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Clinical usefulness of oral itraconazole, an antimycotic drug, for refractory atopic dermatitis

European Journal of Dermatology. Volume 14, Number 6, 400-6, November-December 2004, Therapy

Summary

Author(s) : Z IKEZAWA, M KONDO, M OKAJIMA, Y NISHIMURA, M KONO , Department of Dermatology, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama-shi, Kanagawa 236-0004, Japan.

Summary : We investigated the clinical usefulness of oral itraconazole for refractory atopic dermatitis in a crossover study. Patients with refractory atopic dermatitis were divided into two groups: Group A\; a combination of itraconazole plus a conventional lactobacillus preparation was administered for 8 weeks, followed by lactobacillus preparation alone for 8 weeks, Group B\; lactobacillus preparation alone was administered for 8 weeks, followed by itraconazole plus lactobacillus for 8 weeks. In both groups, a decrease in dose or strength of concomitant topical steroids was observed at the end of the treatment course of itraconazole, and improvement of parameters such as eosinophil count, serum IgE level and specific IgE antibody titers to fungi was also observed after the administration of itraconazole. These results suggest that oral itraconazole is useful for the treatment of intractable atopic dermatitis patients who do not respond to conventional therapeutic approaches.

Keywords : crossover study, itraconazole, lactobacillus, oral administration, refractory atopic dermatitis, steroid

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ARTICLE

Auteur(s) :, Z IKEZAWA^*, M KONDO, M OKAJIMA, Y NISHIMURA, M KONO

Department of Dermatology, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama-shi, Kanagawa 236-0004, Japan

accepté le 1 Février 2004

Recently, the number of adult patients with intractable atopic dermatitis (AD) has been increasing in Japan. Many factors such as genetic and environmental factors, including eating habits, may be involved in the development and progression of AD. In general, food allergy is strongly involved in the development of AD during early childhood, whereas allergy to environmental allergens such as the mite Dermatofagoides and Staphylococcus aureus, in the resident bacterial flora of skin lesions, is presumed to be involved in the development and progression of AD during adulthood. Furthermore, attention has recently been focused on the probable involvement of resident fungal flora of the skin and intestine such as Malassezia furfur (M. furfur) and Candida albicans (C. albicans) in the development, exacerbation and persistence of AD. M. furfur preferentially resides in the pilus pores. In particular, it is known to be frequently distributed in seborrheic regions such as the head, face, neck, upper chest and upper back, and to cause seborrheic dermatitis. Increased specific IgE antibody titers were reported in AD patients with severe dermatological manifestations affecting the head and neck, where M. furfur is frequently distributed. In addition, the antibody titer to M. furfur was correlated with the total IgE level and the severity of AD [1]. Furthermore, Clemmensen et al. reported that ketoconazole, an antimycotic drug, was useful for treating dermatitis of the head and neck in patients with hypersensitivity to M. furfur [2]. On the other hand, C. albicans is a component of the resident fungal flora of the gastrointestinal tract and oral cavity. It has been proposed that proliferation of Candida in the intestine is related to a decrease in the delayed type hypersensitivity reaction, which further accelerates the growth of Candida, resulting in an increased specific IgE antibody titer and exacerbation of AD [3-5]. It has been reported that C. albicans may also exhibit cross-antigenicity with M. furfur [6]. We have already reported that amphotericin B, an antimycotic drug which is not absorbed through the intestine and is thought to selectively act on resident fungal flora like C. albicans, is useful for treating some cases of refractory AD.In a preliminary trial, we experienced cases in which itraconazole was useful for refractory AD not responding or resistant to treatment with amphotericin B. Therefore, in this paper, we report that itraconazole, an antimycotic drug, was clinically very useful for treating refractory AD, based on evaluation of changes in clinical symptoms, the effect on the dose or strength of concomitant topical steroids, safety, serum IgE level and specific IgE antibody titers to fungi in a cross-over study.

