma exacerbations) were all statistically significantly more frequently achieved in group A. At 5 years group B patients also used significantly more additional asthma medications, e.g. inhaled long-acting beta2-agonists by 64% compared with 6% in group A. In group A 43 patients (17%) had been able to stop budesonide treatment compared to five patients (3%) in group B. A subgroup of group B patients with higher mean baseline FEV1 values than group A showed nevertheless significantly poorer response. No treatment-related serious adverse events were reported. Budesonide was well tolerated in both groups. CONCLUSION: Duration of asthma symptoms when starting treatment with an inhaled corticosteroid is an important determinant for the response. Early treatment gives significantly better airway function and asthma control than delayed treatment and at lower maintenance doses.

Studies of cytokine levels in bronchoalveolar fluid lavage from patients with interstitial lung diseases.

Cytokine levels in bronchoalveolar lavage fluid from patients with eosinophilic pneumonia (n = 7), allergic alveolitis (n = 11), (cryptogenic) fibrosing alveolitis (n = 8), sarcoidosis (n = 10) were determined, as well as levels in control samples from healthy non-smoking volunteers (n = 11). Fibronectin levels were increased in all the patient categories, the highest absolute levels of fibronectin (100-fold increase) being found in eosinophilic pneumonia and allergic alveolitis. TGF-beta (transforming growth factor-beta) was significantly elevated in allergic alveolitis only. There was a significant difference between allergic alveolitis on the one hand and both sarcoidosis and fibrosing alveolitis on the other. Tumour necrosis factor-alpha (TNF-alpha) was significantly increased in eosinophilic pneumonia and allergic alveolitis; allergic alveolitis and fibrosing alveolitis differed significantly in this respect. Platelet-derived growth factor-BB (PDGF-BB) levels were significantly elevated in allergic alveolitis and fibrosing alveolitis. It was found that the level of PDGF-BB was significantly decreased in the case of sarcoidosis, with no overlapping with allergic alveolitis or fibrosing alveolitis. Interferon-gamma (IFN-gamma) was decreased in all patient categories. A significant difference in extent of the decrease was found between allergic alveolitis and sarcoidosis. The interstitial lung diseases thus differed in the pattern of cytokines expressed, indicating that these cytokines could well be a part of the pathogenic process, and also that the measurement of cytokine levels could be diagnostically useful.

Sleep apnoea: Finnish National guidelines for prevention and treatment 2002-2012.

