Dupilumab: The first year
By Warren R. Heymann, MD
Jan. 8, 2018
When introduced as dermatologist to a new acquaintance, I’m sure you have heard: “Dermatology is a great field — you don’t cure anybody, so they keep coming back!”
Trust me. It’s no joy to see patients with recalcitrant, severe, life-altering, debilitating diseases such as atopic dermatitis, psoriasis, recalcitrant mycosis fungoides, et cetera, express their frustration, anxiety, and depression, when therapeutic interventions have failed.
What a blessing to have practiced long enough to utilize targeted biologic drugs that were a pipe dream when I was a medical student. Although I displayed skittishness in the early part of this century when prescribing biologics (remember the poor responses of alefacept or the risk of progressive multifocal leukoencephalopathy associated with efalizumab?), I no longer fear prescribing new agents, despite remaining cautious and skeptical for the first handful of patients utilizing a new drug.
This commentary will focus on new data regarding dupilumab for atopic dermatitis (AD).
Mr. K, an octogenarian Bernie Sanders doppelganger with severe AD, is a lovely man with a miserable disease. Occasionally prednisone would help, but phototherapy and other systemic agents were of little value. When we think of how childhood AD affects the whole family, we should remember how it may affect the lives of elderly couples. His remarkably upbeat wife has been a source of strength for him. Somehow he was able to get approved for dupilumab (and get it paid for). A few weeks ago, he was crying as he told me that I gave him his life back. Just as in the remarkable responses I have witnessed for the latest anti-IL-17 biologics for psoriasis (A heartfelt thank you note to my psoriasis research colleagues, DI&I, May 11, 2017), I told Mr. K that the credit doesn’t go to me, but rather those who have devoted their careers to making this possible. I know he is only one anecdotal patient. For evidence-based aficionados, take solace in the statistically significant improvement of quality of life (measured by the QoL Index for AD) in 32 patients with AD compared to 32 patients given a placebo. (1)
In using biological agents for psoriasis, we have been indoctrinated to discuss the risks of infection and malignancy. While there is no concern for cancer with dupilumab, are AD patients at a further increased risk of infection if treated with the drug?
According to Vangipuram and Tyring, “The pathogenesis of AD is complex and includes immunological abnormalities, an impaired epidermal barrier, and altered skin microbiota. An increased susceptibility to infections is also observed in patients with AD. Immunologically, AD is characterized by excessive T-cell activation, with significant skin infiltration by T-cells and dendritic cells (DCs). There is increased expression of Th2 cytokines in the acute lesional skin of AD patients, with a corresponding decrease in the T helper type 1 (Th1) cytokines. T helper type 2 (Th2) cells produce interleukin (IL)-4, IL-5 and IL-13; and activate eosinophils, basophils and mast cells, as well as immunoglobulin E (IgE)-producing B cells, which are all involved in allergic reactions. In addition, the Th2 cytokines have specific effects on the epidermis, including suppression of keratinocyte differentiation and antimicrobial peptide (AMP) production, which contribute to the AD skin phenotype. High levels of the Th2 cytokines IL-4 and IL-13 in AD skin have been shown to act as inhibitors of both epidermal differentiation and production of AMPs.” (2)
The interactions of the immune system, environment, and skin barrier defects (which have been linked to mutations in the filaggrin gene), initiate an inflammatory cycle that alters cutaneous innate immunity and the microbiome, leading to infectious complications. These include Staphylococcus aureus infections, eczema herpeticum, eczema coxsackium, eczema vaccinatum, and eczema molluscatum. (3) Regarding systemic infections, data from the 2002 to 2012 National Inpatient Sample were analyzed, including an approximately 20% sample of all US hospitalizations (n = 72,108,077 adults). AD was associated with extracutaneous, multiorgan, and systemic infections, including infectious arthropathy, endocarditis, encephalitis, methicillin-resistant Staphylococcus aureus infections, aspergillosis, and tuberculosis. (4)
Dupilumab is an anti-interleukin-4-receptor-alpha monoclonal antibody that blocks signaling of interleukin 4 and interleukin 13, type 2/Th2 cytokines implicated in numerous allergic diseases ranging from asthma to atopic dermatitis. (5)
Understandably, the package insert for dupilumab states that patients should tell their healthcare provider if they have a parasitic (helminth) infection. Interesting, to date I cannot find any reports in PubMed about parasitic infections complicating dupilumab therapy.