Subjects and methods

Subjects

Candidates for this study were patients with moderate to severe refractory AD chiefly distributed on the skin of the face, neck, upper chest and shoulders, who attended Urafune Hospital of Yokohama Municipal University between September 1998 and August 1999. These patients showed a serum total IgE level of 1000 IU/mL or higher, and CAP-RAST titers to M. furfur and C. albicans of 3.5 UA/mL or higher. Patients who met the following criteria were excluded from the study: (1) patients receiving terfenadine or astemizole (H1-blocker), triazolam (hypnotic), or cisapride (digestive motilitystimulator); (2) patients with a history of allergic reaction to itraconazole; (3) patients with symptoms of severe liver disease or a history of severe liver disease; (4) pregnant or possibly pregnant women; (5) AD patients younger than 16 years of age; and (6) patients who were thought to be inappropriate to receive treatment with itraconazole because the patient caught a cold.

Informed consent

The purposes, methods, effects and adverse effects expected in this study were verbally explained to the patients, and informed consent was obtained in oral form based on the decision of each patient. In addition, the study was conducted with approval of the Institutional Review Board of Yokohama City University School of Medicine.

Design of crossover study

Using the envelope method, the 40 subjects enrolled were randomly divided into two groups; Groups A and B (( Figure 1 )). In Group A, a combination of itraconazole (100 mg/day) and a lactobacillus preparation (Biolactis powder 3 g/day) was administered for 8 weeks in the first half of the treatment course (first period), and lactobacillus preparation alone was administered for 8 weeks in the second half (later period). On the other hand, in Group B, lactobacillus preparation alone was administered during the former period, and then itraconazole was additionally administered during the later period. We concomitantly used lactobacillus because oral antibacterial agents may affect other indigenous intestinal flora. It was forbidden to administer other antimycotic drugs during the trial. However, it was planned that whenever a patient enrolled in this study in either group did not want to continue administration of itraconazole, the drug would be stopped promptly and changed to other therapeutic measures. Also, the daily dose and duration of concomitant oral antiallergic drugs and topical steroids were recorded on the research chart.

Observation items

Clinical symptoms

Clinical symptoms such as erythema, edema, vesicles/scabs, papules, lichenification, dry skin/exfoliation, pigmentation/depigmentation, and itching were evaluated on the basis of six grades (0: absent, 1: slight, 2: mild, 3: moderate, 4: severe, and 5: serious) during the administration period at 2-week intervals. In principle, patients were photographed during the observation period. The subjects’ sleep was also evaluated on the basis of four grades (0: always sleep well, 1: sometimes sleep well, 2: sometimes cannot sleep well, and 3: frequently cannot sleep well).

Laboratory evaluations

The following hematological examinations were performed at the start of drug administration, at the end of the first period (8 weeks later) and at the end of the later period (16 weeks later); WBC fractions, serum level of total IgE, specific IgE antibody titers for M. furfur, C. albicans and Alterinaria, and liver function represented by GOT and GPT levels. Serum total IgE level was measured by radioimmunoassay, and specific IgE antibody titers to these fungal allergens were measured by CAP-RAST.

Influence of other treatment options

In the case of the necessity for revising the prescriptions of drugs administered, detailed records were made.

Adverse events

During the study period, adverse events in clinical symptoms and laboratory findings were carefully observed. In the case that any abnormal finding was observed, the type of adverse event, severity/grade, time course and substituted treatment were recorded in the patient’s chart, and the causal relationship was considered.

Evaluation of clinical usefulness

Firstly, the clinical efficacy of itraconazole was evaluated at the end of the first period (8 weeks later) and at the end of the later period (16 weeks later) based on the following five grades; 1: extremely effective, 2: effective, 3: slightly effective, 4: ineffective, and 5: worsened. In principle, patients were photographed during the observation period. Secondly, the effect of itraconazole on the dose of concomitant topical steroids was evaluated based on the following four grades; 1: discontinued, 2: decrease in dose or change to another less effective drug, 3: no change, and 4: increase in dose or change to another more effective drug. Thirdly, the safety of itraconazole was evaluated based on the following four grades; 1: safe, 2: moderately safe, 3: of doubtful safety, and 4: unsafe. Finally, based on the above evaluations, the clinical usefulness of itraconazole was evaluated according to the following four grades; 1: very useful, 2: useful, 3: slightly useful, and 4: not useful.

Analyses of the statistical significance of differences were performed using the paired t-test.