(1) After negotiations with the Finnish Ministry of Social Affairs and Health, a national programme to promote prevention, treatment and rehabilitation of sleep apnoea for the years 2002-2012 has been prepared by the Finnish Lung Health Association on the basis of extensive collaboration. The programme needs to be revised as necessary, because of the rapid development in medical knowledge, and in appliance therapy in particular. (2) Sleep apnoea deteriorates slowly. Its typical features are snoring, interruptions of breathing during sleep and daytime tiredness. Sleep apnoea affects roughly 3% of middle-aged men and 2% of women. In Finland, there are approx. 150,000 sleep apnea patients, of which 15,000 patients have a severe disease, 50,000 patients are moderate and 85,000 have a mild form of the disease. Children are also affected by sleep apnea. A typical sleep apnea patient is a middle-aged man or a postmenopausal woman. (3) The obstruction of upper airways is essential in the occurrence of sleep apnoea. The obstruction can be caused by structural and/or functional factors. As for structural factors, there are various methods of intervention, such as to secure children's nasal respiration, to remove redundant soft tissue, as well as to correct malocclusions. It is possible to have an effect on the functional factors by treating well diseases predisposing to sleep apnoea, by reducing smoking, the consumption of alcohol and the use of medicines impairing the central nervous system. The most important single risk factor for sleep apnoea is obesity. (4) Untreated sleep apnoea leads to an increase morbidity and mortality through heart circulatory diseases and through accidents by tiredness. Untreated or undertreated sleep apnoea deteriorates a person's quality of life and working capacity. (5) The goals of the Programme for the prevention and treatment of sleep apnoea are as follows: (1) to decrease the incidence of sleep apnoea, (2) to ensure that as many patients as possible with sleep apnoea recover, (3) to maintain capacity for work and functional capacity of patients with sleep apnoea, (4) to reduce the percentage of patients with severe sleep apnoea, (5) to decrease the number of sleep apnoea patients requiring hospitalisation and (6) to improve cost effectiveness of prevention and treatment of sleep apnoea. (6) The following means are suggested for achieving the goals: (1) to promote prevention of obesity, weight loss and weight control; (2) to promote securing of nasal respiration in child patients and removal of obstructing redundant soft tissues; (3) to promote the correction of children's malocclusions, (4) to enhance knowledge about risk factors and treatment of sleep apnoea in key groups, (5) to promote early diagnosis and active treatment, (6) to commence rehabilitation early and individually as a part of treatment and (7) to encourage scientific research. (7) On the national level, the occurrence of sleep apnoea can be prevented, for example, by encouraging weight control. The programme gives examples of such measures and appeals to various authorities and voluntary organisations to reinforce their collaboration. Preventive measures should be individualised, and based on due consideration. (8) The efficacy of diagnosing sleep apnoea should be increased. Attention should be paid to the symptoms of risk group patients at different units of the primary and occupational health care. Even mild forms of the disease should be treated appropriately. Diagnosis and treatment of the disease involve cooperation between the primary and specialised health-care sectors. Methods of treatment are (1) treatment of obesity, (2) positional therapy, (3) reduction of the use of medicines impairing the central nervous system, (4) reduction of smoking and the consumption of alcohol, (5) devices affecting the position of the tongue and lower jaw, (6) treatment with Continuous Positive Airway Pressure (CPAP-treatment), (7) surgical methods of treatment and (8) rehabilitation. (9) The hierarchy of referrals in the prevention and treatment of sleep apnoea should be revised to accord a greater role to the primary health-care sector. Good exchanges of information and cooperation between the primary health care and specialised medical-care sectors should be developed. Hospitals districts in cooperation with provincial governments and municipalities should ensure that different levels of the health-care system are capable of fulfilling the tasks assigned to them appropriately. (10) Rehabilitation of sleep apnoea should be goal-orientated and cover all forms of rehabilitation: medical, occupational and social. Rehabilitation should prevent the effects caused by the disease. Thus, it is possible to support self-care, increase the patient's resources and improve quality of life. (11) Information and training should be directed primarily towards health-care personnel, patients and their families. Organisations should produce materials for health and patient education as well as organising training events. To support the activities. financing will be needed from organisations such as Finland's Slot Machine Association. The Social Insurance Institution should disseminate information about questions of social security. Regional direction and training will mainly be the responsibilities of hospital districts, provincial governments and local health centres. The media will play an important role in the dissemination in-depth information about prevention and treatment of sleep apnoea.

Safety of formoterol by Turbuhaler as reliever medication compared with terbutaline in moderate asthma.

The present study compared the safety of 4.5 microg formoterol with 0.5 mg terbutaline, both by Turbuhaler and used as needed, in addition to regular formoterol in moderate asthma. In this double-blind parallel-group study, 357 patients taking a moderate-to-high dose of inhaled corticosteroids and additional terbutaline (2-5 inhalations x day(-1) during run-in) were randomised to either formoterol or terbutaline as needed in addition to formoterol 9 microg b.i.d. over 12 weeks. Adverse events, serum potassium levels, electrocardiogram, vital signs and lung function were assessed monthly; peak expiratory flow and severe asthma exacerbations were recorded daily. Patients used 2.16 (range 0.0-6.3) formoterol and 2.34 (range 0.1-7.5) terbutaline relief inhalations x day(-1). No clinically significant differences in safety variables were found between treatments. Statistically greater increases in cardiac frequency (2.6 beats x min(-1), p=0.03) were found on terbutaline. There were 44 and 52 severe asthma exacerbations with formoterol and terbutaline, respectively, with no significant difference in time to first exacerbation. There was also no difference between treatments for other efficacy measures (peak expiratory flow, forced expiratory volume in one second and morning/evening symptom scores). Formoterol 4.5 microg as needed was at least as safe, well tolerated and effective as terbutaline 0.5 mg in stable patients (requiring up to 6 relief inhalations x day(-1)) taking formoterol plus inhaled corticosteroids regularly over 12 weeks.

