JAK inhibitors in AD: Setting the efficacy bar even higher

Systemic Janus kinase (JAK) inhibitors are currently the most potent agents for the treatment of atopic dermatitis (AD). JAK inhibitors such as upadacitinib and abrocitinib are characterised by a rapid onset of action, especially in itch reduction, and provide a safe and effective oral therapy for those who show inadequate or loss of response to biologics.

“We needed something with topical steroid-like efficacy that are not steroids, we needed another option,” Prof. Eric Simpson (Oregon Health & Science University, OR, USA), emphasised in his talk on JAK inhibitors in AD [1]. Although the IL-4/IL-13 blocker dupilumab is highly efficacious in AD, not all patients respond sufficiently to treatment [2]. Besides cases of inadequate response, some patients cannot tolerate therapy with dupilumab due to side effects such as conjunctivitis, facial redness, psoriasiform dermatitis, and inflammatory arthritis [3]. In a recent retrospective study, almost 5% of patients treated with dupilumab for AD were at least minimally affected by inflammatory arthritis [4]. Thus, there is a systemic gap, a medical need for an oral therapy option that is safe and effective and does not induce conjunctivitis. JAK inhibitors can fill this gap. “JAK inhibitors have the potential to inhibit many different cytokines, thus we might push the efficacy a little higher,” Prof. Simpson said.

Advantages of systemic JAK inhibitors are the oral and flexible dosing options and the superior efficacy of high doses of upadacitinib and abrocitinib. As Prof. Simpson pointed out, these agents are the right choice for patients needing a quick response (i.e. within the first week) or for those who show inadequate or loss of response to biologics.

Most potent agents in AD – rapid itch response

Monotherapy studies with JAK inhibitors in patients with moderate-to-severe AD have demonstrated the potency of these agents. High-dose upadacitinib, followed by abrocitinib, achieved the highest proportion of skin clearance in AD when given as monotherapy.

In the Measure Up 1 trial (NCT03569293), 62% of patients treated with a high dose of upadacitinib (30 mg) and 48% with a lower dose achieved clear or almost clear skin according to the Investigator Global Assessment (IGA) after 16 weeks [5]. In the JADE Mono-1 trial (NCT03349060), 44% of patients taking high-dose abrocitinib (200 mg) achieved this endpoint at week 12, compared with 24% with the lower dose [6].

Differences in deeper responses

The JADE Compare study (NCT03720470), a head-to-head trial comparing abrocitinib with dupilumab, showed that an Eczema Area and Severity Index (EASI)75 response at week 12 was achieved in 70.3% of participants taking high-dose abrocitinib (200 mg), 58.7% of participants taking low-dose abrocitinib (100 mg), 58.1% in the dupilumab group, and 27.1% of placebo (P<0.001 for both abrocitinib doses vs placebo) [7]. Similarly, in the Heads Up study (NCT03738397) comparing upadacitinib with dupilumab, upadacitinib showed a faster onset of action regarding EASI75 response. At week 16, 71% of participants treated with upadacitinib and 61.1% with dupilumab achieved this endpoint (P=0.006) [8]. “If you look at the EASI75 response, dupilumab will catch up later. But deeper responses like EASI90 and EASI100, that is where JAK inhibitors are helpful,” Prof. Simpson added. Moreover, these agents achieve the fastest itch relief.

Prof. Simpson emphasised the importance of knowing when not to use this class of agents. “Not many patients with AD stop the drug due to side effects,” he summarised his experience. However, herpes zoster infections are always higher in patients taking JAK inhibitors. He also advised checking lab values when treating patients with a JAK inhibitor. “Just like you would in patients treated with cyclosporin.” Although both abrocitinib and upadacitinib are selective JAK1 inhibitors, they show differences with regard to doses, side effects, and lab controls (see Table).

 

Table: Compare and contrast abrocitinib and upadacitinib. Modified from [1]



 

1. 
   
   1. Simpson EL. S032, AAD 2022 Annual Meeting, 25–29 March, Boston, MA, USA.
   2. Simpson EL, et al. N Engl J Med 2016;375:2335–2348.
   3. Narla S, et al. J Am Acad Dermatol 2022;86:628–636.
   4. Jay R, et al. JAAD Case Rep 2022 Mar;21:14–18.
   5. Guttman-Yassky E, et al. Lancet 2021;397:2151–2168.
   6. Simpson EL, et al. Lancet 2020;396:255–266.
   7. Bieber T, et al. N Engl J Med 2021;384:1101–1112.
   8. Blauvelt A, et al. JAMA Dermatol 2021;157:1047–1055.

 

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Posted on 17 May, 202223 May, 2022