Abstract ORIGINAL ARTICLE. B Engin,* M Özdemir

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1 JEADV ISSN Blackwell Publishing Ltd ORIGINAL ARTICLE Prospective randomized non-blinded clinical trial on the use of dapsone plus antihistamine vs. antihistamine in patients with chronic idiopathic urticaria B Engin,* M Özdemir Dermatology Department, Meram Medical Faculty, Selcuk University, Konya, Turkey Keywords chronic idiopathic urticaria, dapsone, randomized controlled trial *Corresponding author, Dermatology Department, Meram Medical Faculty, Selcuk University, Akyokus 42080, Konya, Turkey, tel ; fax ; burhanengin2000@yahoo.com Abbreviations: CIU, chronic idiopathic urticaria; ASST, autologous serum skin test; UAS, urticaria activity score; VAS, visual analogue score. Received: 24 April 2007, accepted 07 September 2007 DOI: /j x Abstract Background Treatment of chronic idiopathic urticaria (CIU) is difficult. Objective The purpose of this study was to evaluate the efficacy and safety of dapsone in CIU. Methods The response to dapsone was evaluated in 65 CIU patients with a randomized, two armed study: 3-month dapsone + desloratadin and 3-month desloratadin. All were followed for up to 3 months and 3 months after; all took desloratadine 10 mg daily throughout the study. The primary measure of efficacy was a daily urticaria activity score (UAS) of weal numbers and itch (maximum score, 42 per week). Results Sixty-five patients completed the randomized 3-month trial medication. Mean reduction in UAS from baseline at 3 months was 7 [95% confidence interval (95% CI), ] for active group and 5.77 (95% CI, ) for control subjects (P < 0.001). The reduction in visual analogue score (VAS) at 3 months for active group (mean, 2.58; 95% CI, ) and control subjects (mean, 2.55; 95% CI, ) was also significant (P < 0.001). The reduction of UAS and VAS at 3 months compared between active group and control subjects showed no significant difference. Mean reduction in UAS from the end of the study at 3 months after was 1.16 and 4.8 for active and control subjects, respectively. These results were compared with each other, and it was statistically significant (P 0.05). Limitations No placebo was used. The study was not blinded. Lack of blinding may have led to bias. The follow-up period was short. Conclusion This study shows that dapsone leads to a persistent decrease in VAS and UAS and is associated with complete remission in some patients. Chronic urticaria is a 6-week or longer history of daily or almost daily itchy cutaneous weals with individual lesions lasting less than 24 h. 1 It is defined idiopathic if no physical, allergic, infectious, drug-related or vasculitic cause can be identified. 2,3 In chronic idiopathic urticaria (CIU) treatment, antihistamines must be considered as first-line symptomatic treatment for urticaria. 4 However, limited benefit leads us to evaluate the other treatment modalities. Dapsone tends to be retained in skin and muscle. Therefore, we thought that there might be an additional long-term benefit from dapsone treatment that would be an extra benefit for patients with CIU. It seems that neutrophils and neutrophil products are the major targets for Dapsone. 5 However, it was speculated that down-regulation of leukotriene B4 and/or interference with CD11b, which has been shown to play a role in CIU, might be relevant. 6 8 We have investigated the response of patients with severe, unremitting CIU to a 3-month course of dapsone The Authors 481

2 Active group (dapsone plus antihistamine) Control subjects (only antihistamine) Table 1 Baseline clinical characteristics of active group and control subjects. Results expressed as median (range) refer only to age, duration, UAS and VAS Number Women 27 (71%) 20 (74%) Age (years) 34 (16 60) 32 (19 60) Duration (months) 35 (3 144) 24 (3 96) ASST positivity 29 (76%) 18 (67%) Previous treatments antihistamines only 25 (66%) 19 (70%) antihistamines, prednisone 9 (36%) 6 (22%) antihistamines, cyclosporin 2 1 antihistamines, sodium 2 1 cromoglycate, prednisone Baseline urticarial activity score (max. 42) ( ) ( ) Baseline VAS (max. 10) 6.05 ( ) 5.85 ( ) Methods Patients Sixty-eight patients who had had severe daily or almost daily CIU for over 6 weeks were recruited from the urticaria clinic at our Dermatology Department. All had CIU that was poorly responsive to existing