Oral ketotifen and topical antibiotic therapy in the management of pruritus in prurigo nodularis: a randomized, controlled, single-blind, parallel study.

AIMS: To evaluate the role of oral ketotifen and topical antibiotic therapy in the management of pruritus in prurigo nodularis (PN) patients.
MATERIALS AND METHODS: Twenty-seven patients with PN and a history of atopy with raised IgE were included in this study in a dermatology clinic. All patients had positive growth of Staphylococcus aureus on the lesional skin swab. All patients received topical halobetasol and oral hydroxyzine for 4 weeks. In addition, all patients in the study group received oral ketotifen and topical antibiotic therapy for 4 weeks. Randomization was performed by using a table of random numbers, and the participants were randomly allocated to one of the two groups in the study. The study was a single-blind study, and the blinding was done by the investigator.
RESULTS: Of the 14 patients in the study group, 9 had complete relief from pruritus by the end of first week, which was maintained till the end of 4 weeks. In the control group, mild to moderate reduction in the intensity of pruritus in the PN lesions of all patients were noted by the end of the first week. No further improvement in the level of pruritus was noted in the participants during the trial period. The treatment was well tolerated by the patients, and the adverse reactions of drugs were minimal in both groups.
CONCLUSIONS: This study showed that oral ketotifen and topical antibiotic therapy can be helpful in the management of pruritus in PN patients.

RCT Entities:   Population Interventions Outcomes

What was known?

PN is notoriously resistant to therapy.

The difficulty in treating this disease is reflected in the long list of treatment options. Long remission of symptomswith presently available treatment is seldom observed.

This is due to the failure of the currently available treatment protocol to address the aetio-pathology of PN.

Introduction

Prurigo nodularis (PN) is a dermatological condition characterized clinically by chronic, intensely pruritic nodules and histologically by marked hyperkeratosis and acanthoses with downward projections of the epidermis. PN occurs at all ages, but mostly between 20 and 60 years. Both sexes are equally affected by PN. In this study, we aimed to evaluate the role of oral ketotifen and topical antibiotic therapy in the management of pruritus in PN patients.

The aetiology of PN remains unknown. There is uncertainty as to whether PN is a primary cutaneous disease or whether it is a pathological reaction secondary to pruritus and scratching provoked by a different cause. A variety of systemic conditions have been reported to be associated with PN, including emotional stress, anemia, hepatic dysfunction, uremia, myxoedema, venous stasis, folliculitis, nummular eczema, lympjoma, HIV infection, perforating collagenoses, gluten-sensitive enteropathy, and contact dermatitis among others.[1234] It has been observed that approximately 65-80% of PN patients are atopic.[5]

Because aetiology is unknown in majority of PN cases, it is difficult to manage. PN is notoriously resistant to therapy. Once the cycle of pruritus-excoriation-pruritus begins, it is difficult to stop it. The difficulty in treating this disease is reflected in the long list of treatment options. The main issue that PN patients experience is the intense pruritus associated with the PN lesions.

Topical agents recommended for PN includes emollients, oral antihistamines, ultrapotent topical steroid, intralesional corticosteroid injections, coal tar ointment, calcipotrial ointment, capsaicin cream, cryotherapy, pulsed dye laser. Systemic treatments used for PN includes phototherapy, anti-depressants (amitriptyline/doxepin), oral steroids, azathioprine, thalidomide, ciclosporin, acitretin, and naltrexone. Whichever treatment is followed, long remission of symptoms with presently available treatment is seldom observed. The mechanism that leads to the excessive pruritus in PN lesions is not completely understood. However, recent studies have shown that mast cells play an important role in the genesis of pruritus in PN. It has been noted that mast cells in PN lesions are increased in number and show characteristic morphological changes such as an enlarged cell body size and a dendritic shape compared with the round or elongated shape observed in the normal skin.[678] The PN mast cells also have an abundant cytoplasm with a decreased number of granules inside, suggesting that many of the granules have been released into the surrounding tissue.[6] Mast cells in PN have been observed to produce more nerve growth factor (NGF) in the lesional skins. This high level of NGF causes neural hyperplasia in the PN lesions. Subsequently, this neural hyperplasia leads to strong itching caused by increased axon firing.[91011] Apart from neural hyperplasia, there are other mast cell products that may contribute to pruritus in PN; these include histamine, tryptase, prostaglandins, and interleucins.[246] In addition to mast cells, higher level of IL-31[12] has been detected in the lesional skin of prurigo nodularis. IL-31 is pruritogenic, can induce itch in atopic individual, and is upregulated by staphyloccal superantigens. Individuals with atopic eczema (AE) have frequent colonization and infection with S. aureus. It is important to note that approximately 65-80% of N patients are atopic.[5]

