When to Progress to Systemic Therapy

Atopic dermatitis (AD) is one of the most common inflammatory skin diseases. It is characterized as a chronic, type II inflammatory skin disease that exhibits the following prominent features: xerosis, pruritis and ill-defined erythematous plaques. There were limited treatment options until recently, with an increased understanding of the immunological nature of this disease. There is now a rich pipeline of new therapeutics for AD, especially systemic therapies. Eric Simpson, MD, MCR, and professor of dermatology at Oregon Health & Science University, delivered a broad presentation at Maui Derm NP+PA Summer 2022 on systemic therapies of AD, focusing on appropriate use criteria. “This is an exciting time for offering safe and effective novel therapies to patients with moderate-to-severe AD who are inadequately controlled with topical therapy,” Simpson said.

The presentation began with an overview of the current treatment armamentarium for AD, which includes topical medications for mild to moderate disease and systemic treatments for moderate-to-severe disease. As disease severity increases, clinicians should consider moving from topical to systemic medications. However, this decision is sometimes complicated and may differ from 1 clinician to another. Guidelines were presented by the International Eczema Council, which suggested that systemic therapy should be employed if aggressive topical therapy is not achieving control of the disease.¹ However, before moving straight to systemic therapy, clinicians must ensure that adequate education is delivered and any infectious comorbidities (which could make mild AD seem more like a moderate-to-severe presentation) are addressed. Also, phototherapy should be considered before oral or injectable therapy and systemic therapy should be considered early in the patient’s treatment course if their disease is having a large impact on their quality of life.

While the International Eczema Guidelines provide some guidance on the appropriate use of systemic AD treatments, some clinicians feel they are vague, and 1 clinician’s definition of “aggressive topical therapy” may differ from another’s definition. The Atopic Dermatitis Control Tool (ADCT) mitigates this issue by using an extensively validated, 6-item questionnaire to assess the severity of a patient’s AD.² This instrument boasts multiple domains, including sleep, intense itching, emotions, and daily activities. The ADCT is free to download and use and is great for serially tracking a patient’s response in one’s practice. Validation studies performed on this measure concluded that this holistic tool displays good-to-excellent content validity, construct validity, internal consistency, reliability, and discriminating ability.³ “I encourage all dermatology providers to recognize a patient with inadequate disease control prompting a discussion of new options and to not just refill topical or oral steroids,” said Simpson.

Before moving on to systemic treatments for AD, Simpson reminded the audience that this disease could have many comorbidities, including dyspigmentation, infection, and hand/facial involvement.⁴ These issues are especially prevalent in skin-of-color patients and should be considered when selecting an appropriate AD therapy. He warned that overuse of steroids should be considered a topical therapy failure and that clinicians must remember that treating with topical steroids is not without adverse effects. These include perioral dermatitis, atrophy, acne, and steroid withdrawal.⁵ Some inexperienced clinicians may aggressively use high-potency topical steroids in severe cases of AD, which could lead to further complications. This is another reason why tools such as the ADCT are useful in clinical practice.

Systemic treatments were reviewed in depth during the next part of the presentation. “There are now 2 biologics targeting type 2 inflammation and 2 oral JAK inhibitors that provide your patients with AD hope for a life free of itch and eczema,” Simpson said. He reminded the audience that traditional immunosuppressants (such as methotrexate or cyclosporine) and Narrowband Ultraviolet B Phototherapy are also options for systemic treatment of AD, in addition to biologics and JAK inhibitors.⁶ Traditional immunosuppressants (ie, cyclosporine, methotrexate, mycophenolate, azathioprine) still have utility in today’s therapeutic landscape. The biggest factor is cost, as traditional therapies are much cheaper and easier to access than the newer JAK inhibitors and biologics. Cyclosporine at high doses remains 1 of the most efficacious systemic AD therapies.⁷ One of the biggest disadvantages is that these therapies are used off-label. Also, rigorous lab monitoring requirements and solid organ toxicities make these agents difficult to use on a regular basis. Specifically, cyclosporine can cause renal toxicity, and methotrexate can cause liver and blood toxicity. Strict monitoring of creatinine is necessary while using cyclosporine and sometimes a test dose of methotrexate is given to patients to ensure there is no precipitous drop in blood cell counts.

