Hyperkeratotic Hand Eczema Successfully Treated with Dupilumab Therapy: A Series of 3 Case Reports

Introduction

Hyperkeratotic hand eczema (HHE) is characterized by clearly demarcated areas of hyperkeratosis or thick scaling on the palms, which may extend to the palmar surfaces of the fingers. Little or no redness is present, and vesicles are usually absent. Involvement of the plantar aspects of the feet can also occur. Patients are usually middle-aged, and males are more commonly afflicted. This phenotype is currently included in the classification system of hand eczema.¹ The pathogenesis of hand eczema is multifactorial and involves both genetic and environmental factors. Interleukin (IL)-4 and IL-13 play a key role in the pathogenesis of atopic dermatitis (AD)² Hand eczema may also be a manifestation of allergic contact dermatitis.³

Topical corticosteroids remain the mainstay of treatment for mild to moderate hand eczema in combination with emollients and moisturizers.^3,4 Moisturizes which contain keratolytic ingredients can help reduce thickness and scaling in hyperkeratotic hand eczema.³ Dupilumab is a monoclonal antibody that targets interleukin IL-4 and IL-13. It is currently approved for the treatment of atopic dermatitis (AD).⁵ Effective treatment of hand eczema with dupilumab has been previously reported in a few patients^,6–9 however, there is insufficient data regarding its effectiveness in cases from the Middle East and North Africa (MENA) region.

In the current case series, we are presenting 3 patients with HHE who received multiple treatments before starting dupilumab, however the patient did not respond adequately to these treatments. This study aims to discuss the pathophysiology of HHE and assess the effectiveness and safety of dupilumab in its treatment.

Methods

Case reports

Clinical intervention

Initially, patients received dupilumab 600 mg administered subcutaneously as a loading dose, followed by 300 mg every 2 weeks. The course of therapy has been completed until clinical improvement is observed, and the exact duration of treatment was variable depending on disease response, patient’s perspectives, and tolerability of adverse drug reactions ( Table 1).

Physical examination of Patient 1 revealed sharply demarcated hyperkeratotic plaques and thick scaling on the palms, extending to the palmar aspects of the fingers ( Figure 1).

Figure 1. A 47-year-old male patient with sharply demarcated hyperkeratotic plaques and thick scaling on the palms, which extended to the palmar aspects of the fingers (Left hand: a, c; Right hand: b, d).

Histopathological findings in the included patients demonstrated compact orthokeratosis, parakeratosis, acanthosis, and mild spongiosis consistent with HHE ( Figure 2).

Figure 2. The hematoxylin and Eosin (H&E) stained section showed Compact Orthokeratosis, Parakeratosis, acanthosis, mild spongiosis, mixed dermal infiltrate of lymphocytes, macrophages, and prominent dermal capillaries with no eosinophils. a) 4X, b) 10X.

After 4 weeks of dupilumab therapy, Patient 1 showed almost complete resolution of lesions ( Figure 3).

Figure 3. 47-year-old male patient 4 weeks following treatment with Dupilumab with almost complete resolution of HHE lesions, palmar aspects of both hands.

Patient 2 presented with hyperkeratotic plaques and thick scaling involving the palms and fingers ( Figure 4).

Figure 4. A 48-year-old female patient showed hyperkeratotic plaques and thick scaling, which extended to the palmar aspects of the fingers with little or no redness (Right hand: a, b; Palmar aspects of both hands: c).

After 4 weeks of dupilumab therapy, Patient 2 demonstrated complete clinical resolution of the lesions ( Figure 5).

Figure 5. A 48-year-old female with complete resolution of HHE following 4 weeks of Dupilumab therapy (Right hand: a; Palmar aspects of both hands: b).

Patient 3 demonstrated hyperkeratotic plaques involving the palms and fingertips with painful fissures ( Figure 6).

Figure 6. A 52-year-old male patient showed hyperkeratotic plaques and thick scaling was found on the palms and tips of his fingers which had mild or no redness (Right hand: a, b; Palmar aspects of both hands: c; Fingertips of both hands: d).

Complete clinical resolution was observed in Patient 3 following dupilumab therapy for 4 weeks ( Figure 7).

Figure 7. A 52-year-old male patient with complete resolution of HHE following 4 weeks of Dupilumab therapy (Left hand: a; Palmar aspects of both hands: b; Fingertips of both hands: c, d).

