Atopic Dermatitis: Treating Itch and Biologics Review

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Atopic Dermatitis: Treating Itch and Biologics Review

Postby CFH » Wed Jan 18, 2017 9:01 pm

Interleukin (IL) 31 induces in cynomolgus monkeys a rapid and intense itch response that can be inhibited by an IL-31 neutralizing antibody.
Lewis KE, Holdren MS, Maurer MF, Underwood S, Meengs B, Julien SH, Byrnes-Blake KA, Freeman JA, Bukowski TR, Wolf AC, Hamacher NB, Rixon MW, Dillon SR.
J Eur Acad Dermatol Venereol. 2017 Jan;31(1):142-150. doi: 10.1111/jdv.13794.

Why develop biologics in Atopic Dermatitis (AD) ?
-Atopic Dermatitis (AD) is a chronic inflammatory dermatitis and its severity is mostly related to the invalidating itch which can be present. Topicals, and then classical systemic agents are used…but what is to be done when this fails? Targeted molecular treatments are now entering into the therapeutical armamentarium of Atopic Eczema and the understanding of pathogenesis is more important than ever.

The role of Il-31 in AD ?
-IL 31 cytokine mainly produced by Th2 and, in a lesser extent, by Th1. It seems to be involved in both acute and chronic phases of AD. Il-31 is expressed predominantly by activated CD4(+) T cells in AD and other inflammatory skin diseases. Previously, transgenic mice with overexpression of this interleukin had already been able to develop skin lesions similar to those of AD and intense itch (pruritus).
-In this study administration of interleukin 31 (IL-31) was shown to induce a profound itch response in monkeys. In this study published in the JEADV, the authors demonstrated that IL-31 induced pruritus in non-human primates and that treatment with an anti-IL-31 neutralizing monoclonal antibody (mAb) can block the response.

How was the study performed ?
-A series of studies was conducted in cynomolgus monkeys to evaluate the itch response to recombinant cynomolgus IL-31 (cIL-31) administration. Three routes of cIL-31 administration (intravenous, intradermal, and subcutaneous) were evaluated. Subcutaneous treatment with a humanized anti-human IL-31 mAb cross-reactive to cIL-31 was subsequently tested for its ability to block the response to intradermal cIL-31 administration.

What did the study show ?
-Each route of cIL-31 delivery elicited a scratching response immediately after cIL-31 administration and lasted at least 3 h. Treatment with the IL-31 mAb inhibited the cIL-31-mediated scratching response in a dose-dependent manner.

What is the conclusion ?
An antibody directed against Il-31 might relieve itch such as in AD where Il-31 is upregulated. It could offer a therapeutical solution and definately helps us understand the mechanisms involved in itch.

Review on the Biologics used in Atopic Dermatitis (AD)

This review was done 2015 and the link is available below the summary of the review.

-Il-31 Directed therapy

"…Currently, the first two clinical trials with anti-IL-31 antibodies are ongoing.
The first one is a phase I, single-dose, dose-escalation, RCDB trial in order to evaluate the safety and tolerability of the drug. Different subcutaneous and intravenous doses are going to be evaluated. It is still in recruitment process and there is no data available. The second one is a phase II, multiple-dose and RCDB study. It is estimated that a total of 250 patients with AD will be recruited to evaluate the safety, tolerability and drug efficacy. Placebo or one of the four available doses will be assigned. No results are available either.

-Anti-CD20 (Rituximab): Simon et al. reported their experience after treating six patients with severe AD with rituximab.
At week 4, all patients showed a significant improvement in skin lesions and pruritus with a significant
decrease, up to 70%, in the Eczema Area and Severity Index (EASI) score…However, opposite results were observed in two patients with severe

-IgE-directed therapy (Omalizumab): …Despite several promising findings, there is a great variability of results in the AD field. Theoretically, a poorer response to omalizumab in patients with higher levels of IgE could have been expected, due to dosing adjustment and the impossibility of overtaking the maximum tolerated dose. However, favorable results were obtained in both patients with normal and elevated IgE levels [30,32].

-Humanized monoclonal antibody against IgE (Ligelizumab)…no results published at the time of the review

-IL-1 Directed Therapy (Anakinra)…We could not find any study on anakinra efficacy in patients with severe AD

-IL-4 and Il-13 Directed Therapy (Dupilumab)…It currently constitutes one of the biggest therapeutic promises in the AD management and at this moment, it is in phase III clinical trial for such indication (at the time of the review)

-Recombinant human IL-4 protein (Pitrakinra): Like dupilumab, it inhibits the downstream signaling pathways of both IL-4 and IL-13…results not published at the time of the review

-IL-5 Directed Therapy (Mepolizumab)…Although eosinophils exact degree of involvement in the pathogenesis of AD is not well known, this fact confers to mepolizumab options as AD treatment. Although the results are inconclusive, the randomized control results suggest that non responding cases were not treated long enough and that other cytokines (such as eotaxin) could explain the lack of response in these patients.

-IL-12/23 Directed Therapy (Ustekinumab)…Fernández-Antón et al. published a study on 4 refractory and severe AD improving clinically. 2 RCT's were underway at the time of publication.

-IL-22 Directed Therapy
-LFA-1 Directed therapy (Efalizumab)
-LFA-3 Directed therapy (Alefacept)
-TNF-alpha Directed therapy
-TSLP Directed therapy

The full review is available by clicking on the following link (open-access):


References: Biological Treatments in Atopic Dermatitis. Montes-Torres A., Llamas-Velasco M., Pérez-Plaza A., Solano-López G., Sánchez-Pérez J. J. Clin. Med. 2015, 4, 593-613; doi:10.3390/jcm4040593
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