A randomized trial of leukotriene receptor antagonist montelukast in moderate-to-severe atopic dermatitis of adults

ARTICLE

Patients with atopic dermatitis (AD) very often suffer from associated asthma as well; consequently, in recent times many of them have been put on newly marketed leukotriene (LT) receptor antagonists (LTRAs: zafirlukast, montelukast). These drugs are mainly recommended for the long-term treatment of mild persistent bronchial asthma, but their usefulness could expand to all categories of asthma severity [1]. Moreover, they are also active on allergic rhinitis [2]. This innovative therapeutic practice has led to the serendipitous observation of favourable outcomes of concomitant AD, and anecdotal rapid favourable therapeutic results in AD with plain zafirlukast have been published [3]. However, no controlled evaluation of LTRAs in AD was yet available. Given the fact that the treatment of moderate-to-severe AD is often puzzling, it is desirable to identify new drugs putatively active in this clinical setting. Thus we decided to compare the effectiveness of the LTRA montelukast - which offers the potential advantage of once-a-day administration - with a combined standard regimen including an orally administered antibiotic, an orally administered antihistamine, topical high-potency corticosteroids and hydrating preparations in adult patients suffering from AD. This regimen was based on currently available, recently formulated guidelines [4].

Patients and methods

Patients

This was a single-blind study planned and conducted between September 1998 and December 1999. 40 consecutive adult patients (age >= 18 years) with moderate to severe AD (arbitrarily defined as AD characterised by a SCORAD >= 30 - see below), who consulted because of flare-up and/or intolerance to and/or ineffectiveness of previous treatments, were given complete information about our planned study and invited to take part in it; among them, 32 accepted to give informed consent to be enrolled and were randomized to treatment with montelukast ("M group/treatment") or with the control combined regimen ("C group/treatment"; see Table I and Administration of Treatment below). Ethical imperatives forbade the inclusion of a true placebo group. Single-blind design had to be chosen for practical organizing purpose. In all cases AD had existed since infancy. All patients fulfilled the Hanifin-Rajka criteria for diagnosis of AD [5]. Mean total IgE levels at recruitment were 1,434 mug/L (range 90-4,800). In five cases past medical history included skin biopsies with histopathological reports of "spongiotic dermatitis", "eczema", or "dermatitis", and direct immunofluorescence (always negative or aspecific). Other relevant details about past medical history are given in Table I. Patients were required to undergo a washout period of 10 days for any drug active on atopic manifestations, except inhaled or intranasal drugs or eyedrops (corticosteroids, short- and long-acting beta₂-agonists, cromones, spaglumic acid, anticholinergics, alpha₁-agonists) in the event of coexisting allergic asthma, rhinitis, or keratoconjunctivitis, which were allowed for patients from both groups according to specific clinical complaints. The study was not sponsored.

Administration of treatments

Patients in the M group were given oral montelukast, 10 mg od, and one placebo tablet tid, and applied a pharmacologically inert, non-moisturizing, non-greasy gel on AD lesions and on xerotic skin areas bid, whilst patients in the C group were given an oral antihistamine (cetirizine, 10 mg bid) for 6 weeks, an oral antibiotic (clarythromycin, 250 mg bid) for 10 days, and applied corticosteroid creams (mometasone furoate 0.1%, or methylprednisolone aceponate 0.1%, od) on AD lesions (except face and external genitalia) and hydrating topical preparations (emulsions containing urea or ammonium lactate, ad libitum) on xerotic skin areas for 6 weeks. The decision to administer supplementary oral and topical placebos to patients in the M group was taken in order to minimize outward appreciable differences between treatments and to avoid the introduction of a placebo effect bias related to the higher number of administered drugs in the C group. Anyway, to the best of our knowledge, patients were not related and had no means of communicating with each other.

