INTRODUCTION
Hydroxyurea (hydroxycarbamide) is an oral chemotherapeutic agent commonly employed for the therapy of myeloproliferative syndromes, including essential thrombocythemia [1]. Its mechanism of action involves interference with DNA synthesis by inhibiting the activity of ribonucleotide reductase, the enzyme responsible for catalyzing the conversion of ribonucleotides to deoxyribonucleotides, and impairing thymidine incorporation into DNA [2]. Despite the relatively favorable overall tolerability of hydroxyurea, its prolonged use is frequently associated with adverse mucocutaneous manifestations of either inflammatory or neoplastic nature. These manifestations encompass mucosal and cutaneous ulcers, nail discoloration, glossitis, hand-foot syndrome, squamous cell keratosis, and squamous cell carcinoma of the skin [3].
CASE REPORT
A 64-year-old patient, undergoing hydroxyurea treatment for essential thrombocytosis since 2009, was admitted to the Department of Dermatology due to hyperkeratotic lesions, nodules exhibiting significant dryness, and hyperpigmentation of the skin on the dorsa of both hands accompanied by pruritus. The patient attributed the onset of these skin lesions to increased use of disinfectants since the onset of the COVID-19 epidemic in Poland in March 2020, and reported exacerbation of symptoms following sun exposure. Initially, topical treatment with a 10% urea cream was applied, resulting in increased pruritus and increased hyperkeratosis on the dorsa of the hands (fig. 1). Dry skin was also observed on the elbows and back (fig. 2).
Figure 1
Erythematous-desquamative, violaceous papules and plaques on the dorsal hands of the patient
Physical examination revealed no signs of proximal muscle weakness. Laboratory tests revealed elevated levels of creatinine, fasting glucose, CRP, ESR, ferritin, and thrombocytosis. Both antinuclear antibodies and dermatomyositis-associated antibodies (anti-Jo-1, anti-SRP, and anti-Mi-2) were negative. Electromyographic examination (EMG) prior to hospitalization did not reveal features of the myogenic pattern, which would be indicative of primary muscle damage. To assess the likelihood that the described symptoms resulted as an adverse effect of hydroxyurea therapy, the Naranjo Adverse Drug Reaction Probability Scale was applied, yielding a score of 7 points. This result corresponds to a classification of “probable”. These findings suggest a significant association between hydroxyurea therapy and the observed skin lesions in the reported case. A skin biopsy from the dorsum of the left hand was conducted and revealed hyperplastic epidermis without dysplasia, orthokeratotic stratum corneum, and vacuolization with necrotic keratinocytes in the basal layer. Additionally, dermal elastosis alongside dilated vessels was observed. The presentation was suggestive of lichenoid keratosis. The patient was treated with topical 0.1% tacrolimus and advised to use sun protection with UV blocking cream. Due to the rapid resolution of pruritus and improvement of skin lesions to a level tolerated by the patient, after consultation with a hematologist it was decided not to discontinue hydroxyurea therapy.
DISCUSSION
Based on the histopathological examination results and the clinical presentation, dermatomyositislike eruption arising from long-term hydroxyurea therapy was diagnosed [4]. Cutaneous toxicity is a well-known side effect associated with hydroxyurea therapy. A comprehensive multicenter retrospective study investigating patients undergoing hydroxyurea therapy for Philadelphia chromosome-negative myeloproliferative neoplasms demonstrated that 5% of individuals developed significant drug-induced toxicity, predominantly presenting as cutaneous adverse reactions. Among the documented dermatologic manifestations, ulcerations were the most prevalent, primarily localized to the pretibial region. Mucosal involvement was the second most frequent presentation, while a smaller subset of patients exhibited additional cutaneous toxicities, including actinic keratosis, dyschromia, basal cell carcinoma, and dermatitis [5]. Apart from dermatomyositis-like skin lesions, hydroxyurea therapy is linked to other reported skin toxicities, encompassing hyperpigmentation, dry or atrophic skin, alopecia, skin ulcers, non-melanoma skin cancers, premalignant conditions, and mucosal changes, including hyperpigmentation, gingivitis, ulcers, and oral cancer [4].
