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Atopic dermatitis: Fantasizing about a dual approach

DII small banner By Warren R. Heymann, MD
March 9, 2017

Patient photos before and after dupilumab. A, Subject-provided photograph before the start of dupilumab therapy. B, Photograph taken in the clinic 1 year after the patient started dupilumab therapy.
Credit: JAAD
It has been acknowledged that we are on the cusp of biologic therapy for atopic dermatitis (“Dupilumab and the dawn of the biologic era for atopic dermatitis”, August 28th, 2016). My cadre of patients with severe atopic dermatitis (AD) are itching for its release — whenever that will be. Is there another pathway to alleviate pruritus? The itch meisters point to IL-31 as a factor.

In a systematic review of IL-31, Saleem et al note that IL-31 receptors are expressed constitutively on the surface of keratinocytes, eosinophils, and small diameter neurons. Overexpression of interleukin-31, independent of mast cells and lymphocytes, induces clinical and histological features consistent with atopic dermatitis (1). Feld et al have demonstrated that the pruritus- and TH2-associated IL-31 induces a distinct transcriptional program in sensory neurons, leading to nerve elongation and branching both in vitro and in vivo. This finding suggests that patients with atopic dermatitis experience increased sensitivity to minimal stimuli inducing sustained itch (2).

In a phase 2, randomized, double-blind, placebo-controlled, 12-week trial, Ruzicka et assessed the efficacy and safety of nemolizumab (CIM331), a humanized antibody against interleukin-31 receptor A, in treating AD. The authors assigned adults with moderate-to-severe AD that was inadequately controlled by topical treatments to receive subcutaneous nemolizumab (at a dose of 0.1 mg, 0.5 mg, or 2.0 mg per kilogram of body weight) or placebo every 4 weeks or an exploratory dose of 2.0 mg of nemolizumab per kilogram every 8 weeks. The primary end point was the percentage improvement from baseline in the score on the pruritus visual-analogue scale (on which a negative change indicates improvement) at week 12. Secondary end points included changes in the score on the Eczema Area and Severity Index (EASI, on which a negative change indicates improvement), and body-surface area of atopic dermatitis. Results focused on the 216 patients who completed the study. At week 12, among the patients who received nemolizumab every 4 weeks, changes on the pruritus visual-analogue scale were -43.7% in the 0.1-mg group, -59.8% in the 0.5-mg group, and -63.1% in the 2.0-mg group, versus -20.9% in the placebo group (P<0.01 for all comparisons). Changes on the EASI were -23.0%, -42.3%, and -40.9%, respectively, in the nemolizumab groups, versus -26.6% in the placebo group. Respective changes in body-surface area affected by atopic dermatitis were -7.5%, -20.0%, and -19.4% with nemolizumab, versus -15.7% with placebo. Regarding side effects, only nasopharyngitis and exacerbation of AD were noted in > 10% of treated patients, although the limited size and length of the trial precluded conclusions regarding adverse events.  The authors concluded that nemolizumab at all monthly doses significantly improved pruritus in patients with moderate-to-severe atopic dermatitis (3).
As Mollanazar et al state: “Itch is caused by a complex interface between skin, keratinocytes, cutaneous nerve fibers, pruritogenic molecules, and the peripheral and central nervous systems. Atopic dermatitis is one of the most itchy skin dermatoses and affects millions worldwide. The sensation of atopic itch is mediated by the interplay between epidermal barrier dysfunction, upregulated immune cascades, and the activation of structures in the central nervous system.” (4)

If effective, monotherapy is ideal in order to minimize adverse reactions. However, in severe, recalcitrant cases of AD, it may make sense to utilize a multifaceted therapeutic regimen to achieve a synergistic response. Two advertisements indelibly imprinted on my brain are for Certs (‘You get two, two, two mints in one!”) https://www.youtube.com/watch?v=hJzhmxNzZs0 — and Doublemint gum (“Double your pleasure, double your fun!”). I realize the impracticality of suggesting that an injection of two monoclonal antibodies be formulated to be delivered as one, nor do I have any notion if the combination of dupilumab with nemolizumab would be synergistic or detrimental. It is still intriguing to fantasize about the combination!

1. Saleem MD, et al. Interleukin-31 pathway and its role in atopic dermatitis: A systematic review. J Dermatol Treat 2017 Feb 1 [Epub ahead of print].
2. Feld M, et al. The pruritus-and TH2-associated cytokine IL-31 promotes growth of sensory nerves. J Allergy Clin Immunol 2016; 138: 500-8.
3. Ruzicka T, et al. Anti-Interleukin-31 receptor A antibody for atopic dermatitis. N Engl J Med 2017; 376: 826-35.
4. Mollanazar NK, et al. Mediators of chronic pruritus in atopic dermatitis: Getting the itch out? Clin Rev Allergy Immunol 2016; 51: 263-92.

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