Alitretinoin is not a suitable treatment for the majority of chronic hand eczema patients

Chronic hand eczema (CHE), the most common form of hand eczema, is a highly prevalent and debilitating inflammatory skin condition that is empirically categorized based on both aetiology (e.g. irritant contact dermatitis, allergic contact dermatitis and atopic dermatitis) and clinical presentation (e.g. vesicular, fissured and hyperkeratotic CHE).1 Alitretinoin, an oral synthetic vitamin A derivative, remains the only systemic medication labelled for the treatment of severe CHE in Europe and Canada. Since its introduction, predominant hyperkeratotic CHE have been thought to respond better to alitretinoin compared to non-hyperkeratotic forms. While clinical trials have demonstrated its efficacy, real-world data on alitretinoin's effectiveness and tolerability remain limited. In their article titled ‘Drug survival of alitretinoin treatment for chronic hand eczema: A Danish nationwide cohort study’, Rønnstad ATM et al.2 investigated alitretinoin drug survival among 837 Danish adult CHE patients who initiated treatment between 2008 and 2020. The study found a median drug survival of 107 days, with no significant differences observed between hyperkeratotic and non-hyperkeratotic CHE phenotypes. These findings align with clinical experience, suggesting limited long-term adherence. Although the study did not specify reasons for treatment discontinuation, it is likely attributable to a combination of lack of effectiveness and adverse events. Chronic hand eczema is a multifactorial disease characterized by overlapping aetiological drivers and clinical presentations, making it particularly challenging to treat effectively. Alitretinoin, as a retinoid, exerts its therapeutic effects primarily by modulating keratinocyte differentiation and reducing inflammation. However, its mechanism of action does not address the diverse immune pathways that are likely involved in the pathophysiology of CHE, such as T-cell driven inflammation or specific dysregulated immune response. Additionally, adverse events such as headaches or mucocutaneous dryness frequently result in poor adherence and high treatment discontinuation rates. Moreover, the need for regular monitoring due to teratogenic risks and hepatotoxicity imposes additional barriers to its long-term use. In clinical practice, patients are often reluctant to maintain long-term systemic treatments that significantly impair their quality of life, especially when the therapeutic response is limited. These limitations highlight the need for more reliable and patient-tolerant therapeutic options for severe CHE. Recent developments in targeted therapies, including biologics and JAK inhibitors, offer new hope for CHE patients. For instance, dupilumab, an IL-4Rα antagonist approved for atopic dermatitis, has shown promise in preliminary clinical trials for treating CHE.3 Similarly, Janus kinase inhibitors, both oral and topical, have also demonstrated efficacy in reducing CHE symptoms by modulating broader immune pathways. As systemic JAK inhibitors (JAKi) are associated with a less favourable safety profile compared to biologics, the absence of adverse events with topical JAKi such as delgocitinib cream is encouraging.4 However, further research is required to determine whether dupilumab or other treatments targeting Type 2 immunity as well as JAKi could benefit all CHE patients, including both hyperkeratotic and non-hyperkeratotic subtypes, as well as atopic and non-atopic individuals. This would represent a significant step forward in reducing the burden of this condition. In conclusion, while alitretinoin remains the only systemic treatment approved for severe CHE in Europe and Canada, its limited efficacy, short drug survival and adverse effects make it unsuitable for most patients. The real-life study by Rønnstad ATM et al.2 underscores the urgent need to deepen our understanding of CHE's complex underlying mechanisms and to prioritize the development of more effective and better tolerated therapeutic options that address the diverse clinical presentations of this challenging condition. MT served as an investigator, speaker or advisor for AbbVie, Sanofi, Leo Pharma, Almirall, Medac, Janssen and E. Lilly. MAL served as a speaker or advisor for AbbVie, Novartis and Sanofi. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

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