Thus, theoritically, by preventing mast cell degranulation and by controlling PN infection, lesions by S. aureus may allow downregulation of pruritus in PN.

Materials and Methods

Study design and participants

This study was a randomized, controlled, single-blind, parallel, 4-week study conducted in a dermatology clinic. Out of a total of 11342 skin patients who attended the dermatology clinic between August 2010 and August 2011, 51 PN patients (age range: 18-58 years) with personal/family history of atopy and raised IgE level were recruited by the investigator. Participant with recent or present history of worm infestation were excluded from the study. Pregnant and lactating women were not included in this study. Blinding was performed by the investigator. The trial was planned in a manner that the participants were unaware of whether they belonged to the study group or the control group. Concealment in allocation was not performed. The study was explorative and no sample size calculation was made. The study protocol was approved by the institutional review board. A valid written consent was obtained from each patient.

Procedure

Skin swab were obtained from the skin lesions and dispatched for culturing (in nutrient agar media) and anti-microbial sensitivity testing for every patient. The PN lesions were located mainly on the extremities (n = 26), extremities and back (n = 23), and extremities and face (n = 2). Out of 51 patients, 27 showed growth of S. aureus. Patients who had positive growth of S. aureus were randomly divided into two groups. Randomization was performed (by a neutral person, not the investigator) by using a table of random numbers, and the participants were randomly allocated to one of the two groups: Study group orcontrol group. The allocation ratio was 1.07:1, i.e., approximately 1:1.

Study group comprised of 14 patients (M: 8, F: 6, age group: 18-58 years, mean age: 38.7 years).

Control group comprised of 13 patients (M: 7, F: 6, age group: 21-55 years, mean age: 36.4 years).

Treatments and evaluations

The patients in either group were asked to use the following medicines for a period of 4 weeks:

Halobetasol ointment: To be applied once a day.

Hydroxyzine (25 mg tablet): 1 tablet on demand basis only, not routine. Maximum 3 tablets (in divided doses) a day.

The patients in the study group were asked to use the following medicine in addition:

Ketotifen (1 mg tablet): 1 tablet at bed time for 4 weeks.

Topical antibiotic (depending on the culture and sensitivity result): To be applied thrice daily for 10 days.

Each patient was evaluated by the investigator at 7 days interval. Intensity of pruritus was calculated by taking into account the history of every patient in each follow-up by the simple method mentioned below. No changes in trial method were performed after trial commencement.

Intensity of pruritus:

No itch: 0

Mild: Mild itch, only occasionally disturbing night sleep: 1+

Moderate: Moderate itch, disturbing night sleep more than occasionally, but not continually: 2+

Severe: Severe itching continually disturbing night sleep: 3+

Statistical analyses

Statistical analyses were performed using SPSS for Window v.13. All variables were ordinal, thus non-parametric statistical methods were used. As null hypotheses, it was statistically assumed that the effect of drugs in the study group for the control of pruritus was statistically not different from the effect of drugs in the control group. Mann-Whitney test (confirmatory) and Chi-square test (non-confirmatory) were used.

Results

In the study group

Fast reduction in pruritus in the skin lesions of the participants were noted at the end of first week in majority of the patients: 9 out of 14 patients had complete relief from pruritus. Patients were able to discontinue oral hydroxyzine completely. This improvement was maintained till the end of 4 weeks in all 9 patients. Another 5 patients had partial reduction in the severity of pruritus at the end of the first week, of these, 1 patient had complete relief from pruritus by the end of third week and he was able to discontinue oral hydroxyzine. The remaining 4 patients experienced no further improvements in pruritus and had to continue oral hydroxyzine on demand basis. Partial reduction in size of the skin lesions were noted in all of the participants at the end of 4 weeks. Very few participants observed complete reduction in the size of skin lesions in limited lesions. No patient dropped out from the study during the trial period. No patient was excluded from the study during the trial period.

