Efficacy of H, antihistamine, corticosteroids and cyclophosphamide in the treatment of chronic dermographic urticaria

Introduction

It is interesting to realise that H1 antihistamines used for the treatment of urticaria merely block the receptors and do nothing to the mechanism responsible for urticaria. The urticaria is therefore likely to reappear when the antihistamines are withdrawn unless the cause has disappeared during this period. In patients having dermographic urticaria or the recently described auto-immune urticaria,[1],[2],[3] the urticaria generally recurs whenever the antihistamines are withdrawn, leading to the consequent frustration in the patient. Sometimes in addition, the Hi antihistamines are unable to control the disease in a patient, therefore immunosuppressive drugs like methotrexate, cyclosporine and corticosteroids have been used for its treatment.[4],[5],[6] We have compared the therapeutic efficacy of a H1 antihistamine used alone and in combination with oral corticosteroids or cyclophosphamide.

Materials and Methods

Twenty-five patients, 13 males and 12 females, between 18-53 years in age (mean age 31.12 years) having dermographic urticaria for 6 months to 15 years were taken up for this study. The patients having dermographic urticaria of less than 6 months duration, pregnant female, patients below the age of 15 years and patients with any other systemic illness were excluded from the study. A thorough work-up comprising of a detailed history and physical examination was carried out in each patient. Pre-treatment laboratory evaluation in each patient included estimation of haemoglobin, total leucocyte count, differential leucocyte count, blood film morphology, erythrocyte sedimentation rate, fasting and post-prandial blood sugar levels, blood urea, serum creatinine, serum sodium and potassium levels, serum bilirubin, serum proteins, serum transaminases, serum alkaline phosphatase, urinalysis and stools examination for ova and cysts to look for any underlying occult infections, infestations, renal and /or liver disease and to monitor the side- effects, if any due to the subsequent treatment with systemic corticosteroids/ cyclophosphamide. The intensity of the dermographic response in each patient was graded with the help of an instrument called ′Dermograder′ designed by Pasricha et al.[7] The patients were divided into three groups. Group I patients were treated with cetirizine hydrochloride 10 mg per day orally, group II patients were given cetirizine as for group I, along with 2 mg of betamethasone per day orally, while group III patients received cetirizine as for group I along with cyclophosphamide 50 mg per day orally. The patients were evaluated every week during the therapy to assess the response to the treatment and also to monitor the side - effects. The response to the therapy was assessed by roughly grading the percent subjective improvement in itching and the occurrence of the wheals. The patients were also assessed by the dermograder to look for a change in the dermograde. After 4 weeks of therapy, all the drugs were stopped. A complete haemogram, fasting and post prandial blood sugar levels, liver and renal function tests, urinalysis and stools examination were carried out to look for abnormalities in any of these tests after the therapy. Thereafter, the patients were evaluated every month for 6 months or earlier to look for any recurrence.

Results

Out of 9 patients in group I, 6 patients had complete remission, while one patient each had 40%, 60% and 90% relief in their disease. All the patients in group II and group III had complete remission within the first week. Thus a total of 22 (88%) patients had complete relief while 3(12%) patients (group I) had partial response to the treatment Table 1. Three patients belonging to group II experienced a decrease of the dermograde from 4 to 3 after the third week of therapy, but in the remaining patients there was no change.

After stoppage of the treatment, the symptom-free period in group I was 24 hours in 2 patients, 48 hours in 1 patient, 25 days in 1 patient and 6 months in 2 patients. In group II, the symptom-free period was, 24 hours in 1 patient, 48 hours in 2 patients, 72 hours in 2 patients and 5 days in I patient. One patient had no recurrence even at the end of 6 months follow up. The symptom - free period in group III was 24 hours in 3 patients, 48 hours in 3 patients and 72 hours in 3 patients. The side effects in group I patients included drowsiness during the first week of the therapy only in 2 patients. In group II, all the patients complained of weight gain, 4 patients developed acne, 2 had cushingoid features, while 1 patient felt drowsiness during the initial 2-3 days. The weight gain in these patients was 1 kg in 1 patient, 2 kg in 3 patients,3 kg in 2 patients and 5 kg in one patient. In group III, only one patient experienced drowsiness during the initial 4-5 days of the treatment. None of the patients showed any change in the laboratory parameters during the period of the therapy.

