Current and future potential treatment options for allergic skin conditions.
Over the last decade, our treatment options for allergic skin conditions such as atopic dermatitis and chronic urticaria have expanded significantly. The efficacy and safety of approved biologic therapies combined with our better understanding of disease pathophysiology have paved the way for the research of many novel biologics.Â
In clinical practice, these novel treatments provide more options for patients who have failed previous therapies. There are now several approved biologics to treat allergic skin conditions along with more in clinical trials that may be approved for treatment in coming years.
Atopic Dermatitis
Atopic dermatitis is a chronic inflammatory disorder of the skin characterized by T-cell dysregulation and epidermal barrier disruption. Atopic dermatitis is a common and heterogeneous disease that affects up to 20% of children and 10% of adults.1 Atopic dermatitis can cause intense pruritis and significantly affect the quality of life.Â
The pathophysiology for atopic dermatitis is complex, primarily type 2 helper T (TH2) driven and cytokine release mediated by Th22 and Th17.2Â Our increasing understanding of the molecular pathophysiology of atopic dermatitis and its complexities has provided insights into potential biologic therapies.
The current non-biologic therapies of atopic dermatitis include avoiding triggers, barrier repair with emollients, topical corticosteroids and topical calcineurin inhibitors. In uncontrolled atopic dermatitis, options include phototherapy and non-biologic systemic treatments, such as a short course of systemic steroids and immune-suppressive therapies such as cyclosporin, methotrexate, azathioprine and mycophenolate mofetil.3,4Â However, many of these systemic immune suppressive therapies have potential drug interactions or significant side effects such as cytopenia and hepatotoxicity.
To date, dupilumab (Dupixent) is the only FDA-approved biologic to treat moderate to severe atopic dermatitis. Dupilumab is a monoclonal antibody against IL-4Rα that inhibits IL-4 and IL-13 signaling and serves to inhibit key drivers of type 2 immune diseases in atopic dermatitis. Dupilumab has been shown to be highly effective in treating severe atopic dermatitis. In phase 3 trials, 38% of patients receiving dupilumab achieved significant improvement of their atopic dermatitis control vs. 10% in the placebo group.3,5Â
Overall, the safety profile of dupilumab has been shown to be good with no severe adverse reactions.3 Common side effects experienced by patients are injection-site reaction and conjunctivitis.6,7 Conjunctivitis can occur in up to 28% of patients, however most cases are moderate to mild and can be managed with topical anti-inflammatory ocular agents.8 Because of dupilumab’s safety and efficacy in managing atopic dermatitis, several novel biologics are currently being studied in clinical trials. (See Table 1.)
Tralokinumab and lebrikizumab are monoclonal antibodies that target IL-13. Tralokinumab binds IL-13 and prevents IL-13 from binding its receptors and downstream signaling. In a recently completed phase 3 trial, 22% of patients receiving tralokinumab achieved significant improvement of their atopic dermatitis control vs. 11% in the placebo group.9Â
Overall, tralokinumab was well tolerated without serious adverse events. Most frequent side effects included upper respiratory infections and conjunctivitis.Â
Lebrikizumab is also an anti-IL 13 monoclonal antibody. Phase 2 clinical trials have shown promising results and phase 3 trials are ongoing.3
Many cytokines, especially those in Th2 and TH22 pathways, are implicated in the pathophysiology of atopic dermatitis. The cytokine signaling cascade works through the JAK-STAT pathway. Novel therapies known as JAK-inhibitors, such as abrocitinib, baricitinib (Olumiant), ruxolitinib (Jakafi, Jakavi) and upadacitinib (Rinvoq), have completed or are currently in phase 3 trials, but none have yet been FDA approved to treat atopic dermatitis.Â
In phase 3 clinical trials of abrocitinib, an oral JAK-inhibitor, 44 % achieved significant clinical improvement compared to 8% in the placebo group. Overall, no significant serious adverse events were noted, and most common side effects included nausea and nasopharyngitis.10
Table 1 Biologics to Treat Atopic Dematitis
â—Š Completed phase 3 clinical trials
Nemolizumab is another promising monoclonal antibody that targets the IL-31A receptor. IL-31 has been implicated in disrupting the skin barrier in atopic dermatitis and causing itching. Phase 2b trials have shown nemolizumab decreased pruritus 20% more than the placebo and was overall very safe.11 Several other biologics are under phase 2 trials, including the anti-IL-5R-alpha antibody benralizumab (Fasenra), the anti-IL-23 antibody risankizumab (Skyrizi), and tezepelumab, and anti-thymic stromal lymphopoietin antibody.
Chronic Spontaneous Urticaria
Chronic urticaria is a clinical diagnosis characterized by wheals, angioedema or both lasting for more than 6 weeks.12Â Patients without a known trigger for chronic urticaria are classified as chronic spontaneous urticarial (CSU), which can affect up to 1% of the population at any given time.Â
CSU has an unpredictable clinical course and can affect patients for several years at a time. Urticaria is a primarily mast cell driven process – mast cell degranulation leads to increase in histamine, prostaglandin and leukotriene, which in turn causes vasodilation and swelling. Thus, the treatment for urticaria targets histamine and IgE pathways.
