Hydroxyurea: a reappraisal of its cutaneous side effects and their management
Camille A. Bulte1, BS, Karl M. Hoegler1, MD, €Omer Kutlu2, MD, MRCP(UK) and Amor Khachemoune3,4, MD, FAAD, FACMS
1Department of Dermatology, University of Maryland Medical Center, Baltimore, MD, USA, 2Department of Dermatology and Venereology, School of Medicine, tiUsak University, tiUsak, Turkey, 3Brooklyn Campus of the VA NY Harbor Healthcare System, Brooklyn, NY, USA, and 4Department of Dermatology, SUNY Downstate, Brooklyn, NY, USA
Correspondence
Amor Khachemoune, MD, FAAD, FACMS 800 Poly Place
Brooklyn, NY 11209 USA
E-mail: [email protected] Conflict of interest: None. Funding source: None.
doi: 10.1111/ijd.15302
Abstract
Hydroxyurea (HU) is known to cause a broad spectrum of cutaneous side effects, ranging from relatively benign to severe. Although dermatologists are often consulted for the treatment of these side effects, a comprehensive resource discussing the different types and their management is lacking. In this study, we conducted a literature search in order to critically evaluate the reported types and management of hydroxyurea’s cutaneous side effects, as well as review its mechanism of action, dermatologic uses, and common systemic side effects. Relatively common and benign side effects include hyperpigmentation, xerosis, and skin atrophy. While serious cutaneous side effects such as leg ulcers or nonmelanoma skin cancers occur in a substantial proportion of patients, these may resolve with HU discontinuation and proper dermatologic management. Therefore, it is crucial for dermatologists to be aware of these various cutaneous side effects and their management as prompt diagnosis and proper treatment will improve patient outcomes.
Introduction
Hydroxyurea (HU) is an antimetabolite drug most commonly known for its use in the treatment of myeloproliferative disorders (MPD). Although HU was first synthesized in 1869, the first anti-tumor activity was reported in the 1960’s.1 Since then, its use has been expanded to treat essential thrombocythemia, polycythemia vera, sickle cell disease (SCD), head and neck cancer, ovarian cancer, and psoriasis.1,2 While this drug is gen- erally well-tolerated and considered safe,3 it is known to cause a broad spectrum of cutaneous side effects from xerosis and hyperpigmentation to leg ulceration and cutaneous malignancy.2 Although dermatologists are often consulted for the treatment of these side effects, a comprehensive resource discussing the dif- ferent types and their management is lacking. In this study, we conducted a literature search within PubMed, Google Scholar, Embase, and Cochrane for case reports and larger studies under the term “hydroxyurea” in conjunction with “cutaneous adverse/side effects,” “mucocutaneous adverse/side effects,” “skin changes,” “dermatologic uses,” and “psoriasis” in order to critically evaluate the reported types and management of
hydroxyurea’s cutaneous side effects, as well as review its mechanism of action, dermatologic uses, and common systemic side effects.
Mechanism of action and pharmacology
Hydroxyurea, an antimetabolite, prevents the conversion of ribonucleotides to deoxyribonucleotides and halts the cell cycle at the G1/S phase by inhibiting the M2 subunit of ribonucleotide reductase. Keeping cells in the G1 phase interferes with DNA repair and consequently sensitizes them to radiation-induced damage. HU also causes gene hypomethylation, which induces cell differentiation and is thought to be the mechanism behind its treatment of psoriatic skin.4
Following ingestion, HU has almost complete bioavailability and is widely distributed amongst all bodily tissues.1 It has tissue effect after 5 hours, peaking at 8 hours, and persisting for 20 hours.1 Serum concentration peaks in 2 hours and is gone by hour 24, and elimination is primarily renal.1 For most conditions, average dosing is 1–2 g/day, with a maximum dose of 4 g/day.5 Patients on HU therapy should undergo baseline laboratory
1
monitoring of complete blood count, comprehensive metabolic panel, urinary analysis, and a pregnancy test because of hydrox- yurea’s teratogenic effects.1 This should then be followed by complete blood count monitoring every 2–4 weeks.1
Dermatologic uses
Psoriasis
Hydroxyurea was shown to be efficacious in psoriasis in the 1970’s, and several short and long-term studies have since demonstrated its beneficial effect.6 For instance, one study reported a 70% or greater reduction in 55% of patients after a mean treatment time of 36 weeks,5 and another found that 60% had complete or almost complete clearance after an average of
side effects occur with long-term HU use, they have been reported as early as 2 weeks after beginning therapy.5 Resolu- tion rates vary depending upon the side effect and whether HU therapy is discontinued. Most of the serious side effects, such as leg ulcers or malignancy, occur in patients with myeloproliferative disorders that are on higher doses of HU for longer periods of time.5
Hyperpigmentation
Hyperpigmentation of the skin, nails, or mucosa is a common cutaneous side effect, with frequencies ranging from 6% in one larger study17 to 50–94% in several smaller studies.5,11,15 It may be single or multiple and may occur in the skin, nail, and mucosa at the same time. Nail hyperpigmentation is the most common,
16 months.6 However, it is neither FDA approved nor included
5,15,16
with some studies reporting frequencies as high as 55%.