There are numerous factors to consider when prescribing a systemic therapy for AD. While severity of disease and associated comorbidities are important, clinicians need to also consider issues such as access, coverage, age, risk aversion, and previous therapeutic history. Simpson stressed the importance of shared decision-making when discussing systemic therapy. This is critical, as some systemic therapies for AD carry black box warnings that patients may ask about. In short, shared decision-making comprises 3 domains—team talk, option talk, decision talk—and encourages active listening with careful deliberation.⁸ An example of option talk is the following statement: “Let’s compare the possible options for you on systemic therapies of AD.” Simpson used cyclosporine, methotrexate, and dupilumab as examples of option talk highlighting unique adverse events such as hypertension, liver toxicity, and conjunctivitis, respectively.

While biologic agents such as dupilumab and tralokinumab do not have some of these more serious adverse events, they are not good options for needle-phobic patients or for patients who want a short-term solution. These therapies are very versatile and can be used for any patient without adequate control on topical therapy. Simpson reviewed the clinical trial data for dupilumab, an interleukin-4 receptor-α antago-nist, and specifically highlighted its recent FDA approval for patients as young as 6 years. The proportion of patients 18 years or older who were clear or almost clear at week 16 averaged 37% in SOLO 1 [NCT02277743] and SOLO 2 [NCT02277769] phase III clinical trials.⁹ Dupilumab is also FDA-approved for the treatment of asthma and chronic rhinosinusitis with nasal polyps. Data show that treatment with dupilumab improves skin barrier and decreases cutaneous inflammation and staph aureus colonization in AD involved skin.^10,11 Key updates for this medication were highlighted, including documented 4-year, long-term safety data, improvement in efficacy over time in non-responders, and documented safety in elderly patients and in patients with HIV or hepatitis B.

After discussing dupilumab, Simpson reviewed the data for tralokinumab, the newest biologic agent FDA-approved for AD. Traloki-numab is an anti-interleukin-13 blocking agent which has a slower onset than dupilumab but is longer lasting. As with dupilumab, conjunctivitis is a common side effect but it occurs less frequently compared with dupilumab therapy. In the ECZTRA [NCT03363854] phase III clinical trials, tralokinumab achieved an EASI 75 of about 90% at week 32.¹² Drug survival studies indicate that this high response rate is maintained over a 2-year period. Data were presented showing that treatment with tralokinumab leads to a shift towards a non-lesional skin phenotype over a 2-year period.

Simpson ended his presentation13 by discussing JAK inhibitors, the newest class of systemic medications for the treatment of AD. The JAK/STAT signaling pathway was reviewed along with the advantages that JAK inhibitors offer for AD treatment. Not only do JAK inhibitors offer flexible dosing regimens with an oral route of administration, but they can also provide relief of symptoms as early as 1 to 2 weeks after treatment initiation. Simpson reviewed the 2 FDA-approved therapies, abrocitinib and upadacitinib. These are both JAK 1 inhibitors but upadacitinib is approved down to aged 12 years. Unfortunately, these agents have black box warnings so they should not be used in patients with a history of malignancy, severe infections, thrombotic events, severe renal/hepatic disease, or significant cardiovascular disease. He ended the presentation by offering a few practical considerations for JAK inhibitor use in the clinical setting. Drug-to-drug interactions should be checked before prescribing, patients should be up to date on vaccinations, and labs should be drawn at baseline and every 1 to 3 months thereafter. While more research is needed, it is not advised to use these medications during pregnancy or breastfeeding. For any provider who treats even just a few AD patients per week, this talk was certainly not to be missed given the excellent and practical tips that were presented.

Disclosures:

Simpson is a consultant for Arena Pharmaceuticals, BenevolentAI, BiomX Ltd, Bluefin Biomedicine, Boehringer Ingelheim, Collective Acumen LLC, Coronado Biosciences, Evidera, Forte Biosciences Inc, Janssen Pharmaceuticals, Ortho Galderma, Laboratoires Pierre Fabre, Roivant Sciences, SPARC India, Trevi Therapeutics, and Bausch Health.

