The Treatment of Atopic Dermatitis and Other Dermatoses with Leukotriene Antagonists

J.M. Rackal³, HBsc, MHSc, R.B.Vender^1,2 MD, FRCPC

¹Dermatrials Research, Hamilton, ON, Canada
²Faculty of Medicine, McMaster University, Hamilton, ON, Canada
³Faculty of Medicine, Queens University, Kingston, ON, Canada

ABSTRACT

Atopic dermatitis (AD) is a chronically relapsing eczematous disorder of the skin that occurs in persons of all ages but is more common in children. AD is associated with other atopic diseases such as allergic rhinoconjunctivitis or bronchial asthma. Nearly 80% of children with AD eventually develop allergic rhinitis or asthma. AD can be classified as “mixed” (cases associated with respiratory allergies) and “pure”. Pure AD has “intrinsic” and “ extrinsic” variants. In the extrinsic type, interleukin-4 is secreted by T-cells isolated from spontaneous lesions and skin-derived T-lymphocytes express more IL-13. Due to the different immunopathogenesis, it has been suggested that antileukotriene agents may be more successful in the treatment of the extrinsic subgroup. Leukotrienes (LTs) are a class of potent biological inflammatory mediators derived from arachidonic acid through the 5-lipoxygenase pathway. There is evidence of enhanced LT production in the pathogenesis of AD. Evidence in the literature provides a pathophysiological rationale for the use of cysLT receptor blockers in the treatment of AD. However, the exact mechanism of action of leukotriene receptor antagonists in AD is not known. In small clinical and case studies, montelukast was found to be a safe and effective alternative or steroid-sparing therapy in the management of patients with atopic dermatitis.
Key Words: atopic dermatitis, dermatoses, leukotriene antagonists

Atopic Dermatitis

Atopic dermatitis (AD) is a chronically relapsing eczematous disorder of the skin that occurs in persons of all ages but is more common in children. AD has been reported to affect more than 10% of children in most countries.¹ Approximately 60-70% of those with mild to severe dermatitis will continue to experience symptoms into adulthood.² The condition is characterized by intense pruritus and a course marked by exacerbations and remissions. Patients with AD may have disrupted sleep with consequent daytime fatigue and compromised school and work quality.³ Skin hydration, avoidance of irritants, antihistamines, topical corticosteroids and newer topical immunomodulators are the mainstay of therapy for AD. However, AD is usually refractory to treatment and the local and systemic side effects of topical steroids are widely recognized. AD is associated with other atopic diseases such as allergic rhinoconjunctivitis or bronchial asthma.⁴ Nearly 80% of children with AD eventually develop allergic rhinitis or asthma.⁵ It is estimated that in the U.S, $364 million is spent annually on the treatment of childhood AD.⁶

Immunologic Abnormalities in AD

An understanding of the immunologic basis of AD is necessary for the development of novel approaches to treating this disease. A recent review by Leung⁵ summarized the following immunologic findings. Most patients with AD have elevated numbers of circulating eosinophils and increased immunoglobulin E (IgE) levels. This is caused by T-cell dysfunction. An increased frequency of Th2 cells that produce increased IL-4, IL-5 and IL-13 has been demonstrated in the peripheral blood of patients with AD. Factors contributing to Th2 cell development in AD include cytokines, genetic differences in cytokine (IL-4) production, pharmacologic factors (monocytes with increase CAMP phosphodiesterase activity) and antigen presenting cells (increased IgE-bearing Langerhans’ cells with a role in cutaneous allergen presentation to Th2 cells).

IL-4 and IL-13 are the only cytokines that promote an increase in IgE production at the level of germline transcription. IL-5 induces eosinophilopoiesis, activation and chemotaxis.⁷ Eosinophils secrete cytokines and mediators that injure tissue via reactive O2 intermediates and the release of toxic granule proteins.⁸ Eosinophil granule proteins are increased in AD sera and correlate with disease activity.⁹ Urinary eosinophil protein X has also been found to correlate with AD disease activity.¹⁰

