May a different kinetic mode explain the high efficacy/safety profile of inhaled budesonide?

The claimed functional basis for ICSs in asthma and COPD is airway selectivity, attained by inhaling a potent, lipophilic compound with long local dissolution/absorption time. The development has been empirically based, resulting in five widely used ICSs. Among them, budesonide (BUD) deviates by being less lipophilic, leading to a more rapid systemic uptake with plasma peaks with some systemic anti-inflammatory activity. By this, BUD fits less well into the current pharmacological dogma of optimal ICS profile. In this review we compared the physicochemical, pharmacological and clinical properties of BUD, fluticasone propionate (FP) and fluticasone furoate (FF), representing different levels of lipophilicity, airway and systemic kinetics, focusing on their long-acting ß2-agonist (LABA) combinations, in line with current GINA and GOLD recommendations. We are aware of the differences between formoterol (FORM) and the not rapid acting LABAs such as e.g. salmeterol and vilanterol but our comparisons are based on currently available combination products. A beclomethasone dipropionate (BDP)/FORM combination is also commented upon. Based on clinical comparisons in asthma and COPD, we conclude that the BUD/formoterol (BUD/FORM) combination is as effective and safe as the FP and FF combinations, and is in some cases even better as it can be used as "maintenance plus reliever therapy" (MART) in asthma and as maintenance in COPD. This is difficult to explain by current views of required ICS's/LABAs pharmacokinetic profiles. We propose that BUD achieves its efficacy by a combination of airway and systemic activity. The airway activity is dominating. The systemic activity contributes by plasma peaks, which are high enough for supportive anti-inflammatory actions at the blood and bone marrow levels but not sufficiently long to trigger a similar level of systemic adverse effects. This may be due to BUD's capacity to exploit a systemic differentiation mechanism as programmed for cortisol's various actions. This differentiation prospect can be reached only for an ICS with short plasma half-life. Here we present an alternative mode for an ICS to reach combined efficacy and safety, based on a poorly investigated and exploited physiological mechanism. A preference of this mode is broader versatility, due to that its straighter dose-response should allow a better adaptation to disease fluctuations, and that its rapid activity enables use as "anti-inflammatory reliever".

The Finnish experience to save asthma costs by improving care in 1987-2013.

The Finnish National Asthma Program 1994-2004 markedly improved asthma care in the 1990s. We evaluated the changes in costs during 26 years from 1987 to 2013. Direct and indirect costs were calculated by using data from national registries. Costs from both the societal and patient perspectives were included. The costs were based on patients with persistent, physician-diagnosed asthma verified by lung function measurements. We constructed minimum and maximum scenarios to assess the effect of improved asthma care on total costs. The number of patients with persistent asthma in the national drug reimbursement register increased from 83,000 to 247,583. Improved asthma control reduced health care use and disability, resulting in major cost savings. Despite a 3-fold increase in patients, the total costs decreased by 14%, from €222 million to €191 million. Costs for medication and primary care visits increased, but overall annual costs per patient decreased by 72%, from €2656 to €749. The theoretical total cost savings for 2013, comparing actual with predicted costs, were between €120 and €475 million, depending on the scenario used. The Finnish Asthma Program resulted in significant cost savings at both the societal and patient levels during a 26-year period.

Budesonide Attains Its Wide Clinical Profile by Alternative Kinetics.

