Clinical Assessment of Patients With Recalcitrant Psoriasis in a Randomized, Observer-Blind, Vehicle-Controlled Trial Using Indigo Naturalis FREE

Psoriasis is a chronic dermatosis for which only remissive, as opposed to curative, treatments are available. Traditional Chinese medicine is one of the most frequently chosen alternative therapies in China and Taiwan, and psoriasis has been treated for centuries with topical and oral herbal preparations.^1- 2 Indigo naturalis is 1 of the Chinese herbal remedies that has been reported to exhibit potential antipsoriatic efficacy.³ However, long-term systemic use has been occasionally associated with irritation of the gastrointestinal tract and adverse hepatic effects.⁴

To avoid the adverse systemic effects but retain the demonstrated efficacy of indigo naturalis as an antipsoriasis medicine, we initiated an alternative approach in 2003 by applying the drug topically on skin lesions. Primary observations showed that treatment with topical indigo naturalis ointment was beneficial for patients with recalcitrant psoriasis.^5- 6 Then, an 8-week pilot study to evaluate the efficacy and safety of topically applied indigo naturalis on treating plaque-type psoriasis and analyze the histologic change in skin tissue was performed. Although the study had a limited number of patients, the results showed significant clinical improve ment and marked skin biopsy improvement in proliferating, inflammatory, and differentiation markers.⁷ We present the results of a randomized, investigator-blinded, intrapatient comparative trial. This trial, which addresses the safety and efficacy of indigo naturalis for the treatment of psoriasis, was performed longer term with a larger number of patients compared with our previous study.

This was a randomized, observer-blinded, intrapatient comparison of topical indigo naturalis vs vehicle alone to treat recalcitrant plaque-type psoriasis within a 12-week period (depending on the date of enrollment in the study). The trial was conducted at the Department of Traditional Chinese Medicine, Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, in Taoyuan and Taipei, Taiwan. All patients provided written informed consent before inclusion in the study, and the study protocol was approved by the institutional review board of Chang Gung Memorial Hospital.

Patients with chronic plaque psoriasis were recruited from the Divisions of Internal Chinese Medicine and Dermatology in Chang Gung Memorial Hospital Linkou Branch and Taipei Branch from May 1, 2004, to April 30, 2005. The diagnosis of plaque psoriasis was based on clinical diagnosis by 2 dermatologists (Y.-C.C. and W.-R.W.). Recalcitrance was defined as a history of plaque-type psoriasis present or recurring for at least 2 years and a history of at least 2 antipsoriatic treatment failures. The inclusion and exclusion criteria are listed in Table 1. A baseline evaluation of the patients was performed, including hemogram and blood biochemical analysis (including glutamic-oxaloacetic transaminase, glutamic-pyruvic transaminase, and creatinine measurement). The baseline total body surface area involvement and Psoriasis Area Severity Index (PASI) scores were also calculated. Two symmetrically comparable psoriatic plaques on each patient were identified for the trial and baseline lesion areas calculated. Whenever possible, the arms, elbows, legs, and knees were selected as target areas because cross-contamination was less likely to occur at these sites.

Indigo naturalis used in this study was identified and provided by the Chinese pharmacy of our institution. It is a powder prepared from the plant Strobilanthes formosanus Moore (Acanthaceae) (Figure 1). The fingerprints and quantity analysis of standard samples, indirubin and indigo, were established by Leu Yann-Lii, PhD. A voucher specimen was deposited in the herbarium of Chang Gung University, Taoyuan, Taiwan. The indigo naturalis used in our study contained 1.4% indigo and 0.16% indirubin based on the data from high-performance liquid chromatography analysis. The indigo naturalis ointment used was a mixture of indigo naturalis powder and vehicle (1:10). The vehicle consisted of petroleum jelly, yellow wax, and olive oil mixed in the ratio of 5:6:9. The formulations were stable for the duration of the study. Containers were labeled to assist compliance with the left or right application. Indigo naturalis ointment and placebo ointment (vehicle) were prepared by a research pharmacist who was aware of the treatment assignment. The active formulation was applied to 1 side and the vehicle base to the opposite side (Figure 2). Patients were instructed to avoid cross-contamination between the 2 treatment sites by washing hands thoroughly between applications. The amount of ointment that should be used by the patient was assessed by estimating the surface area involved by each psoriatic lesion.⁸ This was then used to calculate the number of fingertip units (FTUs) that should be used by the patient (1 FTU = 0.5 g = 100 cm² of surface area).⁹ The patients were instructed in how to use FTUs to manage treatment application. All test containers were weighed after the study, and the amount of ointment applied to the skin was determined.