Evaluation

Severity of AD was evaluated jointly by the authors at baseline and after 6 weeks, according to the study design, with the SCORAD index system [6]. SCORAD was calculated by means of the Dermo Index software (1998, Novartis Pharma Italia, Origgio, Italy). Owing to the fact eosinophilic cationic protein (ECP) [7, 8] and eosinophilic protein X (EPX) [9] levels in AD seem to reflect activity of AD, and are influenced even by plain treatment with orally administered antibiotics [9], we monitored and studied the levels of such reactants before and after treatment in both patient groups as well. Moreover, blood from both groups of patients was taken as well for a routine panel of examinations, including kidney and liver functions, eosinophil and basophil counts. Blood was taken from all patients on day 0 (baseline) and 42 (except 2 patients from M group and 2 from C group, who underwent the second blood tests on day 49 - i.e., one week after suspension of treatment - because of organisational problems). Baseline and after-treatment data are summarized in Table II. Serum ECP and EPX levels were measured by means of commercial research kits (UniCAP ECP; EPX RIA, both from Pharmacia, Uppsala, Sweden). As regards to atopy-related asthma, rhinitis, and keratoconjunctivitis, all involved patients were referred to proper specialist care.

Statistical analysis

A statistical analysis of results was performed by means of the Instat2 software package (version 2.04. 1990-1993, GraphPad Software, San Diego, Ca., USA) run on a PC-compatible hardware. We assumed the difference between SCORAD before treatment and SCORAD after treatment in each patient (SCORAD, i.e. SCORAD variation) to be a reliable indicator of effectiveness of the treatment itself. Accordingly, a nonparametric test (Mann-Whitney) was used to evaluate statistical differences between medians of SCORAD variations (delta_iSCORAD = [SCORAD_{time = 0} - SCORAD_{time = 6 weeks}]_i, where i refers to the i-th patient) between M and C groups (minimum difference to be detected as significant 20; type II error [beta] 0.10), whereas the unpaired t test (Welch's approximate t) was chosen to evaluate statistical differences between "before" and "after treatment" means of biological markers (ECP, EPX, eosinophils, basophils) within each group. All tests were two-tailed, with a significance probability of 0.05.

Results

The results are summarized in Table II. All patients completed the study. M or C treatments were both excellently tolerated: no side effects were reported by the patients or observed by the authors. SCORAD improvements were marked in both groups, but no statistically significant difference between groups resulted. Both treatments compared similarly also in term of biological response, measured through ECP and EPX levels, which were statistically significantly reduced within both the M and the C group. On the contrary, no differences were observed in eosinophil and basophil counts in the two treatment groups. Indeed, differences between "before" and "after treatment" values of such indicators within each group resulted statistically not significant. According to the patients' impressions, pruritus was the most influenced SCORAD item by both M and C treatments, immediately followed by sleep loss and inflammatory signs. On the contrary, montelukast seemed to be completely devoid of acitivity on xerosis.

Discussion

The exact mechanism of action of LTRAs in AD is not known. In various forms of asthma, including allergic asthma of atopic patients, the effectiveness of these drugs seems to be related to their specific action on the receptor for cysteinyl leukotrienes (Cys LTs, i.e. LTC₄, LTD₄, and LTE₄) [10]. According to their experimental results (enhanced synthesis of Cys LTs in AD), Fauler et al. [11] recommended the use of 5-lipooxygenase inhibitors in this disease since 1993. However, other authors criticised quite recently such results on a methodological basis [12], and expressed reservation regarding the role of Cys LTs in the pathogenesis of AD. Synthetic LTs, including Cys LTs, elicit erythema and wheal formation when injected into human skin [13]. LTB₄, an arachidonic acid other than Cys LTs, was found to be increased in the skin of patients with AD [14], and releasability of eicosanoids from peripheral blood leukocytes is enhanced in patients with AD [15].

IgE-involving mechanisms seem to play a role in the dynamics of LTC₄ in human basophils [16]: accordingly, LTRAs could intervene at a lower level of the inflammatory cascade, i.e. on the merging node of the interactions between IgE and basophils, which are known to release large amounts of LTC₄ in patients with severe forms of AD [17].

