Janus Kinase Inhibitors as first line therapeutic option in atopic dermatitis: a selection of phenotypes to start from

Introduction

Atopic dermatitis (AD) is a chronic, systemic, inflammatory skin disorder associated with a heterogeneous clinical presentation and a significant disease burden affecting multiple aspects of patients’ life.^1,2 Conventional systemic therapies, such as cyclosporine A (CsA) and corticosteroids (SCS), present limited efficacy, and long-term toxicity. Hence, long-term control of AD poses a challenge for both clinician and patients.³ During the last decade, thanks to a deeper insight into the complex pathogenesis of AD, great and rapid advances in drug development have been made.^3,4

Target therapies for the treatment of moderate to severe AD with different mechanisms of action have been developed, such as interleukin (IL)-4 and/or IL-13 inhibitors and the most recent Janus kinase inhibitors (JAKi).³ While IL-4 and/or IL-13 inhibitors play a crucial role in type 2 driven inflammation of AD,⁵ JAKi can reversibly control multiple inflammatory pathways, including Th22 and Th1, which have been shown to be involved in both the acute and the chronic stage of AD, respectively.^6,7 Currently, three JAKi have been approved by the European Medicine Agency (EMA) for the treatment of moderate to severe AD: baricitinib, upadacitinib and abrocitinib.^8-10 Clinical trials data have shown a favorable benefit-risk profile for the three molecules, characterized by high efficacy and rapid resolution of skin lesions and pruritus.⁶ Furthermore, upadacitinib 30 mg and abrocitinib 200 mg showed superior efficacy in resolving AD skin lesions (assessed as a ≥75% or a ≥90% improvement in Eczema Area and Severity Index (EASI75/EASI90) and in reducing significantly itch, compared to dupilumab 300 mg, in adult patients with moderate to severe AD, after 16 weeks of treatment.^11,12 Furthermore, among all available targeted systemic therapies, upadacitinib 30 mg showed the highest efficacy, measured as Investigator Global Assessment (IGA)-AD 0/1 and EASI90, according to a recent network meta-analysis.^12-14 High clinical efficacy, due to deeper and more profound clinical responses, is associated with improvement in multiple domains of the disease such as sleep, overall quality of life (QoL), anxiety, and depression.^15-17 These findings on efficacy make JAKi a promising therapeutic option for patients with moderate-to-severe AD.¹⁸
An EMA review, based on the results from an open-label clinical trial (ORAL Surveillance study) of the JAKi tofacitinib¹⁹ in patients with rheumatoid arthritis and cardiovascular risk factors, confirmed measures to minimize risk of serious side effects, and recommended JAKi for chronic inflammatory disorders only if no suitable treatment alternatives are available in patients with the following conditions:²⁰

• 65 years of age and older;
• history of atherosclerotic cardiovascular disease or other cardiovascular risk factors (such as to be current or past long-time smokers);
• malignancy risk factors (e.g. current malignancy or history of malignancy).

However, available safety data about JAKi in dermatology are reassuring,^21-23 as also stated by the Italian Society of Medical, Surgical, Aesthetic Dermatology and Sexually Transmitted Diseases (SIDeMaST).²⁴ To date, given the recent approval of JAKi in Italy, there is a need of a therapeutic algorithm that may guide clinicians in the clinical practice,²⁵ as the AD Group of the Portuguese Society of Dermatology and Venereology has already assessed.²⁶ Therefore, the aim of this work is to provide a clinical guidance about patients’ selection, based on clinical phenotypes, for identification of moderate-to-severe AD patients’ that can benefit from JAKi. Authors’ considerations and opinions will be based on the available literature and the authors consolidated clinical experience on JAKi use and management in AD. Our contribution aims to open up a discussion in identifying clinical AD phenotypes, which may gain the maximum benefit in terms of efficacy and safety from a JAKi therapy. However, this represents only a starting point, which can be enriched and periodically updated by the scientific community.