In the literature, instances of skin lesions resembling dermatomyositis are predominantly documented in clinical case reports. Dermatomyositis-like cutaneous eruptions frequently manifest as a delayed adverse effect of prolonged hydroxyurea therapy, with reported cases emerging after between 2 and 10 years of treatment. The variability in onset is influenced by factors such as cumulative drug exposure and individual patient susceptibility, contributing to the heterogeneous timing of lesion development. In a more extensive study involving a cohort of 158 patients undergoing hydroxyurea treatment, these lesions were reported in 4.4% of cases (n = 7) [3, 4]. They manifest as erythematous and scaly violaceous papules and plaques localized to the skin on the dorsa of the hands, exhibiting associated atrophy and telangiectasias. Notably, they may bear a resemblance to Gottron’s papules. Histopathological examination reveals lichenoid inflammation, vacuolization of basal cells, dyskeratosis, and hypo- or hypergranulosis as characteristic features [4]. Persistent papules exhibit traits such as epidermal atrophy, sparse inflammatory infiltrate, and telangiectasias [3]. The identification of lichenoid keratosis or interface dermatitis on histopathology is thus indicative of the diagnosis of a dermatomyositis-like eruption.
The precise pathomechanism underlying the dermal toxicity associated with hydroxyurea remains incompletely elucidated. It is suspected to result from the cytotoxic impact of the drug on actively dividing cells within the basal layer of the epidermis, leading to subsequent atrophy. The reparative process in certain individuals gives rise to patchy hyperkeratosis and hyperpigmentation, attributed to heightened melanocyte activity involved in free radical reduction [3, 6, 7]. During the administration of hydroxyurea, it is plausible that a phototoxic reaction occurs upon exposure to ultraviolet (UV) radiation, contributing not only to the development of neoplastic skin lesions but also dermatomyositis-like eruptions [3].
Dermatomyositis is included in the differential diagnosis of dermatomyositis-like eruptions. Distinguishing between these dermatoses in histopathological examinations poses significant diagnostic challenges, while their clinical manifestations exhibit greater diversity [8]. In addition to characteristic skin lesions, dermatomyositis manifests systemic symptoms such as weakness, elevated temperature, and weight loss [9–11]. Furthermore, muscle weakness and an elevation in markers of muscle damage, including increased creatine kinase (CK), aspartate aminotransferase (AST), or alanine aminotransferase (ALT) activity, are observed. The diagnosis of dermatomyositis-like eruption induced by hydroxyurea is substantiated by symptoms such as dry or atrophic skin, which represent characteristic side effects of this therapy [8]. If dermatomyositis-like eruption is associated with hydroxyurea treatment, it is advisable to discontinue or modify the therapy [4]. For patients with suspected dermatomyositis, an electromyographic (EMG) examination, nuclear magnetic resonance (NMR) or muscle biopsy are indicated as additional tests. The described patient was assessed using the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) classification criteria for idiopathic inflammatory myopathies. Due to the absence of blood, immunological and electromyography results indicating dermatomyositis as well as lack of proximal muscle weakness, and thus a low score on the scale (< 5), hydroxyurea was identified as the likely cause of the dermatomyositis-like skin lesions [12].
Kalajian et al. conducted an immunohistochemical analysis of a skin biopsy from a patient with hydroxyurea-associated dermatomyositis-like eruption. The results revealed focal, confluent nuclear expression of p53 along the lower layers of the epidermis, indicative of a precancerous condition. While the authors presented a singular case, and the literature lacks additional reports regarding the malignancy of dermatomyositis-like eruption induced by hydroxyurea, regular dermatologic follow-up in patients exhibiting such skin lesions alongside hydroxyurea therapy seems prudent [7].
Hydroxyurea has been proven to increase the risk of non-melanoma skin cancers (NMSC), such as cutaneous squamous cell carcinoma (cSCC), basal cell carcinoma (BCC), and Merkel cell carcinoma (MCC), as well as actinic keratosis (AK), which is precancerous lesion. The average time to develop NMSC after beginning hydroxyurea treatment was 75 months, at a median daily dose of 1.25 grams [13, 14]. Patients are advised to avoid sun exposure and rigorously use photoprotection [13]. During long-term hydroxyurea therapy, it is also recommended to undergo a dermatological examination, including cancer screening, preferably once a year [15].
CONCLUSIONS
The manifestation of dermatomyositis-like eruption represents one of the rarest side effects of hydroxyurea therapy. When such skin lesions occur, a skin biopsy followed by histopathological examination is recommended. In patients who develop a hydroxyurea-induced dermatomyositis-like eruption and do not respond to topical treatment, it is advisable to reduce the dose or discontinue hydroxyurea therapy.
