Barriers and solutions to stepping down asthma treatment

Asthma is a chronic airway disease with two characteristic features: (1) chronic airway infl ammation (the most common eosinophilic airway infl ammation) and (2) airway hyperresponsiveness (excessive airway constriction by normal triggers) [1]. Management of asthma requires long-term treatment to achieve well-controlled symptoms and prevent the risk of exacerbation in future. Inhaled corticosteroid (ICS) is the mainstay therapy of asthma with strong evidences [2]. Nonetheless it is still the existence of gap in knowledge “what is the most appropriate dose of ICS to treat asthmatic patient?”. Beside physicians are always concerned about unnecessary side effects of long-term treatment with ICS, especially high dose, including osteoporosis, cataracts, chronic adrenal insuffi ciency, thinning skin and bruise, risk of pneumonia and diabetes mellitus [2]. Therefore almost national and international guidelines recommend the stepwise treatment in management of asthma (reducing ICS dose consistently 2550% when asthmatic patients achieved well-controlled at least three months) to approach the lowest effective ICS dose and the lowest risk of side effects [3-5]. However, stepping down asthma treatment in real world is still limited. The study at England revealed that the low proportion of asthmatic patients (6%) was stepped down although 62% of them was wellcontrolled during one-year [6]. We need to analyze the benefi ts of the step-down strategy and barriers in clinical practice to apply it more effectively.


C L I N I C A L G R O U P
https://dx.doi.org/10.17352/oja DOI: 2640-8082 ISSN: Asthma is a chronic airway disease with two characteristic features: (1) chronic airway infl ammation (the most common eosinophilic airway infl ammation) and (2) airway hyperresponsiveness (excessive airway constriction by normal triggers) [1]. Management of asthma requires long-term treatment to achieve well-controlled symptoms and prevent the risk of exacerbation in future. Inhaled corticosteroid (ICS) is the mainstay therapy of asthma with strong evidences [2].
Nonetheless it is still the existence of gap in knowledge "what is the most appropriate dose of ICS to treat asthmatic patient?".
Beside physicians are always concerned about unnecessary side effects of long-term treatment with ICS, especially high dose, including osteoporosis, cataracts, chronic adrenal insuffi ciency, thinning skin and bruise, risk of pneumonia and diabetes mellitus [2]. Therefore almost national and international guidelines recommend the stepwise treatment in management of asthma (reducing ICS dose consistently 25-50% when asthmatic patients achieved well-controlled at least three months) to approach the lowest effective ICS dose and the lowest risk of side effects [3][4][5]. However, stepping down asthma treatment in real world is still limited. The study at England revealed that the low proportion of asthmatic patients (6%) was stepped down although 62% of them was wellcontrolled during one-year [6]. We need to analyze the benefi ts of the step-down strategy and barriers in clinical practice to apply it more effectively.

Benefi ts from stepping down strategy of inhaled corticosteroid dose
Guidelines encourage the rapid acquirement of wellcontrolled asthma with the initial treatment without specifi c recommendations of initial ICS dose appropriately in association of both effi ciency and safety [5]. It results in overtreatment at initial ICS dose and risk of systemic side effects. With stepping down strategy, we can resolve the over-treatment to reach the minimum effective ICS dose [3,4,7]. Moreover the results of published studies showed additional benefi ts with stepping down strategy including (1) higher proportion of therapeutic adherence in asthmatic patients [3,4] with several factors such as higher age, initial severity of asthma, and shortening duration of well-controlled asthma before stepping down [12]. Hence asthmatic patients could be stepped down successfully if the investigation of risk factors is undertaken comprehensively. Asthma guidelines usually recommend the stepping down treatment when achieving well-controlled at least three months [5]. However, the study of Omar S. Usmani, et al. (2017) showed that the history of exacerbation during previous 12 months was a signifi cant predictor of occurring exacerbation when stepping down [13].
In 2019 Luis Pérez de Llano, et al. developed a simple score for future risk prediction in asthmatic patients undergoing step-down strategy which included four factors (FEV1/ FVC < 0.7, current FEV1 < 80%, ≥ 1 episode of exacerbation during previous one year, and ACT score < 25) [14]. Recently the measurement of FeNO, an useful biomarker for guiding management of asthma and evaluating the control of asthma [15], have been suggested as a biomarker guiding for stepping down in mild to moderate well-controlled asthma [1,16]. All together support to be over the failure risk when undergoing stepping down strategy. An additional concern about longterm effi ciency of stepping-down strategy, Matthew A Rank, et al. (2015) reported the rate of 32% asthmatic patients with exacerbation during two years on stepped-down therapy [17].
However it is diffi cult to conclude the correlation between exacerbation and step-down therapy because this study had no control group. Further research need be undertaken to answer the long-term effi ciency of this strategy.