urticaria treatment modalities. Sixteen had required prednisolone for their urticaria at some time before the study, reflecting the severity of their disease. Use of systemic steroids and cyclosporin within 2 weeks and 1 month of entry the study, respectively was an exclusion criterium. Chronic urticaria due to physical causes, urticarial vasculitis and C1 esterase inhibitor deficiency were excluded. We took a biopsy from lesional skin to exclude urticarial vasculitis in two suspected patients. One patient showed histopathologic feature related to the vasculitis. This patient was not included in the study at the beginning. The following investigations were done to investigate the cause of urticaria in all subjects: full blood count, erythrocyte sedimentation rate, liver function tests, urea and electrolytes, immunoglobulins and protein electrophoresis, thyroid function tests, complement factors C3 and C4, hepatitis B and C serology and a chest X-ray. In view of the self-reported fever, an infection screen was done: antistreptolysin antibody, a Mantoux test, toxoplasmosis and cytomegalovirus and Epstein Barr virus antibodies. An autologous intradermal serum test was done to all patients at the beginning. Antihistamines were discontinued at least 48 h prior to skin testing. Patient s venous blood was left to clot in sterile glass tubes for 20 min at room temperature. Fifty-microlitre aliquots of autologous serum, saline and histamine (10 mg/ml in saline) were injected intradermally into clinically uninvolved volar forearm skin. A positive autologous serum skin test (ASST) was defined as a 30-min pink weal of diameter 1.5 mm than a saline control skin test. No patient was taking immunosuppressive treatment at the time of the study. Before starting therapy with dapsone, patients underwent some routine tests: full blood cell count (including differential white blood cell count, platelet and reticulocyte count), liver and renal function tests, and urinalysis and glucose 6-phosphate dehydrogenase levels. Full blood cell count was repeated weekly in the first month and twice monthly in the second and third month. The baseline clinical characteristics of the patients are summarized in Table 1. Design of study and randomization The study was designed as randomized and prospective. Each subject was labelled. And then we used a table of random numbers to select from the labelled subjects. The patients were randomly allocated to one of the following two treatment arms: dapsone and antihistamine and only antihistamine. The latter group was recorded as control subjects. Active group was treated with dapsone (Dapsone fatol ) 50 mg/day for 3 months. During the study, patients took the same antihistamine desloratadine 10 mg daily whether or not their symptoms disappeared. Patients were followed up for 3 months after the end of the study, and they did not take anything. There are no known interactions between desloratadine and dapsone. Control subjects were also on the same antihistamine treatment. Patient assessments Patient assessments were carried out at baseline (week prior to treatment), monthly during the treatment period, The Authors

3 at day 1 post-treatment, and 3 months after. Withdrawal from the study was occasioned by a decrease of haemoglobin and haematocrite to a level of 10 and 30 mg/dl, respectively. Patients who left the study for other reasons were classed as discontinued. The urticaria activity score and visual analogue score 3 The urticaria activity score (UAS) was recorded by each patient daily. And they obtained from patients weekly. The number of weals was scored from 0 to 3: 0, < 10 small weals (diameter < 3 cm); 1, 10 to 50 small weals or < 10 large weals (> 3 cm); 2, > 50 small weals or 10 to 50 large weals; 3, almost covered. Severity of itch was scored as 0, none; 1, mild; 2, moderate; and 3, severe. One has to add each score together for both number of weals and the severity of itch on a given day for each the 7 days in a given week to get the weekly UAS. The possible weekly aggregate UAS thereby ranged from 0 to 42. Patients also completed a 10-cm visual analogue score (VAS) at each visit, indicating the overall severity of their urticaria over the previous months from 0 (none) to 10 (severe urticaria). Statistical analysis In two groups, the UAS and VAS pretreatment, posttreatment and follow-up period