Clinical AD phenotypes to guide patient’s selection for treatment with JAKi as firstline therapeutic option

Clinical management of AD should consider clinical, pathogenic, and individual variability; it depends on disease severity, including difficult-to-treat areas.²⁷ Given the high heterogeneity of AD, as demonstrated by the existence of several well characterized clinical AD phenotypes, the choice of a treatment, based on a specific clinical presentation of the disease, may increase the chances of a therapeutic success.⁴ Both clinical trials^28-30 and real-world studies^31-35 have proven the efficacy of baricitinib, upadacitinib and abrocitinib in the treatment of AD. To finalize this paper, authors have been involved in a Workshop consisting of two meetings, with the aim of identifying AD phenotypes of patients, who are candidates for systemic therapy, in which they would feel confident in prescribing a JAKi as a first-line therapeutic option. This patients’ selection has been corroborated by the clinician experience and by the literature evidence, as following. Lichenified/exudative flexural dermatitis is a typical clinical presentations of AD in adult.³⁶ In clinical trials^28-30 the patients enrolled typically present this disease phenotype which is the one that can be diagnosed using the Hanifin and Rajka criteria.³⁷ Therefore, the efficacy data reported for JAKi are primarily related to this AD phenotype. The flexural phenotype is often associated with eczema of the head and neck and/or eczema of the hands.³⁶ The head-and-neck AD has been significantly associated with deterioration of patients’ QoL, greatly than other areas:³⁸ upadacitinib and baricitinib have shown to be effective in the treatment of this sensitive area.^39,40 Flares are an integral part of the AD disease course and are generally defined as disease worsening requiring escalation/intensification of treatment. Choice of a systemic treatment for flare management should be based mainly on the rapid onset of action, and JAKi are in general effective fast-acting drugs.²⁷ The AD with frequent seasonal flare could benefit from JAKi therapy: clinical trials showed that the number of flares is reduced with upadacitinib and abrocitinib.^29,41 Both upadacitinib and baricitinib showed to be effective in the treatment of psoriasiform AD.^42,43

Prurigo-type AD is a morphological variant more common in adults that is especially difficult to treat; only a report is available about efficacy of baricitinib for the treatment of the AD phenotype prurigo-nodularis like.⁴⁴ Over 50% of AD patients, in the clinical population, present hand involvement; despite the high prevalence, functional impairment and decreased QoL, treatment options for patients with hand eczema, refractory to topical corticosteroids, are limited.⁴⁵ Upadacitinb and abrocitinib have shown to be efficacious in the treatment of acute and recurrent vescicular hand eczema.^45,46

Furthermore, two cases of chronic hand eczema have been successfully treated with baricitinib.⁴⁷ The severe generalized AD is usually widespread, mainly affecting the face, neck, hands, and flexures, although all body regions can be affected. It is possible to distinguish 2 clinical patterns: inflammatory and lichenoid.³⁶ The maximum expression of inflammatory pattern is erythroderma. In this patients with generalized AD, the speed of action of JAKi is an important weapon and can influence the therapeutic choice.³⁶ Erythrodermic AD, resistant to multiple systemic treatments, has been successfully treated with upadacitinib.⁴⁸

Table 1 summarizes the identified phenotypes of AD for which treatment with JAKi could be advised as first-line optional treatment, based upon data from published literature and authors clinical experience.

According to the Italian Consensus,²⁵ candidates for systemic therapies in Italy have moderate-to-severe AD, defined by an EASI Score ≥16, or with EASI Score <16, when at least one of the following conditions is present:

• localization on the face, hands, or genitals;
• itch with Numerical Rating Scale (NRS) Score ≥7;
• sleep disturbances with NRS Score ≥7;
• QoL impairment with Dermatitis Life Quality Index (DLQI) ≥10.

Moreover, according to AIFA prescriptions, abrocitinib, baricitinib and upadacitinib are reimbursed for the treatment of severe AD (EASI score ≥24) in adult patients’ candidates for systemic therapy:⁴⁹

• in the absence of risk factors indicated by EMA: in case of failure of treatment with cyclosporine.
• in the presence of the risk factors indicated by EMA: solely upon failure of all therapeutic options reimbursed in the indication (CsA and anti-IL) clinically deemed appropriate/possible by the prescribing doctor.