Discussion

The pathogenesis of HHE remains unclear^.1 Nonetheless, multiple studies have demonstrated changes in epidermal proliferation, differentiation, and barrier function. Increased proliferative cell activity as determined by Ki-67 and decreased loricrin expression in palmar lesional skin biopsies with normalization following alitretinoin treatment were observed in a study examining gene and protein expression in 15 individuals with chronic hyperkeratotic-fissured hand eczema.¹² Another study has also shown an increase in keratinocyte host defense proteins (S100A7, S100A8, and S100A9) in 6 patients with chronic hand eczema, including various subtypes, compared with healthy control skin.¹³ Additionally, a study of protein expression in 7 individuals with HHE revealed an elevation in proliferative cell activity as shown by Ki-67, an upregulation of keratin (K)16, and a reduction in loricrin expression in lesional palmar skin relative to perilesional skin and healthy control skin.¹ These data collectively indicate that HHE is marked by epidermal hyperproliferation and impaired barrier function, features that overlap with those observed in atopic dermatitis. Patients with atopic dermatitis who were treated with dupilumab have exhibited a considerable reduction in the gene expression of K16 and MKi67, a decreased expression of S100As genes, and an increase in loricrin expression following treatment.¹⁴ Moreover, current evidence suggests that IL-4 and IL-13 are crucial cytokines in the pathogenesis of AD.² Several studies have shown beneficial results of dupilumab on hand eczema in patients with atopic dermatitis and isolated vesicular hand eczema.^7,9 Consequently, the positive effect of dupilumab on HHE may be related to shared epidermal pathology, as patients with AD and HHE exhibit similarities such as epidermal hyperproliferation and impaired barrier function.¹⁵

A case series of 3 patients with non-atopic hyperkeratotic hand eczema who were treated with dupilumab demonstrated that 2 patients had major improvement after 4 weeks and their symptoms cleared completely after 16 weeks of treatment. However, one patient noticed minimal clinical response, although there was an improvement in itching and quality of life. The authors explained that the lack of improvement may be due to the patient’s occupational activities as a bricklayer, where his hand eczema was caused and worsened by frequent exposure to irritants and friction while working.¹⁵ The successful treatment of occupational irritant hand dermatitis with dupilumab has been reported in only 1 case report.¹⁶

Based on our current reports, all three patients demonstrated bilateral involvement of the palms and fingers with mild itching, while a previous case report published in 2021 included patients with HHE affecting only the palms and accompanied by severe itching. In addition, a significant clinical improvement and complete resolution of the lesions were also demonstrated in all our cases after receiving dupilumab compared to previous study.¹⁵ Considerable efficacy and an acceptable safety profile were noted as well, which is consistent with previous records.^17,18 We consider our case reports to be complementary to those previously published and support our suggestion that HHE is a distinct condition that should not be overlooked and considered as non-atopic variant of chronic hand eczema. Moreover, our case reports are the first to be published in the Middle East and North Africa (MENA) region.

The diagnosis of HHE is often a challenge by dermatologists as it can be confused with another differential diagnosis of palmar keratoderma, such as psoriasis, atopic dermatitis, occupational hand eczema, hereditary keratoderma, lichen planus, or pityriasis rubra pilaris.¹⁹ A later age of onset, pure hands involvement, mild itching, negative family history of atopy or psoriasis, absence of nail and joint involvement, and histopathological findings excluding other causes of keratodermas, minimal response to conventional therapy can be considered as criteria for diagnosis of HHE. Our view is that HHE should be classified as a separate entity to be presented alongside other causes of acquired keratoderma. Considering dupilumab’s positive effect on HHE, it might be hypothesized that, despite differences in clinical phenotype, there are similarities in the underlying pathogenesis with an IL-4/IL-13-driven inflammation between different subtypes of hand eczema.¹⁵ As such, dupilumab serves as a promising agent for hyperkeratotic hand eczema. However, further investigations are recommended on a larger population to determine the safety and efficacy of dupilumab in HHE.

Conclusion

Dupilumab appears to be an effective and well-tolerated treatment for HHE, particularly in patients unresponsive to conventional treatments. These findings also suggest that HHE may share underlying inflammatory mechanisms with other forms of hand eczema, particularly those driven by IL-4 and IL-13 pathways. However, further studies on larger populations are needed to confirm its efficacy and safety in this condition.

Ethical approval

All subjects participated voluntarily. The Declaration of Helsinki was adequately addressed. The study was approved by the institutional review board of the Research Ethics Committee at AlQasimi Hospital, UAE (2022/379).

Consent

Written informed consent for publication of anonymized clinical details and clinical images was obtained from all patients prior to submission of the manuscript.