The introduction of inhaled corticosteroids (ICSs) changed over a few decades the treatment focus of mild-to-moderate asthma from bronchodilation to reduction in inflammation. This was achieved by inhaling a suitable corticosteroid (CS), giving a high, protracted airway concentration at a low total dose, thereby better combining efficacy and tolerance than oral therapy. Successful trials with the potent, lipophilic "skin" CS beclomethasone dipropionate (BDP) paved the way, suggesting that ICSs require a very low water solubility, prolonging their intraluminal dissolution within airways. The subsequent ICS development, with resulting clinical landmarks, is exemplified here with budesonide (BUD), showing that a similar efficacy/safety relationship is achievable by partly alternative mechanisms. BUD is much less lipophilic, giving it a 100-fold higher water solubility than BDP and later developed ICSs, leading to its more rapid intraluminal dissolution and faster airway and systemic uptake rates. In airway tissue, a BUD fraction is reversibly esterified to intracellular fatty acids, a lipophilic conjugate, which prolongs airway efficacy. Another mechanism is that the rapidly absorbed bulk fraction, via short plasma peaks, adds anti-inflammatory activity at the blood and bone marrow levels. Importantly, these plasma peaks are too short to provoke systemic adverse actions. Controlled clinical trials with BUD changed the use of ICS from a last resort to first-line treatment. Starting ICS treatment immediately after diagnosis ("early intervention") became a landmark for BUD. An established dose response made BUD suitable for the treatment of patients with all degrees of asthma severity. With the development of the budesonide/formoterol combination inhaler (BUD/FORM), BUD contributed to the widely used BUD/FORM maintenance and reliever therapy (MART). Recent studies demonstrated the value of BUD/FORM as a generally recommended as-needed therapy for asthma ("anti-inflammatory reliever", AIR). These abovementioned qualities have all influenced international asthma management and treatment guidelines.

Skin thickness in children treated with daily or periodical inhaled budesonide for mild persistent asthma. The Helsinki early intervention childhood asthma study.

In adults, asthma treatment with high doses of inhaled corticosteroids has resulted in dermal thinning. The aim of this study was to investigate the skin thickness in children with asthma during budesonide treatment. In a double-blind study, 113 children, 5-10 y old, with persistent asthma received budesonide 400 microg twice daily for 1 mo and thereafter 200 microg twice daily for 5 mo. Thereafter, 56 children received 100 microg twice daily for 1 y, whereas 57 other children used budesonide periodically for exacerbations. An additional 54 children were treated with disodium cromoglycate (DSCG) for 18 mo. Skin thickness was measured on each forearm before and after treatment for 6, 12, and 18 mo using a 20-MHz high-resolution ultrasonic device. The initial 6-mo budesonide treatment resulted in a greater reduction in mean skin thickness in the forearms compared with DSCG (right: -35.9 versus -5.9 microm; p = 0.004; left: -30.6 versus -7.3 microm; p = 0.03). At month 18, the inter-group differences were no longer significant. Budesonide inhalations in daily doses of 400-800 microg in prepubertal children with newly detected asthma may cause minor dermal thinning. The changes were reversible during low dose or periodic treatment with budesonide.

Bone mineral density in children treated with daily or periodical inhaled budesonide: the Helsinki Early Intervention Childhood Asthma study.

In a double-blind, randomized study, 136 children, 5-10-y-old, with newly detected persistent asthma received budesonide (BUD) 400 microg twice daily for 1 mo and thereafter 200 microg twice daily for 5 mo. Thereafter, 50 children were treated with BUD 100 microg twice daily, whereas 44 children used BUD as needed for 1 y; an additional 42 children received disodium cromoglycate (DSCG). Asthma exacerbations were treated with BUD for 2 wk in a dose of 400 microg twice daily in all groups. In this secondary analysis, bone mineral density (BMD) of the lumbar vertebrae was measured before and after the 18-mo treatment. Compared with DSCG, regular BUD treatment resulted in a significantly smaller increase in BMD (0.023 versus 0.034 g/cm; p = 0.023) and height (7.75 versus 8.80 cm; p = 0.001). Periodic treatment did not affect BMD. No intergroup differences were observed when BMD data were adjusted for changes in height. Daily BUD treatment in prepubertal children may slow down the increment in BMD and standing height. This was not observed in children receiving BUD periodically after the initial regular BUD treatment. The correlation between height and BMD suggests that following children's height might afford an estimation of inhaled corticosteroid effects on bone.

