Systemic Therapy of Atopic Dermatitis: Welcome to the Revolution Lawrence F. Eichenfeld, MD,* and Linda F. Stein Gold, MD† Recognizing that there are many individuals with atopic derma- ■ Abstract titis who are inadequately controlled with topical medications and Until recently, systemic therapy of atopic dermatitis was appropriate skin and adjuvant care, and the tremendous impact limited to off-label use of immunomodulators, which can of atopic dermatitis on the lives of affected individuals, there pose significant safety concerns, and treatment with systemic is a great clinical need for systemic therapies with effcacy and corticosteroids, not recommended in the most recent superior safety profles. The introduction of the biologic agent guidelines. The introduction of dupilumab in 2017 marked a dupilumab in early 2017 represented a milestone for patients who major advance in systemic therapy for atopic dermatitis. It need treatment beyond conventional and topical interventions. has demonstrated long-term efficacy in adults with moderate to severe disease, and is being studied in children. Several At least seven other biologic therapies or small molecular agents other biologic agents and “small molecules” with varying are in phase 2 or 3 study for atopic dermatitis at this writing. mechanisms of action are in phase 2 or 3 development. When to Consider Systemic Therapy Semin Cutan Med Surg 36(supp4):S103-S105 Atopic dermatitis can have signifcant impact on quality of © 2017 published by Frontline Medical Communications life of patients, family, and caregivers. Consequently, when ■ Keywords standard nonpharmacologic and topical treatments prove Atopic dermatitis; dupilumab; fezakinumab; JAK inhibitors; ineffective, clinicians should consider a more aggressive lebrikizumab; nemolizumab; systemic therapy; tralokinumab systemic approach. Before initiating systemic therapy for atopic dermatitis, it is ost patients with atopic dermatitis may be adequately important to evaluate whether other therapies have been opti- managed with nonpharmacologic measures mized and whether factors other than unresponsive atopic M(eg, emollients), topical anti-inflammatory thera- dermatitis might account for the patient’s lack of relief. A panel pies, environmental modification (eg, avoiding triggers), of the International Eczema Council has issued recommenda- and for some, phototherapy. However, for patients who do tions for assessing patients prior to starting systemic therapy not respond to treatment, available options have been both (Table 1). A different or comorbid diagnosis, such as allergic limited and problematic. Immunosuppressive agents have contact dermatitis, cutaneous T-cell lymphoma, or infection, been used—azathioprine, cyclosporine, methotrexate, and may explain signs, symptoms, or disease exacerbation. Patients mycophenolate—but are unapproved in the United States may not be using topical therapy as prescribed, perhaps because for atopic dermatitis and are associated with serious adverse they have not been taught how best to apply the medication or effects. Although systemic corticosteroids are prescribed clini- because they underuse the agent out of fear of steroid or other cally, guidelines advise against their use for most patients, side effects. Individual patient factors also should be evaluated, again due to their potential adverse effects.1 including comorbid conditions, use of concomitant medications that may interact with systemic therapy, a plan to become preg- * Professor of Dermatology and Pediatrics, Vice Chair, Department of nant, and insurance coverage. As with any treatment decision, a Dermatology, Chief, Pediatric and Adolescent Dermatology, University of change of medication should be the topic of an open discussion California, San Diego School of Medicine and Rady Children’s Hospital- San Diego, University of California † Director of Dermatology Research, Henry Ford Health System, Detroit, Michigan ■ TABLE 1 International Eczema Council Publication of this CME/CE article was jointly provided by University Recommendations for Evaluating of Louisville, Postgraduate Institute for Medicine, and Global Academy Candidates for Systemic Therapy for Medical Education, LLC, and is supported by an educational grant from Pfzer Inc. The authors have received an honorarium for their Consider alternative or concomitant diagnoses, including participation in this activity. They acknowledge the editorial assistance of allergic contact dermatitis Eileen McCaffrey, MA, medical writer, and Global Academy for Medical Education in the development of this continuing medical education Optimize topical therapy and/or phototherapy journal article. Screen for and treat any coexisting infection Lawrence F. Eichenfeld, MD, Advisory