It
in current guidelines for the treatment of psoriasis,7 largely because of the emergence of newer and more effective drugs.5 Although there are no clear indications for its use in the treat- ment of psoriasis,7 some authors still recommend HU in patients with psoriasis and HIV because of its antiretroviral properties.8 If used for the treatment of psoriasis, it is recom- mended to begin HU at an initial dose of 500 mg BID and then increase up to 1.5 g/day as tolerated.7
Hypereosinophilic syndrome
As a result of HU’s favorable side effect profile, low cost, and efficacy, it is also used in the treatment of hypereosinophilic syndrome (HES).9 HU is the preferred second line agent after glucocorticoids for those who do not have the lymphoid variant or myeloid features.9 Additionally, once a maintenance dose of glucocorticoids has been reached, the dose may be reduced by adding HU as a steroid-sparing agent, especially for those who require more than 10 mg of prednisone daily or suffer significant side effects.9
It is recommended to begin HU at an initial dose of 500– 1,000 mg daily and eventually increase to 2,000 mg daily as tol- erated.9 Several studies have shown a beneficial effect, and a majority of patients started on HU therapy have either a com- plete or partial response.9,10
Cutaneous side effects
The pathologic mechanism behind the cutaneous side effects of HU is not entirely understood, but it is thought to be because of the drug’s cytotoxic effects on rapidly dividing cells.11 While many studies report a frequency of cutaneous
11–14
side effects of 5–35%, several studies have reported fre- quencies in the range of 65–96%,5,15,16 suggesting that the actual rate may be higher. This wide variation may be attribu- table to the differences in methods between studies, such as those with a higher frequency having patients undergo regular examinations by a dermatologist. Although most cutaneous
can present in single or multiple nails as longitudinal melanony- chia, transverse bands, generalized hyperpigmentation, or local- ized pigmentation to the lunula (Fig. 1).5,11 Time to onset ranges from 4 weeks5 to 5 years17 after initiation of therapy, but the majority of studies report an average latency period of 6– 12 weeks.5,12 Rarely, other nail changes, such as dystrophy, thinning, and scarring, have been described.5,12 Nail hyperpig- mentation is typically not bothersome enough to the patient to warrant HU discontinuation, and many cases self-resolve within a
Figure 1 Nail hyperpigmentation caused by hydroxyurea treatment
few months.5,11 Thus, these lesions are typically observed with no changes to HU therapy.
Skin hyperpigmentation has reported frequencies as low as 0.21% in one large retrospective study14 but ranges from 19 to
5,14,16
58.6% in several smaller studies.
It presents as black-gray
patches or diffuse body pigmentation11 and typically occurs on the trunk, arms, forearms, shins, or forehead (Fig. 2).5,18 Histo- logic exam may show perivascular melanin pigmentation or iron deposition within the dermis, suggesting that HU or its metabo- lite may form a complex with iron.18 Time to onset ranges from 2 weeks5 to 4 years,18 but a majority of studies report an aver- age latency period of 4–12 weeks.5,11
Oral mucosal hyperpigmentation is less common, with two reported frequencies of 3.4 and 17.6% (Fig. 3).5,15 Details regarding the presentation and histology of these lesions are not well-described. Scleral pigmentation has also been reported.5 Hyperpigmentation of the skin or mucosa are also typically not concerning enough to warrant HU discontinuation and may fade or resolve on its own within a few months.5,11 However, persistence of these lesions, even after HU discontin- uation, has been described.5,12
Figure 3 Mucosal hyperpigmentation caused by hydroxyurea treatment
Xerosis
Xerosis is also common during HU therapy with several
12,13,15,16
reported frequencies ranging from 20 to 100%.