Results

Participation and background of patients

( Figure 2 ) shows the participation of patients in the safety and clinical evaluations. For this study, 40 AD patients were enrolled. Of 20 patients enrolled in Group A, one dropped out of the study because he did not attend our clinic after the initial itraconazole administration, and 2 patients did not complete the study, having an insufficient observation period of only 4 weeks. Thus, all scheduled examinations were completed in 17 of 20 patients in Group A, and the clinical efficacy of itraconazole was evaluated in 17 patients and the safety in 19 patients. In Group B, 5 of 20 patients enrolled dropped out of the study because they did not attend our clinic after the initial consultation. Additionally, 5 patients did not complete the study because of noncompliance (2) and discontinuation due to adverse events (2) or the development of common cold (1). Thus, in Group B the clinical efficacy of itraconazole was evaluated in 10 patients, and safety in 15 patients. Table I( Table I ) shows the background of the 19 and 15 patients, respectively in Groups A and B, in whom safety was evaluated.
Table I Background of patients for safety evaluation

		Group A (n = 19)	Group B (n = 15)
Sex
	Male	8	10
Female	11	5
Age (years)		25.7 ± 5.8	25.2 ± 5.7
(17−39)	(16−35)
Duration of AD (years)		16.4 ± 9.3	22.3 ± 6.4
Allergic history
	No	5	1
Yes	14	14
Symptom score
	Slight	0	0
Mild	2	0
Moderate	8	4
Severe	8	11
Serious	1	0
(mean ± SD)	3.4 ± 0.8	3.7 ± 0.5

Evaluation of anti-mycotic therapy with oral itraconazole

Clinical efficacy of oral itraconazole

In Group A (itraconazole in the first period), the clinical score of all evaluated items including the sleeping score was improved at the end of the former period (8 weeks later), but after that each score became worse (( Figure 3a )). On the contrary, in Group B (itraconazole in the later period), each clinical score was unchanged or worse at the end of the first period, but that of all evaluable items was improved at the end of the later period (16 weeks later) (( Figure 3b )). As shown in ( Figure 4 ), the total score was significantly improved in patients in Group A after administration of itraconazole during the first period, and the improvement persisted for the subsequent 8 weeks. Although the total score did not significantly change in Group B following administration of lactobacillus preparation during the former period, it was significantly improved after administration of itraconazole (p < 0.05). ( Figure 5 ) shows the clinical efficacy of oral itraconazole in Groups A and B. In 17 patients of Group A, clinical efficacy was evaluated as “extremely effective” in 6 (35%), “effective” in 9 (53%), and “slightly effective” in 2 (12%) at the end of the former period, while it was evaluated as “effective” in 1 (6%), “slightly effective” in 7 (41%), and “ineffective” in 9 (53%) at the end of the later period. There were no patients in Group A in whom the clinical efficacy of itraconazole was evaluated as “extremely effective” at the end of the later period. The percentage of patients in whom itraconazole was “effective” or better was 88% at the end of the first period, while the percentage decreased to 6% at the end of the later period. In 10 patients of Group B, the clinical efficacy of itraconazole was evaluated as “slightly effective” in 1 (10%) and “ineffective” in 9 (90%) at the end of the former period, while it was evaluated as “extremely effective” in 1 (10%), “effective” in 5 (50%) and “slightly effective” in 4 (40%) at the end of the later period. The percentage of patients in whom itraconazole was “effective” or better was 0% at the end of the first period, while the percentage increased to 60% at the end of the later period.

Effect of oral itraconazole on dose and strength of concomitant topical steroids

As shown in ( Figure 6 ), a decrease in the dose or strength of concomitant topical steroids was observed in 13 (76%) of 17 Group A patients at the end of the first period with itraconazole, and its effect persisted in 5 patients (29%) even 8 weeks after the treatment course of itraconazole was completed. On the other hand, a similar decreasing effect on concomitant topical steroids was observed in only 2 (20%) of 10 Group B patients at the end of the first period without itraconazole, but in 6 patients (60%) at the end of the later period with itraconazole. Therefore, it was confirmed that administration of itraconazole contributed to a decrease in the dose and strength of topical steroids used in both groups.

