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Dyeing for a “new” topical agent for psoriasis? Think indigo

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By Warren R. Heymann, MD
April 9, 2018

Despite the magnificent revolution of biologics for psoriasis, topical agents remain the cornerstone of treatment, either alone, or in combination with phototherapy or systemic treatments. Patients clamor for “natural” products and are increasingly steroid phobic (please see “Countering Corticophobia with Assistance from Dr. Albert Kligman”, DI&I, October 19th, 2017). It would be marvelous to offer such a product, in addition to the usual — topical steroids, vitamin D analogues, calcineurin inhibitors, retinoids, salicylic acid, and tar preparations.

Formulations of Indigo naturalis may fit the bill. Its use can be traced to ancient Asian civilizations; it is a staple of traditional Chinese medicine, where it is named “Qing Dai”. The composition of indigo containing plant species differs, with compounds of different origins, including Baphicacanthus cusia, Polygonum tinctorium, and Isatis tinctoria. Although indigo is blue, the indigo derivatives have different shades and colors: red (indirubin) yellow, green, brown, violet. (1)
Indigo naturalis has been used for centuries to treat eczema, aphthae, mumps, and furuncles. In China, it has been used systemically for treating psoriasis, however its use has been limited by poor absorption, gastrointestinal irritation and hepatitis. Topical therapy with Indigo naturalis ointment has been reported to be effective while avoiding systemic toxicity. (2)

Lin et al (the lead author has written the lion’s share of manuscripts on this topic) reported the case of an 8-year-old boy with recalcitrant pediatric psoriasis, who, after multiple treatment failures with conventional antipsoriatic medications and phototherapy, demonstrated marked clinical improvement within 8 weeks of treatment with Indigo naturalis composite ointment. He remained in remission for at least 2 years. (3) In a study of patients with nail psoriasis, 18 patients used Indigo naturalis extract in oil (Lindioil) on the right hand and 15 used it on the left hand, compared to calcipotriol on the opposite hands, for 24 weeks. Twenty-eight patients completed the study. At week 24 there was a statistically significant improvement in the NAPSI (Nail Psoriasis Severity Index) scores for the Lindioil treated nails, with the greatest effects on onycholysis and subungual hyperkeratosis. (4)
Mechanistically, immunohistochemical studies have demonstrated decreased proliferating cell nuclear antigen and involucrin expression when Indigo naturalis has been added to cultured keratinocytes. These effects were attributed to indirubin. (1)  Indirubin, has also been reported to inhibit cyclin-dependent kinase and signal transducer and activator of transcription-3 (STAT3) activity.  Cheng et al performed a randomized, double-blind, placebo-controlled study using Indigo naturalis as topical monotherapy to treat moderate plaque psoriasis in a Chinese cohort (n = 24). Patients were treated with Indigo naturalis ointment (n = 16) or matched placebo (n = 8) twice daily for 8 weeks, with 1 week of follow-up. At week 8, a significant improvement in Psoriasis Area and Severity Index (PASI) scores from baseline was observed in Indigo naturalis-treated patients (56.3% had 75% improvement [PASI 75] response) compared with placebo (0.0%). A gene expression signature of moderate psoriasis was established from baseline skin biopsies, which included the up-regulation of the interleukin (IL)-17 pathway as a key component; Indigo naturalis treatment resulted in most of these signature genes returning toward normal, including down-regulation of the IL-17 pathway. Using an in vitro keratinocyte assay, an IL-17-inhibitory effect was observed for tryptanthrin, a component of Indigo naturalis. (5)
Homing in on indirubin as the active ingredient in Indigo naturalis, Lin et al studied different concentrations of the agent in a randomized, double-blind trial of indirubin in Lindioil. The authors found that the most effective concentration was 200 micrograms per gram of Lindioil. In this study, there were 105 treatment-emergent adverse effects reported by 60 participants. The most common were nasopharyngitis (17%) and upper respiratory infection (8%). Severe adverse reactions (bone fracture, myocardial infarction, urinary tract infection with hemolytic anemia) were not believed to be related to indirubin. Only 8 cutaneous adverse reactions were noted – with the exception of one case of allergic contact dermatitis that necessitated discontinuation of therapy, the other cases of mild erythema allowed treatment to continue for the duration of the study. (6).

I concur with the conclusions of the editorial by Sekhon and Koo that accompanies reference 6 — topical indirubin appears to provide a safe and effective treatment for psoriasis without the concerns of topical steroids. By utilizing different mechanisms of action, it could be beneficial as monotherapy, or as part of a combined therapy, acting additively or synergistically with other modalities.
Patients may be blue about using topical steroids but probably will not be about using indigo!

Point to remember: Indigo naturalis may be an effective topical therapy for psoriasis of the skin and nails.

1. Stasiak N, et al. Modern industrial and pharmacological applications of indigo dye and its derivatives – a review. Acta Pol Pharm 2014;71(2):215-21.
2. Lin Y-K, et al. Anti-psoriatic effects of indigo naturalis on the proliferation and differentiation of keratinocytes with indirubin as the active component. J Dermatol Sci 2009; 54: 168-74.
3. Lin Y-K, et al. Successful treatment of pediatric psoriasis with Indigo naturalis composite ointment. Pediatr Dermatol 2006; 23: 507-10.
4. Lin Y-K, et al. A Chinese herb, Indigo naturalis, extracted in oil (lindioil) used topically to treat psoriatic nails: A randomized clinical trial. JAMA Dermatol 2015; 151: 672-4.
5. Cheng H-M, 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: 439.
6. Lin Y-K, et al. Comparison of indirubin concentrations in indigo naturalis ointment for psoriasis treatment: A randomized, double-blind, dosage-controlled trial. Br J Dermatol 2018; 178: 124-31.
7. Sekhon S, Koo J. Indirubin: A novel topical agent in the treatment of psoriasis. Br J Dermatol 2018; 178: 21.

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