Although one study of patients on HU therapy for psoriasis reported a much lower frequency of only 6.9%, the author points out that dry skin may have been masked by the regular use of emollients.5 Xerosis is usually not bothersome enough to warrant HU dose reduction or discontinuation and occasionally resolves without altering HU dosage.5,15
Skin atrophy
Skin atrophy is another relatively common side effect with two
5,13
reported frequencies of 10 and 13%.
It most commonly
affects the legs and sun-exposed areas and can be associated with telangiectasias.13 Histology demonstrates epidermal thin- ning and collagen fiber attenuation. Atrophic lesions may improve but not fully resolve following HU discontinuation.12
Alopecia
Alopecia has also been associated with HU with several
Figure 2 The occurrence of skin hyperpigmentation 1 month after initiation of the hydroxyurea
5,12,16
reported frequencies ranging from 7.7 to 10.3%. Similar to other chemotherapeutic agents, it is thought to cause alopecia through anagen effluvium because of its cytostatic effects.19 It
generally presents on the scalp and may be partial or dif- fuse.5,12 Although one study reported an average latency period of 8 weeks, it has also occurred several years after HU ther-
often cause pain and difficulty with ambulation (Fig. 4).14 They present as small, well-defined, shallow ulcers with a yellow fibri- nous and occasionally necrotic base and may be associated
5,12
apy.
While its course is less well-described than for other
with surrounding erythema, white stellate scarring, or bacterial
cutaneous side effects, one study reported resolution in 2 of 3 patients after HU discontinuation.5 Treatment with HU discontin-
infection.14,23,25 Histologic exam findings include epidermal atro- phy, dermal fibrosis and scarring, panniculitis with venous ves-
uation or dose reduction requires careful consideration of the
14,25,26
sel ectasia, and reduction of elastic fibers.
Ulcers are
risks and benefits by both the physician and the patient. Although therapeutic regimens such as scalp cooling or topical minoxidil have been shown to improve outcomes in chemother- apeutic-induced anagen effluvium,19 its efficacy in HU-induced alopecia specifically is not well described.
Mucosal involvement
In addition to mucosal hyperpigmentation, oral stomatitis, ulcer- ation, and rarely oral cancer have been associated with
seen with long-term HU use, typically after 5 or more years.2 Unfortunately, care providers have insufficient awareness of HU-induced ulcers, and thus diagnosis is often delayed or missed.23 In addition to standard wound therapy, HU discontinu- ation is often necessary and leads to either complete or partial
20,23,25,26
resolution. If HU discontinuation is not an option, reso- lution has also been described with dose reduction, intermittent scheduling,23 or even simply standard wound therapy including decompression chambers, wound surgical toilets, and local
HU.14,20 Occurring in 0.08–5.9% of patients, oral ulcers are
2,14,27,28
antibiotics and heparin.
For nonsurgical candidates, the
associated with pain and burning, occasionally leading to weight use of collagenase, saline washes, amukine, betadine, and
5,14,20
loss and tooth decay.
Histologic exam may show a non-
occlusive dressings may also help.27 Other advanced therapies
specific phlogistic reaction.14 Reported latency periods range from as early as 7 weeks to several months of HU therapy. One larger study reported an average of 9 weeks.5,20 Some lesions resolve without modifying HU therapy,5 and a majority have either partial or complete resolution after 1 month of HU dose reduction or termination.14,20 Complete resolution typically occurs within 3 months. Symptomatic improvement may be seen with folic acid and vitamin A mouthwash.14
Two cases of oral squamous cell carcinoma (SCC) associ- ated with HU therapy have been described. The first was a case report of oral SCC in a patient with multiple SCC eruptions 2 years after cessation of HU therapy and 13 years of previous use.21 The second was a case of oral SCC that presented as a persistent ulcerative lesion after 15 years of HU therapy.22 However, the authors state that a causal role of HU could not be unequivocally determined because of the high rates of oral SCC in the elderly.22 Nevertheless, in the case of persistent oral ulceration under HU treatment, histopathologic examination should be performed in order to exclude malignancy.