Safety of oral itraconazole

With regard to the side effects in Group A, anemia (hemoglobin level: 11.2 ± 9.8 g/dl) was noted in one patient, although the causal relation with itraconazole was unclear. In Group B, gastrointestinal symptoms and increased GOT/GPT levels were observed in 2 patients, and an increased uric acid level in one patient. These side effects were mild and improved or disappeared without any specific treatment. In view of these side effects, the safety of itraconazole was evaluated at the end of the first and later periods as follows (( Figure 7 )). Namely, in Group A, in the first period itraconazole was evaluated as “safe” in 16 (84%) of 19 patients, “almost safe” in 2 (11%) and “of doubtful safety” in 1 (5%) 8 weeks later, and in the later period with only lactobacillus preparation was evaluated as “safe” in 15 (83%) of 18 patients, “almost safe” in 2 (11%), and “of doubtful safety” in 1 (6%) 16 weeks later. On the other hand, in Group B, in the first period the lactobacillus preparation was evaluated as “safe” in all 15 patients (100%) 8 weeks later, and in the later period itraconazole was evaluated as “safe” in 8 (57%) of 14 patients, “almost safe” in 5 (36%), and “of doubtful safety” in 1 (7%) 16 weeks later.

Usefulness of oral itraconazole

Based on the clinical efficacy, effect on the dose or strength of concomitant topical steroids, and safety, the clinical usefulness of treatment with or without itraconazole was evaluated at the end of the first and later periods (( Figure 8 )). In 17 Group A patients, it was evaluated as “very useful” in 6 (35%), “useful” in 9 (53%) and “slightly useful” in 2 (12%) at the end of the first period with itraconazole, but it was evaluated as “useful” in 1 (6%), “slightly useful” in 7 (41%), and “not useful” in 9 (53%) at the end of the later period with lactobacillus preparation without itraconazole, while it was not evaluated as “very useful” in any patient. On the other hand, in 10 Group B patients, treatment was also evaluated as “slightly useful” in 2 (20%) and “not useful” in 8 (80%) at the end of the first period with lactobacillus preparation without itraconazole, while it was not evaluated as “very useful” or “useful” in any patient, but it was “very useful” in 1 (10%), “useful” in 5 (50%), “slightly useful” in 3 (30%), and “not useful” in 1 (10%) at the end of the later period with itraconazole. Therefore, itraconazole was evaluated as “very useful” or “useful” in 88% of Group A patients at the end of the first period, but this significantly decreased to 6% at the end of the later period with lactobacillus preparation without itraconazole. In Group B, there were also no patients in whom treatment was evaluated as “very useful” or “useful” at the end of the first period with lactobacillus preparation without itraconazole, but the percentage of such patients increased to 60% after 8 weeks of administration of itraconazole at the end of the later period. These results indicate that administration of itraconazole was significantly useful for treating AD in both groups.

Effects on eosinophil count, serum total IgE level and specific IgE antibody titers to M. furfur, C. albicans and Altenaria

Changes in the eosinophil count, serum IgE level and specific IgE antibody titers were evaluated using the ratio of these parameters obtained at the end of the first period and at the end of the later to those obtained before treatment. The eosinophil count (( Figure 9a )) significantly (p < 0.01) decreased in Group A at the end of the first period with itraconazole, and increased significantly at the end of the later period without itraconazole (p < 0.05). On the other hand, in Group B, the mean eosinophil count rather increased at the end of the first period without itraconazole and slightly decreased from the end of the first period to the end of the later period, although the difference was not significant. The serum total IgE level (( Figure 9b )) also significantly (p < 0.01) decreased in Group A after administration of itraconazole during the first period and further decreased significantly thereafter to the end of the later period without itraconazole (p < 0.001). On the other hand, in Group B, serum total IgE level did not change significantly at the end of the first period without itraconazole, but tended to decrease after administration of itraconazole during the later period (p < 0.07). The specific IgE antibody titers to M. furfur (( Figure 10a )), C. albicans (( Figure 10b )) and Alterinaria (( Figure 10c )) all also decreased significantly (p < 0.005, p < 0.001 and p < 0.001, respectively) in Group A at the end of the first period with itraconazole, and this effect also persisted at least until the end of the later period, similar to the serum IgE level in Group A. On the other hand, in Group B, the IgE antibody titers to none of these fungal allergens changed significantly at the end of the first period. However, the IgE antibody titers to C. albicans and Altenaria decreased significantly (p < 0.05) thereafter to the end of the later period, probably because their mean had slightly increased at the end of the first period. On the contrary, the decrease in IgE antibody titer to M. furfur was not significant, probably because it had decreased at the end of the first period.