values were compared with each other (Wilcoxon matched pairs test, Mann Whitney test). P 0.05 was considered statistically significant. Ethics approval The study was approved by the ethics committee of our university. All patients gave written informed consent. Results Sixty-five patients completed the randomized 3-month trial medication and were followed up for another 3 months. All had normal haematochemical parameters, liver and renal function tests. also In addition, infection screen tests were negative. Clinical response (UAS and VAS) Mean reduction in UAS from baseline at 3 months was 7 [95% confidence interval (95% CI), ] for active group and 5.77 (95% CI, ) for control subjects (fig. 1; P < 0.001). The reduction in VAS at 3 months for active group (mean, 2.58; 95% CI, ) and control subjects (mean, 2.55; 95% CI, ) was also significant (fig. 2; P < 0.001). The reduction of UAS and VAS at 3 months was compared between active group and control subjects. There was no significant difference in fig. 1 Mean reduction in UAS at 3 months and 3 months after. fig. 2 Mean reduction in VAS at 3 months and 3 months after The Authors 483

4 fig. 3 Mean reduction in UAS monthly. fig. 5 The individual improvement of the patients with active therapy at 6 months. UAS at 6 months = baseline UAS (r = 0.56; P < 0 01). fig. 4 Mean reduction in VAS monthly. reduction of the UAS or VAS between the treatment groups. Urticarial activity ceased within as little as 48 h in two patients. Mean reduction in UAS from the end of the study at 3 months after was 1.16 and 4.8 for active group and control subjects, respectively (fig. 1). These results were compared with each other, and it was statistically significant (P 0.05). Mean reduction in UAS and VAS from baseline and each month of 3-month treatment period was depicted in figs. 3 and 4; also in addition, scatterplots were provided to visualize the individual improvement of the patients at 6 months (figs 5 and 6). Overall response Four of 38 subjects who received active therapy responded completely at first month, whereas none of the control subjects did so. All patients were evaluated 3 months after the end of the study with respect to the disease responsiveness. Nine patients who use active therapy had complete response, 27 had partial response, and 2 had no response. However, complete response was not recorded in any control subjects. Five of the 9 complete responders were still clear at 6 months. fig. 6 The individual improvement of the control group at 6 months. UAS at 6 months = baseline UAS (r = 0.72; P < 0 01). The autologous intradermal serum skin test Baseline ASST revealed no significant differences between the two groups (P > 0.05). There was no relation between ASST results and UAS of the active group and control subjects. In addition, the response rates were not dependent on the ASST positivity. Withdrawals and rescue medication Two patients on active medication discontinued the study after 2 weeks and 1 month. This was because they felt The Authors

5 nauseated and their urticaria had not responded. These two patients discontinued the study at their own request, and they were excluded from the statistical analysis. One control subject discontinued the study due to being well at 2 weeks of the treatment. She was also excluded from the statistical analysis. Patients who suffer from severe CIU would not accept being left completely untreated for 3 months in two groups. Almost all patients took the same antihistamine at various times but not regularly. However, there were no differences between the groups in the amount of rescue medication taken by the patients. Side-effects Clinical side-effects during dapsone treatment were uncommon and not severe enough to require withdrawal from the study. Three of the 38 patients reported symptoms that were probably drug related: nausea but not vomiting in two patients and fatigue and headache in the other patient. In control subjects, only gastrointestinal upset was recorded in one patient. Altogether, 5 of 38 patients (13%) in the active group experienced side-effects (nausea) vs. 0 patients in the control group. Discussion This study shows that dapsone treatment can, as defined by decreased UAS and VAS, provide a lower level of activity. The mean differences of UAS between the two groups consider us that some patients may benefit from