Furthermore, AD can be classified as “mixed” (cases associated with respiratory allergies) and “pure”. Pure AD has “intrinsic” and “ extrinsic variants. Patients with the intrinsic or “non-allergic” form of AD have no associated respiratory diseases, such as bronchial asthma or allergic rhinitis, show normal total serum IgE levels, no specific IgE, and negative atopy patch tests.¹¹ In the extrinsic type, 1) interleukin-4 is secreted by T-cells isolated from spontaneous lesions, 2) the atopy patch test is positive; and 3) skin-derived T-lymphocytes express more IL-13 than T cells from the intrinsic type.¹² Due to the different immunopathogenesis, it has been suggested that antileukotriene agents may be more successful in the treatment of the extrinsic subgroup.¹³

There are pathogenic mechanisms that are central to both AD and asthma. An exaggerated inflammatory response (including increased production of IgE and eosinophilia) to environmental triggers, including irritants and allergens is characteristic of both AD and asthma.¹⁴ Total IgE levels are elevated in both AD and asthma. Genetic studies have demonstrated common chromosomal linkages between AD and asthma.¹²

Leukotrienes and AD

Leukotrienes (LTs) are a class of potent biological inflammatory mediators derived from arachidonic acid through the 5-lipoxygenase pathway¹⁵ (Fig. 1) Leukotrienes are divided into two groups according to their chemical structure: those with a sulphur linkage (cysteinyl LTs: LTC₄, LTD₄, LTE₄), and those that do not (LTB₄). Eosinophils, basophils and mast cells are the most important sources of LTs.⁴ Epidermal cells are able to transform neutrophil derived LTA₄ into LTB₄ and LTC₄.¹⁶ Thus the epidermis can also contribute significantly to LT synthesis. It has been shown that cysteinyl leukotrienes (cysLTs) mediate asthma and allergic rhinitis and when the LT receptors are antagonized, symptoms resolve.^17,18 Leukotrienes are important proinflammatory mediators that are capable of inducing airway smooth muscle constriction, airway hyperresponsiveness, eosinophil migration, vascular permeability, edema, and chemotaxis.¹⁹ A role for LTs in AD has been suggested in the literature. There is evidence of enhanced LT production in the pathogenesis of AD. The cysteinyl LTs increase vascular permeability and dilate skin blood vessels.²⁰ LTC₄ has been found in the skin of AD patients using the suction blister technique.²¹ Patients with AD have activated circulating basophils and increased basophil releasability of LTC₄.²² Cysteinyl LT release from basophils and eosinophils isolated from AD patients is increased compared to healthy controls.¹² Enhanced spontaneous and stimulated releasability of LTC₄ from leukocytes of patients with AD compared with normal controls has been reported.²³ Increased production of LTs has been reported in the skin of atopic patients after allergen specific challenge.¹² There is conflicting evidence in the literature on urinary LTE₄ levels, an index of whole-body cysteinyl LT production in vivo. LTE₄ is a stable urinary metabolite of LTC₄ and LTD₄.⁴ Sansom, et al.²⁴ found that urinary LTE levels in seven AD patients were not significantly different during or after an acute exacerbation when compared with the normal range. However, another study demonstrated mean urinary LTE₄ levels in 20 patients with AD were significantly higher than in 17 healthy volunteers, and a significant correlation between urinary LTE₄ and total serum IgE levels in AD patients was observed.²⁵

Leukotriene receptor blockers and AD

There are at least two types of LT receptors: cysLT1 and cysLT2. Montelukast (Singulair®‚ Merk-Frosst), zafirlukast (Accolate®, Zeneca), and pranlukast (Ultair®, SmithKline Beecham) are LT receptor antagonists that demonstrate high-affinity binding to the cysLT1 receptor. Montelukast is currently indicated for the prophylaxis and chronic treatment of asthma in adults and pediatric patients 12 months of age and older and for the relief of symptoms of seasonal allergic rhinitis in adults and pediatric patients 2 years of age and older. Montelukast is generally a safe drug during long term treatment; side effects are minimal.²⁶ Asthma and allergic rhinitis have numerous pathophysiological elements in common with AD, and together these three diseases are referred to as the “atopic triad”. As outlined above there are pathogenic mechanisms that are central to both AD and asthma. Therefore scientific inquiry into the use of leukotriene receptor blockers in the treatment of AD is warranted. Evidence in the literature provides a pathophysiological rationale for the use of cysLT receptor blockers in the treatment of AD however the exact mechanism of action of leukotriene receptor antagonists in AD is not known. Intradermal LTD₄ causes a wheal-and-flare response that could be blocked by a LTD₄ antagonist.²⁷ Montelukast has been shown to decrease eosinophils by 15%.²⁸ LTD₄ stimulates proliferation of eosinophil hematopoietic progenitor cells, and this increase can be suppressed by Montelukast.²⁹ Zafirlukast has been shown to inhibit LTD₄ and histamine mediated cutaneous vascular permeability.³⁰ In 16 AD adults treated with montelukast, there was a significant reduction in eosinophilic cationic protein and eosinophilic protein X levels compared to their baseline.³¹