Thirteen-year follow-up of early intervention with an inhaled corticosteroid in patients with asthma.

BACKGROUND: In a 3-year study, adult patients who recently developed asthma (symptoms for less than 1 year) were treated for 2 years with the inhaled corticosteroid (ICS) budesonide (early therapy) or terbutaline. During the third year of the study, terbutaline-treated patients received budesonide (delayed therapy). Differences in lung function and bronchial responsiveness to histamine were observed between the 2 groups. OBJECTIVE: We compared the effects of early versus delayed budesonide therapy after a 10-year follow-up period (13 years after the study began) and current real-life data. METHODS: Of the original 103 patients, 90 were re-examined 13 years after study initiation. After the third year of the study, all patients had their medications, including the dose of ICS, individually adjusted. RESULTS: After the follow-up period, lung function was within the normal range for the entire group (all patients); bronchial responsiveness significantly improved compared with baseline data. No statistically significant differences in clinical or functional variables were found between patients given early or delayed budesonide therapy. However, the delayed therapy group had a higher neutrophil count and higher concentrations of eosinophilic cationic protein and myeloperoxidase in induced sputum. This group had also used more asthma medication and hospital days. CONCLUSIONS: Patients with relatively mild asthma who received ICS within 12 months of their first asthma symptoms or after a 2-year delay achieved equally good functional control of asthma after 10 years of individualized therapy. However, the delayed therapy group exhibited slightly less optimal disease control and more signs of airway inflammation.

Budesonide/formoterol as effective as prednisolone plus formoterol in acute exacerbations of COPD. A double-blind, randomised, non-inferiority, parallel-group, multicentre study.

BACKGROUND: Oral corticosteroids and inhaled bronchodilators with or without antibiotics represent standard treatment of COPD exacerbations of moderate severity. Frequent courses of oral steroids may be a safety issue. We wanted to evaluate in an out-patient setting whether a 2-week course of inhaled budesonide/formoterol would be equally effective for treatment of acute COPD exacerbations as standard therapy in patients judged by the investigator not to require hospitalisation. METHODS: This was a double-blind, randomised, non-inferiority, parallel-group, multicentre study comparing two treatment strategies; two weeks' treatment with inhaled budesonide/formoterol (320/9 microg, qid) was compared with prednisolone (30 mg once daily) plus inhaled formoterol (9 microg bid) in patients with acute exacerbations of COPD attending a primary health care centre. Inclusion criteria were progressive dyspnoea for less than one week, FEV1 30-60% of predicted normal after acute treatment with a single dose of oral corticosteroid plus nebulised salbutamol/ipratropium bromide and no requirement for subsequent immediate hospitalisation, i.e the clinical status after the acute treatment allowed for sending the patient home.A total of 109 patients (mean age 67 years, 33 pack-years, mean FEV1 45% of predicted) were randomized to two weeks' double-blind treatment with budesonide/formoterol or prednisolone plus formoterol and subsequent open-label budesonide/formoterol (320/9 microg bid) for another 12 weeks. Change in FEV1 was the primary efficacy variable. Non-inferiority was predefined. RESULTS: Non-inferiority of budesonide/formoterol was proven because the lower limit of FEV1-change (97.5% CI) was above 90% of the efficacy of the alternative treatment. Symptoms, quality of life, treatment failures, need for reliever medication (and exacerbations during follow-up) did not differ between the groups. No safety concerns were identified. CONCLUSION: High dose budesonide/formoterol was as effective as prednisolone plus formoterol for the ambulatory treatment of acute exacerbations in non-hospitalized COPD patients. An early increase in budesonide/formoterol dose may therefore be tried before oral corticosteroids are used. CLINICAL TRIAL REGISTRATION: NCT00259779.

Exome Sequencing Identifies Susceptibility Loci for Sarcoidosis Prognosis.

