Dermatologists are well aware of the difficulty in managing itchy patients. Itch can be caused by a number of cutaneous and extracutaneous diseases. Regardless of the etiology, itch is one of the most frustrating symptoms of patients and management dilemmas for dermatologists. At the 16th Annual ODAC conference, Dr. Brian Berman reviewed some of the emerging therapies for the treatment of itch and the etiologies for which they are currently under investigation.
Nemolizumab is a monoclonal antibody directed at the IL-31 receptor A. It is currently being studied for use in atopic dermatitis. Recent phase II data have shown improvement for itch in atopic dermatitis over 64 weeks1. A few of the less common side effects that were seen in this study included peripheral edema and elevations in blood CPK levels.
Tapinarof cream is a first-in-class, naturally derived, non-steroidal topical agent. It is currently being investigated for use in psoriasis and atopic dermatitis. Tapinarof is a therapeutic aryl hydrocarbon modulating agent (or TAMA) and inhibits specific proinflammatory mediators, including IL-6 and IL-17A2. One of the more interesting targets of tapinarof is nuclear factor-erythroid 2-related factor-2 (Nrf2), which happens to be one of the mechanisms through which coal tar produces its beneficial effects.
Hypochlorous acid gel is being used for its anti-inflammatory properties. This topical has potential utility for atopic and seborrheic dermatitis-related itch.
Serlopitant is an oral NK1 receptor antagonist. It is currently being investigated for use in chronic pruritus, pruritus in psoriasis, and prurigo nodularis. Substance P binds to the NK1 receptor peripherally, in the ganglion and brain to cause/increase the perception of itch, and as such, NK1 receptor antagonists are an up and coming mechanistic target for itch. Phase II data appear to be promising3.
Remetinostat (previously referred to as SHAPE), a topical histone deacetylase inhibitor, is currently under investigation for treating pruritus in patients with stage IA-IIA mycosis fungoides4. Preliminary data are promising as the topical route of the medication appears to decrease itch while limiting side effects compared to systemic histone deacetylase inhibitors.
Omalizumab, an anti-IgE monoclonal antibody, is approved for use for chronic idiopathic or chronic spontaneous urticaria5. It is notable that in the pivotal, phase 3 study published in the New England Journal of Medicine, the primary endpoint was itch-severity score rather than urticarial lesion counts. The use of this endpoint highlights the magnitude of itch in urticaria.
Physician assurance reduces itch. In a recent study6, a physician administered a histamine skin prick to 76 participants. After 3 minutes, half of the randomly selected participants were assured by the physician in the following way. “From this point forward your allergic reaction will start to diminish, and your rash and irritation will go away.” In the assured group, it was found that over the next 15 minutes, itchiness of the area declined significantly faster than the group not assured by the physician.
Itch and Cancer
In a cross-sectional study of patient with itchy, 16,925 pruritic patients were compared with 4.6 million patients without itch. Patients with itch were significantly more likely to have an underlying malignancy (odds ratio 5.76, 95% confidence interval 5.53-6.00)7. The most strongly associated malignancies were liver, biliary tree, hematopoietic, cutaneous lymphoma, and skin cancer.
Genetics of Itch
Regarding the genetics of itchy skin in atopic dermatitis and psoriasis, a few of the genes in common that seem to play a role in itch include those for IL-6, Substance P, and NK1-R.
- Kabashima, K. et al. Nemolizumab in patients with moderate-to-severe atopic dermatitis: Randomized, phase II, long-term extension study. J Allergy Clin Immunol. 2018 Oct;142(4):1121-1130.e7.
- Smith, SH. et al. Tapinarof Is a Natural AhR Agonist that Resolves Skin Inflammation in Mice and Humans. J Invest Dermatol. 2017 Oct;137(10):2110-2119.
- Yosipovitch, G. et al. Serlopitant for the treatment of chronic pruritus: Results of a randomized, multicenter, placebo-controlled phase 2 clinical trial. J Am Acad Dermatol. 2018 May;78(5):882-891.e10.
- Duvic, M. et al. 607 Anti-pruritic properties of remetinostat (SHAPE), a topical histone deacetylase inhibitor (HDACi); data from a randomized phase 2 study in patients with stage IA- IIA mycosis fungoides. Journal of Investigative Dermatology , Volume 138 , Issue 5 , S103.
- Maurer, M. et al. Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria. N Engl J Med. 2013 Mar 7;368(10):924-35.
- Leibowitz, KA. et al. Physician Assurance Reduces Patient Symptoms in US Adults: an Experimental Study. J Gen Intern Med. 2018 Dec;33(12):2051-2052.
- Larson, VA. et al. Association between itch and cancer in 16,925 patients with pruritus: Experience at a tertiary care center. J Am Acad Dermatol. 2018 Sep 11. pii: S0190-9622(18)32500-3.
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