Heterogeneity of step-down strategies
There are many steps of control asthma suitable with the severity of individual asthmatic patients such as ICS monotherapy, leukotriene receptor antagonist, combination of ICS and Long-Acting Beta-Agonist (LABA) (early onset of bronchodilator action or not), or combination of ICS-LABA and long-acting muscarinic receptor antagonist [5]. To every specifi c step treatment, it will be a step-down strategy respectively. However there is no consensus to guide physicians reduce asthma treatment. For instance the step-down strategy from treatment with combination ICS-LABA, whether withdrawal LABA or reducing ICS dose should be undertaken fi rstly, it is more favorable to reduce ICS dose suggested via the majority of asthma guidelines. Particularly in patients with mild asthma or well-controlled with step 2 treatment, there are several stepping down options (reducing ICS dose to lowest dose, switching regimen of scheduled ICS to regimen of "as needed" ICS when using SABA) but what optimal option is obscured [9]. The study of Michael R. Gionfriddo, et al. 2015 showed insuffi cient evidence to switch scheduled to "as needed" [18]. Although the results of SYGMA-1 and SYGMA-2 studies supported more evidence to "as needed" strategy [19,20], , further study in real world is necessary because this strategy will depend on the patient's asthma perception.

Barriers from physician's perception
"Patients are well controlled with current treatment, why I need to change the regimen?". Although aforementioned evidences of benefi t, the minority of physician would refuse the stepping down strategy [21]. The study of Deirdre Siddaway (2018) revealed that the primary care staff were lack of knowledge and confi dent in stepping down asthma treatment [22]. In England only small proportion (6%) of asthmatic patients were stepped down during one year follow-up, although the rate of well-controlled asthma was 62% in the same year [6].

Characteristics of asthmatic patients
Personalized therapy has an important role in management of asthma. Pathogenesis of eosinophilic airway infl ammation is common in asthmatic patients and responsive to ICS treatment. In another hand several asthmatic patient with non-eosinophilic infl ammation, reduction of ICS dose also showed successfully in two-thirds of these subjects (the study of S. Demarche, et al. 2018) [23]. Moreover, differences in race/ ethnicity could infl uence the effect of asthma medications [24].
For instance with the same of severity of stabilize asthma, it will be well-controlled with low ICS dose but another patient will require higher ICS dose to control. This feature also affects to the effi ciency of stepping-down strategy. In clinical practice, few asthmatic patients even refuse reducing ICS dose because they worries their symptoms worsening [22]. It is very important to communicate with patient about stepping down strategy completely and have specifi c action plan when stepping down [25].

Recommendation and solutions to step down asthma treatment
With more published studies, stepping down asthma treatment could be undertaken more effectively with the low risk of both loss of control asthma and development of exacerbation.
Physicians should consider stepping down asthma medications when asthmatic patients are well controlled and normal pulmonary function. The evaluation of risk factors of failure, calculating the score of future prediction and measuring FeNO are essential to secure success of the stepping down strategy.
Besides the complete communication between physician and asthmatic patient about benefi ts of stepping down strategy, specifi c action plan to deal with loss of asthma control when reducing ICS dose, and scheduled appointments to check is pivotal factor to enhance patient's adherence to this strategy.