He has also received grants from AbbVie, Amgen, Aslan Pharmaceuticals, Celgene Corporation, Dermia LLC, Dermavant Sciences, Eli Lilly and Company, Galderma, Incyte, Kymab Ltd, Kyowa, Leo Pharma, Merck & Co, Novartis, Pfizer Inc, and Regeneron Pharmaceuticals, Inc.

References:

1. Simpson EL, Bruin-Weller M, Flohr C, et al. When does atopic dermatitis war-rant systemic therapy? Recommendations from an expert panel of the International Eczema Council. J Am Acad Dermatol. 2017;77(4):623-633. doi:10.1016/ j.jaad.2017.06.042

2. Simpson E, Eckert L, Gadkari A, et al. Validation of the Atopic Dermatitis Control Tool (ADCT) using a longitudinal survey of biologic-treated patients with atopic dermatitis. BMC Dermatol. 2019 ;19 (1):15. doi :10.118 6/s12895- 019 -0095-3

3. Pariser DM, Simpson EL, Gadkari A, et al. Evaluating patient-perceived control of atopic dermatitis: design, validation, and scoring of the Atopic Dermatitis Control Tool (ADCT). Curr Med Res Opin. 2020;36(3):367-376. doi:10.1080/03007995. 2019.169 9516

4. Kaufman BP, Guttman-Yassky E, Alexis AF. Atopic dermatitis in diverse racial and ethnic groups-variations in epidemiology, genetics, clinical presentation and treat-ment. Exp Dermatol. 2018 ;27(4):340-357.doi :10 .1111/ exd .13514

5. Hajar T, Leshem YA, Hanifin JM, et al. A systematic review of topical corticosteroid withdrawal (“steroid addiction”) in patients with atopic dermatitis and other dermatoses. J Am Acad Dermatol. 2015;72(3):541-549.e2. doi:10.1016/j.jaad.2014.11.024

6. Sidbury R, Tom WL, Bergman JN, et al. Guidelines of care for the management of atopic dermatitis: section 4. Prevention of disease flares and use of adjunctive therapies and approaches. J Am Acad Dermatol. 2014;71(6):1218 -1233. doi:10.1016/ j.jaad.2014.08.038

7. Drucker AM, Ellis AG, Bohdanowicz M, et al. Systemic immunomodulatory treatments for patients with atopic dermatitis: a systematic review and network meta-analysis. JAMA Dermatol. 2020;156(6):659- 667. doi:10.10 01/jamadermatol.2020.0796

8. Elwyn G, Frosch D, Thomson R, et al. Shared decision making: a model for clinical practice. J Gen Intern Med. 2012;27(10):1361-1367. doi:10.10 07/s11606-012-2077-6

9. Simpson EL, Bieber T, Guttman-Yassky E, et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016;375(24):2335-2348. doi:10.1056/ NEJMoa1610 020

10. Callewaert C, Nakatsuji T, Knight R, et al. IL-4Rα blockade by dupilumab decreases staphylococcus aureus colonization and increases microbial diversity in atopic dermatitis. J Invest Dermatol. 2020;140(1):191-202. e7. doi :10 .1016 / j .jid.2019.05.024

11. Guttman-Yassky E, Bissonnette R, Ungar B, et al. Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis. J Allergy Clin Immunol. 2019 ;143(1):155-172. doi :10 .1016 / j. j a c i .2018.08.022

12. Silverberg JI, Toth D, Bieber T, et al. Tralokinumab plus topical corticosteroids for the treatment of moderate-to-severe atopic dermatitis: results from the double-blind, randomized, multicentre, placebo-controlled phase III ECZTRA 3 trial. Br J Dermatol. 2021;184(3):450-463.doi :10 .1111/ b jd.19573

13. Simpson E, Eichenfield, L. Atopic dermatitis update 2022. Presented at: Maui Derm NP+PA Summer 2022; June 23-25, 2022, Colorado Springs, Colorado.