Hydroxychloroquine

Comparison of effectiveness of topical tacrolimus 0.1% vs topical halobetasol propionate 0.05% as an add-on to oral hydroxychloroquine in discoid lupus erythematosus

Deva Pratim Barua1 | Mohammad Ismail Hossain Chowdhury1 |

Abstract

In recent years, calcineurin inhibitors have been used as the first line alternative to topical corticosteroids in the treatment of discoid lupus erythematosus (DLE). We aim to evaluate the efficacy and safety of topical tacrolimus 0.1% vs topical halobetasol propionate 0.05% in patients with DLE. This comparative study was carried out in the Department of Dermatology and Venereology, Chittagong Medical College Hospital (CMCH), Bangladesh between the period of July 2018 and June 2019. The change of DLE activity assessed with the cutaneous lupus erythematosus disease area and severity index was used as a primary outcome measure. The effective sample was 40 patients in each group. Both groups were similar in terms of baseline demographic and clinical characteristics. After 8 weeks of treatment, the mean total erythema score decreased significantly in both groups (in tacrolimus treated group [TTG] from 12.53 ± 8.05 to 8.03 ± 5.69, [P < .001] and in halobetasol propionate treated group [HTG] from 11.83 ± 7.17 to 7.30 ± 4.56 [P < .001]), as well as the mean total scale/hypertrophy score (in TTG from 8.08 ± 5.30 to 4.33 ± 3.21; [P < .001] and in HTG from 7.40 ± 4.73 to 3.68 ± 2.01, [P < .001]. The magnitude of reduction was significantly better in HTG [P = .032]). The mean total activity score decreased significantly in both groups (in TTG from 22.95 ± 13.40 to 14.33 ± 8.89, [P < .001] and in HTG from 22.15 ± 11.95 to 13.7 ± 7.22, [P < .001]). The present study demonstrated that tacrolimus 0.1% ointment and halobetasol propionate 0.05% ointment had a comparable efficacy in DLE patients; however, halobetasol showed significantly better improvement regarding scaly, hypertrophic lesions.

KEYWORDS
connective tissue disorders, discoid lupus erythematosus, halobetasol propionate, ointment, tacrolimus, therapy-topical

1 | INTRODUCTION

Common manifestations of cutaneous lupus erythematosus (CLE) in Bangladeshi patients are reported as photosensitivity, discoid lupus erythematosus (DLE), oral ulcer, malar rash, non-cicatricial diffuse alopecia, cutaneous vasculitis, urticaria, Raynaud’s phenomenon, and so forth.1 DLE is probably the most disfiguring form of CLE which presents as erythematous, indurated plaques and papules, which may resolve with significant scarring, dyspigmentation, and alopecia,2 and can have a high impact on the quality of life of the patients. DLE is considered to be the third most common cause of industrial disability from dermatologic disease, with 45% of CLE patients experiencing some form of vocational handicap.3 Hydroxychloroquine (HCQ) or chloroquine (CQ) is the first-line systemic treatment for disfiguring and widespread skin manifestations and for the prevention of systemic disease. Topical corticosteroids (CS) are the mainstay of treatment for all different subtypes of the disease and effectively reduce inflammatory symptoms in all types of CLE.4 Due to the unwanted side effects of topical CS, the calcineurin inhibitors such as tacrolimus and pimecrolimus have been studied for their long-term therapeutic potential in DLE.5 Side effects are usually limited to transient burning, erythema, and irritation.6
Although there are some studies on the efficacy of topical tacrolimus in diverse forms of CLE, including DLE,7-9 they were performed on limited number of patients and our knowledge about its usefulness is still limited. In addition, information about halobetasol propionate in DLE is scarce. To our knowledge, no trial has so far been performed of halobetasol propionate in the treatment of DLE. Therefore, we aimed to evaluate the efficacy and safety of topical tacrolimus 0.1% vs topical halobetasol propionate 0.05% as an add-on to oral hydroxychloroquine in patients with DLE.