Many sarcoidosis-associating immunological genes have been shown to be shared between other immune-mediated diseases. In Finnish sarcoidosis patients, good prognosis subjects more commonly have HLA-DRB1*03:01 and/or HLA-DRB1*04:01-DPB1*04:01 haplotype, but no marker for persistent disease have been found. The objective was to further pinpoint genetic differences between prognosis subgroups in relation to the HLA markers. Whole-exome sequencing was conducted for 72 patients selected based on disease activity (resolved disease, n = 36; persistent disease, n = 36). Both groups were further divided by the HLA markers (one/both markers, n = 18; neither of the markers, n = 18). The Finnish exome data from the Genome Aggregation Database was used as a control population in the WES sample. Statistical analyses included single-variant analysis for common variants and gene level analysis for rare variants. We attempted to replicate associated variants in 181 Finnish sarcoidosis patients and 150 controls. An association was found in chromosome 1p36.21 (AADACL3 and C1orf158), which has recently been associated with sarcoidosis in another WES study. In our study, variations in these genes were associated with resolved disease (AADACL3, p = 0.0001 and p = 0.0003; C1orf158, p = 7.03E-05). Another interesting chromosomal region also peaked, Leucocyte Receptor Complex in 19q13.42, but the association diminished in the replication sample. In conclusion, this WES study supports the previously found association in the region 1p36.21. Furthermore, a novel to sarcoidosis region was found, but additional studies are warranted to verify this association.

Effect of disease duration on dose-response of inhaled budesonide in asthma.

BACKGROUND: Inhaled corticosteroids (ICS) represent first-line treatment in persistent asthma with clinical studies showing benefits of initiating therapy early. Whether treatment should be started with a high or low dose remains controversial. We investigated the importance of disease duration on the response to the starting dose of the ICS, budesonide, in asthma patients not previously treated with ICS. METHODS: Forty patients with newly detected asthma (symptoms for <12 months) and 41 patients with established asthma (mean duration 5.2 years, range 2-11) were randomized (double-blind, parallel-group) to treatment with budesonide Turbuhaler 100 or 400microg twice daily or placebo for 12 weeks. RESULTS: For morning peak expiratory flow (mPEF), all four budesonide treatments resulted in statistically significant improvements from baseline and, after 12 weeks, the changes in all four groups were statistically significantly greater than placebo. In patients receiving early treatment, no significant differences were seen between budesonide doses. In patients with established symptoms, 800 mg/day [corrected] improved mPEF significantly more than 200 mg/day [corrected] The 200 mg/day [corrected] dose in the early treatment group improved mPEF significantly more than in the delayed treatment group. Changes in forced expiratory volume in 1s (FEV(1)), the concentration of inhaled histamine causing a 20% drop in FEV(1), and use of as-needed medication behaved in very similar ways to mPEF. Asthma symptoms were reduced in all budesonide groups without a difference between doses. CONCLUSION: In patients with newly detected asthma treated early the initial ICS dose is not important. In contrast, in patients with symptoms for a longer duration a high starting dose improves airway function and hyperresponsiveness significantly better than a low dose.

ACE gene variants and sarcoidosis in a Finnish population.