Fig. 1: Leukotriene synthesis inhibitors

Leukotriene Receptor Blockers and Other Skin Conditions

Leukotriene receptor antagonists have also been studied in chronic urticaria. Chronic urticaria (CU) may manifest as a reaction to a known cause such as cold, pressure, food additives or nonsteroidal anti-inflammatory drugs. In some patients there is no specific causative agent, this is referred to as chronic idiopathic urticaria (CIU). H1-receptor antagonists are the major class of therapeutic agents used in the management of urticaria. Nevertheless, CU is often difficult to treat and may not be controlled by antihistamines alone. Like AD, there is pharmacological plausibility of LTRAs effectiveness in the treatment of CIU and CU. Though the pathogenic mechanisms can vary, the final common pathway for lesion induction in most cases is cutaneous mast cell activation with release of histamine and other vasoactive or proinflammatory mediators.³² While histamine is considered to be the principle mediator in immediate urticarial responses, a late-phase reaction caused by substances such as LTs seem to prolong the inflammatory process in some types of urticaria.^33,34 The prevalence of aspirin sensitivity among patients with CU is estimated to be between 20-30%.³⁵ The pathogenesis of aspirin sensitivity likely involves the inhibition of cyclooxygenase by aspirin, thus altering the balance of arachidonic acid metabolites, leading to an increase in leukotriene LTB₄, C₄, D₄ and E₄.³⁶ It is postulated that due to this imbalance, patients with aspirin sensitivity and CU may be more likely to respond to LTRAs than those without this particular sensitivity.³³ There is evidence from anecdotal case reports^33,37-43 and controlled trials^29,44,45 of improvement in CU and CIU with LTRA treatment including montelukast and zafirlukast. Nevertheless, montelukast was not found to be more effective than placebo in decreasing the early and late cutaneous allergic responses.⁴⁶ Low doses of pranlukast have been reported to cause provocation of aspirin sensitive urticaria in two patients.⁴⁷ More experimental research and long term clinical studies are required to determine the role of LTs in the pathogenesis and treatment of CU and CIU.

Leukotriene Synthesis Inhibitors

Zileuton (Zylflo®‚ Abbott Laboratories) is an inhibitor of the 5- lipoxygenase enzyme, which prevents the production of not only the cysteinyl leukotrienes but also of LTB₄ (see Fig. 1). The production of other metabolites in the arachidonic acid cascade including 5-HETE and 5-oxo-ETE will be blocked. This is important in AD since LTB₄ and 5-oxo-ETE are chemoattractants for eosinophils,48 which as outlined above are implicated in the pathophysiology of AD. In a prospective open-label pilot study, six female subjects with severe AD received 600mg zileuton QID for 6 weeks.49 All six patients experienced a significant reduction in disease dissatisfaction (p=0.03). There was no significant difference in the subjective report of pruritus. Objective skin scores (based on erythema of 20 different body parts) were conducted by a physician prior to and following treatment and a significant decrease was found (p=0.03).

Future directions

There currently is no cure for AD. All of our current management strategies aim to control the symptoms of this immunocutaneous dysfunction. Montelukast might be a safe and effective alternative or steroid-sparing therapy in the management of patients with AD. In four randomized controlled trials^28,52-54 with a total of 75 subjects, three of the trials found significant improvement of AD with montelukast treatment^52-54 and one found no significant difference from placebo.³¹ There are three case series with a total of 13 patients that report improvement in AD with zafirlukast^50,51 and montelukast.⁴ Long-term, larger double-blind placebo controlled studies are needed to determine the role of LTs in the pathogenesis of AD, to confirm the efficacy of leukotriene receptor inhibitors, and to determine the optimal timing and dosing for the treatment of AD.

Table 1: Clinical evidence supporting the use of montelukast and zafirlukast in patients with AD

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