Cutaneous ulcers
Since its first description in 1985, cutaneous ulcers, classically found on the leg, have become an increasingly recognized HU
2,23–25
side effect.23 Reported frequencies range from 7 to 10%
but have been as low as 3.5–5% in larger studies.14,20 Chaine et al. observed cutaneous ulcers in 29% of patients, however a majority of these patients had a previous history of SCD ulcers, suggesting that HU could act synergistically with other vascular abnormalities.15 Similarly, Antonioli et al. found that over half of their patients with ulcers had at least one concurrent risk factor, such as hypertension, peripheral vascular disease, diabetes, or preceding trauma.14
Ulcers typically occur on the distal lower extremities in the perimalleolar or pretibial regions, can be single or multiple, and
have led to improvement or recovery including dextranomer dressing, prostaglandins E1 and I2, topical granulocyte stimulat- ing factor, topical fibroblast growth factor, skin grafting, and hyperbaric oxygen.23
Dermatomyositis-like eruption
Hydroxyurea therapy has also been associated with an interface dermatitis initially described in 1975 as a lichen planus-like eruption.12 This was later re-characterized by Senet et al. as a dermatomyositis-like eruption (DM-LE) because of its clinical and histologic similarities to dermatomyositis.29,30 Although described mostly in case reports, one larger study reported a frequency of 4.4% of patients on HU.13 DM-LE presents as ery- thematous, violaceous, and desquamative papules and plaques
Figure 4 Leg ulcers associated with hydroxyurea on the perimalleolar area and squamous cell carcinoma in the ankle (black arrow)
on the dorsal hands and the face, specifically in the periorbital that HUSD may be a more appropriate term as it elucidates the
29,31
region.
Unlike dermatomyositis, it is not associated with
underlying neoplastic process, while DM-LE has historically
myopathy or malignancy.30 Histologic exam findings include interface dermatitis, vacuolar alteration of basal cells, dyskera- totic keratinocytes, and hyper- or hypogranulosis.30,31 Average latency periods reported by three studies were 49.4 months,30 60 months,29 and 61 months of HU therapy.32 DM-LE typically resolves 10 days to 180 months after HU discontinuation, but skin atrophy may persist.30
Nonmelanoma skin cancers and premalignant conditions Numerous HU-associated nonmelanoma skin cancers (HU- NMSC) and premalignant conditions have been described,
been considered a benign entity.30 Nonetheless, they suggest considering HU-associated DM-LE as a premalignant precursor of HU-NMSC that may warrant HU discontinuation and close follow-up.30
Other
Rarely, HU therapy may lead to cutaneous side effects other than those mentioned above. There have been two reports of panniculitis associated with long-term HU that presented as an erythematous swollen knee in one patient and multiple erythe- matous plaques and subcutaneous nodules on the lower
including actinic keratoses, Bowen’s disease, keratoacan-
40,41
extremities and back in the other.
The first case improved
thomas, SCC, squamous dysplasia, basal cell carcinoma (BCC), and Merkel cell carcinoma.33,34 Reported frequencies include 3.1613 and 3.8%33 of patients on HU, and over 20 cases have been reported.33 These may be more common in those treated for MPD than for SCD because of the darker skin tone, younger age, and shorter treatment duration of SCD patients.15 Lesions may be isolated or present as part of a multiple NMSC eruption in photodistributed areas,30 and eruptions often involve multiple different types of skin cancers.34,35 NMSC typically develops after long-term HU use with an average latency period of 79 months, although it has been reported after only 6 months of HU.36 Treatment often requires HU discontinuation in con- junction with standard surgical intervention, however, improve- ment in lesions after only HU discontinuation has occurred.30 If HU therapy must be continued, chemoprevention with the use of oral retinoids, photoprotection, and aggressive surgical ther- apy may be indicated.30,33 Details regarding specific types of HU-NMSCs and premalignant conditions are summarized in Table 1.
Dermatomyositis-like eruption vs. HU-associated squa- mous dysplasia
Two studies describe patients with DM-LE who were found to have dysplastic keratinocytes as well as p53 mutation expres- sion within lesions, some of whom developed multiple NMSCs (Fig. 5).30,31 Similarly, HU-associated squamous dysplasia (HUSD) was first described by Sanchez-Palacios and Guitart in 2004 as a premalignant condition with p53 mutation expression that acts as a precursor to multiple SCC eruptions. Several additional cases have since been reported. All patients diag- nosed with HUSD have had rashes resembling those seen in DM-LE, albeit with more actinic damage and less resemblance
with low-dose prednisone but required HU discontinuation for complete resolution.40 The second case was also associated with medium-sized vessel vasculitis and while HU cessation was not an option, treatment with 7.5 mg of methotrexate daily led to significant improvement.41
There have been three cases of HU-associated vasculitis including a case of leukocytoclastic vasculitis identified within a leg ulcer,42 leukocytoclastic vasculitis observed in a patient with multiple skin lesions including keratotic papules, psoriasiform plaques, and keratoderma,43 and the case of medium-sized vessel vasculitis associated with panniculitis described above.41 HU has also been associated with one case of systemic and one case of cutaneous lupus erythematosus, with patients showing positive antinuclear antibodies and high antihistone immunoglobulin G levels.44,45 There has been one case of HU- associated scleroderma-like syndrome in a patient on HU for 12 years who had complete resolution after HU discontinua- tion.46 Other less well-described cutaneous side effects include ichthyosis,5,15 porokeratosis,47 erythema,12,13 palmoplantar ker- atoderma,15 actinic psoriasis,5 and edema of the face and
5,12
legs.
