JAK inhibitors: a major advance in the treatment of atopic eczema

Atopic eczema (AE) is a common skin condition that affects up to 20% of children and 3% of adults.1

Recommended treatments include emollients and intermittent use of topical corticosteroids. For those with moderate-to-severe disease and where topical therapy fails, oral immunosuppressive treatments, for example, prednisolone, ciclosporin, azathioprine and methotrexate are used and while effective, apart from methotrexate, long-term use of oral treatments is not recommended.2 The introduction of the first monoclonal antibody dupilumab, in August 2019, for patients with moderate-to-severe AE was a major treatment advance although a proportion of patients do not achieve a satisfactory response from the drug,3 hence the need for alternative and effective therapeutic options.

In recent years much interest has centred on a new-class of drugs, the Janus kinase inhibitors (JAKis) of which there are three (tofacitinib, baricitinib and upadacitinib) currently licensed for rheumatoid arthritis and psoriatic arthritis (tofacitinib only). The Janus kinase (JAK) pathway facilitates transmission of chemical signals from outside of the cell (that is, once a ligand binds to its receptor) to the nucleus and the subsequent activation of genes involved in a variety of processes such as immune cell division, activation, recruitment and in the context of AE, inflammation. The Janus family consists of four receptor-associated kinases (JAK1, JAK2, JAK3 and TYK2) and a signal transducer and activator of transcription (STAT) pathway. While the precise aetiology of AE remains to be determined, it is characterised by barrier impairment which is thought, in part due to an exaggerated T-helper 2 (Th2) cell response. Keratinocytes activate dendritic and Langerhans cells which subsequently stimulate Th2 cells to produce a range of pro-inflammatory cytokines including interleukin (IL)-4, IL-5, IL-13, IL-31 and IL-33.4 Furthermore, both IL-4 and IL-13 activate the JAK-STAT pathway, leading to the production of pro-inflammatory cytokines5 and through their action on gene expression, downregulate the production of many of the proteins essential for skin-barrier function.6 As a result, JAKis have a potentially important role in attenuating the downstream activation of many different inflammatory cytokines, hence their role in rheumatoid arthritis. However, the recent publication of the results from two Phase III trials, suggest that oral JAKis represent a potentially important new development in the management of moderate-to-severe atopic eczema.

Clinical studies
The first trial involved baricitinib, which inhibits JAK1 and JAK2. In two identical, double-blind, 16-week, Phase III trials, 1239 adults with moderate-to-severe AE who had failed to adequately respond to topical therapies, received either placebo, or 1, 2 or 4mg oral baricitinib daily.7 Emollients were allowed throughout the trial but any other oral or topical therapies were stopped but permitted as rescue treatment if required. The primary outcomes were an investigator global assessment (IGA) score of 0 (clear) or 1 (almost clear) and a > 2-point improvement from baseline in IGA score. After 16 weeks, 16.8% of patients taking baricitinib 4mg achieved the primary outcome, 11.4% (baricitinib 2mg) and 11.8% (baricitinib 1mg) compared with 4.8% in the placebo group. Baricitinib 4mg was most effective and improvements in itch, sleep disturbance and skin pain were evident after one week of treatment.

The second trial involved abrocitinib (a JAK1 inhibitor) with 391 patients, aged 12 years and over, given the drug at a daily dose of 200mg or 100mg compared with placebo for 12 weeks.8 As in the baricitinib trials, all patients had a documented inadequate response to topical corticosteroids and topical calcineurin inhibitors. The study employed the same primary outcome measures as the baricitinib trials. At the study end, 38.1% of those given abrocitinib 200mg achieved the primary outcome, 28.4% (abrocitinib 100mg) vs 9.1% in the placebo group. As with baricitinib, patients receiving abrocitinib, improvements in signs and symptoms of AE, were apparent within two weeks. Trials of a third agent, upadacitinib, which is also a JAKi, are underway.

In terms of adverse effects, these occurred in up to 58% of patients receiving baricitinib 4mg although no more than 2.5% of these, which included nasopharyngitis and upper respiratory tract infections, were considered as severe. In the abrocitinib trial, 65.8% of those given the 200mg dose experienced an adverse effect, compared to 62.7% in the lower dose group and 53.8% in those taking placebo. The most common adverse effect was nausea in the high dose groups (14.2%), followed by nasopharyngitis (7.7%).

Place in therapy
To date, the information on the efficacy of JAKis in the management of atopic eczema is promising but limited. There are several Phase II studies of other oral and topical JAKis and the results from Phase III studies of these agents are eagerly awaited. Nevertheless, there is a need for studies to assess the longer-term effectiveness of this class of drugs and if there are any important trade-offs between efficacy and safety. None of these agents are currently licensed for the use of atopic eczema and there is an FDA black box warning for the risk of severe infection with baricitinib 2mg (brand name Olumiant) when used for rheumatoid arthritis.9 It is also important to ascertain where this class might sit in the treatment hierarchy. Despite these reservations, it is likely that JAKis represent a potentially useful addition to the treatment armamentarium of doctors managing patients with atopic eczema and their introduction, once it occurs, should be welcomed.

References

1. Nutten S. Atopic dermatitis: global epidemiology and risk factors. Ann Nutr Metab 2015;66 (Suppl1):8–16.
2. Wollenberg A et al. Consensus-based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults and children: part II. J Eur Acad Dermatol Venereol 2018;32:850–78.
3. Hendricks AJ, Lio PA, Shi VY. Management recommendations for dupilumab partial and non-durable responders in atopic dermatitis. Am J Clin Dermatol 2019;20:565–9.
4. Boguniewicz M, Leung DY. Atopic dermatitis: a disease of altered skin barrier and immune dysregulation. Immunol Rev 2011;242(1):233–46.
5. Bao L, Zhang, Chan LS. The involvement of the JAK-STAT signally pathway in chronic inflammatory skin disease atopic dermatitis. JAKSTAT 2013;2(3): e24137.
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7. Simpson EL et al. Baricitinib in patients with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids: results from two randomized monotherapy phase III trials. Br J Dermatol 2020; Jan 5. doi: 10.1111/bjd.18898
8. Silverberg JI, Simpson EL, Thyssen JP et al. Efficacy and safety of abrocitinib in patients with moderate-to-severe atopic dermatitis. A randomised clinical trial. JAMA Dermatol 2020 Jun 3: e201406.
9. FDA Olumiant. www.accessdata.fda.gov/drugsatfda_docs/label/2018/207924s000lbl.pdf