Genetic predisposition and pathogenetic mechanisms of interstitial lung diseases of unknown origin.

Understanding of the cellular and cytokine interactions associated with inflammation and fibrosis in interstitial lung diseases (ILDs) has increased substantially during the past few years. Presently, many agents are known to have the ability to induce ILDs, although only a small percentage of exposed individuals will develop the disease. In addition, the majority of ILDs are of unknown origin and many are labelled "idiopathic". Therefore, host susceptibility, genetic factors and, possibly, environmental cofactors may be important for the clinical expression of ILDs. The present review reports evidence of the genetic predisposition to develop ILDs of unknown origin, more specifically sarcoidosis, idiopathic pulmonary fibrosis (IPF), lymphangioleio-myomatosis and ILDs, in systemic sclerosis. For instance, for sarcoidosis and IPF several histocompatibility antigens have been associated with the development and/or the clinical presentation of the disease. Furthermore, there are also several types of ILD that are associated with inherited disorders, of which the tuberous sclerosis complex is only one example. This clearly indicates that pulmonary fibrosis can be influenced by genetic factors. Familial occurrence of sarcoidosis and IPF is also well known, although the exact modes of inheritance are debatable. Several studies have shown that extrinsic factors, such as single or multiple fibrosing agents, probably contribute to the development of clinical ILDs of unknown origin. It is probable that some of these studies deal with patients who do not have classical IPF, as recently defined by the American Thoracic Society (ATS)/European Respiratory Society (ERS) consensus. Therefore, the true role of these extrinsic factors in the development of IPF, or even sarcoidosis, remains speculative. With the help of animal studies and, more specifically, by using knock-out mice, it may be possible in the near future to unravel at least some of the genes that are responsible for the increased susceptibility of the development of interstitial lung diseases.

The prognosis of pulmonary sarcoidosis in Finland and Hokkaido, Japan. A comparative five-year study of biopsy-proven cases.

BACKGROUND AND AIM OF THE STUDY: The frequency and clinical picture of sarcoidosis are different in Finland and Hokkaido, Japan. The aim of this study was to compare the normalisation rate of chest radiographic changes in patients with biopsy-proven sarcoidosis. METHOD: The chest radiographs of 437 Finnish and 457 Japanese patients were used and, for the purpose of this study, double-checked in order to make sure that the interpretations were identical. On a yearly basis the radiographs were classified as normalised, improved, unchanged or deteriorated. RESULTS: Normalisation of chest radiographs occurred in 73% of the Japanese and 40% of the Finnish patients. The difference between the two series was significant (p < 0.001). Gender, young age, presence or absence of symptoms or extrapulmonary lesions at diagnosis or treatment with corticosteroids did not influence the difference between the two series. Of the 191 Finnish and 309 Japanese patients with initial stage I disease a normal chest radiograph was obtained in 47% of the Finnish and 76% of the Japanese patients (p < 0.001), despite the fact that the Finnish series included patients with erythema nodosum, who had a 59% normalisation rate. Of the 186 Finnish and 125 Japanese patients with initial stage II disease, normalisation of the chest radiographs was seen in 36% of the Finnish and in 73% of the Japanese patients (p < 0.001). No difference in normalisation rate was seen between stage III patients. CONCLUSION: The prognosis of pulmonary sarcoidosis in Japanese patients in Hokkaido is significantly better than that in Finland defined as normalisation rate of the chest radiographs.

Familial sarcoidosis in Finland and Hokkaido, Japan--a comparative study.

Two or more cases of sarcoidosis in one family is not unusual. To compare the frequencies of familial sarcoidosis in Finland and Hokkaido, Japan, and to analyse the type of associations reported, we collected data on all patients visiting hospitals for sarcoidosis in 1984 in Finland (1378 patients) and Hokkaido (208 patients), including information about familial sarcoidosis. We also analysed the familial cases seen among 571 sarcoidosis patients diagnosed at the Mjölbolsta hospital in Finland from 1955 to 1987 and among 686 Japanese patients seen in Sapporo from 1964 to 1988. In 1984, 50 sarcoidosis patients visiting Finnish hospitals and nine sarcoidosis patients in Hokkaido reported as familial cases. Of the sarcoidosis patients seen in Finland at the Mjolbolsta hospital in 1955-1987, 27 had a family member with the same disease, while this number was 20 in the Sapporo hospital in 1964-1988. Those surveys give a prevalence of familial sarcoidosis in Finland of 3.6-4.7% and in Hokkaido of 2.9-4.3%. Among familial cases, the dominating relationships were sister-brother and mother-child relationships.