Systemic side effects
Although HU is generally well-tolerated,3 it has several systemic side effects that are characterized in Table 2.
Management and reappraisal
Many of the common and less serious cutaneous HU side effects, such as hyperpigmentation, xerosis, or mucosal lesions, are manageable and eventually resolve.5 Furthermore, most
33,37,38
to the rash observed in dermatomyositis.
Sanchez and
patients do not want to alter HU therapy for these lesions.11 For
Palacios suggested the concept of HUSD as a separate condi- tion than DM-LE, whereas Kalajian et al. proposed they are manifestations of a common underlying HU-associated photo- toxic process.30,33 Thus, controversy exists over whether DM- LE and HUSD represent a clinical spectrum of the same condi- tion or are two separate entities. Kalajian et al. also suggests
the more serious conditions including ulcers, DM-LE, HUSD, and NMSC, HU discontinuation should be the first line treatment option, followed by dose reduction or intermittent scheduling. Dermatologists should also consider the use of the previously described surgical or topical therapies for cutaneous ulcers and standard surgical intervention along with chemoprevention for
Table 1 Hydroxyurea-associated nonmelanoma skin cancers and premalignant conditions
Average latency
Type Frequency Clinical/histologic presentation period Outcomes
Actinic
keratoses
0.22–30.7%16 Isolated or part of multiple NMSC
eruption16,35
46 months14
– After HU d/c, may improve or resolve16
– Without HU d/c, may develop into SCC14
HUSD
8reported
33,37,38
cases
Photodistributed patches of erythema with actinic damage and xerosis, may resemble DM-LE33,37
Biopsy may reveal areas of AKs, SCC, and
BCC
Lesions have p53 mutation33
7–20 years33,37,38 – Course following HU d/c not well-described
– Treatment with ingenol mebutate gel had 87.5% response in one study38
SCC
0.09–3.0%14–16
May be part of a multiple NMSC eruption21 May present as chronic nonhealing ulcer28 Over 90% contain p53 mutation30
6 months to
>2 years33,36
Developed 2 years after HU d/c21
– Most resolve with HU d/c and surgical excision, but metastasis and death has been reported33
– Remission with 6–10 weeks of 5% imiquimod observed36
BCC
0.09% in
one study14
May be part of a multiple NMSC eruption34,35 60 months14
– Resolution after surgical excision34,35
– Course following HU d/c not well described
Merkel cell
carcinoma
2 reported cases34,39,*
May be part of a multiple NMSC eruption May show high mitotic activity and CK20
positivity34,39
9years34
8 years after HU cessation and
2 years
of prior use39
– Course following HU d/c not well described
NMSC, nonmelanoma skin cancer; HU, hydroxyurea; d/c, discontinuation; SCC, squamous cell carcinoma; HUSD, hydroxyurea-associated squamous dysplasia; DM-LE, dermatomyositis-like eruption; AKs, actinic keratoses; BCC, basal cell carcinoma.
*Uncertain whether associated with HU therapy.
Therefore, while these serious cutaneous side effects occur in a substantial proportion of patients, most resolve with HU dis- continuation and proper dermatologic management. Thus, it appears that the benefits outweigh the risks in a majority of patients, especially since those who do discontinue HU therapy often succumb to their hematologic illness.13,33 Nonetheless, these conditions may result in significant morbidity and even mortality,33 and prompt diagnosis and treatment is vital to good patient outcomes. As many providers may be unaware or unable to identify these serious conditions, all patients on HU therapy should undergo regular dermatologic screening.23 This is especially important for patients on long-term HU therapy because of their increased risk for serious conditions, and screening may be warranted even after HU discontinuation as NMSC after cessation has been reported.21,39 Therefore, it is crucial for dermatologists to be aware of these various cuta-
Figure 5 Squamous cell carcinoma arising from the
dermatomyositis-like eruption on dorsum of hands
NMSC. Although previously considered to be benign, multiple studies have suggested the potential premalignant state of DM- LE. Thus, in addition to HU discontinuation, close dermatologic follow-up and biopsy of any ulcerated lesions is warranted.30 In general, any persistent ulcerative lesion should be biopsied to rule out malignancy.22,28
neous side effects and their management.
