Systemic Therapy Advances for AD

Dermatology Times, Dermatology Times, March 2021 (Vol. 42, No. 3), Volume 42, Issue 3

The limited armamentarium of systemic therapies for atopic dermatitis has already been expanded with the approval of dupilumab. Forthcoming systemic therapies are expected to include a new biologic and three new Janus kinase (JAK) inhibitors.

Adequate control of atopic dermatitis (AD) gives patients and their families a new life. A discussion of systemic therapies is definitely warranted for anyone whose disease is not well-controlled using topical therapies, said Eric L. Simpson, MD, MCR, professor of dermatology, Oregon Health & Science University, Portland, Oregon during Maui Derm Live. Maui Live was an in-person dermatology continuing medical education (CME) conference in Hawaii held concurrently with Maui Derm Connect, a virtual CME conference, from January 25 to January 29, 2021.

Simpson discussed his decision-making process for choosing and using systemic treatments for AD and provided an update on dupilumab (Dupixent, Sanofi Genzyme/Regeneron Pharmaceuticals) and forthcoming systemic agents.

“Because of dupilumab’s remarkable efficacy and favorable safety, its approval for the treatment of moderate to severe AD introduced an exciting era for patients needing systemic therapy, and new options are coming, including oral JAK inhibitors that may be just as effective albeit associated with very rare severe adverse events,” said Simpson.

According to Simpson, communication is key when it comes to AD therapy. “Clinicians should be developing their skills for shared decision-making because patients of all ages whose AD is not adequately controlled by topical therapy deserve a discussion of the pros and cons of systemic therapies,” he said.

DETAILS FOR DEFINING CANDIDACY

Simpson said the answer to the question of when to use systemic therapy can be distilled down to 1 concept—it is indicated if aggressive topical therapy is infeasible or has failed to achieve adequate control of the disease.

“A role for systemic therapy is not determined by an AD or itch severity score,” Simpson said. “Rather, it is something to consider and offer patients if moderate- to high-potency topical corticosteroids were used in a safe manner along with topical calcineurin inhibitors or crisaborole and the AD was still not controlled. Also, systemic therapy may be considered as the initial choice for patients whose disease is so severe or so extensive that it requires more than topical therapy.”

Qualifying his remarks, Simpson pointed out the need to first take a careful patient history to identify any modifiable factors that explain the insufficient response to topical therapy. Communication with patients is also crucial. Issues to explore include whether patients lack an understanding of the chronic nature of their disease and the need for maintenance therapy, if they are following instructions on adjunctive measures such as bathing and moisturization, and if they are using their topical agents properly.

Similarly, once systemic therapy is started, clinicians should carefully review the idea that a particular treatment is not effective or intolerable before it is abandoned, according to Simpson.

“Currently, we do not have many options for systemic treatment, so we don’t want to waste what we have without first making sure that perhaps a longer trial or dose adjustment could improve the therapeutic response or mitigate an adverse event,” he explained.

Simpson also suggested accessing a downloadable, brief patient-reported outcome tool to quickly learn how AD is impacting an individual as this information can help with the decision to start aggressive therapy (adcontroltool.com).1 Then, the consultation conversation should identify the patient’s outcome goals and provide information about the risks and benefits of the available options to support shared decision-making.

SYSTEMIC CHOICES

According to Simpson, there is no need to consider any particular biomarker or AD phenotype when deciding among available systemic agents.

“Because the Th2 cytokine axis is involved in the pathogenesis of AD regardless of phenotype, Th2 blockade is likely to help almost all patients with AD,” Simpson said.

Corresponding with that idea, results of an Italian study including 221 patients representing 6 phenotypes of AD found significant improvements from baseline to week 16 in all outcomes measured and persistent benefit to week 52.2

“The same holds true in my experience,” Simpson said when referring to the study results.

Simpson said he considers cyclosporine if patients need rapid relief or to get off an “oral steroid roller coaster”, if they have failed dupilumab or if the biologic is not covered by insurance, as well as in children aged more than 6 years for whom nothing else is approved when deciding whether or not to use specific systemic therapy. He avoids cyclosporine in older patients on multiple medications and in patients with hypertension or a history of cancer.

“Cyclosporine can be used safely for about 1 year. I use it at a starting dose of 5 mg/kg with tapering over 4 to 12 months while transitioning with overlap to alternative therapy, usually to phototherapy or methotrexate,” Simpson said.

There is another systemic therapy to consider in certain patient populations. According to Simpson, methotrexate is considered for systemic treatment in patients with more moderate AD or for older patients with chronic AD, if dupilumab is not covered, as an add-on to dupilumab, or if he is unsure about the diagnosis. He also uses it in children at a dose of 0.2 to 0.6 mg/kg. Patients with liver disease, women of childbearing potential not using adequate contraception, and anyone who drinks alcohol heavily are not candidates for methotrexate.

Simpson discussed the ease of use of dupilumab compared with the other systemic therapies. According to him, it can be used without laboratory monitoring and is suitable for a long-term approach, including a patient population with viruses.