Clinical assessment of psoriatic lesion severity and photographic documentation during treatment were performed at baseline and weeks 2, 4, 6, 8, 10, and 12 (end of treatment). At each visit, all participants were requested to clean their skin thoroughly before the photographs were taken. The assessment of efficacy was performed using the scores of scaling, erythema, induration, sum of these scores, and clearing percentage of target plaque by 2 blinded observers (Y.-C.C. and W.-R.W.) assessing the photographs. Scaling, erythema, and induration were scored on a scale of 0 to 8 (0 indicating none; 2, mild; 4, moderate; 6, severe; and 8, very severe). The bilateral plaque area was rated as 0% to 100% (0% indicating clearance and 100% baseline). In Figure 3 and Figure 4, clinical photographic examples of rating of percentage of clearing and rating scaling, erythema, and induration are shown.

Treatment was performed until complete clearing or for a maximum period of 12 weeks and immediately stopped if significant local or systemic adverse events occurred possibly related to treatment. Safety assessments consisted of monitoring and recording all adverse events by their severity and potential relationship to the study medication.

The intent-to-treat population consisted of all patients enrolled, with each patient receiving both indigo naturalis and vehicle-only treatment, making the main population for the evaluation of safety and efficacy. All statistical analyses were performed using a commercially available software program (SAS version 9.1.3; SAS Institute Inc, Cary, North Carolina).

All efficacy end points at weeks 2, 4, 6, 8, 10, and 12 were compared between the 2 treatment lesions. A paired t test was conducted to establish the differences between the pretreatment and posttreatment values and the active and placebo group values. All statistical tests were 2 sided and performed at an α level of .05. The mixed-effect model was used to account for time dependency of the repeated treatment measurement and differences between the 2 groups.

A total of 51 patients were screened for the study; 42 (32 men, 10 women) were included in the intent-to-treat analysis (Figure 5). The mean (SD) patient age was 34.6 (11.5) years (age range, 18-58 years); the median disease duration was 10 years (range, 2-41 years). The median pretreatment PASI score was 14.7, with a median body surface area of 18%. Target lesions were located on the upper extremities (17 participants), lower extremities (21 participants), and trunk (4 participants). Lesions statistically similar in area, redness, thickness, and scaling were assigned for treatment by indigo naturalis and vehicle ointments in baseline (Table 2). Of the 42 patients, 34 completed the study, 3 patients withdrew because they were dissatisfied with the treatment progress (slow efficacy), 3 patients could not continue because of their work, and 2 patients failed to complete the course of follow-up appointments.