Recently, more attention to the management of the overall AD patients’ status was highlighted by the published EDF/EuroGuiDerm Guidelines on Atopic Eczema:⁵⁰ candidates for systemic treatment may be either patients with a high composite score such as a SCORAD above 50 (scale definition), or patients clinically failing to respond to an appropriately conducted topical therapy (functional definition), or patients unable to participate in normal daily life activities whilst following an adequate treatment regimen (social definition).⁵⁰ Hence, it is important to address patients’ needs and to take accurately into account the presence of comorbidities and the patient’s medical history.⁵¹ Comorbidities of AD include atopic disorders (asthma, allergic rhinoconjunctivitis, food allergy, eosinophilic esophagitis), and nonatopic disorders (psychiatric disorders, ichthyosis vulgaris, cutaneous and noncutaneous infections, cardiometabolic disease).¹⁸ Therefore, we propose here a two-step patients’ profile assessment for the selection of candidates for systemic therapy with JAKi. At first the identification of a specific AD phenotype (based on morphology and localization of lesions) as per Table 1.
Then, the analysis of the patients’ overall medical history. As per label, patients need to be 65 years old or younger, without cardiovascular and malignancy risk factors.^8-10,20
Among this category, EMA inserts long-term smokers, based upon the smoking status of patients enrolled in the Oral Surveillance trials with a smoking history.¹⁹ Hence, in case of smoker’s patients, the following parameters should be considered: older age, presence of other cardiovascular risk factors for major adverse cardiovascular events (MACE), smoking status – as it is known that risk in smokers is cumulative and that heavy and long-term smokers might be at higher risk with older age.⁵² Among CV risk factors for MACE, hypertension and dyslipidemia can be well controlled with pharmacological treatment.⁵²

Comorbidities are important, not only for the assessment of the overall patient’s profile, but also because sometimes can be also treated with JAKi. For instance, Alopecia Areata (AA) is often associated with AD.⁵³ While evidence about efficacy of IL-4 and IL-13 blockers for the treatment of AA is controversial, ⁵⁴ baricitinib recently received approval for the treatment of severe AA in adult patients.⁸ Upadacitinib was also shown to be effective for the treatment of AA^55-57 and a phase 3 clinical trial is currently ongoing.⁵⁸ Hence, the presence of this condition can also drive the treatment choice. Similarly, even if less frequent, the presence of rheumatoid arthritis or inflammatory bowel diseases (ulcerative colitis and Crohn’s disease) would encourage the treatment with a JAKi, as upadacitinb is also approved for these indications.⁹

Regarding atopic comorbidities, clinical trials showed that patients with AD and asthma have been successfully treated with JAKi^28-30 and in this selection of phenotypes, characterized by severe forms of AD, a mild to moderate asthma is not a reason to avoid JAKi prescription.⁵⁹ Likewise, when choosing a systemic treatment option for patients with history of severe ocular surface disease (OSD), as conjunctivitis and blefaritis, the treating dermatologist could consider starting with a JAKi, since OSD may be exacerbated by Th2 inhibition with biologics in patients with AD.⁶⁰

Conclusions

The aim of our work is to support goals in the treatment of moderate to severe AD, which consist of:

• an itch-free life to patients, as this is what they strive for;¹
• a significantly reduced number of flares on a long term prospective;²⁷
• an improvement in skin clearance, to a clear/almost clear skin level, as it has been shown that this affects all other disease domain;¹
• a rapid onset of action, both in skin and itch improvement;¹¹
• a multidimensional control of the disease, addressing all QoL parameters.^15-17

JAKi, with their high efficacy, coupled to a favorable and well-characterized safety profile, can be an important therapeutic option for the above identified patient’s AD phenotypes, as well as more data will be needed for supporting the selection of responder patients, based on clinical characteristics and AD phenotypes.