True or False educational questions (answers provided after references)
1Hydroxyurea desensitizes cells to radiation-induced damage.
2The dose of corticosteroids used in the treatment of hypere- osinophilic syndrome can be reduced by adding hydroxyurea as a steroid-sparing agent.
Table 2 Systemic side effects of hydroxyurea
2Simeonovski V, Breshkovska H, Duma S, et al. Hydroxyurea associated cutaneous lesions: a case report. Open Access
Side effects
Hematologic
Gastrointestinal
Fever
Hepatitis
Renal failure
Neurologic
Azoospermia
Pulmonary
Characteristics
Leukopenia, anemia, thrombocytopenia, rarely bleeding or leukemic transformation3,23
Most common side effect, typically mild and
reversible3
Nausea, vomiting, abdominal pain, and
diarrhea14
Very common, typically transient and occurs
at high doses14
May be associated with macular and papular
rash23
May resolve after HU cessation suggesting
possible drug fever48
Transient and reversible, associated with elevated LFTs,8 although some studies suggest HU has no effect on liver function3
Transient and associated with elevated RFTs,8 although some studies suggest HU has no effect on renal function3
Rarely observed, includes headache, dizziness, disorientation, hallucinations, and convulsions49
Reversible inhibition of spermatogenesis
leading to infertility50
Rare, includes pulmonary fibrosis,
pneumonitis, and bronchiolitis obliterans8,23
Maced J Med Sci 2018; 6: 1458–1461.
3McGann PT, Ware RE. Hydroxyurea therapy for sickle cell anemia. Expert Opin Drug Saf 2015; 14: 1749–1758.
4Yarbro JW. Mechanism of action of hydroxyurea. Semin Oncol 1992; 19(3 Suppl 9): 1–10.
5Kumar B, Saraswat A, Kaur I. Mucocutaneous adverse effects of hydroxyurea: a prospective study of 30 psoriasis patients. Clin Exp Dermatol 2002; 27: 8–13.
6Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 4. Guidelines of care for the management and treatment of psoriasis with traditional systemic agents. J Am Acad Dermatol 2009; 61: 451–485.
7Menter A, Gelfand JM, Connor C, et al. Joint American Academy of Dermatology-National Psoriasis Foundation guidelines of care for the management of psoriasis with systemic nonbiologic therapies. J Am Acad Dermatol 2020; 82: 1445–1486.
8Lee ES, Heller MM, Kamangar F, et al. Hydroxyurea for the treatment of psoriasis including in HIV-infected individuals: a review. Psoriasis Forum 2011; 17: 180–187.
9Ogbogu PU, Bochner BS, Butterfield JH, et al. Hypereosinophilic syndrome: a multicenter, retrospective analysis of clinical characteristics and response to therapy. J Allergy Clin Immunol 2009; 124: 1319.
10Dahabreh IJ, Giannouli S, Zoi C, et al. Management of hypereosinophilic syndrome: a prospective study in the era of molecular genetics. Medicine 2007; 86: 344.
11O’branski EE, Ware RE, Prose NS, Kinney TR. Skin and nail
HU, hydroxyurea; LFTs, liver function tests; RFTs, renal function tests.
3The dosage and duration of hydroxyurea therapy does not relate to the risk of serious side effects such as cutaneous ulceration or malignancy.
4Nail hyperpigmentation is the most common type of hyper- pigmentation.
5Cutaneous hyperpigmentation may present as isolated patches or diffuse body hyperpigmentation.
6Mucosal ulcers often persist, and this is not a cause for con- cern.
7Hydroxyurea discontinuation is the only treatment option shown to lead to cutaneous ulcer resolution.
8Dermatomyositis-like eruption may represent a premalignant precursor to a multiple nonmelanoma skin cancer eruption.
9Because of the serious cutaneous side effects of hydrox- yurea therapy, the benefits do not outweigh the risks, and the drug should be avoided.
10All patients on hydroxyurea therapy should undergo regular dermatologic screening.
References
1 Boyd AS, Kenneth H, Neldner MD. Hydroxyurea therapy. Acad Dermatol 1991; 25: 518–524.
changes in children with sickle cell anemia receiving hydroxyurea therapy. J Am Acad Dermatol 2001; 44: 859–861.
