Flagellate Drug Eruption (Flagellate Erythema, Flagellate Hyperpigmentation, Bleomycin Drug Eruption)
Are You Confident of the Diagnosis?
What you should be alert for in the history
The diagnosis of flagellate drug eruption is usually made in the context of a patient receiving chemotherapeutic agents. Bleomycin is most commonly implicated, but peplomycin (a bleomycin derivative) docetaxel and cisplatin have also been reported as causes. The causative medication may have been administered intravenously or intramuscularly. Flagellate erythema has also been reported after intralesional bleomycin injections for plantar warts, or after intrapleural or intraperitoneal instillation.
Characteristic findings on physical examination
Flagellate erythema is usually itchy. It may begin within 12 to 24 hours of medication administration, or its onset may be delayed for up to 6 months. Initially there are erythematous, or occasionally violaceous, linear streaks that may look like the skin has been whipped. These linear streaks may be urticarial or papulovesicular.
The eruption classically occurs on the chest, upper back, and shoulders, and is also reported to occur on the arms and legs. When the erythema fades, it leaves hyperpigmentation in the same configuration; the hyperpigmentation may persist for months. In some patients, the pruritus and erythema are minimal and hyperpigmentation is the predominant presenting sign.
Expected results of diagnostic studies
The clinical impression may be confirmed by a skin biopsy. Histopathologically, in the acute phase, the epidermis shows hyperkeratosis and focal parakeratosis, spongiosis, exocytosis of lymphocytes, and irregular acanthosis. There is vasodilation and edema in the dermis, along with a superficial perivascular lymphocytic infiltrate. Some eosinophils or neutrophils may be seen. Full thickness acantholysis, necrotic keratinocytes, or vacuolar degeneration of the basal layer have also been reported. More advanced lesions show less inflammation, along with basal layer hyperpigmentation and melanophages.
This very distinctive and striking eruption may be mimicked by the following diagnoses:
Dermatomyositis: flagellate erythema is a rare dermatologic manifestation in dermatomyositis. In one series, it was present in 5% of eighty-four patients. The linear streaks are more erythematous and violaceous, and less brown than those in bleomycin-induced flagellate erythema. They are also pruritic, usually raised, and typically located on the trunk.
Adult-onset Still’s disease: this is an uncommon acute or subacute systemic illness that presents with a high spiking fever, a sore throat, and a rash. The characteristic eruption consists of salmon-pink macules that wax and wane with the fever. The eruption is usually more prominent in sites of pressure. The Koebner phenomenon may be a feature. More rarely, a chronic eruption eventuates. This may resemble flagellate erythema. There are linear itchy reddish and brownish plaques that occur truncally and are persistent.
Shiitake mushroom dermatitis: cases are most frequently seen in Japan. The typical eruption occurs 24 to 48 hours after eating raw or partially cooked shittake mushrooms. Clinically, there are erythematous pruritic papules that coalesce to form linear plaques on the trunk, extremities, and sometimes, the face. Areas that the patient can’t reach are spared. The associated hyperpigmentation is short-lived. The eruption is thought to occur secondary to a reaction to lentinan, a polysaccharide with antitumor properties that is found in the mushroom.
Who is at Risk for Developing this Disease?
This is an idiosyncratic eruption and, as such, anyone receiving bleomycin is at risk. The incidence of the eruption with bleomycin therapy has been reported to be in the range of 8 to 20%. In one study, 66% of fifteen patients developed it. Although most cases occur after a dose of 100U, doses as low as 14U have been reported to initiate it.
A review of the reported literature showed that women and men are equally affected. However, the subgroup that seemed to develop the eruption most rapidly, even after low doses, was women with lymphoproliferative malignancies. Those who developed flagellate erythema a week or more out from treatment were men with nonlymphoproliferative malignancies.
What is the Cause of the Disease?
As stated above, bleomycin is the most common drug culprit. Peplomycin (a bleomycin derivative) and docetaxel have also been implicated.
The pathophysiologic events leading to this eruption are not entirely clear. Bleomycin is metabolized by a cysteine proteinase known as bleomycin hydrolase. In the skin, the enzyme has been shown to be present subcorneally, but not in the dermis. Bleomycin would therefore accumulate cutaneously, and dermatologic manifestations are thought to be due to a toxic effect of the drug.
Microtrauma, due to scratching, for example, is thought to play a role through disruption of the dermal vasculature with subsequent leakage of the drug into the dermis. Immunologic mechanisms, such as a type I response from bleomycin degranulating mast cells directly, or a type II response through antigen presentation, have also been proposed, but not proven.
Systemic Implications and Complications
There are no systemic complications from flagellate erythema.
Optimal Therapeutic Approach for this Disease
The acute pruritic phase of flagellate erythema may resolve spontaneously. In widespread or severely symptomatic cases, potent (betamethasone diproprionate 0.05% or equivalent) or ultrapotent (clobetasol 0.05% or equivalent) topical steroids or oral corticosteroids, along with orally administered antihistamines, provide relief. The eruption will occur on subsequent treatment cycles. Whether to continue bleomycin or not should be decided based on the risk/benefit ratio in each case. Factors such as the underlying malignancy and the severity of the eruption should be taken into account.
No treatment has been reported for the hyperpigmented phase. This manifestation has been reported as taking up to 6 months to resolve spontaneously.
The patient should be made aware that this eruption is due to the bleomycin (or peplomycin, or docetaxel) component of their chemotherapy. Topical and/or oral therapies for symptom and erythema relief should be offered. Future treatment decisions should be made in conjunction with the patient and his or her oncologist, and should be based on the severity of the eruption, the ease of its response to treatment, and the treatment options for the underlying malignancy.
Unusual Clinical Scenarios to Consider in Patient Management
Always bear in mind the differential diagnosis of flagellate erythema in these patients to ensure the unlikely scenario of a coexistent problem.
What is the Evidence?
Parodi, A, Caproni, M, Marzano, AV, De Simone, C, La Placa, M, Quaglino, P. "Dermatomyositis in 132 patients with different clinical subtypes: cutaneous signs, constitutional symptoms and circulating antibodies". Acta Derm Venereol. vol. 82. 2002. pp. 48-51.(An outstanding clinical series detailing the dermatologic findings, including flagellate erythema, in patients with dermatomyositis.)
Tallon, B, Lamb, S. "Flagellate erythema induced by docetaxel". Clin Exp Derm. vol. 33. 2008. pp. 276-7.(A case of docetaxel inducing the eruption.)
Yamamoto, T, Nishioka, K. "Flagellate erythema". Int J Dermatol. vol. 45. 2006. pp. 627-31.(An outstanding review of bleomycin-induced flagellate erythema and its differential diagnosis.)
Yamamoto, T. "Flagellate erythema induced by cisplatin". Clin Exp Dermatol. 2016 Mar 1.(A case of cisplatin inducing the eruption.)
Ziemer, M, Goetze, S, Juhasz, K, Elsner, P. "Flagellate dermatitis as a bleomycin-specific adverse effect of cytostatic therapy: a clinical-histopathologic correlation". Am J Clin Dermatol. vol. 12. 2011. pp. 68-76.(An excellent review detailing a clinical and histopathologic summary of bleomycin-induced flagellate erythema.)
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