Fleming and Drucker examined the impact of dupilumab on rates of skin and other infections in patients with moderate-to-severe AD by conducting a systematic review and meta-analysis of randomized controlled trials of dupilumab for AD. Eight randomized controlled trials in 4 publications with 2706 participants were included, with follow-up time ranging from 4 to 52 weeks. Meta-analysis including all dosing schedules and follow-up times showed a RR of skin infection of 0.54 and an odds ratio of eczema herpeticum of 0.34 for dupilumab compared with placebo. No significant association was found for dupilumab with herpesvirus infections or overall infections. The authors concluded that dupilumab is associated with a decreased incidence of skin infections and eczema herpeticum in adults with moderate-to-severe AD. Although the mechanism in this improvement is uncertain, the authors surmise that it is likely related to improvement in AD severity. (6)
In their meta-analysis of 8 randomized controlled trials, Ou et al demonstrated that patients treated with dupilumab had a lower risk of skin infection (risk ratio [RR] 0.54), but had a higher risk of injection-site reaction (RR 2.24), headache (RR 1.47) and conjunctivitis (RR 2.64) than did patients treated with a placebo. Nasopharyngitis, urinary tract infection, upper respiratory tract infection, and herpes virus infection were found balanced in dupilumab groups and placebo groups. (7) Regarding conjunctivitis, it has been demonstrated that allergic conjunctivitis is more common with dupilumab compared to placebo, while infectious conjunctivitis rates are similar in both groups. Barnes et al reported the case of a 61 year-old man who developed a cicatricial ectropion approximately 2 months after beginning dupilumab (which was helping his skin); there was improvement following discontinuation of the drug as he received prednisone. (8)
Prior to the release of dupilumab, I wrote “Perhaps dupilumab won’t be the game changing biologic that patients are pining for. At the least, it represents the dawn of the biologic era for AD. That alone offers hope for our long-suffering patients as next-generation drugs will surely follow.” (Dupilumab and the dawn of the biologic era for atopic dermatitis. DI&I, August 28, 2016). I am pleased to report that dupilumab has exceeded my expectations. I trust that the two biggest problems with the medication — cost and the lack of a pediatric indication — will be overcome. If this is the biologic starting point for AD, we can all be optimistic about future developments.
1. Tsianakas A, et al. Dupilumab treatment improves quality of life in adult patients with moderate-to-sever atopic dermatitis. Results from a randomized, placebo-controlled clinical trial. Br J Dermatol 2017; Aug 27 [Epub ahead of print].
2. Vangipuram R, Tyring SK. Dupilumab for moderate-to-severe atopic dermatitis. Skin Therapy Lett 2017; 22:1-4.
3. Sun D, Ong PY. Infectious complications in atopic dermatitis. Immunol Allergy Clin N Am 2017; 37: 75-93.
4. Narla S, Silverberg JI. Association between atopic dermatitis and serious cutaneous, mutiorgan and systemic infections in US adults. Ann Allergy Asthma Immunol 2018; 120: 66-72.
5. Blauvelt A, et al. Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year randomised, double-blinded, placebo-controlled, phase 3 trial. Lancet 2017; 389: 2287-2303.
6. Fleming P, Drucker AM. Risk of infection in patients with atopic dermatitis treated with dupilumab: A meta-analysis of randomized controlled trials. J Am Acad Dermatol 2018; 78: 62-9.
7. Ou Z, et al. Adverse events of dupilumab in adults with moderate-to-severe atopic dermatitis: A meta-analysis. Int Immunopharmacol 2018; 54: 303-10.
8. Barnes AC, et al. Cicatricial ectropion in a patient treated with dupilumab. Am J Ophthal Case Rep 2017; 7: 120-2.
*I have no financial arrangements or conflicts of interest with Regeneron Pharmaceuticals
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