“I would not use dupilumab during pregnancy, but I see few contraindications for treatment with dupilumab based on medical comorbidities,” he said. “It appears safe to use in HIV-positive patients, and I do not hesitate to use in patients with hepatitis B or C who are on antiviral therapy. Underinsurance is a barrier to its use, as is needle phobia, but there are patient assistance programs for dupilumab, and patients can get over their fear of needles.”

COVID-19 CONSIDERATIONS

Although there was concern about potential safety issues with the use of biologics and nontargeted immunosuppressive agents at the onset of the coronavirus disease 2019 (COVID-19) pandemic, accumulating experience indicates that these medications do not put patients at risk for a worse outcome and may even have a favorable impact on the disease course.

For example, reports show better outcomes in hospitalized patients receiving cyclosporine compared with patients not on cyclosporine and in kidney transplant patients maintained on a full dose of cyclosporine versus those whose dose was reduced. In vitro evidence that cyclosporine inhibits COVID-19 replication provides a biological basis for these findings.

According to Simpson, regarding dupilumab, dermatology and allergy guidelines state its use should be continued during the pandemic. However, the American Academy of Dermatology recommends stopping biologic treatment if a patient becomes infected with COVID-19. Nevertheless, early evidence from registries show that patients may do better if they are on the biologic, which makes sense because it reduces the cytokine storm, Simpson said.

DUPILUMAB RESEARCH UPDATES

The latest research results on dupilumab shows that it improves the skin barrier and reduces Th1- and Th2-mediated inflammation and Staphylococcus aureus colonization. As another advantage, it is effective in treating allergic comorbidities, including asthma and chronic rhinosinusitis with nasal polyposis.

New data from an open-label extension study of adults treated with dupilumab for moderate to severe AD show responses are sustained and increase overall during ongoing use to 3 years. In addition, the long-term benefit occurs without any new safety signals. In fact, rates of new skin infections and conjunctivitis decreased over time.

The same efficacy and safety patterns are seen during 52 weeks of available follow-up in adolescent patients (aged 12-17) treated with dupilumab. Impressive efficacy was also observed in a 16-week study of school-aged children (6-11 years) whose AD characteristics at baseline were consistent with severe disease. Notably, in the latter trial, the incidence of skin infections was lower in dupilumab-treated groups than in the placebo-treated controls, and the rate of conjunctivitis was lower than what was reported in adults and lower in the study group treated with dupilumab every 4 weeks compared with the group treated every 2 weeks.

Simpson recommends checking the information on the drug’s website when prescribing dupilumab as the dosage regimen for dupilumab in pediatric patients varies depending on weight.

EXPANDING OPTIONS

New systemic agents for the treatment of AD are anticipated in 2021, including 1 biologic and 3 oral JAK inhibitors. Based on results achieved in completed phase 3 trials, the oral JAK inhibitors hold promise to be “real game changers” for the treatment of moderate to severe AD, Simpson said.

Overall, the 3 JAK inhibitors investigated in AD pivotal trials provided rapid improvement in overall AD and itch severity ratings, albeit with some distinctions among them in their efficacy and safety profiles.

Of the 3, upadacitinib (Rinvoq, AbbVie Inc) seemed to be the most potent, with 62% of patients treated achieving clear or almost clear status per the Investigators Global Assessment score. However, acne was common (17%) at higher doses of upadacitinib. The efficacy of abrocitinib was comparable if not slightly better than dupilumab, and abrocitinib relieves itch faster. Baricitinib had more modest efficacy but seemed to be the best tolerated of the 3 JAK inhibitors. Compared with abrocitinib, baricitinib was associated with lower rates of headache and nausea.

Simpson has a little apprehension about the 3 therapies.

“My biggest concern with these drugs was a risk of pulmonary embolism that have occurred as rare events with JAK inhibitors,” said Simpson. “Thus far in the AD clinical trials, single cases have been reported with baricitinib and abrocitinib. Nevertheless, all patients on a JAK inhibitor will need risk mitigation for venous thrombosis along with some monitoring of the complete blood count and for herpes zoster virus and herpes simplex virus.”

A new biologic that completed an AD pivotal trial, tralokinumab, is an IL-13 inhibitor. Based on cross-study comparisons with dupilumab, tralokinumab may have slightly lower efficacy with a slower onset, but its benefit may also be longer-lasting, and tralokinumab appears to be associated with a lower rate of conjunctivitis.

“Head-to-head studies are needed to confirm any differences,” Simpson said.

Disclosure:

Simpson is a consultant, speaker, and/or investigator for companies that market or are developing products for the treatment of AD.

References:

  1. Comprehensive assessment of atopic dermatitis (AD) control in six brief questions. Atopic Dermatitis Control Tool. Need accessed date. https://www.adcontroltool.com
  2. Tavecchio S, Angileri L, Pozzo GF, Marzano AV, Ferrucci S. Efficacy of dupilumab on different phenotypes of atopic dermatitis: one-year experience of 221 patients. J Clin Med. 2020;19(9):2684. doi:10.3390/jcm9092684