12Kennedy BJ, Smith LR, Goltz RW. Skin changes secondary to hydroxyurea therapy. Arch Dermatol 1975; 111: 183–187.
13Vassallo C, Passamonti F, Merante S, et al. Muco-cutaneous changes during long-term therapy with hydroxyurea in chronic myeloid leukaemia. Clin Exp Dermatol 2001; 26: 141–148.
14Antonioli E, Guglielmelli P, Pieri L, et al. Hydroxyurea-related toxicity in 3,411 patients with Ph’-negative MPN. Am J Hematol 2012; 87: 552–554.
15Chaine B, Neonato MG, Girot R, Aractingi S. Cutaneous adverse reactions to hydroxyurea with sickle cell disease. Arch Dermatol 2001; 137: 467–470.
16Salmon-Ehr V, Leborgne G, Vilque JP, et al. Secondary cutaneous effects of hydroxyurea: prospective study of 26 patients from a dermatologic consultation. Rev Med Interne 2000; 21: 30–34.
17Nguyen AL, K€orver JE, Theunissen CC. Longitudinal melanonychia on multiple nails induced by hydroxyurea. BMJ Case Rep 2017; 2017. https://doi.org/10.1136/bcr-2016-218644
18Lee KP, Vangipuram RK, Klimas NK, et al. Hydroxyurea- induced hyperpigmentation with iron deposition. Dermatol Online J 2019; 25.
19Shapiro J, Otberg N. Hair Loss and Restoration. Boca Raton: CRC Press, 2015.
20Latagliata R, Spadea A, Cedrone M, et al. Symptomatic mucocutaneous toxicity of hydroxyurea in Philadelphia chromosome-negative myeloproliferative neoplasms: the Mister Hyde face of a safe drug. Cancer 2012; 118: 404–409.
21Esttieve E, Georgescu V, Heitzmann P, Martin L. Multiple skin and mouth squamous cell carcinomas related to long-term
treatment with Hydroxyurea. Ann Dermatol Venereol 2001; 128: 919–921.
22De Benedittis M, Petruzzi M, Giardina C, et al. Oral squamous cell carcinoma during long-term treatment with hydroxyurea. Clin Exp Dermatol 2004; 29: 605–607.
23Quattrone F, Dini V, Barbanera S, Zerbinati N, Romanelli M. Cutaneous ulcers associated with hydroxyurea therapy. J Tissue Viability 2013; 22: 112–121.
24Herntiandez-Boluda JC, Alvarez-Larrtian A, Gtiomez M, et al. Clinical evaluation of the European LeukaemiaNet criteria for clinicohaematological response and resistance/intolerance to hydroxycarbamide in essential thrombocythaemia. Br J Haematol 2011; 152: 81–88.
25Hwang S-W, Hong S-K, Kim S-H, Seo J-K, Lee D, Sung H-S. A hydroxyurea-induced leg ulcer. Ann Dermatol 2009; 21: 39–41.
26tiDemircay Z, C€omert A, Adıg€uzel C. Leg ulcers and hydroxyurea: report of three cases with essential thrombocythemia. Int J Dermatol 2002; 41: 872–874.
27Fioramonti P, Fino P, Parisi P, et al. A case of hydroxyurea- induced leg ulcer after definitive treatment suspension in a patient affected by thrombocythemia: effectiveness of a new collagenase. In Vivo 2012; 26: 1053–1056.
28Antar A, Ishak RS, Otrock ZK, et al. Successful treatment of hydroxyurea-associated chronic leg ulcers associated with squamous cell carcinoma. Hematol Oncol Stem Cell Ther 2014; 7: 166–169.
29Senet P, Aractingi S, Pornkuf M, Perrin P, Duterque M. Hydroxyurea-induced dermatomyositis-like eruption. Br J Dermatol 1995; 133: 455–459.
30Kalajian AH, Cely SJ, Malone JC, et al. Hydroxyurea-associated dermatomyositis-like eruption demonstrating abnormal
epidermal p53 expression: a potential premalignant manifestation of chronic hydroxyurea and UV radiation exposure. Arch Dermatol 2010; 146: 305–310.
31de Unamuno-Bustos B, Ballester-Stianchez R, Sabater Marco V, Vilata-Corell JJ. Dermatomyositis-like eruption associated with hydroxyurea therapy: a premalignant condition? Actas Dermosifiliogr 2014; 105: 876–878.
