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Ustekinumab: A topic for atopics?

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

Atopic dermatitis patient shows drastic improvement at week 19 of ustekinumab treatment.
Credit: JAAD
If you’re like me, you have a cadre of patients with severe atopic dermatitis (AD) patients who are counting the minutes for the release of dupilimab (a human monoclonal antibody against interleukin-4 receptor alpha, that inhibits signaling of interleukin-4 and interleukin-13, type 2 cytokines that may be important drivers of atopic or allergic diseases such as atopic dermatitis).

The latest article from the New England Journal signals that this will be a winner —  in two phase 3 trials of identical design involving patients with atopic dermatitis, dupilumab improved the signs and symptoms of atopic dermatitis, including pruritus, symptoms of anxiety and depression, and quality of life, as compared with placebo (1).
While I certainly hope that dupilumab will be as effective as the initial reports suggest, I always remind my patients that in my hands, these are often wonder drugs – once I prescribe them, I wonder why they aren’t as terrific as I had hoped. Our current systemic agents for severe AD – cyclosporine, mycophenolate mofetil, azathioprine, and methotrexateleave much to be desired; perhaps dupilumab will be the revolutionary agent we have been waiting for.

To date, biologics have not been very useful for severe AD. Biologic agents of different classes used to treat AD (TNF-a inhibitors, anti-IgE antibodies, anti-T cell agents, anti-B cell antibodies, etc.) have been reviewed by Taïeb et al, confirming their lack of efficacy. The authors conclude that future success of biologics for AD will (1) influence the inflammatory skin pattern towards less pruritogenic effects, requiring first a better understanding of pruritogenic inflammation and (2) limit the amplification loop of disease by attacking abnormal regulatory mechanisms which perpetuate skin autoinflammation (2).

Weiss et al studied the course of 3 patients with severe AD who were administered 45 mg of subcutaneous ustekinumab (Stelara) over a period of 16 weeks. Clinical scores and skin biopsy specimens, taken at baseline and at week 8, were used to assess changes in disease severity. All patients showed a gradual improvement of the disease, achieving a 50% reduction in the Eczema Area and Severity Index score by week 16. Immunohistology of skin biopsy specimens revealed a significant decrease in the degree of epidermal hyperplasia/proliferation and the number of infiltrating dermal T cells, dendritic cells, and mast cells after treatment. Using quantitative real-time polymerase chain reaction of lesional skin, the authors found a clear reduction of T-helper 2-/22-associated molecules after therapy. The authors concluded that blocking IL-12/-23 p40 could be beneficial for a subgroup of patients with severely infiltrated AD (3).

 Khattri et al performed a phase II, double-blind, placebo-controlled study, of 33 patients with moderate-to-severe AD who were randomly assigned to either ustekinumab (n=16) or placebo (n=17), with subsequent crossover at 16 weeks, and last dose at 32 weeks. Background therapy with mild topical steroids was allowed to promote retention. Study endpoints included clinical (SCORAD50) and biopsy-based measures of tissue structure and inflammation, using protein and gene expression studies. The ustekinumab group achieved higher SCORAD50 responses at 12, 16 (the primary endpoint) and 20 weeks compared to placebo, but the difference between groups was not significant (4).
The three patients presented in Weiss’ paper improved slowly, but perceptibly. Any one of my severe AD patients would be delighted to have that degree of improvement. I will certainly discuss this option with them, explaining that ustekinumab is completely off-label for AD, and almost certainly not paid for by their insurance company. As hard as it is to find a regimen that helps our most severe AD patients, it is easier than trying to figure out how to get certain drugs covered!

1. Simpson EL, et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis in atopic dermatitis. N Engl J Med 2016; 375: 2335-48.
2. Taïeb A, et al. Biologics in atopic dermatitis. J Dtsch Dermatol Ges 2012; 10: 174-8.
3. Weiss D, et al. Ustekinumab treatment in severe atopic dermatitis:
 Down-regulation of T-helper 2/22 expression. J Am Acad Dermatol 2017; 76: 91-7.e3
4. Khattri S, et al. Efficacy and safety of ustekinumab treatment in adults with moderate-to-severe atopic dermatitis

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