Current international guidelines recommend second-generation antihistamines as the first line of treatment for CSU12. However, up to 50% of patients will still have uncontrolled symptoms.Â
The next line of treatment is to add on the biologic omalizumab (Xolair).12 Omalizumab is the first FDA-approved biologic to treat CSU. It is a monoclonal antibody that binds free IgE heavy chain, the site which typically binds IgE receptors on basophils and mast cells. Omalizumab also downregulates IgE receptors on mast cells and basophils to diminish response. Omalizumab will help 60% of patients with previously uncontrolled symptoms achieve response by week.13Â
Omalizumab is generally well tolerated, with common side effects that include injection site reactions and urticaria. There have been cases of anaphylactic reaction to omalizumab that can result in hypotension, bronchospasms and urticaria. Because 60% of systemic reactions occur in the first three doses, most practitioners will have a 2-hour observation during the first three injections.13,14Â (See Table 2.)
A novel high-affinity anti-IgE monoclonal antibody, ligelizumab, has just been approved by the FDA to be used for CSU in patients who have failed antihistamine monotherapy. Ligelizumab works similarly to omalizumab in that it binds free IgE heavy chain site and downregulates IgE receptors on mast cells and basophils. However, studies have shown ligelizumab can bind IgE with 88-times more affinity than omalizumab. The standard dosage is 72mg every 4 weeks.Â
Overall ligelizumab is well tolerated; the most common adverse reaction is injection site reactions, which can occur in 4% of patients. To date, no deaths or anaphylactic reactions were reported. In a phase 2b randomized control trial, 51% of patients who received ligelizumab every 4 weeks achieved disease control. Phase III trials comparing ligelizumab to omalizumab are ongoing.15
Several biologics are undergoing phase 2 trials, as preliminary case studies have demonstrated CSU relapse on these therapies. One biologic under investigation is dupilumab (Dupixent), a monoclonal antibody against IL-4Ra that inhibits IL-4 and IL-13 signaling. Six patients have reported improvement of CSU unresponsive to omalizumab. Phase 2a RCT are currently ongoing. By inhibiting IL-13, dupilumab could potentially block B-cell to plasma cell subclass switching and decrease IgE production.16Â
Table 2Â Biologics to Treat Chronic Spontaneous Urticaria
The anti-Siglec-8 monoclonal antibody is another candidate. Siglec-8 is expressed on the surface of mast cells, eosinophils and basophils. Blocking Siglect-8 signaling inhibits mast cell activity and decreases eosinophil levels. In addition, bruton tyrosine kinase (BTK) inhibitors are another potential drug target. BTK is crucial to B cell maturation and mast cell activation.16
The pathogenesis of allergic skin conditions such as atopic dermatitis and CSU are complex, with multiple pathways leading to symptoms. Currently, several biologics approved to treat these disease processes have been shown to be both efficacious and safe. Many new biologics, including monoclonal antibodies targeting key receptors, mediators and cytokines, are currently being studied.Â
Allergic skin disease treatment has progressed far beyond only topical treatments. In the coming years, additional bio- logic options will likely be available for patients with refrac- tory disease and offer more complete treatments and relief.
References
1. Barbarot, S., et al., Epidemiology of atopic dermatitis in adults: Results from an international survey. Allergy, 2018. 73(6): p. 1284-1293.
2. Gittler, J.K., et al., Progressive activation of T(H)2/T(H)22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis. J Allergy Clin Immunol, 2012. 130(6): p. 1344-54.
3. Chun, P.I.F. and H. Lehman, Current and Future Monoclonal Antibodies in the Treatment of Atopic Dermatitis. Clin Rev Allergy Immunol, 2020. 59(2): p. 208-219.
4. Langan, S.M., A.D. Irvine, and S. Weidinger, Atopic dermatitis. The Lancet, 2020. 396(10247): p. 345-360.
5. Thaçi, D., et al., Efficacy and safety of dupilumab monotherapy in adults with moderate-to-severe atopic dermatitis: a pooled analysis of two phase 3 randomized trials (LIBERTY AD SOLO 1 and LIBERTY AD SOLO 2). J Dermatol Sci, 2019. 94(2): p. 266-275.
6. Castro, M., et al., Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma. N Engl J Med, 2018. 378(26): p. 2486-2496.
7. 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. The Lancet, 2017. 389(10086): p. 2287-2303.
8. Akinlade, B., et al., Conjunctivitis in dupilumab clinical trials. Br J Dermatol, 2019. 181(3): p. 459-473.
9. Wollenberg, A., et al., Tralokinumab for moderate-to-severe atopic dermatitis: results from two 52-week, randomized, double-blind, multicentre, placebo-controlled phase III trials (ECZTRA 1 and ECZTRA 2). Br J Dermatol, 2021. 184(3): p. 437-449.
10. Simpson, E.L., et al., Efficacy and safety of abrocitinib in adults and adolescents with moderate-to-severe atopic dermatitis (JADE MONO-1): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet, 2020. 396(10246): p. 255-266.
11. Kabashima, K., et al., Trial of Nemolizumab and Topical Agents for Atopic Dermatitis with Pruritus. New England Journal of Medicine, 2020. 383(2): p. 141-150.
12. Zuberbier, T., et al., The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. Allergy, 2018. 73(7): p. 1393-1414.
13. Zhao, Z.T., et al., Omalizumab for the treatment of chronic spontaneous urticaria: A meta-analysis of randomized clinical trials. J Allergy Clin Immunol, 2016. 137(6): p. 1742-1750.e4.
14. Sussman, G., et al., Omalizumab Re-Treatment and Step-Up in Patients with Chronic Spontaneous Urticaria: OPTIMA Trial. J Allergy Clin Immunol Pract, 2020.
15. Maurer, M., et al., Ligelizumab for Chronic Spontaneous Urticaria. N Engl J Med, 2019. 381(14): p. 1321-1332.
16. Kolkhir, P., et al., New treatments for chronic urticaria. Ann Allergy Asthma Immunol, 2020. 124(1): p. 2-12.