ECP has been demonstrated to be a marker of activity of AD [7, 8], and either ECP and EPX serum levels have been demonstrated to be increased in vernal keratoconjunctivitis, a possibly nonatopic disorder related in its pathogenesis to eosinophilic inflammation [18], and to fall after antibiotic treatment of AD [9]. The finding that montelukast induced lowering of ECP and EPX serum levels in AD patients could be related to some feed-back effect of the inhibition of LT synthesis on the activation of eosinophils. However, this has not been demonstrated so far. Despite such abundance of experimental data and theoretical perspectives, the «real weight» of Cys LTs in the pathogenesis of AD has not yet been determined. Thus we will turn to consider the practical implications of clinical evidence provided by Carucci et al. [3] and by the present study. It is worth underscoring that we evaluated two alternative short-term treatments (a regimen based on a combination of commonly used drugs versus a potentially innovative one) for "quick-fixing" in an acute/refractory AD setting: such regimens were found substantially to be equivalent. However, orally administered antibiotics and topical steroids are not suitable for prolonged maintenance therapy, while LTRAs were expressly designed for long-term treatment of atopy-related chronic airway disorders. This statement could also apply to cetirizine: we did not plan to include a third group treated with plain cetirizine, but it should be highlighted that this drug can interfere with the synthesis of eicosanoids other than Cys LTs in neutrophils from subjects with allergic rhinitis [19]. Although patients were formally evaluated only after six weeks, those with positive responses from both groups testified that the amelioration of AD manifestations was rapid and ensued within two weeks from the beginning of the treatment. Patients from the "M group" have enjoyed fairly good long-term results even after the study phase, as reflected by their requests to go on with the new remedy after the conclusion of the study, when they were told which was the drug they had used. We have met such requests. Among SCORAD items, pruritus seemed to be the most influenced one, both by M and C treatments, and it is welcome that montelukast is active on this most bothersome symptom of AD. Also sleep loss and inflammatory signs appeared to be influenced, although to a lesser extent. Because of its eminently antiinflammatory properties, it seems logical that montelukast lacks activity on xerosis.

Reductions of ECP and EPX levels were relevant. Indeed, it is known that these reactants are markers of AD activity [7-9]. With regard to the SCORAD system, a combined index resulting from the sum (ECP + EPX) (mug/L) has been shown to correlate with the SCORAD index (r_s * 0.56, p = 0.0002; Franchi C, Capella GL, unpublished data).

The "M treatment" was less expensive than the "C" one (Table III). Clearly, montelukast costs are inclusive of the effect on respiratory manifestations, which is not constantly shared by the other regimen. Anyway, nothing prevents montelukast from being coupled with other conventional drugs, such as antihistamines, antibiotics, or antiinflammatory aerosols whenever necessary. Montelukast was excellently tolerated, and no described adverse effects such as asthenia or drowsiness, fever, abdominal pain, dyspepsia, dizziness, headache, cough, maculopapular rash or Churg-Strauss syndrome [21] were either observed by the authors or reported by the patients. Indeed, in patients with asthma the incidence of adverse events and discontinuation of therapy has been reported to be similar in the montelukast and placebo groups [22].

According to our results, montelukast, as a monotherapy, could be as safe and as effective a drug as a combined systemic and topical treatment regimen for treatment of moderate-to-severe AD. Of course, montelukast is also suitable for the concurrent treatment of AD and associated respiratory conditions, for which the drug was originally designed. In such conditions, montelukast has proven to be effective as a long-term maintenance drug. Accordingly, LTRAs could usefully add to the available panoply of treatments available for AD, allowing the planning of more flexible and effective therapeutic strategies, although we consider that further, more extended studies in this direction are required.

The pilot part of this study was presented as a poster at the 74th National Congress of the Italian Society of Dermatology and Venereology (SIDEV), Sienna, Italy, June 9-12, 1999.

While this work was considered for publication, Yanase and David-Bajar reported a randomized, double-blind, placebo-controlled, crossover study of the efficacy of montelukast in 8 atopic dermatitis patients (Journal of the American Academy of Dermatology 2001; 44 . 89-93). The results of our study are in substantial agreement with theirs.

Article accepted on 13/3/01

REFERENCES

1. Tan RA, Spector SL. Asthma in adolescents and adults. In: Rakel RE, ed. Conn's Current Therapy 1999. Saunders, Philadelphia 1999: 760-4.

2. Donnelly AL, Glass M, Minkwitz MC, Casale TB. The leukotriene D4-receptor antagonist, ICI 204.219, relieves symptoms of acute seasonal allergic rhinitis. Am J Respir Crit Care Med 1995; 151: 1734-9.

3. Carucci JA, Washenik K, Weinstein A, Shupack J, Cohen D. The leukotriene antagonist zafirlukast as a therapeutic agent for atopic dermatitis. Arch Dermatol 1998; 134: 785-6.

4. Van Leent EJM, Bos JD. Atopic dermatitis. In: Katsambas AD, Lotti TM, eds. European Handbook of Dermatological Treatments. Springer Verlag, Berlin-Heidelberg-New York 1999: 58-68.