dapsone treatment much more. The variation in responses following dapsone may reflect variation in individual disease factors, or the non-specific aggravation of CIU by stress, hormonal factors, diet and drugs. Cassano et al. 9 reported a complete response after dapsone in 9 of 11 patients within 3 months of treatment. They used 25 mg daily of dapsone. Two patients were unresponsive to treatment at 4 weeks; the increase of the daily dosage to 50 mg caused a complete response after 2 months in one case and a partial response in the other. Boehm et al. 6 used 50 mg daily of dapsone in a chronic recurrent urticaria patient with a good response rate. Similarly, the same dose was used for an idiopathic angioedema patient with a satisfactory result. 10 These trials lead a newer treatment modality for some unresponsive patients who need immunosuppressive agents. Our study indicates that dapsone offers the possibility of a prolonged remission. A significantly greater reduction in UAS vs. control subjects was still present at 3 months after the end of the study period. This finding was consistent with the results of other trials. 6,9 For instance, at follow-up evaluation of variable duration, no relapse occurred in seven of nine patients who had complete response. The half-life of dapsone in the circulation is approximately 30 h. Its retention in the body, however, is prolonged, perhaps because of its enterohepatic recirculation. It tends to be retained in skin and muscle: traces of the drug are present in these organs up to 3 weeks after therapy cessation. 5 However, this was not the case for the long-lasting effect obtained from dapsone. The long-lasting effect of dapsone possibly may be explained by a placebo-effect. It seems us that dapsone provides a lower level activity which lasts for months. Treatment with dapsone was well tolerated. Adverse events and alterations of haematochemical parameters due to dapsone treatment were not recorded. Smaller doses of dapsone were well tolerated in the abovementioned studies and in our patients. The optimal dose and duration of dapsone in CIU still needs to be established. It is possible that the very early cessation of wealing in two patients (within 48 h) was due to antihistamine therapy. Cassano et al. 9 reported the mean overall onset of response at 3 to 4 weeks. However, a complete response was obtained within 3 months. In our patients, only four responded at the first month. Monthly evaluations determined a positive correlation. Therefore, we consider that the overall response for dapsone treatment needs to be 3 months to determine the optimal response. The design of the study did not allow the detection of a dose-dependent response to dapsone. The dosage of dapsone may need to be re-evaluated. Because dapsone-induced side-effects (e.g. methemoglobinemia) are in most cases dose dependent, the risk under our treatment dosage is extremely low. A positive ASST is suggestive but not diagnostic of an autoimmune basis The presence of a positive ASST response does not seem to be a prerequisite for a good clinical response to dapsone or antihistamine therapy. New-generation antihistamines, with a very low adverse effect profile and good patient compliance, seem us practical treatment approach. 4,14 Our study shows strong evidence that 10 mg daily 3-month desloratadine may cause significant improvement in patients. However, prolonged remission was not achieved in these control subjects. Severely affected patients may need to use alternative medications such as corticosteroids or cyclosporine, which has unfavourable adverse effects. 2,4,15,16 Dapsone is a classical treatment for leprosy, dermatitis herpetiformis, urticarial vasculitis and bullous eruptions. 5,17 Today, we are much more aware of the anti-inflammatory effects of the drug than antibacterial properties. 5 It has been proposed in cases of severe chronic urticaria to avoid side-effects of corticosteroids. 4,18 Still, the mechanism of action of dapsone in CIU is not completely understood. Histamine is the most important preformed mediator in urticaria. 19 Neutrophil infiltration was higher in affected CIU skin and in autologous 2007 The Authors 485