Discussion

We evaluated the clinical usefulness of itraconazole, an oral antimycotic drug, in patients with refractory AD. The effects of this antimycotic drug were evaluated in a cross-over study in which the subjects, 27 AD patients, were divided into two groups; in Group A, the patients was followed without itraconazole for the second 8 weeks after oral administration of itraconazole for 8 weeks in the first period, while the patients in Group B were followed without itraconazole for the first 8 weeks before oral administration of itraconazole for 8 weeks in the later period. The therapeutic value of itraconazole was evaluated at the end of the first period and the end of the later period, in comparison with the start of drug administration, based on the clinical efficacy, effect on dose or strength of concomitant topical steroids, and safety. In both groups, clinical symptoms were improved and the dose of concomitant steroids was decreased after the administration of itraconazole.

In addition, it was shown that parameters such as eosinophil count, serum total IgE level and specific IgE antibody titers to fungal allergens significantly decreased after administration of itraconazole in Group A, and this effect was still observed until 8 weeks after discontinuation of itraconazole for both serum IgE level and specific IgE antibody titers, but not for eosinophil count, which reflects the disease activity in the acute phase. In Group B, the mean value of these parameters also decreased after the administration of itraconazole during the later period, although the difference was not significant for the eosinophil count (p = 0.55), serum IgE level (p = 0.06) and IgE antibody titer to M. furfur (p = 0.50), while it was almost significant for the IgE antibody titers to C. albicans (p < 0.05) and Altenaria (p = 0.05). Such a statistically significant difference in the changes in parameters between Group A and B patients probably derives from the fact that the number of patients used for the analysis was low, 10 (a half of 20 patients enrolled), because 5 patients dropped out during the former period without itraconazole and the other 5 patients discontinued taking itraconazole because of noncompliance or the development of adverse events or common cold. Also, the decrease in IgE antibody titer to M. furfur might not have been significant (p = 0.50) because the IgE antibody titer to M. furfur had decreased slightly at the end of the former period, even though the ratio was lower than that for the IgE antibody titers to C. albicans and Altenaria. The value to M. furfur in Group B decreased during the non-administration period of itraconazole and increased after administration. However, this change could have been caused by the large variation in levels of Malassezia-specific antibodies, as it is not statistically significant.

Several specific treatments have been attempted in refractory AD patients who did not respond to these conventional therapeutic approaches. In principle, the treatment for AD consists of improvement of inappropriate daily life, control of clinical symptoms including itching, and removal of causative and exacerbating factors. Although the relationship between AD and fungi has not yet been sufficiently clarified, it is known that some AD patients do respond to antimycotic drugs [7]. Itraconazole is a lipid-soluble antimycotic drug which is absorbed from the intestinal mucosa and is efficiently transported to the skin. Thus, itraconazole is presumed to be effective for inhibiting the proliferation of M. furfur, in the resident fungal flora of the skin, as well as for inhibiting the proliferation of C. albicans, in the resident fungal flora of the intestine. In fact, the results obtained in this study strongly indicate that oral itraconazole is very useful for treating refractory AD, suggesting that these fungi may be involved in the development and progression of AD. Such antiallergic activity as well as antimycotic activity may contribute to the clinical usefulness of itraconazole shown in this study. How fungal allergens such as M. furfur and C. albicans are involved in the pathogenesis of AD is unclear. It is necessary to investigate the effect of M. furfur and C. albicans, respectively on disturbance of the skin barrier and mucosal immunity to fungus and food, and also the antiallergic activity of itraconazole in AD. From this viewpoint, a study of the relationship between proliferation of M. furfur and the skin barrier and measurement of secretary IgA antibody titers to M. furfur and C. albicans in patients with AD are in progress.

Conclusions

This crossover study of itraconazole strongly demonstrated its clinical efficacy in refractory AD. A decrease in dose or strength of concomitant topical steroids was observed after treatment with itraconazole in both groups. Also, it was shown that parameters such as eosinophil count, serum IgE level and specific IgE antibody titers to fungal allergens significantly improved or tended to improve after the administration of itraconazole. These results together indicate that oral itraconazole should be considered as an applicable treatment regimen for refractory AD not responsive to conventional therapy.

Acknowledgements

There is no potential conflict of interest with itraconazole manufacture.

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