2 | MATERIALS AND METHODS

2.1 | Patient selection

DLE was diagnosed based on typical clinical manifestations and was confirmed by histopathology and direct immunofluorescence examination. All patients (96 patients) of DLE attending the Department of Dermatology and Venereology, CMCH during study period were invited to participate in this trial. Among them 84 patients were selected according to selection criteria and randomly allocated into two treatment arms (42 patients in each arm).

2.2 | Selection criteria
The DLE patients of both sexes with age range from 18 to 65 years were included. Pregnant and lactating women and patients with preexisting maculopathy, visual field defect, hepatic, renal, hematological or other disorders which would contraindicate the use of tacrolimus, halobetasol propionate or hydroxychloroquine were excluded.

2.3 | Randomization

After obtaining the informed written consent, the eligible patients were randomly allocated in two groups. Block randomization was done by simple lottery method. A box was filled with equal number of slips coded with TTG and HTG. Patients were asked to collect a slip from the sealed box. The intervention was given according to the taken slip.

2.4 | Study design

This study was an open-label, randomized, comparative study. Patients from TTG were advised to apply tacrolimus 0.1% ointment and from HTG halobetasol propionate 0.05% ointment. Both treatments were applied twice daily, 12 hours apart on the areas of actively diseased skin for 8 weeks. In addition, both groups took an oral hydroxychloroquine 5 mg per kg body weight daily at night after meal for 8 weeks. Other topical and systemic treatments were not allowed. There was a two-week wash out period for any treatment prior to initiating current treatment.

2.5 | Assessments

Patients’ baseline characteristics, such as age, sex, economic and educational level, and disease related variables, presenting features, baseline dermatological findings and the baseline cutaneous lupus erythematosus disease area and severity index (CLASI) score along with baseline investigations were recorded. All patients were evaluated at second, fourth, sixth and eighth week after treatment initiation by visual assessment and digital photography of DLE lesions and were asked about possible adverse events related to the therapy. For efficacy evaluation, researchers calculated activity score using CLASI. Disease activity score is the sum of erythema score (0-absent, 1-pink; or faint erythema, 2-red, 3-dark red; or purple/violaceous/crusted/ hemorrhage) and scale/hypertrophy score (0-absent, 1-scale, 2-verrucous hypertrophy) of all anatomic location (ears, nose including malar area, rest of face, V-area neck frontal, posterior neck and/or shoulder, chest, abdomen, back and buttock, arms, hands, legs, feet). Physician global assessment scores were also used for treatment efficacy evaluation. Patients were also evaluated regarding the level of improvement in relation to disease status before study initiation (0-not improved, 1-mild improvement (1%-25%), 2-moderate improvement (26%-50%), 3-marked improvement (51%-75%), and 4-excellent improvement (75%-100%). Adverse events such as erythema, itching, telangiectasia, difficulty in vision, joint and muscle pain in each group were also recorded.

2.6 | Statistical analysis

After collection, all data were entered into Microsoft Excel spread sheet to generate a master sheet. Then they were fed into the Statistical Package for Social Science (SPSS) version 23 for processing and analysis. Continuous data were reported as the means ± SDs. Means were compared using Student’s t test for two groups. Qualitative or categorical data were described as frequencies and proportions. Proportions were compared using chi-square or Fisher’s exact test whichever was applicable. Baseline characteristics were compared by either Student’s t-test for continuous variables or the chi-square test for categorical data. Between groups treatment effect over time was analyzed by repeated measures of analysis of variance (ANOVA) and within group’s treatment effects over time by paired sample t test. Statistical significance was defined as P < .05 and confidence interval was set at 95% level.

2.7 | Ethical clearance

Ethical approval was taken before starting the study from the Ethical Review Committee of CMCH (Ref: CMC/PG/ 2018/446).

