Bullous Pemphigoid-like Skin Eruption during Treatment with Rivaroxaban: A Clinical Case Study.

Little has been documented about hypersensitivity reactions caused by treatment with rivaroxaban. This paper reports a bullous pemphigoid-like skin eruption that occurred in a 76-year-old female patient during rivaroxaban treatment. This case highlights the vigilance required by healthcare workers in recognising potential adverse effects of newly marketed drugs and in making medication changes when necessary. A bullous pemphigoid-like eruption due to treatment with rivaroxaban has not, to the best of the Authors' knowledge, been reported previously in the literature. LEARNING POINTS: Rivaroxaban can cause a bullous eruption apparently similar to epithelial toxic necrolysis (or to Stevens-Johnson syndrome).There is an apparent similarity between skin adverse events caused by the different anticoagulants.The anticoagulant responsible for the skin side-effects can be identified on clinical grounds by the correct differential diagnosis.

INTRODUCTION

Cutaneous drug eruptions are among the most common adverse drug reactions and may often represent a challenging diagnostic problem. While a single drug can elicit a range of reaction patterns, no reaction pattern is specific to a particular drug. Although the temporal link between initiation of drug therapy and the onset of a drug rash is critical for the diagnosis, drug reactions may also occur during chronic drug administration.

Blisters are a well-known manifestation of cutaneous reactions to drugs. In many types of drug reactions, bullae and vesicles may be found in addition to other manifestations. Bullae are usually noted in erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria, vasculitis, porphyria cutanea tarda, and phototoxic reactions[. Although drug-induced bullous pemphigoid eruptions are rare, they can be caused by certain drugs, such as furosemide, heparin, ibuprofen, captopril, and many others[.

Rivaroxaban (Xarelto®, Bayer Corporation, Pittsburgh, PA) is a new oral anticoagulant drug. It acts as a direct factor Xa inhibitor and is used in venous thromboembolism prophylaxis. This drug is increasingly prescribed because, as an oral drug, it is easily handled during therapy; moreover, no coagulation monitoring is needed, and it has a wide therapeutic index. However, phase III studies have listed hypersensitivity to rivaroxaban as ‘undetermined’[.

CASE DESCRIPTION

A 76-year-old female patient with a medical history of paroxysmal atrial fibrillation and depression was hospitalised on 10 January 2016 due to a pulmonary thromboembolism. During hospitalisation, the patient started sertraline 100 mg daily, rivaroxaban 20 mg daily, and furosemide 10 mg twice daily. Fifteen days after the start of therapy, the patient developed a rash characterised by urticarial plaques on her back, upper limbs, and anterior surfaces of her thighs. In addition, tense, sero-haemorrhagic blisters developed on both legs (Figs. 1 and 2). No lesions were observed on mucosae.

Figure 1

Bullous pemphigoid-like skin eruption on the legs

Figure 2

Bullous pemphigoid-like skin eruption on the legs

The patient was followed in the Internal Medicine and Dermatology Service. The tentative diagnosis was that of a bullous pemphigoid secondary to drug use or neoplastic aetiology. Given the known association between furosemide and bullous pemphigoid, its use was discontinued and the patient started on therapy using a topical corticosteroid, betamethasone cream, twice a day.

The results on the patient’s diagnostic exams were as follows: a WBC of 7220 with 14.4% eosinophils, platelets 197,000/μl, and ESR 60 mm/hr. The CEA, Ca 15-3, Ca 19-9, and Ca 125 results were within normal ranges. The search for anti-skin, anti-basement, epidermal membrane and anti-keratinocyte autoantibodies (indirect immunofluorescence [IIF] in peripheral blood) was negative. Histological examination disclosed intraepidermal blistering with eosinophils and apoptotic keratinocytes inside, with significant spongiosis in the neighbouring epidermis (Fig. 3). Discrete infiltrates of eosinophils were diffusely represented among spongiotic areas and throughout the upper part of the dermis in a perivascular and interstitial infiltrate pattern (Fig. 4). Immunofluorescence was negative for IgA, IgG, IgM, C3, and C1q.

Figure 3

Histological examination using H&E staining and low power magnification revealed intraepidermal blistering

Figure 4

Histological examination using H&E staining and medium power magnification revealed eosinophils in tiny collections that were abundantly present among spongiotic areas in the epidermis (arrow) and throughout the upper part of the dermis (arrowhead)

Two weeks after the use of furosemide had been discontinued, the cutaneous condition worsened; bullous lesions now appeared on the forearms (Fig. 5). At that time, rivaroxaban was discontinued and replaced with warfarin, while furosemide was reintroduced. A rapid improvement in the lesions was noted within 1 week, and no relapse occurred during the 12-month follow-up.