Background: Sarcoidosis is a systemic inflammatory disease with unknown etiology. However, there is a strong evidence of genetic influence in sarcoidosis. Objectives: We wanted to extend our knowledge of the role of the whole ACE gene, not only insertion/deletion (I/D) polymorphism, in a Finnish sarcoidosis population by genotyping the ACE gene region from 5' upstream to the 3' downstream. Methods: We genotyped 29 single nucleotide polymorphisms (SNPs) spanning the ACE gene from 188 sarcoidosis patients (resolved disease, n=90; persistent disease, n=98) and from 150 controls. These SNPs included tag SNP rs4343 for I/D polymorphism. To replicate the study we genotyped 11 of these SNPs from 139 Czech sarcoidosis patients (resolved disease, n=47; persistent disease, n=92) and 176 healthy controls. Results: No association was detected between I/D genotypes and disease susceptibility or prognosis. We found a novel SNP (rs9905945) in the 5'upstream region of the ACE gene to be moderately associated with favourable disease prognosis in Finnish patients [p=0.035, OR=2.034 (95%CI 1.045-3.960)]. However, in the replication study in Czechs, the SNP rs9905945 did not show association with prognosis of sarcoidosis. Conclusions: This study further characterizes genetic distinctions between Finnish sarcoidosis patients with different prognosis and population-specific genotype distribution of ACE variants. Nevertheless it seems that variants in the ACE gene do not considerably influence the course of the disease in Finnish sarcoidosis patients. (Sarcoidosis Vasc Diffuse Lung Dis 2017; 34: 104-114).

SNP Variants in Major Histocompatibility Complex Are Associated with Sarcoidosis Susceptibility-A Joint Analysis in Four European Populations.

Sarcoidosis is a multiorgan inflammatory disorder with heritability estimates up to 66%. Previous studies have shown the major histocompatibility complex (MHC) region to be associated with sarcoidosis, suggesting a functional role for antigen-presenting molecules and immune mediators in the disease pathogenesis. To detect variants predisposing to sarcoidosis and to identify genetic differences between patient subgroups, we studied four genes in the MHC Class III region (LTA, TNF, AGER, BTNL2) and HLA-DRA with tag-SNPs and their relation to HLA-DRB1 alleles. We present results from a joint analysis of four study populations (Finnish, Swedish, Dutch, and Czech). Patients with sarcoidosis (n = 805) were further subdivided based on the disease activity and the presence of Löfgren's syndrome. In a joint analysis, seven SNPs were associated with non-Löfgren sarcoidosis (NL; the strongest association with rs3177928, P = 1.79E-07, OR = 1.9) and eight with Löfgren's syndrome [Löfgren syndrome (LS); the strongest association with rs3129843, P = 3.44E-12, OR = 3.4] when compared with healthy controls (n = 870). Five SNPs were associated with sarcoidosis disease course (the strongest association with rs3177928, P = 0.003, OR = 1.9). The high linkage disequilibrium (LD) between SNPs and an HLA-DRB1 challenged the result interpretation. When the SNPs and HLA-DRB1 alleles were analyzed together, independent association was observed for four SNPs in the HLA-DRA/BTNL2 region: rs3135365 (NL; P = 0.015), rs3177928 (NL; P < 0.001), rs6937545 (LS; P = 0.012), and rs5007259 (disease activity; P = 0.002). These SNPs act as expression quantitative trait loci (eQTL) for HLA-DRB1 and/or HLA-DRB5. In conclusion, we found novel SNPs in BTNL2 and HLA-DRA regions associating with sarcoidosis. Our finding further establishes that polymorphisms in the HLA-DRA and BTNL2 have a role in sarcoidosis susceptibility. This multi-population study demonstrates that at least a part of these associations are HLA-DRB1 independent (e.g., not due to LD) and shared across ancestral origins. The variants that were independent of HLA-DRB1 associations acted as eQTL for HLA-DRB1 and/or -DRB5, suggesting a role in regulating gene expression.

Maintenance plus reliever budesonide/formoterol compared with a higher maintenance dose of budesonide/formoterol plus formoterol as reliever in asthma: an efficacy and cost-effectiveness study.

