Interferon‐α in corticosteroid‐resistant asthma and Churg–Strauss syndrome
Authors: L. Mouthon, L. Guillevin
Journal: Allergy (2003)

Allergic asthma is characterized by airway hyperreactivity to a variety of specific and nonspecific stimuli, chronic airway inflammation and increased serum IgE levels. The inflammatory process is believed to be a result of inappropriate immune responses to common aero-allergens in genetically susceptible individuals (1). As such, CD4+ T cells that produce a T helper 2 (Th2) pattern of cytokines seem to play a pivotal role in the pathogenesis of the disease (2). These cells orchestrate the recruitment and activation of the primary effector cells of the allergic response, the mast cell and the eosinophil, through the release of cytokines such as IL-4, IL-5, and IL-13. Activation of these cells results in the release of a plethora of inflammatory mediators that individually or in concert contribute to produce the symptoms of the disease (3). Although their exact role in the control of allergic immune responses remains to be determined, Th1 cytokines such as interferon (IFN)-γ can inhibit Th2 cell development in vitro, and antagonize the actions of Th2 cytokines in vivo in animal models (4). In addition, CD4+ T regulatory cells that produce TGF-β have been identified in the respiratory mucosa. These cells seem to play an important role in asthma by regulating Th2-induced airway hyperreactivity and inflammation (5). For decades, physicians relied on bronchodilators to treat asthmatic symptoms. Although steroids were also well known to control airway hyperreactivity, their side effects caused them initially to be used only in the most severe cases. Since then, the appreciation that asthma is an inflammatory disorder, the availability of effective aerosol steroid preparations, and the belief that chronic unchecked inflammation leads to airway remodeling, all contributed to a change in this pattern of practice, and steroids are at present the cornerstone of anti-inflammatory treatment (6). However, in some patients asthma may be resistant to corticosteroids and there is a need for alternative therapies. Churg–Strauss syndrome (CSS) is a rare diffuse primary vasculitis that occurs usually in the context of severe, recent onset cortico-dependent asthma (7). Some factors may play a role in the initiation of the disease, such as desensitization (8), vaccination (8), and administration of leucotriene inhibitors such as zafirlukast and montelukast (9). CSS is an antineutrophil cytoplasmic antibody (ANCA)-positive systemic vasculitis involving small vessels and characterized by eosinophilic extra-vascular tissue infiltrates. Activated eosinophils are able to induce vascular endothelial cell activation and may be directly responsible for some of the classical disease features of CSS, by virtue of the release of its stored cationic proteins, which are implicated in the cardiotoxicity (7). ANCA directed toward myeloperoxydase are found in approximately 50% of all patients with CSS, but their pathogenic role is unknown. Cytokine profile findings on the cells involved in CSS remain contradictory and it is still debated if CSS may be a Th2-mediated disease. Treatment consists of glucocorticoid monotherapy or glucocorticoid plus cyclophosphamide in the context of poor prognosis markers, especially cardiovascular involvement (8). Advances in our understanding of the pathogenesis of asthma and CSS have opened the door to immunotherapeutic strategies aiming at reversing the development of pathogenic Th2-mediated immune responses. Recombinant IFNs have been proved to be a very effective therapy in a wide range of diseases. IFN-α is a cornerstone treatment in viral hepatitis C, with at least 55% of sustained virological response (10), and in chronic myelogenous leukemia (11). IFN-α promotes differentiation of Th1 cells in vitro, and may influence cytokine production by Tr1 cells, increasing the expression of IL-10 and IL-10-induced differentiation of functional Tr1 cells (12). IFN-α is reported to have a beneficial effect on patients with idiopathic hypereosinophilic syndrome and may represent a therapeutic option in diseases associated with increased Th2 activation, such as bronchial asthma and CSS. In this issue of the Journal, Simon and colleagues administered IFN-α to 10 patients with corticosteroid-resistant asthma, including three CSS patients (13). All patients presented early clinical improvement of pulmonary function tests and their prednisone dose could be tapered. Under IFN-α treatment, leukocyte numbers were decreased, CD4+ T cells were increased, with increased differentiation of Th1 cells, and increased expression of IL-10 in peripheral blood mononuclear cells. The authors discuss potential mechanisms of action, such as the establishment of an adequate Th1–Th2 balance and the induction of the anti-inflammatory IL-10 gene. Treatment with IFN-α has been previously reported to be effective in CSS patients refractory to glucocorticoid plus cyclophosphamide (14). Four patients with biopsy-proven CSS received IFN-α. Remission of the disease and reduction in prednisolone requirement was obtained in two patients who had attained incomplete remission with cyclophosphamide or methotrexate. The third patient's condition stabilized and the fourth patient maintained remission. The blood eosinophil count in all patients decreased in a dose-dependent manner under IFN-α treatment (14). However, whether the clinical effect of IFN-α can be explained by its potential anti-eosinophil activity is controversial. Indeed, Simon and colleagues observed that in some patients the eosinophil number increased in spite of IFN-α treatment, probably as a consequence to reduction in the corticosteroid dose. This observation points to a potential risk associated with IFN-α treatment: rapid or exaggerated reduction in the corticosteroid dose may indirectly provoke eosinophilic inflammation and consequently deteriorate asthma. As mentioned by the authors, the use of IFN-α raises the question of the benefit/risk balance of such a treatment: on the one hand, improving a severe disease, on the other, taking the risk of the occurrence of adverse effects. Most patients experience adverse effects of IFN-α such as flu-like symptoms, nausea, and headache. Treatment with IFN-α can also cause (severe) neuropsychiatric side effects such as depressive symptoms which sometimes lead to suspension of therapy. Less frequently, IFN-α-induced cardiotoxicity may occur (15), and careful monitoring of cardiac function will be necessary, particularly in CSS patients. Other adverse effects of IFN-α therapy might lead to cautious use of this treatment in CSS patients. Thus, acute exacerbation of vasculitis may occur in patients with hepatitis-C associated cryoglobulinemia treated with low dose IFN-α therapy (16). Moreover, worsening of peripheral neuropathy in patients with systemic vasculitis has been previously reported (17), although the mechanisms responsible for these adverse effects remain poorly understood. Individual factors might contribute to drive the immune response to IFN-α. In a Japanese population of HCV infected patients, the IFN-α regulatory factor-1 (IRF-1) promoter polymorphisms influenced cytokine production in certain conditions. IFN-α significantly increased Th1-type CD4+ cell population and increased IFN-γ and decreased IL-10 production only in subjects homozygous for a −300 mutation of the IRF-1 promoter (18). Thus, some of the adverse effects observed in IFN-α-treated patients might be the consequence of genetic predisposition. Interferon-α, by reversing the development of pathogenic Th2-mediated immune responses, might represent an alternative option to corticosteroids in severe asthma and refractory CSS. However, careful clinical monitoring is recommended and additional studies are needed to evaluate the true efficacy and mechanism of action of IFN-α in these conditions.