Pityriasis lichenoides et varioliformis acuta subsequent to mifepristone and misoprostol: Mere coincidence or something more?

A 32-year-old primigravida woman presented to the dermatology outpatient department with multiple intensely itchy, erythematous papules with central vesiculation and hemorrhagic crusts for 1 week. She had received combipack containing oral mifepristone (200mg) and sublingual misoprostol (800 µg), 20 days prior to the cutaneous eruption for medical termination of pregnancy (MTP) with successful procedure. Currently, she was in a post-abortive state (on ultrasound confirmation from gynecologist) during the presentation. Despite repeated inquiries, the patient did not reveal any other drug intake or prodrome such as fever, sore throat, cough, or gastrointestinal symptoms. She denied prior history of a similar episode.

Cutaneous examination revealed multiple lesions in various stages of evolution, including barely elevated, dusky erythematous papules with central haemorrhagic and necrotic crusts and vesiculation producing a targetoid appearance and violaceous macules with a fine collarette of scales, on the trunk and extremities, with sparing of palms, soles, and mucosae [Figures 1a and b]. Her systemic examination was normal. Possibilities of drug-induced erythema multiforme and pityriasis lichenoides et varioliformis acuta (PLEVA) were considered. Histopathological evaluation from a fresh papule revealed basket-weave hyperkeratosis, focal parakeratosis, irregular acanthosis, multiple necrotic keratinocytes in suprabasal epidermis, vacuolar basal cell degeneration with mild papillary dermal infiltrate of eosinophils and lympho-histiocytesand extravasation of erythrocytes, confirming the diagnosis of PLEVA [Figures 2a and b]. The Naranjo causality score was 4, indicating a ‘possible’ adverse drug reaction. Her blood investigations, such as complete blood count, liver and renal function tests, chest x-ray, stool and urine analysis, were normal. She was treated with oral prednisolone (30mg/day tapered 10mg every weekly over 3 weeks.) along with levocetrizine 5 mg at night and methotrexate 15mg per week tapeered 5 mg per week over 1.5 months, and her lesions subsided within 2 weeks [Figures 3a and b].

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Figure 1:

Multiple erythematous to targetoid papules with central haemorrhagic necrosis crusting, and healing with violaceous macules a) on the chest b) over the right forearm.

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Figure 2a:

Skin biopsy from a papule showed basket weave orthokeratosis, vacuolar interphase change (green arrow) along with perivascular moderate infiltrates (red arrow) (Haematoxylin & eosin, 50x).

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Figure 2b:

Histopathology demonstrates multiple basal and suprabasal necrotic keratinocytes (white arrows), confluent basal cell vacuolar degeneration, moderate upper dermal and perivascular lymphohistiocytic and eosinophilic infiltrates (green arrow) with extravasated erythrocytes (black circles) (Haematoxylin & eosin, 400x).

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Figure 3:

Complete clearance of vesicles and necrosis with post inflammatory hyperpigmentation a) on the chest and b) forearms.

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Pityriasis lichenoides is a rare inflammatory eruption that encompasses PLEVA and pityriasis lichenoides chronica (PLC). PLEVA generally presents as an acute-to-subacute polymorphous skin eruption of erythematous macules that evolve into papules with micaceous scale at the periphery, distributed symmetrically on the trunk, buttocks, and proximal extremities. Lesions may undergo haemorrhagic necrosis and heal with varioliform scars and post-inflammatory hyper- or hypopigmentation.¹ The etiopathogenesis remains unclear, with few authors considering it to be a hypersensitivity reaction to various antigens (viral or bacterial antigens).² Drug-induced PLEVA secondary to cephalexin, antidepressants, statins, tafasitamab, lenalidomide, pemetrexed, and infliximab has been described, after an incubation period ranging from a few weeks to 5 months.²

It is often difficult to differentiate drug-induced PLEVA from classical PLEVA clinically and histopathologically. A strong temporal correlation with drug intake, its complete resolution following drug cessation, unlike classical PLEVA which undergoes a remitting and relapsing course, and a dermal eosinophilic infiltrate may somewhat favour drug-induced PLEVA.³ Drug rechallenge is the gold standard for confirming the diagnosis, which, however, could not be undertaken in our patient since MTP drugs cannot be administered to normal individuals.²,³ Nevertheless, a four-month follow-up period after discontinuation of methotrexate showed no recurrence of cutaneous lesions.

Erythema multiforme (EM) shows acute, self-limiting episodes of inflammatory, targetoid papules with or without mucosal involvement. Histopathology demonstrates basket-weave orthokeratosis often without parakeratosis, apoptotic keratinocytes, intercellular spongiosis, basal layer hydropic degeneration, and lichenoid lymphocytic infiltrates with or without eosinophils.⁴ Differentiating EM from PLEVA becomes particularly challenging in the absence of key histopathological features such as parakeratosis and lymphocytic vasculitis. The diagnostic complexity was further compounded in our patient by reported cases of EM induced by misoprostol and mifepristone.⁴ However, the morphology of lesions with sparing of the mucosal and palmo-plantar region and presence of parakeratosis and extravasated dermal RBCs, tip the diagnosis towards PLEVA over EM. Misoprostol has been shown to produce cutaneous adverse drug reactions (CADR), such as anaphylactic shock, erythema multiforme, toxic epidermal necrolysis, and lichenoid drug eruption. However, CADR to mifepristone is rare, with few reports of mifepristone-induced erythema multiforme.^5-7

Although we could not clearly explain the exact patho-mechanism of drug-induced PLEVA subsequent to mifepristone and misoprostol, we hereby emphasise the rare phenomenon where the drug could be a trigger for PLEVA rather than a mere coincidence.