Clinical Efficacy of Topical Indigo naturalis in Psoriasis

A randomized, placebo-controlled trial

By Michael Traub, ND, DHANP, FABNO

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Reference

Cheng HM, Wu YC, Wang Q, et al. Clinical efficacy and IL-17 targeting mechanism of Indigo naturalis as a topical agent in moderate psoriasis. BMC Complement Altern Med. 2017;17(1):439.

Objectives

  • To evaluate the effect of Indigo naturalis ointment as monotherapy in moderate plaque psoriasis
  • To establish a molecular signature of moderate psoriasis with global gene expression analysis
  • To evaluate components of Indigo naturalis for anti-interleukin (IL)-17-induced cytokine release in cultured keratinocytes.

Design

Randomized, double-blind, placebo-controlled clinical trial

Participants

Twenty-four Taiwanese patients, 17 men and 6 women, mean age of 40 ± 10 years, with approximately 9% body surface area (BSA) involvement of psoriasis. Participants had mean Psoriasis Area and Severity Index (PASI) approximately 10 and mean Physician’s Global Assessment (PGA) approximately 3, consistent with moderate psoriasis.

Study Parameters Assessed

Adverse event assessments and tolerability using weekly PASI, BSA, PGA, and Overall Target Plaque Severity Scores (OTPSS); punch biopsy from lesional and nonlesional skin at week 0 and from lesional skin at week 8 for gene expression microarray.

Normal human adult keratinocyte cultures stimulated with IL-17A were treated with varying concentrations of the 3 major Indigo naturalis constituents: isatin, tryptanthrin, and indirubin, and a control IL-17 inhibitor. Tissue cultures were analyzed for pro-inflammatory cytokines IL-6 and IL-8 using MesoScale Discovery V-plex assay.

Primary Outcome Measures

Changes in weekly PASI, BSA, PGA, and OTPSS scores from baseline to 9 weeks; changes in gene expression microarray of skin biopsy specimens pre- and post-treatment; and tissue culture cytokine analysis of IL-6 and IL-8.

Key Findings

Psoriasis Area and Severity Index score was significantly improved (P=0.02) in Indigo naturalis–treated patients vs controls by week 2, and at week 8, the PASI had significantly improved from baseline (P=0.01) and was significantly different vs placebo (P=0.01). Of Indigo naturalis–treated patients, 56.3% achieved at least a 75% improvement (PASI 75) at week 8 vs none of the placebo patients (P=0.02). One week following treatment termination, the mean PASI score for the treated patients dropped, indicating diminished efficacy following suspension of treatment. Mean PGA score was also significantly different in Indigo naturalis patients compared to the placebo group (P<0.003). Indigo naturalis ointment was well-tolerated.

Treatment with Indigo naturalis successfully targets the IL-17 pathway similarly to other systemic therapies that are much more expensive and carry significant risk of harm.

Gene expression revealed that the top 15 pathways included the IL-17 pathway and that it was upregulated in psoriatic lesions and downregulated after Indigo naturalis treatment. Interleukin-17A stimulation of cultured human keratinocytes resulted in a 4.5-fold increase in IL-6 and a 5.5-fold increase in IL-8; IL-17A stimulation was not affected by the presence of isatin and indirubin, but tryptanthrin showed significant inhibition of IL-6 and moderate reduction of IL-8 at the highest concentration tested. Tryptanthrin showed no impact on cell viability at any tested concentration.

Disease signatures of the Taiwanese study population were compared to those of a predominantly Caucasian population and found to be mostly overlapping.

Practice Implications

The characteristic scaly plaques of psoriasis and the increased levels of T helper (Th) 1 and Th17 cells in psoriatic lesions have been found to benefit from neutralizing tumor necrosis factor-alpha (TNF-alpha), IL-12/23, and IL-17A. Thus, Th1/Th17 cells have been found to underpin the pathogenesis of psoriasis.1,2 Traditional treatments for psoriasis, although palliative, do not address the role of Th1/Th17. Newer biologic therapies are more effective, but are costly and confer significant risks of adverse effects.