Figure 5

Bullous pemphigoid-like skin eruption on forearm

DISCUSSION

The diagnosis of bullous pemphigoid-like skin eruption due to rivaroxaban was established. Our differential diagnoses included haemorrhagic toxic necrolysis / heparin-induced thrombocytopenia and Stevens-Johnson syndrome (Table 1). However, the patient’s normal platelet count, negative Nikolsky’s sign, results on the direct immunofluorescence test, bullous eruption in the dermis-epidermis junction, and histologic findings ruled out these diagnoses. Histologically, drug-induced variants of bullous pemphigoid are similar to the typical form and are characteristically composed of eosinophil-rich subepidermal blisters[. In the initial stage, only eosinophilic spongiosis and numerous dermal eosinophils are present, with eosinophils lining up along the basement membrane[. At later stages, the blisters may appear to be intraepidermal as a result of keratinocyte regeneration. In the present case, these various morphological features were present and, in a concordant clinical context, were diagnostic for the disease. Negative immunofluorescence studies, as in this case, occur in 4% of the patients with bullous pemphigoid[.

Table 1

Differential diagnosis of a bullous skin eruption in patients undergoing anticoagulant therapy

	Steven-Johnson syndrome (SJS)	Bullous pemphigoid		Haemorragic skin eruptions
		Idiopathic	Drug-induced	Heparin-induced skin necrosis	Coumarin-induced skin necrosis
Clinical features	Rusty macules with or without epidermal detachment (<10% BSA) Atypical target lesions (papular lesions with two zones of colour changes, with papular, vesicular or flaccid bullous centre)	Multiple tense bullae arising on normal or erytemathous skin Bullae can rupture, leaving circular erosions with haemorragic crusts Urticarial papules and plaques, along with bullae containing serous fluid Pruritus and nonspecific eczematous lesions can precede At least 50% of patients have peripheral eosinophilia		Often associated with heparin-induced thrombocytopenia with thrombosis Necrosis starts with a small, erythematous and painful lesion that later extends to areas of necrosis	Pain, oedema and small subcutaneous haematoma, followed by erythematous or haemorrhagic changes in demarcated lesions that become bullous and can progress to gangrenous necrosis
Mucosal involvement	Severe	Rare	No
Distribution	Face, neck, trunk	Lower abdomen, thighs, forearms, legs		Injection site, but can also be generalised	Subcutaneous fatty tissue, eg breasts, thighs, abdomen and buttocks
Histological findings	Subepidermal blister with overlyng confluent necrosis of the entire epidermis; keratinocyte apoptosis is a hallmark of SJS Sparse perivascular infiltrate composed primarily of lymphocytes	Subepidermal bullae Infiltrate composed of neutrophils and eosinophils in the dermis and bulla cavity	Subepidermal bulla or intraepidermic	Microvascular thrombi in small vessels with minimal inflammation	Areas with thrombosis, microvascular injury and fibrin deposits in the postcapillary veins and small vessels
Presence of autoantibodies	Negative	DIF with IgG and/or C3 in the basement membrane zone IIF (+) in 70% of patients	DIF and IIF can be negative	Antibodies against heparin platelet factor-4 complexes
Others	Systemic symptoms are usually present (fever, hepatitis, cytopenias) Progression to toxic epidermal necrolysis is possible Nikolsky (+/−)	Nikolsky (−)		Platelet count drops by 50% compared with the baseline value within first 10–14 days of treatment	10 days after the onset of therapy Protein C or protein S deficiencies

Cutaneous reactions have been reported during anticoagulant therapy with coumarin derivatives and with unfractionated and low-molecular-weight heparins and heparinoids[. However, very few data regarding hypersensitivity reactions to rivaroxaban are available; we were only able to find two such cases in the literature[. Even though heparins, warfarin, and rivaroxaban have very different mechanisms of action, the clinical similarity of their epithelial side-effects is remarkable. In spite of this similarity, a differential diagnosis between the offending agents can be made with high confidence (Table 2).

Table 2

Bullous skin reactions to various substance groups with anticoagulant effects

Substance group according to site of action	Chemical name	Bullous skin reaction
Vitamin K antagonists	Coumarins	Haemorrhagic bullous eruption Skin necrosis
Antithrombin-III activators (heparins)	Glycosaminoglycans	Haemorrhagic bullous eruption Bullous-like eruption Stevens–Johnson syndrome / Toxic epidermal necrolysis Bulbous pemphigoid Skin necrosis
Direct factor Xa inhibitors	Xabans	Toxic skin eruption