OBJECTIVE: To evaluate efficacy and cost-effectiveness of budesonide/formoterol (Symbicort) maintenance (one dose once or twice daily) plus additional doses as needed (Symbicort Maintenance And Reliever Therapy, SMART) compared with a higher fixed dose of budesonide/formoterol with formoterol as needed in patients with persistent asthma. STUDY DESIGN AND METHODS: 6-month, open, randomised study of 465 patients either not well controlled on an inhaled corticosteroid (ICS), or well controlled on a combination of ICS and a long-acting beta(2)-agonist (LABA). TREATMENTS: budesonide/formoterol 160/4.5 microg, one inhalation, once or twice daily maintenance plus additional doses as-needed (1 x SMART or 2 x SMART), or budesonide/formoterol 160/4.5 microg two inhalations twice daily plus formoterol 4.5 microg as needed (2 x 2 FIX + F). Children 6-11 years old used an 80/4.5 microg dose strength. Primary variables of efficacy were the changes in the Asthma Control Questionnaire (ACQ(5)) and morning peak expiratory flow (PEF). RESULTS: Mean age of patients 40 years (range 6-82 years); 53% female. No differences between the groups were found in ACQ(5) scores or asthma exacerbation rates. Morning PEF was higher in the 2 x 2 FIX + F group vs. the 1 x SMART and 2 x SMART groups (differences 13 L/min and 9 L/min, respectively; p < 0.002). The 1 x SMART group showed a significant decrease in asthma controlled days compared with the two other groups. No difference was seen between the 2 x SMART group and the 2 x 2 FIX + F group. Treatment costs were significantly lower in the SMART groups compared with the 2 x 2 FIX + F group. CONCLUSION: Compared with the 2 x 2 FIX + F treatment the use of budesonide/formoterol was 30-40% lower in the SMART groups while maintaining equal ACQ(5) scores. Daily asthma control improved equally with 2 x SMART compared to 2 x 2 FIX + F with a reduction in asthma medication cost. The one dose once daily maintenance treatment (1 x SMART) resulted in a low level of treatment failure (exacerbations) but led to more days with symptoms. Therefore, a daily dose of two inhalations seems to be the lowest appropriate dose in patients with moderate persistent asthma.

Performance of Turbuhaler((R)) in Patients with Acute Airway Obstruction and COPD, and in Children with Asthma : Understanding the Clinical Importance of Adequate Peak Inspiratory Flow, High Lung Deposition, and Low In Vivo Dose Variability.

The dry-powder inhaler (DPI) Turbuhaler((R)) has been on the market for nearly two decades. Products containing terbutaline, formoterol, budesonide, and the combination budesonide/formoterol are widely used by patients with asthma and COPD. Most patients and physicians find Turbuhaler((R)) easy to use, and local side effects are rare. This is thought to arise from the lack of additives or only small amounts in the formulation, in addition to minimal deposition of the drug in the oropharynx and on the vocal cords during inspiration.The function of Turbuhaler((R)) has frequently been questioned. This article aims to review and clarify some key issues that have been challenged in the literature (e.g. the effectiveness of Turbuhaler((R)) in patients with more restricting conditions), to discuss the importance of lung deposition, and to explain the low in vivo variability associated with Turbuhaler((R)) and the lack of correlation with the higher in vitro variability.Turbuhaler((R)), like other DPIs, is flow dependent to some degree. However, a peak inspiratory flow (PIF) through Turbuhaler((R)) of 30 L/min gives a good clinical effect. These PIF values can be obtained by patients with conditions thought to be difficult to manage with inhalational agents, such as asthmatic children and adult patients with acute severe airway obstruction and COPD. Excellent clinical results with Turbuhaler((R)) in large controlled studies in patients with COPD and acute severe airway obstruction provide indirect evidence that medication delivered via Turbuhaler((R)) reaches the target organ.Due to the large amount of small particles and the moderate inbuilt resistance in Turbuhaler((R)), which opens up the vocal cords during inhalation, Turbuhaler((R)) is associated with a high lung deposition (25-40% of the delivered dose) compared with pressurized metered-dose inhalers (pMDIs) and other DPIs. A good correlation has been found between lung deposition and clinical efficacy. A high lung deposition always results in the best ratio between clinical efficacy and risk of unwanted systemic activity. Studies with Turbuhaler((R)) also show that the in vivo variation in lung deposition is significantly lower compared with a pMDI or, for example, the Diskus((R)) inhaler, and much lower than the in vitro dose variability seen in laboratory tests. Turbuhaler((R)) appears to be a reliable DPI which can be used with confidence by patients with airway diseases, including those with clinical conditions believed to be difficult to manage with inhalational therapy.