After 12 weeks of treatment with the indigo naturalis ointment, scaling, erythema, and induration all showed significant improvement when compared with the vehicle ointment–treated lesions. For the indigo naturalis ointment–treated lesions, at the start of the study, mean (SD) scores for scaling, erythema, induration, and the sum of all 3 were 6.8 (1.31), 6.0 (1.42), 6.1 (1.28), and 18.9 (2.97), respectively, and after 12 weeks of treatment improved to 1.5 (1.46), 2.6 (1.60), 2.2 (1.49), and 6.3 (4.28), respectively, whereas the lesion area reduced to 38.5% (39.58%) of the original (P < .001). In comparison, for the vehicle ointment–treated lesions, at the start of the study, scores for scaling, erythema, induration, and the sum of all 3 were 6.7 (1.31), 6.0 (1.40), 6.0 (1.32), and 18.7 (3.08), respectively, and after 12 weeks of treatment improved to 3.7 (1.60), 4.9 (1.50), 4.2 (1.37), and 12.8 (3.92), respectively, whereas the lesion area reduced to 90.0% (38.06%) of the original (P < .14) (Figure 6A-D). Reliability studies demonstrated an intraclass correlation coefficient for interrater reliability of 0.69 for the erythema score (95% confidence interval [CI], 0.62-0.75), 0.54 for the scaling score (0.45-0.62), 0.66 for the induration score (0.58-0.72), and 0.93 for the percentage of clearing (0.91-0.94).

Weighting the sum of scaling, erythema, and induration scores by the lesion area and comparing between the start and end of the study, the indigo naturalis ointment–treated lesions showed an 81% (95% CI, 73%-90%; P < .001) improvement, whereas the vehicle ointment–treated lesions showed a 26% (16%-36%; P < .001) improvement (Figure 6E). The efficacy of indigo naturalis treatment increased with the duration of treatment, with scaling, erythema, and induration all making statistically significant improvement as the study progressed (Figure 6F). Therapy outcome was grouped into 6 categories of global improvement compared with baseline: clearance (≥90% improvement), near clearance (75% to <90% improvement), moderate improvement (50% to <75% improvement), mild improvement (25% to <50% improvement), no change (0% to <25% improvement), and worse. Of the 34 patients who completed the study, no patient experienced worsening of psoriasis in the indigo ointment–treated lesion, whereas 25 of 34 patients (74%) experienced clearance or near clearance of their psoriasis (Figure 7).

To examine whether the disease severity was a significant factor in the success of the treatment, the results were divided into 2 groups based on the original PASI scores (>14.7 and ≤14.7) or divided into 2 groups based on the original total body surface area involvement scores (>18% and ≤18%). In both cases, no statistically significant difference was seen (using paired t test) in their response to treatment between these 2 groups (Table 3). Figure 8 shows the degree of improvement observed in psoriatic lesions before and after the use of indigo naturalis and vehicle.

None of the patients experienced serious adverse events during the study. Among the 34 patients who completed the treatment, 4 patients reported itching after applying the indigo naturalis ointment to their psoriatic plaque, but the itching was only present for a couple of days at the start of treatment, and no tenderness, vesicles, or other serious problems were noted during the subsequent treatment period. The results of blood tests, including complete blood cell and differential cell counts and glutamic-oxaloacetic transaminase, glutamic-pyruvic transaminase, and creatinine measurement, indicated that the liver and renal functions of all these patients seemed to be normal after the trial (data not shown).

Within the last 5 years, we have been using an alternative approach to treat thousands of patients with psoriasis by applying the indigo naturalis ointment topically on plaque lesions. We designed this study to assess the clinical benefit and safety of indigo naturalis monotherapy in patients with plaque psoriasis and to provide evidence-based research of traditional Chinese medicine therapy for psoriasis

In this study, indigo naturalis ointment–treated lesions experienced a significant clinical improvement over vehicle-treated lesions. The improvement of the 12-week trial was similar to the result of our prior pilot study. We could find distinct improvement in the scaling and induration scores by treating with indigo naturalis ointment or vehicle only; however, the erythema and area scores revealed obvious changes only by indigo naturalis ointment. Besides, most responding lesions (25 of 34 [74%]) had either an excellent or clear rating (≥75% improvement) in the scores of erythema, induration, scaling, and plaque lesion area. Further statistical analysis showed that the clinical improvement increased significantly as the trial progressed. On the basis of the analysis of PASI and total body surface area involvement scores, it indicated that severity was not a significant factor in predicting treatment success. From the results of our trial, we found a less pronounced but still significant improvement reflected by decreased scores for scaling and induration in the vehicle group. This result may not be explained by a placebo effect alone. Emollients have known beneficial effects in the treatment of psoriasis through increasing hydration of the stratum corneum and through the keratolytic effect.^10- 11 Application of an emollient seems effective in producing a slight modification of proliferation and differentiation.¹²