Oral prednisolone followed by inhaled budesonide in newly diagnosed pulmonary sarcoidosis: a double-blind, placebo-controlled multicenter study. Finnish Pulmonary Sarcoidosis Study Group.

STUDY OBJECTIVE: To evaluate the efficacy of oral prednisolone, followed by inhaled budesonide, in patients with newly diagnosed (<3 months) stage I and stage II pulmonary sarcoidosis. DESIGN: Double-blind, placebo-controlled, parallel-group, multicenter study. SETTING: Twenty pulmonary medicine departments in Finland. PATIENTS: One hundred eighty-nine adult patients were randomized to treatment. Patients with erythema nodosum or stage IV sarcoidosis (pulmonary fibrosis), and patients requiring immediate treatment with oral corticosteroids for extrapulmonary lesions or chronic illnesses were excluded. TREATMENT: The patients received either oral prednisolone for 3 months (20 mg/d for 8 weeks, 15 mg/d for 2 weeks, and 10 mg/d for 2 weeks) followed by inhaled budesonide (Pulmicort Turbuhaler; Astra Draco; Lund, Sweden) for 15 months at 800 microg bid, or placebo tablets followed by placebo inhaler therapy. MEASUREMENTS: Chest radiographs, lung volumes (FVC), diffusing capacity of the lung for carbon monoxide (D(LCO)), serum angiotensin-converting enzyme (SACE), and beta2-microglobulin at 3-month intervals. RESULTS: After 3 months of treatment, radiographic improvements were seen in the active-treatment group when compared to the placebo-treatment group. At 6 months, the difference was still statistically significant. Later, no differences were found. In patients with initial stage I lesions, neither the FVC nor the D(LCO) (the percent predicted mean values) changed during the study, as they were normal from the beginning. In patients with initial stage II disease, the difference in the FVC mean values between the groups also remained unchanged throughout the study. In stage II patients treated for 18 months, but not earlier, the difference in D(LCO) became statistically significant; the largest differences were seen in patients with initial FVC values <80% of predicted and D(LCO) values <75% of predicted. The decrease in SACE in the active-treated stage II patients was significantly larger than in the placebo-treated patients. No difference was observed in adverse events between the active-treated patients and the placebo-treated patients. CONCLUSION: Treatment is not required for patients with stage I disease. An initial treatment with prednisolone followed by long-term inhalation of budesonide is more effective than placebo in patients with stage II disease. Sequential oral and inhaled corticosteroid therapy may be an alternative treatment regimen for stage II sarcoidosis patients, rather than long-term oral corticosteroid therapy alone.

The angiotensin-converting enzyme DD gene is associated with poor prognosis in Finnish sarcoidosis patients.

Angiotensin-converting enzyme (ACE) genotypes may reflect prognosis in sarcoidosis. They were determined in 59 Finnish sarcoidosis patients and 70 healthy control subjects. The prognosis of the sarcoidosis patients was determined after follow-up for 1, 2, 3, 5 and >5 yrs and classified as good (normal chest radiograph and lung function, no signs of extrapulmonary disease activity within 2 yrs from diagnosis), intermediate (neither good nor poor) or poor (persisting unstable pulmonary infiltrates, vital capacity and diffusing capacity of the lung for carbon monoxide <50% predicted and/or extrapulmonary disease activity after >5 yrs follow-up). The DD, ID and II genotypes were found in 31 and 27%, in 54 and 49%, and in 15 and 24% of patients and control subjects respectively. The odds ratio (DD+ID to II) was 1.45 (95% confidence interval 0.60-3.49). The D alelle was found more often in patients (58%) and in control subjects (51%) than the I allele but the difference was not statistically significant. Statistically significantly more patients with the DD genotype had a poor prognosis compared with patients with II homozygotes and ID heterozygotes. Among 11 patients with Löfgren's syndrome (bilateral hilar lymphadenopathy and erythema nodosum), four had the DD genotype. Three of these patients had a prognosis despite presenting a clinical picture usually associated with a good prognosis. The angiotensin-converting enzyme genotype may be a prognostic marker in sarcoidosis and larger studies are warranted to define its clinical utility.