Characteristics of reversible and nonreversible COPD and asthma and COPD overlap syndrome patients: an analysis of salbutamol Easyhaler data.

The choice of inhaler device for bronchodilator reversibility is crucial since suboptimal inhalation technique may influence the result. On the other hand, bronchodilator response also varies from time to time and may depend on patient characteristics. In this study, patients with airway obstruction (forced expiratory volume in 1 second [FEV1]/forced vital capacity [FVC] ratio <70% in chronic obstructive pulmonary disease [COPD]; <80% in asthma) were included (n=121, age: 57.8±17.3 years). Bronchodilator reversibility (American Thoracic Society/European Respiratory Society criteria) was tested in patients with COPD (n=63) and asthma and COPD overlap syndrome (ACOS; n=12). Forty-six asthmatics served as controls. Reversibility was tested with 400 µg salbutamol dry powder inhaler (Buventol Easyhaler, Orion Pharma Ltd, Espoo, Finland). Demographic data and patients' perceptions of Easyhaler compared with ß2-agonist pressurized metered dose inhalers (pMDIs) were analyzed. American Thoracic Society/European Respiratory Society guideline defined reversibility was found in 21 out of 63 COPD patients and in two out of 12 ACOS patients. Airway obstruction was more severe in COPD patients as compared with controls (mean FEV1 and FEV1% predicted both P<0.0001). Average response to salbutamol was significantly lower in COPD patients compared with asthma controls (P<0.0001). Reversibility was equally often found in smokers as in never-smokers (33% vs 34%). Nonreversible COPD patients had higher mean weight, body mass index, and FEV1/FVC compared with reversible COPD patients. Most patients preferred Easyhaler and defined its use as simpler and more effective than use of a pMDI. Never-smokers and patients with asthma experienced Easy-haler somewhat easier to use than smokers and patients with COPD. In conclusion, a substantial part of patients with COPD or ACOS showed reversibility to salbutamol dry powder inhaler. Nonreversible patients with COPD were characterized by higher weight and body mass index, and a higher FEV1/FVC ratio. Most patients preferred Easyhaler compared with a pMDI.

Revisiting early intervention in adult asthma.

The term "early intervention" with inhaled corticosteroids (ICS) in asthma is used in different ways, thereby causing confusion and misinterpretation of data. We propose that the term should be reserved for start of ICS therapy in patients with a diagnosis of asthma but within a short period of time after the first symptoms, not from the date of diagnosis. Prospective clinical studies suggest a time frame of 2 years for the term "early" from the onset of symptoms to starting anti-inflammatory treatment with ICS. The current literature supports early intervention with ICS for all patients with asthma including patients with mild disease, who often have normal or near-normal lung function. This approach reduces symptoms rapidly and allows patients to achieve early asthma control. Later introduction of ICS therapy may not reduce effectiveness in terms of lung function but delays asthma control and exposes patients to unnecessary morbidity. Results of nationwide intervention programmes support the early use of ICS, as it significantly minimises the disease burden. Acute asthma exacerbations are usually preceded by progressing symptoms and lung function decline over a period of 1-2 weeks. Treatment with an increased dose of ICS together with a rapid- and long-acting inhaled ß2-agonist during this phase has reduced the risk of severe exacerbations.

National and regional asthma programmes in Europe.