32Daoud MS, Gibson LE, Pittelkow MR. Hydroxyurea dermopathy: a unique lichenoid eruption complicating long-term therapy with hydroxyurea. J Am Acad Dermatol 1997; 36: 178–182.
33Sanchez-Palacios C, Guitart J. Hydroxyurea-associated squamous dysplasia. J Am Acad Dermatol 2004; 51: 293–300.
34Wiechert A, Reinhard G, T€uting T, et al. Multiple skin cancers in a patient treated with hydroxyurea. Hautarzt 2009; 60: 651–652, 654.
35Disdier P, Harle JR, Grob JJ, et al. Rapid development of multiple squamous cell carcinomas during chronic granulocytic leukemia. Dermatologica 1991; 183: 47–48.
36Saraceno R, Teoli M, Chimenti S. Hydroxyurea associated with concomitant occurrence of diffuse longitudinal melanonychia and multiple squamous cell carcinomas in an elderly subject. Clin Ther 2008; 30: 1324–1329.
37Schleußinger TM, Dyall-Smith D, Field LM. Hydroxyurea- associated squamous dysplasia in a monozygotic twin. J Am Acad Dermatol 2011; 65: 679–680.
38Grandi V, Delfino C, Pimpinelli N. Ingenol mebutate in the treatment of ’Hydroxyurea-induced Squamous Dysplasia’: a single centre experience. J Eur Acad Dermatol Venereol 2016; 30: 1129–1132.
39Bouldouyre MA, Avril MF, Gaulier A, Sigal-Grinberg M. Association of cutaneous side-effects of hydroxyurea and neuroendocrine carcinoma. Eur J Dermatol 2005; 15: 268–270.
40Ogawa Y, Akiyama M. Non-infectious panniculitis during hydroxyurea therapy in a patient with myeloproliferative disease. Acta Derm Venereol 2016; 96: 566–567.
41Mattessich S, Ferenczi K, Lu J. Successful treatment of hydroxyurea-associated panniculitis and vasculitis with low-dose methotrexate. JAAD Case Rep 2017; 3: 422–424.
42Kato N, Kimura K, Yasukawa K, Yoshida K. Hydroxyurea- related leg ulcers in a patient with chronic myelogenous leukemia: a case report and review of the literature. J Dermatol 1999; 26: 56–62.
43Worley B, Glassman SJ. Acral keratoses and leucocytoclastic vasculitis occurring during treatment of essential thrombocythaemia with hydroxyurea. Clin Exp Dermatol 2016; 41: 166–169.
44Layton AM, Cotterill JA, Tomlinson IW. Hydroxyurea-induced lupus erythematosus. Br J Dermatol 1994; 130: 687–688.
45Yanes DA, Mosser-Goldfarb JL. A cutaneous lupus erythematosus-like eruption induced by hydroxyurea. Pediatr Dermatol 2017; 34: e30–e31.
46Garctiıa-Marttiınez FJ, Garctiıa-Gavtiın J, Alvarez-Ptierez A, et al. Scleroderma-like syndrome due to hydroxyurea. Clin Exp Dermatol 2012; 37: 755–758.
47Kanitakis J, Arbona-Vidal E, Faure M. Porokeratosis in patients with polycythemia rubra vera: a new side effect of hydroxyurea? J Eur Acad Dermatol Venereol 2012; 26: 1040–1041.
48Braester A, Quitt M. Hydroxyurea as a cause of drug fever. Acta Haematol 2000; 104: 50–51.
49DeAngelis LM, Posner JB. Side effects of chemotherapy. In: LR Rogers, eds. Neurologic Complications of Cancer, 2nd edn. New York: Oxford University Press, 2009: 447.
50Masood J, Hafeez A, Hughes A, Barua JM. Hydroxyurea therapy: a rare cause of reversible azoospermia. Int Urol Nephrol 2007; 39: 905–907.
Answers to questions
1False. Hydroxyurea sensitizes cells to radiation-induced dam- age.
2True.
3False. Cutaneous ulceration and malignancy are typically seen in patients on higher doses for longer periods of time.
4True.
5True.
6False. Most mucosal ulcers resolve within 3 months and per- sistent ulceration warrants histopathologic examination to exclude malignancy.
7False. Hydroxyurea dose reduction or intermitted scheduling, as well as standard surgical wound therapy have led to cuta- neous ulcer resolution.
8True.
9False. As many of the more common side effects are benign and many serious conditions resolve with hydroxyurea dis- continuation, the benefits appear to outweigh the risks for most individuals.NSC-32065
10True.