Studies by Lin et al have previously shown efficacy of topical Indigo naturalis ointment in the treatment of psoriasis.3Indigo naturalis is a traditional Chinese medicine known as Qing Dai, and consists of a dried pigment obtained from a number of plants including Baphicacanthus cusia. This study is the first randomized, double-blind, placebo-controlled clinical trial to evaluate Indigo naturalis ointment as monotherapy for moderate plaque psoriasis in a Taiwanese population. It is a joint venture from a Taiwanese-based group of investigators and Janssen Research and Development, LLC, a subsidiary of Johnson & Johnson. Despite the fact that the researchers were employees of Janssen, and 6 of them own stock in Johnson & Johnson, this was a very well-designed, thorough study.

The investigators published novel findings on the profile of molecular changes associated with moderate plaque psoriasis. They also found that treatment with Indigo naturalis successfully targets the IL-17 pathway similarly to other systemic therapies that are much more expensive and carry significant risk of harm. The discovery that tryptanthin possesses IL-17 activity, and the disease signatures of Taiwanese psoriatic patients mostly overlap with Caucasians’, suggest that Indigo naturalis should also be effective in a broader population of people with psoriasis.

The authors state that the short benefit duration of topical Indigo naturalis treatment could be due to lack of deeper penetration in the skin and less systemic absorption, or short half-life of the active ingredients. Although these suggestions could be true, it is perhaps more likely that topical Indigo naturalis cannot effectively address the chronic inflammatory systemic nature of psoriasis, and that other approaches, including contributory lifestyle factors, must also be effectively addressed to downregulate the phenotypic expression of the underlying genetic susceptibility to psoriasis.

Author’s disclosure: I consult for Kamedis, Ltd, a skin care company that has developed and marketed a topical indigo-based psoriasis formulation.

About the Author

Michael Traub, ND, DHANP, FABNO, completed pre-med studies at the University of California at Irvine. He graduated from National University of Naturopathic Medicine in 1981 and completed a residency there in Family Practice and Homeopathy. In 2006, Traub was honored with the American Association of Naturopathic Physicians (AANP) Physician of the Year Award in recognition for his many years of service, which included serving as AANP president from 2001 to 2003. His father was a dermatologist, and this inspired Traub to undertake extra study in this subject and become the leading expert in dermatology in the naturopathic profession. He has taught dermatology at 5 of the 7 accredited naturopathic medical schools in North America and is the author of Essentials of Dermatologic Diagnosis and Integrative Therapeutics. A fellow of the American Board of Naturopathic Oncology, Traub has been actively engaged in clinical research throughout most of his career and is currently a co-investigator in the Canadian/US Integrative Oncology Study. His most recent major publication, “Impact of Vitamin D3 Dietary Supplement Matrix on Clinical Response,” appears in a 2014 issue of the Journal of Clinical Endocrinology and Metabolism. Traub has served as medical director of Lokahi Health Center in Kailua Kona, Hawaii for the past 31 years.

References

  1. Russell CB, Rand H, Bigler J, et al. Gene expression profiles normalized in psoriatic skin by treatment with brodalumab, a human anti–IL-17 receptor monoclonal antibody. J Immunol. 2014;192(8):3828-3836.
  2. Sofen H, Smith S, Matheson RT, et al. Guselkumab (an IL-23–specific mAb) demonstrates clinical and molecular response in patients with moderate-to-severe psoriasis. J Allergy Clin Immunol. 2014;133(4):1032-1040.
  3. Lin YK, Leu YL, Huang TH, et al. Comparison of refined and crude indigo naturalis ointment in treating psoriasis: randomized, observer-blind, controlled, intrapatient trial. Arch Dermatol. 2012;148(3):397-400.
  4. Traub ML, Finnell JS, Bhandiwad A, Oberg E, Suhaila L, Bradley R. Impact of vitamin D3 dietary supplement matrix on clinical response. J Clin Endocrinol Metab. 2014;99(8):2720-2728.