This review presents seven national asthma programmes to support the European Asthma Research and Innovation Partnership in developing strategies to reduce asthma mortality and morbidity across Europe. From published data it appears that in order to influence asthma care, national/regional asthma programmes are more effective than conventional treatment guidelines. An asthma programme should start with the universal commitments of stakeholders at all levels and the programme has to be endorsed by political and governmental bodies. When the national problems have been identified, the goals of the programme have to be clearly defined with measures to evaluate progress. An action plan has to be developed, including defined re-allocation of patients and existing resources, if necessary, between primary care and specialised healthcare units or hospital centres. Patients should be involved in guided self-management education and structured follow-up in relation to disease severity. The three evaluated programmes show that, thanks to rigorous efforts, it is possible to improve patients' quality of life and reduce hospitalisation, asthma mortality, sick leave and disability pensions. The direct and indirect costs, both for the individual patient and for society, can be significantly reduced. The results can form the basis for development of further programme activities in Europe.

Early treatment of stage II sarcoidosis improves 5-year pulmonary function.

STUDY OBJECTIVE: To evaluate the 5-year prognosis of patients with stage I and stage II newly detected (< 3 months) pulmonary sarcoidosis treated immediately after diagnosis with prednisolone for 3 months followed by inhaled budesonide for 15 months. DESIGN: Randomized, double-blind, placebo-controlled, parallel-group study for 18 months. Thereafter, open follow-up without treatment. SETTING: Twenty pulmonary medicine departments in Finland. PATIENTS: One hundred eighty-nine adult patients, most of them with normal lung function, were randomized to treatment. One hundred forty-nine patients were followed up for 5 years: 79 patients with initial stage I disease and 70 patients with stage II disease. TREATMENT: Oral prednisolone for 3 months followed by inhaled budesonide for 15 months (800 microg bid), or placebo tablets followed by placebo inhaler therapy. Thereafter, treatment only on an individual basis in the case of clinical deterioration. MEASUREMENTS: Yearly follow-up visits with chest radiographs, lung function tests (FEV(1), FVC), diffusion capacity of the lung for carbon monoxide (DLCO), serum angiotensin-converting enzyme (SACE), and serum and urinary calcium measurements. RESULTS: No initial differences were observed in chest radiographic findings between the active-treatment and placebo-treatment groups, either in patients with initial stage I or stage II(-III) disease. However, after the 5-year follow-up, 18 steroid-treated patients (26%) and 30 placebo-treated patients (38%) still had remaining chest radiographic changes. Placebo-treated patients more frequently required treatment with corticosteroids during the 5-year follow-up (p < 0.05). Steroid-treated patients with initial stage II(-III) disease improved more in FVC and DLCO (p < 0.05). No differences in reported adverse events or in SACE, serum calcium, or urinary calcium values were seen. CONCLUSION: Immediate treatment of pulmonary stage II(-III) sarcoidosis-but not stage I disease-improved the 5-year prognosis with regard to lung function variables.

The place of inhaled corticosteroids in chronic obstructive pulmonary disease.

The role of systemic corticosteroids in the treatment of exacerbations of chronic obstructive pulmonary disease (COPD) is well established. However, despite being frequently prescribed for the treatment of COPD, the clinical utility of inhaled corticosteroids (ICS) is less clearly defined. This review article seeks to clarify the role of ICS in the clinical management of COPD through a review of key pivotal short-, medium- and long-term studies in this field. Studies for inclusion in this review were identified by means of a computerised search of several databases (including MEDLINE, BIOSIS and EMBASE) from 1980 to 2003. While individual clinical and epidemiological studies have yielded conflicting results, meta-analysis of available data suggests that ICS may reduce the frequency and severity of exacerbations, the number of hospitalisations and the mortality rate, as well as yielding improvements in lung function and health-related quality of life (HRQL) in some subgroups of COPD patients. More recently, clinical trials evaluating the effect of combination therapy with ICS and long-acting beta2-agonists (LABA) have shown significant effects on the prevention of exacerbations and HRQL. Emerging data are expected to clarify the role of ICS in the management of patients with COPD of different severities as well as the place of treatment with ICS/LABA combinations in the management of this chronic and disabling disorder.