Board/Speaker: Valeant Pharmaceuticals North America LLC. Consultant: Eli Lilly and Ensure adequate patient/caregiver education to avoid trigger Company, Genentech, Inc., Otsuka America Pharmaceutical, Inc./ factors and manage disease Medimetriks Pharmaceuticals, Inc., Pfzer, Sanof Genzyme/Regeneron Pharmaceuticals, TopMD, Valeant. Investigator: Sanof Genzyme/Regeneron. Assess the impact of the disease on the patient’s quality Linda F. Stein Gold, MD, Consultant: Pfzer. Grant/Research: of life GlaxoSmithKline and Pfzer. Data Monitoring Committee: Otsuka. Disease severity alone is an insufficient basis to start Address reprint requests to: Lawrence F. Eichenfeld, MD, Rady systemic therapy Children’s Hospital, 8010 Frost Street, Suite 602, San Diego, CA 92123; Source: Simpson EL, et al.2 [email protected] 1085-5629/13/$-see front matter © 2017 Frontline Medical Communications doi:10.12788/j.sder.2017.051 Vol. 36, No. 4S, December 2017, Seminars in Cutaneous Medicine and Surgery S103 ■ ■ ■ Systemic Therapy of Atopic Dermatitis: Welcome to the Revolution with the patient about options, benefts, adverse effects, follow- Unlike in the pivotal studies, patients received concomitant up frequency, and patient preferences. Disease severity alone is therapy with topical corticosteroids.5 As in the pivotal trials, an insuffcient basis for initiating systemic therapy; a holistic more than one-third of patients attained the primary endpoint evaluation is required.2 (IGA 0 or 1 plus ≥2-point reduction from baseline) at week 16 (39%, 39%, and 12%; dupilumab q2w, dupilumab qw, placebo, Dupilumab respectively; P<0.0001 vs placebo). This level of response A human monoclonal antibody, dupilumab, inhibits inter- persisted at week 52. Roughly two-thirds of patients receiving leukin (IL)-4 and IL-13 signaling. It is indicated for adults with dupilumab attained EASI-75 at week 16; a similar response rate moderate to severe atopic dermatitis whose disease is inad- was observed at week 52. Half of patients treated with dupil- equately controlled with topical therapies or for whom topical umab had reached EASI-90 by week 52.5 therapies are inadvisable, and it is approved by the US Food Similar rates of adverse events were observed in all treatment and Drug Administration (FDA) for use in combination with groups over the 52-week treatment period (84%, 88%, 83% with topical corticosteroids.3 ≥1 adverse event; placebo, dupilumab q2w, dupilumab qw, respec- Pivotal Trials tively). More patients discontinued placebo than dupilumab SOLO 1 and SOLO 2 (N=671 and N=708, respectively) were therapy due to adverse events (8%, 2%, 3%; placebo, dupilumab two identically designed phase 3 trials leading to FDA approval q2w, dupilumab qw, respectively). In more than half the cases, of dupilumab. Adults enrolled in the study had moderate to patients withdrew from placebo therapy due to atopic dermatitis severe atopic dermatitis. By many measures, this population fares. Rates of infections were similar across treatment groups.5 was severely affected by their disease. Depending on treat- Conjunctivitis has emerged as a side effect associated with ment group, patients had a median of ~50% body surface area dupilumab. The rates of allergic conjunctivitis and conjunc- affected by atopic dermatitis. Nearly half of participants (47% tivitis of unspecifed cause were higher in the active therapy to 49%) had severe disease. The mean peak score on the Pruritus groups of the SOLO studies than they were in the placebo Numerical Rating Scale (0 to 10, with 10 as worst itch) was group.4 In the 52-week trial, the incidence of conjunctivitis 7.6, 7.7, or 7.8, depending on treatment group. Roughly a third was higher with dupilumab than with placebo (8%, 14%, 19%; of patients had received systemic corticosteroids previously. placebo, dupilumab q2w, dupilumab qw, respectively). Most Patients were randomized 1:1:1 to subcutaneous injections of cases were mild to moderate in severity, and resolved with dupilumab 300 mg every other week, dupilumab 300 mg once topical ocular therapy. One patient discontinued dupilumab weekly, or placebo. Concomitant use of topical corticosteroids therapy due to conjunctivitis.5 and calcineurin inhibitors was prohibited except as rescue therapy.4 Results of the SOLO 1 and SOLO 2 trials are shown Pediatric Study in the Figure. A phase 2a pharmacokinetics study evaluated dupilumab in adolescents (ages 12-17 years; n=40) with moderate to severe Long-Term Study disease, and in children (ages 6 to 11 years; n=37) with severe Dupilumab demonstrated long-term effcacy in a 1-year random- disease. Patients received single doses of either 2 mg/kg or ized, double-blind, placebo-controlled phase 3 study (N=740). 4 mg/kg at week 0, then again at weeks 8, 9,