6 weals. 20,21 Dapsone may exert part of its anti-inflammatory effect by prevention of the generation of 5-lipoxygenase products in neutrophils. The anti-inflammatory property described may play a role in dapsone therapy of inflammatory dermatoses, especially those in which the neutrophils is a key feature. 22,23 Newly synthesized leukotrienes, platelet-activating factor, and prostaglandin D2 may contribute to the subsequent inflammatory events. 2,24 Dapsone seems to down-regulate leukotriene and to inhibit spontaneous and induced synthesis of prostaglandin E2 by neutrophils. 6,10 We think all of above described mechanisms would only be relevant if the neutrophil was a key cell in most cases of CIU. There were some limitations of the study. First, the study was not blinded. Lack of blinding may have led to bias. Moreover, the follow-up period was short. This study showed that the addition of dapsone in low dose to antihistamine led to a persistent decrease in activity scores of urticaria. Although there is no extra benefit of a symptomatic treatment with dapsone in addition to antihistamines, there might be a long-term effect that can not be achieved by antihistamines alone. References 1 Greaves MW. Chronic urticaria. N Engl J Med 1995; 332: Grattan CEH, Sabroe RA, Greaves MW. Chronic urticaria. J Am Acad Dermatol 2002; 46: Grattan CEH, O Donnell BF, Francis DM et al. Randomized double-blind study of cyclosporin in chronic idiopathic urticaria. Br J Dermatol 2000; 143: Zuberbier T, Bindslev-Jensen C, Canonica W et al. EAACI/GA 2 LEN/EDF guideline: management of urticaria. Allergy 2006; 61: Wolf R, Tüzün B, Tüzün Y. Dapsone: unapproved uses or indications. Clin Dermatol 2000; 18: Boehm I, Bauer R, Bieber T. Urticaria treated with dapsone. Allergy 1999; 54: Maloff BL, Fox D, Bruin E, Di Meo TM. Dapsone inhibits LTB4 binding and bioresponse at the cellular and physiologic levels. Eur J Pharmacol 1988; 158: Debol SM, Herron MJ, Nelson RD. Anti-inflammatory action of dapsone: inhibition of neutrophil adherence is associated with inhibition of chemoattractant-induced signal transduction. J Leukoc Biol 1997; 62: Cassano N, D Argento V, Filotico R, Vena GA. Low-dose dapsone in chronic idiopathic urticaria: Preliminary results of an open study. Acta Derm Venereol 2005; 85: González P, Soriano V, Caballero T, Niveiro E. Idiopatic angioedema treated with dapsone. Allergol Immunopathol (Madr) 2005; 33: Baßkan EB, Türker T, Gülten M, Tunali 1. Lack of correlation between Helicobacter pylori infection and autologous serum skin test in chronic idiopathic urticaria. Int J Dermatol 2005; 44: Sabroe RA, Greaves MW. Chronic idiopathic urticaria with functional autoantibodies: 12 years on. Br J Dermatol 2006; 154: Nettis E, Dambra P, D Oronzio L et al. Reactivity to autologous serum skin test and clinical features in chronic idiopathic urticaria. Clin Exp Dermatol 2002; 27: Merk HF. Standard treatment. The role of antihistamines. J Invest Dermatol Symp Proc 2001; 6: Reimers A, Pichler C, Helbling A, Pichler WJ, Yawalkar N. Zafirlukast has no beneficial effects in the treatment of chronic urticaria. Clin Exp Allergy 2002; 32: Shahar E, Bergman R, Guttman-Yassky E, Pollack S. Treatment of severe chronic idiopathic urticaria with oral mycophenolate mofetil in patients not responding to antihistamines and/or corticosteroids. Int J Dermatol 2006; 45: Juhlin L. Alternative treatments for severely affected patients with urticaria. J Invest Dermatol Symp Proc 2001; 6: Stanaland B. Treatment of patients with chronic idiopathic urticaria. Clin Rev Allergy Immunol 2002; 23: Tharp MD. Chronic urticaria: pathophysiology and treatment approaches. J Allergy Clin Immunol 1996; 98: Caproni M, Giomi B, Volpi W et al. Chronic idiopathic urticaria: infiltrating cells and related cytokines in autologous serum-induced wheals. Clin Immunol 2005; 114: Caproni M, Volpi W, Macchia M et al. Infiltrating cells and related cytokines in lesional skin of patients with chronic idiopathic urticaria and positive autologous serum skin test. Exp Dermatol 2003; 12: Wozel G, Blasum C, Winter C, Gerlach B. Dapsone hydroxylamine inhibits the LTB4-induced chemotaxis of polymorphonuclear leukocytes into human skin: results of a pilot study. Inflamm Res 1997; 46: Wozel G, Lehmann B. Dapsone inhibits the generation of 5-lipoxygenase products in human polymorphonuclear leukocytes. Skin Pharmacol 1995; 8: Gach JE, Sabroe RA, Greaves MW, Kobza Black A. Methotrexate-responsive chronic idiopathic urticaria: a report of two cases. Br J Dermatol 2001; 145: The Authors