3 | RESULTS

A total of 40 patients in each group completed the study, as two patients from halobetasol treatment group (HTG), and one patient from tacrolimus treatment group (TTG) were lost to follow up and one patient from TTG discontinued the treatment due to irritation and burning sensation. The mean age was 32 (±10) years in both groups with female predominance (M:F = 1:4.7). However, both groups were comparable in respect to their distribution of age, sex, educational level, place of residence and monthly family income. In both groups, 37 (46.3%) patients suffered from DLE for >1 to 5 years, 46 (57.5%) patients suffered localized DLE and 51 (63.8%) patients received combined topical and systemic treatment previously (Table 1). The most common anatomical site was face in both groups followed by scalp, ear, and nose including malar area.
After 8 weeks of treatment, the mean erythema score of TTG decreased significantly from 12.53 ± 8.05 to 8.03 ± 5.69 and in HTG from 11.83 ± 7.17 to 7.30 ± 4.56. The mean scale/hypertrophy score in TTG decreased significantly from 8.08 ± 5.30 to 4.33 ± 3.21 and in HTG from 7.40 ± 4.73 to 3.68 ± 2.01. The mean total activity score of TTG decreased from 22.95 ± 13.40 to 14.33 ± 8.89 (P < .001) and of HTG decreased from 22.15 ± 11.95 to 13.7 ± 7.22 (P < .001) (Figure 1). ANOVA showed that there was a significant effect of time on the reduction of the mean activity score in both groups (P = <.001). However, the magnitude of the reduction was similar in both groups (P = .72).
There were no significant changes in the total activity score (CLASI score) at second and fourth week of treatment compared to baseline in both TTG and HTG (P values >.05). However, in both groups there was a significant reduction in the total activity score after 6 and 8 weeks of treatment comparing to the baseline score (P values <.001) (Table 2 and Figure 2).
Though the percentage reduction of the total disease activity was higher in TTG than in the HTG (mean [±SD] of percentage change were 37.97% [±10.17%] and 36.45% [±9.77%] in TTG and HTG, respectively), the difference was not statistically significant (P = .42 derived from independent sample t test).
Majority of patients irrespective of the study groups (80% and 77.5% in TTG and HTG, respectively) showed moderate improvement (26%-50% improvement from baseline) after 8 weeks of treatment. Both groups were similar with respect to their physician global assessment score regarding the treatment efficacy (P = .76). (Table 3).
Regarding safety profile, both drugs were well tolerated during the 8-week treatment period. One patient (2.5%) complained of severe burning sensation in TTG that disappeared after stopping of the treatment. After 8 weeks of therapy, three patients (7.5%) had developed telangiectasia in HTG, but all of these cleared after stopping of the treatment.