Discussion

Antihistamines have been the mainstay of treatment ever since histamine was discovered to be the main mediator in urticaria. Although, these drugs are very effective in controlling the symptoms provided the dose of the antihistamine used is adequate, it is being increasingly realised that the antihistamines act only at the peripheral level and mask the symptoms. These drugs do not alter the course of the disease and have to be continued till the cause of the disease disappears spontaneously. That is why in chronic urticaria, the symptoms tend to reappear whenever the antihistamines are withdrawn. In a fixed dose schedule as used in this study, some patients may not obtain complete relief if the dose of the drug is less than the dose required to control the symptoms completely. Cetirizine is a fairly potent antihistamine which suppresses the urticaria effectively in most of the patients, and one dose a day is generally sufficient for 24 hours. Hence it was given to all the patients as the baseline treatment. With this dose alone (group) 3 patients could not obtain complete relief suggesting that some patients require a higher dose.

Systemic corticosteroids act at multiple levels, they suppress the formation of antibodies, they have a strong anti-inflammatory effect and in addition are known to decrease the production of histamine - releasing factors.[8] In combination with cetirizine therefore, the control of urticaria is expected to be better and in group II therefore ( betamethasone 2 mg along with cetirizine hydrochloride 10 mg per day orally) all the patients had complete remission.

Cyclophosphamide belongs to the nitrogen mustard family of alkylating agents and is one of the most effective cytotoxic and immunosuppressive agents. The action of cyclophosphamide is not cell cycle specific and it can affect non-cycling cells also.[9] It can cause differential cytotoxicity to various lymphoid cell populations, with selective suppression of the B cells.[9] Hence, this drug is considered to be most effective in suppressing the humoral immunity. All the patients treated with cyclophosphamide 50 mg per day orally along with cetirizine hydrochloride 10 mg per day orally obtained complete relief, and they were symptomatically better controlled than the other groups. These results correspond to the beneficial effects reported with cyclosporine in chronic idiopathic urticaria.[5],[10],[11]

Drowsiness was observed in our study in 4 (16%) of the patients in the three respective groups, but in all the patients this side effect was transitory and disappeared within the first few days. In group II in addition, all the patients had weight gain by 1-5 kg, 4 ( 57) % patients had acne, and 2 ( 29%) patients had cushingoid features. All these side effects are attributable to the systemic corticosteroids used in these patients. The weight gain however, was mild in a large proportion of the patients and returned to normal within 3 weeks after the corticosteroid was withdrawn. In group III in contrast, none of the patients had any side effects attributed to cyclophosphamide. This low dose of cyclophosphamide has been known to produce no side effects even when given for very long periods.[12],[13] The laboratory parameters also in all the patients remained within the normal range.

After stopping the treatment, 7 (77%) patients in group I, 5 (71%) patients in group II and all the (100%) patients in group III relapsed within 2-3 days indicating that the additional treatment with betamethasone or cyclophosphamide had made no significant difference in preventing a future relapse in these patients. This shows that a four week supplementation is not adequate to significantly alter the course of dermographic urticaria. In future studies therefore, it will be necessary to use either a larger dose and/or a longer duration of the treatment to significantly affect the pathogenic mechanisms responsible for this type of urticaria.

The study therefore, shows that cetirizine 10 mg per day used alone is sufficient to control dermographic urticaria in 67% of the patients. When combined with 2 mg betamethasone per day, all the patients experienced complete relief but weight gain, acne and cushingoid features were seen in 100%, 57%, and 29% of these patients. Combination with 50 mg cyclophosphamide per day, also produced complete relief but no side effects. Majority of the patients however relapsed within 3 days of withdrawing the drug suggesting that a four week supplementation with these immunosuppressive drugs is not adequate to significantly alter the course of the disease in dermographic urticaria.