Tolerability to high doses of formoterol and terbutaline via Turbuhaler for 3 days in stable asthmatic patients.

This randomized, double-blind, crossover study in two parts compared tolerability to high doses of formoterol (Oxis Turbuhaler) with that of high doses of terbutaline (Bricanyl Turbuhaler). After Holter monitoring at home, 12 patients were treated with 4+4+4 doses of formoterol Turbuhaler, 6 microg x dose(-1), (total daily metered dose 72 microg) or 4+4+4 doses of terbutaline Turbuhaler, 0.5 mg x dose(-1) (daily dose 6 mg) given in the morning, after lunch and in the evening, for 3 consecutive days. After a one week washout period at home, patients received the alternative treatment. Thereafter, 15 other patients received 8+6+6 doses of formoterol Turbuhaler (total daily metered dose 120 microg) or 8+6+6 doses of terbutaline Turbuhaler (daily dose 10 mg). Pulse, cardiac frequency, blood pressure, serum potassium, electrocardiogram and forced expiratory volume in one second (FEV1) were registered at regular intervals and Holter monitoring was applied during all 4 treatment days. Terbutaline 6 mg showed significantly greater systemic effects than formoterol 72 microg on pulse, blood pressure, cardiac frequency and QTc (QT interval corrected for heart rate). Terbutaline 10 mg had significantly greater effects than formoterol 120 microg on serum potassium levels, pulse, cardiac frequency and QTc. No differences in FEV1 levels were found. Both drugs were safe and generally well tolerated on both dose levels. In conclusion, high doses of formoterol Turbuhaler over 3 days were generally safe and well tolerated. Daily doses of 6 mg and 10 mg terbutaline Turbuhaler were systemically more potent than 72 microg and 120 microg formoterol, respectively. The safety margin thus appears to be wide if patients happen to use extra doses of formoterol in addition to those prescribed for regular use.

The bronchoprotective efficacy of salbutamol inhaled from a new metered-dose powder inhaler compared with a conventional pressurized metered-dose inhaler connected to a spacer.

The aim of this study was to compare the efficacy of 100 micrograms of salbutamol inhaled from a new metered-dose powder inhaler (MDPI, Leiras Taifun, Finland) with that of a same dose of salbutamol inhaled from a conventional pressurized metered-dose inhaler with a large volume spacer (pMDI + S) in protecting against methacholine (Mch) induced bronchoconstriction. This was a 3 day, randomized, cross-over, partly blinded, placebo-controlled multicentre study where the pMDI + S was used as an open control. Twenty-six asthmatic outpatients with a baseline FEV1 > or = 60% of predicted and with bronchial hyperreactivity (PD20 FEV1 < or = 890 micrograms of Mch) were studied. On each study day the patients underwent an Mch provocation 30 min after inhaling placebo from the MDPI or a dose of 100 micrograms of salbutamol from the MDPI and from the pMDI + S. PD20 FEV1 and dose-response slope [DRS; maximal change in FEV1 (%)/dose of Mch (mumol)] were used to evaluate efficacy. The median values of PD20 FEV1 were 250, 622 and 1737 micrograms after placebo MDPI, salbutamol pMDI + S and salbutamol MDPI, respectively. The corresponding DRS values were -11.0%, -4.5% and -2.0% mumol-1. With both parameters, all differences were statistically significant (P < 0.05). In conclusion, 100 micrograms of salbutamol inhaled from Leiras Taifun MDPI offers better protection against Mch-induced bronchoconstriction than 100 micrograms of salbutamol from a pMDI connected to a large volume spacer device.

The mode of presentation of sarcoidosis in Finland and Hokkaido, Japan. A comparative analysis of 571 Finnish and 686 Japanese patients.