We recognize that our prospective study was limited in its absence of patient masking and lack of a direct comparison with a current topical medicine (eg, corticosteroid) control group. Furthermore, data are unavailable to assess the efficacy and safety of the therapy in a follow-up period. However, a double-blind, placebo-controlled trial would have been difficult in this case, because indigo naturalis is a natural crude drug that appears dark blue. The use of patients as their own controls in the present study helped to reduce interindividual variation, thereby increasing the power of the study to detect the effect of indigo naturalis treatment. Because of the low solubility of indigo naturalis, we assume that the efficacy of psoriasis treatment will be accelerated when using indigo naturalis powder formulated in an ointment base. However, we have not performed pharmacologic studies to assess the transdermal drug delivery of indigo naturalis in its ointment vehicle formulation. The color and smell of indigo naturalis may affect compliance of the patients and the longer-term durability of the benefit simultaneously. The indigo naturalis ointment slightly stains the skin and clothing, which can be cleaned thoroughly by common detergents. Repeated application has no significant effect on skin color and will not change the skin appearance.

To our knowledge, the present trial is the first attempt to provide evidence-based medicine using topical indigo naturalis for the treatment of chronic plaque psoriasis. Although the current standard western medicine therapies, such as topical corticosteroid, can be effective in controlling psoriasis to a certain degree, they have significant drawbacks, such as relapse or exacerbation of the disease on therapy discontinuation and well-known adverse effects, such as skin atrophy, telangiectasia, burning, purpura, irreversible striae, or even adrenocortical suppression, in long-term use. Also, important advances have occurred in new biological treatments of psoriasis. However, the fear of adverse events in long-term use and the high cost may reduce the compliance of patients with the treatment. Indigo naturalis ointment treatment has neither adverse effects, such as those found with corticosteroid treatment, nor other toxic effects based on our past 5 years of clinical observation. Furthermore, it costs much less in comparison with other topical agents.⁶ We anticipate that indigo naturalis ointment can be an alternative or complementary therapy for psoriasis and believe it will be a great benefit to this large patient population.

In conclusion, we present a randomized controlled trial showing the use of topical indigo naturalis ointment for the treatment of chronic plaque psoriasis to be both safe and effective. Future research for a more potent extraction from this crude herb that can provide better absorption and convenience would help improve patient compliance with the treatment regimen. However, much more research will be necessary to clarify the pharmacology of indigo naturalis.

Correspondence: Jong-Hwei Su Pang, PhD, Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, 259 Wen-Hwa First Rd, Kwei-Shan, Taoyuan 333, Taiwan (jonghwei@mail.cgu.edu.tw).

Accepted for Publication: January 29, 2008.

Author Contributions: Dr Lin had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Lin and Su Pang. Acquisition of data: Lin, Y.-C. Chang, and Wong. Analysis and interpretation of data: Lin, C.-J. Chang, and S.-C. Chang. Drafting of the manuscript: Lin. Critical revision of the manuscript for important intellectual content: Lin, Y.-C. Chang, Wong, C.-J. Chang, S.-C. Chang, and Su Pang. Statistical analysis: C.-J. Chang and S.-C. Chang. Obtained funding: Lin. Administrative, technical, or material support: Lin, Y.-C. Chang, and Wong. Study supervision: Lin and Su Pang.

Financial Disclosure: None reported.

Funding/Support: This study was supported by grant CMRPG33024 from Chang Gung Memorial Hospital (Dr Lin).

Additional Contributions: Chung Yin Hui, BSc, prepared the study medication; Leu Yann-Lii, PhD, performed the fingerprint calculations; and Bill Ressl, MEng, and Chang Chieh Hsueh, BAcc, revised the manuscript.