4 | DISCUSSION

The study was conducted to evaluate the efficacy and safety of topical tacrolimus 0.1% vs topical halobetasol propionate 0.05%% as an add-on to oral hydroxychloroquine in patients with DLE. At the end of the 8-week treatment, activity scores in both groups showed a substantial improvement, which was confirmed by statistical analysis. Improvement was apparent 6 and 8 weeks after initiation of treatment the in both groups.
DLE can be improved by the topical application of corticosteroids to a varying extent and the treatment has been restricted to medium potent and super potent topical glucocorticosteroids such as fluocinonide 0.05%, betamethasone 17-valerate 0.1%, clobetasol propionate 0.05%.10,11 According to the recent Cochrane Database review, fluocinonide cream may be more effective than hydrocortisone in clearing DLE skin lesions. Hydroxychloroquine and acitretin appear to be of equal efficacy in terms of complete resolution, although adverse effects might be more frequent with acitretin, as well as clearing of erythema in at least 50% of lesions occurred less often in participants applying acitretin. To date there is not enough reliable evidence about other drugs used to treat DLE. Overall, the quality of the trials and levels of uncertainty were such that there is a need for further trials of sufficient duration comparing, in particular, topical steroids with other agents.12 Halobetasol propionate 0.05% is a synthetic class I ultra-potent topical corticosteroid, containing 0.05% 6-α-fluoro-clobetasol 17-propionate. Its chemical structure is similar to that of clobetasol 17-propionate. In addition, it has an extra fluorine atom in the 6-α position that increases its anti-inflammatory and antiproliferative properties.13
As the sample populations were randomly selected and distributed, no significant difference between two treatment groups was observed regarding demographic and baseline characteristics. Therefore, patients in both treatment arms were balanced and most of the confounding factors were eliminated.
The mean patients' age was 32 years with female predominance. It is in agreement with other studies.14-16 Most of the patients had disease duration for 1 to 5 years (in TTG 37.5% and in HTG 55.0%). Majority of the patients had localized disease (55% in TTG and 60% in HTG) which is also in concordance to another study where 57.14% patients demonstrated localized disease.15
Majority of patients had received combined topical and systemic drugs for their disease (in TTG 62.5% and in HTG 65.0%). This is consistent with the study of Madan et al17 where 61.11% patients received combined topical and systemic drugs.
To analyze the treatment efficacy we have used CLASI as this measure was shown to have good content validity addressing the most relevant aspects of DLE. It is noteworthy that not all previous researches used this measure and it is thus difficult to compare our results with those authors.
The mean of total erythema score of both treatment arms showed a significant improvement by about 30% to 40%. In the study of Tzung et al,14 it decreased significantly from 2.22 to 1.17 in the tacrolimus group and from 2.36 to 1.47 in clobetasol group. The mean of scale/hypertrophy score in TTG also significantly decreased. This difference was probably due to methodological differences as; only facial lesions were included in that study. Kuhn A et al reported that CLE lesions in face persisting for less than or equal to 6 months did respond better to 0.1% tacrolimus ointment compared to lesions persisting more than 6 months.18
The mean total activity score of TTG decreased significantly from 22.95 to 14.33 and in HTG also decreased significantly from 22.15 to 13.7. In the study of Barikbin et al,16 the mean activity score in pimecrolimus group from 4.2 to 0.67 and in betamethasone group decreased significantly from 4.4 to 1.2. Pothinamthong and Janjumratsang,15 observed that, on tacrolimus treated side, the mean activity score decreased significantly from 6.24 to 2.71 and within clobetasol treated side also decreased significantly from 6.14 to 0.86. The magnitude of reduction in clobetasol treated side was significantly greater than after tacrolimus treatment (P = .002). Moreover, some therapeutic effect in our patients could be a result of hydroxychloroquine treatment, as it is recommended as the first line oral therapy for DLE, however, long term clinical response to hydroxychloroquine is observed in less than 50% of patients. Nonresponders to hydroxychloroquine frequently required oral steroid to achieve disease control.19
According to Physician's Global Assessment, both drugs (tacrolimus and halobetasol) can improve DLE after 8 weeks of treatment, and both drugs had similar efficacy in decreasing the disease activity score. In both groups most of the patients were moderately improved (26%-50% improvement) at the end of the study.
The result of this study indicates that short term treatment (8 weeks) with 0.1% tacrolimus ointment and 0.05% halobetasol propionate ointment in DLE patients is safe and well tolerated. Only one patient (2.5%) in the TTG had to discontinue the drug for irritation and burning sensation within 1 week of starting the treatment which disappeared 2 weeks after stopping tacrolimus. Three patients (7.5%) in HTG developed rosacea after 8 weeks of treatment. Steroidinduced rosacea resolved spontaneously after discontinuation of the steroid and administration of oral tetracycline or macrolides.20
In our study we are able to include a reasonable number of DLE patients and most of these patients completed the study as per protocol. This is the strength of our trial and it adds to the growing body of evidence about the effectiveness of tacrolimus and halobetasol in DLE patients.
We must draw some limitations of this study. First of all it was a single center study. It is also not possible to make any comment about the persistence of the treatment effect, and the long term adverse effects as follow up was stopped after 8 weeks. In addition, it was an open-label trial, the researcher himself was the investigator and the evaluator and the study was not blinded regarding the treatment received by the patients. The study, moreover, has not included a placebo control group.

5 | CONCLUSION

Present study demonstrates that both halobetasol propionate (0.05%) and tacrolimus (0.1%) have comparable efficacy in the treatment of DLE and the safety profiles of both drugs over 8-week treatment periods were similar. Halobetasol propionate was significantly more effective in scaly, hypertrophic lesions. This study is a good evidence to support the use of topical halobetasol and topical tacrolimus in DLE. However, the management of DLE includes routine assessment for systemic disease, as well as the prevention of new lesions and treatment of existing lesions with optimal protection against UV exposure, with broad-spectrum sunscreen as an effective means of preventing development of UV-induced DLE.

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