Comparison of Refined and Crude Indigo Naturalis Ointment in Treating Psoriasis: Randomized, Observer-Blind, Controlled, Intrapatient Trial FREE

Our group's previous studies^1- 2 have shown that topical application of indigo naturalis significantly improves psoriatic symptoms. However, patient compliance is hindered because the preparation is unsightly and stains clothing.

To improve patient compliance, we have developed a refined formulation in which the blue dye component is removed, leaving only a purple-red color that is closer to natural skin tones and less prone to stain clothing. Herein, we describe a study of the efficacy and safety of this new product.

The refined indigo naturalis ointment was prepared for our study by mixing indigo naturalis powder with olive oil, filtering, and then mixing with petroleum jelly and wax. The crude form was prepared as described previously.¹ The concentrations of indirubin, previously identified as the main active ingredient in indigo naturalis, were found to be 0.105 mg/g and 0.138 mg/g for the refined and crude ointments, respectively.

After institutional review board approval, we recruited patients from November 2009 to May 2010 using the criteria listed in the Table. At baseline, data on the duration of psoriasis, total body surface area involvement (BSA), and Psoriasis Area Severity Index (PASI) were collected. Two symmetrically comparable plaques on each patient were identified, one randomly assigned to receive refined ointment, and the other assigned to receive crude ointment. Patients were instructed to avoid cross-contamination between the 2 treatment sites by washing their hands thoroughly between applications. Treatment was performed until complete clearing, up to a maximum period of 8 weeks, and immediately stopped if adverse events occurred that were possibly related to treatment.

After the skin was cleaned, photographs of the lesions were taken, and lesion severity was evaluated at baseline and at weeks 2, 4, 6, and 8. Efficacy was assessed by PSI, representing a composite of scaling, erythema, induration, and clearing percentage of each target plaque, with 0% representing clearance. Using a photograph from a previous study² as the standard, 2 observers (Y.-H.H. and Y.-C.C.) independently rated each photograph without knowing which ointment had been used. At the end of the trial, the patients were asked which ointment they preferred.

Adverse events were recorded at each visit, and it was determined whether they were related to the study medication. Findings of blood tests and assays of liver and renal function were also evaluated.

Statistical analyses were performed using SAS software, version 9.1.3 (SAS Institute Inc). The paired t test and mixed-effect model were used, with significance level (alpha) set at 0.05. The trial was registered under clinicaltrials.gov Identifier: NCT01022502.

Of 38 enrolled patients, 35 completed the study. Mean (SD) age was 42.0 (12.6) years; duration of psoriasis was 11.6 (10.7) years; PASI was 11.5 (7.9); and BSA was 18.4% (15.1%). The mean (SD) areas of lesions targeted for treatment with refined and crude ointment were 69.3 (85.2) cm² and 73.0 (85.1) cm², respectively (P  =  .58), while the PSIs were 9.1 (2.4) and 8.8 (2.3), respectively (P  =  .14). Three patients were withdrawn from the study at weeks 4, 5, and 6 owing to employment-related conflicts, severe itching, and failure to follow up, respectively.

Throughout the study, lesions treated with refined ointment and those treated with crude ointment both showed significant improvement (Figure 1A and B). For lesions treated with refined ointment, the combined PSI and lesion area score showed a 74.28% improvement (P   <  .001) (Figure 1C). For lesions treated with crude ointment, the improvement was 74.80% (P   <  .001) (Figure 1C).

Clearance or near clearance was achieved in 24 of the 35 target lesions (69%) after treatment with refined ointment, compared with 23 of the 35 target lesions (66%) treated with crude ointment (P   >  .65) (Figure 1D). Representative photographs illustrating the degree of improvement are shown in Figure 2.

At week 8, 31 of 35 patients reported a preference for the refined ointment; 1 patient preferred the crude ointment; and 3 had no preference.

Itching sensation was reported by 8 and 11 patients, while erythematous changes were reported by 1 and 3 patients at the lesions treated with refined and crude ointments, respectively. However, these adverse effects occurred at the beginning of treatment and resolved after a couple of days. Patch test results revealed no allergic responses, while blood tests and assays of liver and renal function showed no significant findings.

Our group has previously analyzed the antipsoriatic effects of indigo naturalis.³ The major active ingredient, indirubin, a red 3,2'-bisindole isomer, mediates the process by promoting differentiation and inhibiting proliferation of epidermal keratinocytes. We speculate that indirubin plays a similar role in the refined ointment.

Patient acceptance of indigo naturalis has been handicapped by its dark blue color, which is aesthetically problematic in exposed areas like the face, and it stains clothing. By removing the blue dye indigo and retaining the indirubin, our refining process produces an ointment that is less visible in exposed areas and less likely to stain clothing. From the results of this study, we conclude that this new refined formulation is not only more user friendly but has no disadvantage in efficacy or safety. This is a significant milestone in establishing indigo naturalis as a widely acceptable alternative psoriasis treatment.