Side effects

Five patients experienced sedation and the remaining nine experienced drowsiness in the first week. Eight patients experienced mild drowsiness in the second week, among them 2 patients continued having mild drowsiness by the end of forth week.

The summary of result is shown in Table 1.

Table 1

Result of the study group

In the control group

Mild to moderate reduction in the intensity of pruritus in the skin lesions of all the participants were noted by the end of first week. However, no further reduction in the level of pruritus were noted in the participants and the patients had to continue with oral hydroxyzine on demand basis during the trial period. No complete reduction in the size of skin lesions were observed in any of these patients at the end of 4 weeks, only a few of the participants observed partial reduction of skin lesions in limited lesions. No patient dropped out from the study during the trial period. No patient was excluded from the study during the trial period.

Seven patients experienced moderate drowsiness and 6 patients experienced mild drowsiness during the first week. Four patients experienced moderate drowsiness and 9 patients had mild drowsiness since the second week lasting until the end of trial period.

The summary of result is shown in Table 2. Participant flow in the study is shown in Figure 1. The participants and result of the trial is represented by Figure 2 and Bar diagram in Figure 3 respectively.

Table 2

Result of the control group

Figure 1

Participant flow in the study is shown by flow chart

Figure 2

(a) Female patient with PN lesions, (b) Male patient with PN lesions

Figure 3

The result of the trial showed by Bar diagram

Differences in the result of two groups are statistically significant. Chi-square statistic highly significant at 0.01% level of significance. Mann-Whitney test is significant at α=0.05 (P < 0.05), clearly showing that result of study group is superior to control group.

Discussion

In the present study, 71.4% patients had complete relief from pruritus in the study group. Nine of 14 patients (64.28%) had complete relief from pruritus at the end of the first week. Patients were able to discontinue the oral hydroxyzine completely. This improvement was maintained until the end of 4 weeks in all 9 patients. Another patient had complete relief from pruritus by the end of third week and he was able to discontinue oral hydroxyzine. In the remaining 4 patients, pruritus was much reduced and they took oral hydroxyzine only on need basis.

On the other hand, only mild to moderate reduction in the intensity of pruritus in the skin lesions of all participants were noted by the end of first week in the control group. However, no further reduction in the level of pruritus were noted in the participants and the patients had to continue with oral hydroxyzine on demand basis during the trial period.

The present study is the first study of its kind. In this study, effort was made to reduce the severity of pruritus in PN patients by promoting oral ketotifen therapy with topical antibiotic to the patients.

Ketotifen is a second-generation noncompetitive H1-antihistamine and mast cell stabilizer. It has been successfully used in the management of asthma and atopic allergies because of its mast cell stabilizing property. It is important to note that low dose of ketotifen was used in this present study. In addition to ketotifen, anti-S. aureus antimicrobial topical agents were used based on the culture-sensitivity report. The purpose of these two was to reduce the intensity of pruritus in PN lesions by (1) preventing mast cell degranulation through oral ketotifen therapy and (2) by controlling infection caused by S. aureus through the topical application of anti-S. aureus antibiotics.

This study showed that oral ketotifen, even in a low dose of 1 mg/day and topical antibiotic therapy was helpful in the management of pruritus in PN patients. The treatment was well tolerated by the patients and the adverse reactions of drugs were minimal.

Conclusion

This study showed that oral ketotifen and topical antibiotic therapy can be helpful in the management of pruritus in PN patients. However, the present study is a single-blind, clinic-based study, and the study group is small. A further multicentric study comprising of large number of patients with longer follow-up will be more informative.

What is new?

The treatment used in the present study was designed considering the atopic background of PN.

Addition of ketotifen and control of S. aureus infection had lead to significant improvement in the study group and it appears to be a new therapeutic option for PN.

Specifically designed treatment protocol, which can target the basic pathology of PN, can bring faster relief than the conventional treatment.