We compared the clinical picture of sarcoidosis in patients diagnosed at Mjölbolsta hospital in Finland in 1955-1987 with those diagnosed in Sapporo in 1964-1988. The female:male ratios showed a slight female predominance. The mean age (SD) at diagnosis was 41.5 (13.0) years at Mjölbolsta and 30.0 (15.4) years in Sapporo. In both series, half of the patients had been detected at mass x-ray surveys. The presenting symptoms varied considerably among the symptomatic patients. At Mjölbolsta hospital, 189 patients (33%) had cough, 21% fever, 21% general malaise, 18% dyspnoea, 18% erythema nodosum, 16% joint pain and only 27 patients (5%) had eye symptoms. In Sapporo, 245 patients (41%) had eye symptoms, 18 (4%) had enlarged peripheral lymph nodes, 14 (3%) had cough, 10 (2%) had fever. Erythema nodosum did not occur as a presenting symptom in Sapporo. The chest radiographs showed bilateral hilar lymphadenopathy (BHL, stage I) in 48% of the Mjölbolsta patients and in 57% of the Sapporo patients. Stage II lesions were seen in 39% and 20%, and stage III lesions in 12% and 5% respectively. Only 1% had a normal chest radiograph at Mjölbolsta hospital as compared with 18% in Sapporo. The Sapporo patients were more obstructive but the proportion of smokers was also higher. No difference in diffusion capacity was seen.

Effect of early vs late intervention with inhaled corticosteroids in asthma.

One hundred five consecutive patients with mild or moderate asthma not earlier treated with inhaled corticosteroids and with a need of an inhaled bronchodilator of three or more doses a week, and/or asthma symptoms during day or night, and/or peak expiratory flow (PEF) or FEV1 less than 75% of predicted normal values were given an inhaled corticosteroid for 2 years (budesonide delivered via an inspiratory flow-driven multidose dry powder inhaler [Turbuhaler]). According to duration of symptoms, they were divided into six groups; from a duration less than 6 months up to a duration more than 10 years. PEF and FEV1 were measured before and after treatment for 3 months, 1 year, and 2 years. In the groups of patients with a duration of symptoms less than 2 years, mean FEV1 and PEF were significantly higher at all time points as compared with the baseline and as compared with the groups of patients with a longer duration of asthma symptoms. The maximum effects were usually seen after 1 year's treatment with maintained control during the second year. A significant negative correlation was found between duration of symptoms and maximum increases in PEF (r = -0.34; p = 0.0006) and FEV1 (r = -0.32; p = 0.0012), a correlation remaining also after correcting for baseline airway function. No correlation was found between the age of the patients or earlier regular use of beta 2-agonists and improvements in airway function. The results give some evidence that early treatment of asthma with an inhaled steroid may prevent patients from developing chronic airway obstruction. They also support current asthma treatment guidelines advocating early introduction of inhaled anti-inflammatory drugs.

The frequency of sarcoidosis in Finland and Hokkaido, Japan. A comparative epidemiological study.

Finland and Hokkaido resemble each other; the four season climate with cold winters and cool summers is the same as is the frequency of tuberculosis. The size of the population is almost the same. From the 1984 Japanese nationwide sarcoidosis survey we got the data from Hokkaido (288 patients) in order to compare the information with similarly collected data in Finland from 1984 (1,378 patients). The crude prevalence of sarcoidosis was 28.2 per 100,000 in Finland and 3.7 per 100,000 in Hokkaido. The annual incidence was 11.4 per 100,000 in Finland and 1.0 per 100,000 in Hokkaido. The sex distribution was similar; 63% vs 67% women in Finland and Hokkaido, respectively. At diagnosis the Hokkaidoan patients were significantly younger. In Hokkaido more cases were detected via mass X-ray survey (43% vs 34%). Among symptomatic patients eye symptoms were more frequent in Hokkaido, whereas respiratory and joint symptoms and erythema nodosum were more frequent in Finland. Bilateral hilar lymphadenopathy (BHL) was equally distributed (82% vs 84% whereas parenchymal lesions were seen more often in Finland (49% vs 25%) as well as peripheral lymphadenopathy (16% vs 8%).