5. Hanifin JM, Rajka J. Diagnostic features of atopic dermatitis. Acta Derm Venereol (Stockh) 1980; 92 (suppl. 144): 44-7.

6. European Task Force on Atopic Dermatitis. Severity scoring of atopic dermatitis: the SCORAD index. Dermatology 1993; 186: 23-31.

7. Kapp A, Czech W, Krutmann J, Schöpf E. Eosinophil cationic protein in sera of patients with atopic dermatitis. J Am Acad Dermatol 1991: 555-8.

8. Czech W, Krutmann J, Schöpf E, Kapp A. Serum eosinophil cationic protein (ECP) is a sensitive measure for disease activity in atopic dermatitis. Br J Dermatol 1992; 126: 351-5.

9. Capella GL, Franchi C, Altomare GF, Frigerio E, Fracchiolla C. Serum eosinophil cationic protein (ECP) and eosinophil protein X (EPX) levels in atopic dermatitis (AD) patients without allergic respiratory or ophthalmic disease drop significantly after simple antibiotic treatment (abstract). Allergologie 1998; 21: 511.

10. Fischer AR, Drazen JM. Antileukotriene drugs in the treatment of asthma. In: Middleton E Jr, Reed CE, Ellis EF, Franklin Adkinson N Jr, Yunginger VW, Busse WW, eds. Allergy. Principles and Practice. 5th edition. Mosby, St. Louis 1998: 678-84.

11. Fauler J, Neumann Ch, Tsikas D, Frölich JC. Enhanced synthesis of cysteinyl leukotrienes in atopic dermatitis. Br J Dermatol 1993; 128: 627-30.

12. Sansom JE, Taylor GW, Dollery CT, Archer CB. Urinary leukotriene E₄ levels in patients with atopic dermatitis. Br J Dermatol 1997; 136: 790-1.

13. Soter NA, Lewis RA, Corey EJ, Frank Austen K. Local effects of synthetic leukotrienes (LTC₄, LTD₄, LTE₄, and LTB₄) in human skin. J Invest Dermatol 1983; 80: 115-9.

14. Ruzicka T, Simmet T, Peskar BA, Ring J. Skin levels of arachidonic acid-inflammatory mediators and histamine in atopic dermatitis and psoriasis. J Invest Dermatol 1986; 86: 105-8.

15. Ruzicka T, Ring J. Enhanced releasability of prostaglandin E₂ and leukotrienes B₄ and C₄ from leukocytes of patients with atopic eczema. Acta Derm Venereol (Stockh) 1987; 67: 469-75.

16. Marone G, Casolaro V, Paganelli R, Quinti I. IgG anti-IgE from atopic dermatitis induces mediator release from basophils and mast cells. J Invest Dermatol 1989; 93: 246-52.

17. James JM, Kagey-Sobotka A, Sampson HA. Patients with severe atopic dermatitis have activated circulating basophils. J Allergy Clin Immunol 1993; 91: 1155-62.

18. Tomassini M, Magrini L, Bonini S, Lambiase A, Bonini S. Increased serum levels of eosinophil cationic protein and eosinophil-derived neurotoxin (protein X) in vernal keratoconjunctivitis. Ophthalmology 1994; 101: 1808-11.

19. Cheria-Sammari S, Aloui R, Gormand F, Chabannes B, Gallet H, Grosclaude M, et al. Leukotriene B₄ production by blood neutrophils in allergic rhinitis - effects of cetirizine. Cl Exp Allergy 1995; 25: 729-36.

20. L'Informatore Farmaceutico 2000. Edizione per il Medico. Organizzazione Editoriale Medico Farmaceutica, Milan 2000.

21. Wechsler ME, Finn D, Gunawardena D, Westlake R, Barker A, Haranath SP, et al. Churg-Strauss syndrome in patients receiving montelukast as treatment for asthma. Chest 2000; 117: 708-13.

22. Reiss TF, Chervinsky P, Dockhorn RJ, Shingo S, Seidenberg B, Ed-wards TB. Montelukast, a once-daily leukotriene receptor antagonist, in the treatment of chronic asthma: a multicenter, randomized, double-blind trial. Montelukast Clinical Research Study Group. Arch Intern Med 1998; 158: 1213-20.