Acute generalised exanthematous pustulosis following intravitreal Ranibizumab

Abstract

Acute generalised exanthematous pustulosis, or AGEP, is a well documented cutaneous drug reaction. It typically occurs within 48 hours of oral antibiotics, but can be caused by other medications and, occasionally, after viral infections. We present a case of AGEP following intravitreal injection of Ranibizumab, a monoclonal antibody vascular endothelial growth factor inhibitor.

INTRODUCTION

Acute generalised exanthematous pustulosis (AGEP) is a well described cutaneous drug reaction, but has also been reported following viral infections (1). Typically, the reaction usually occurs within 48 hours following antibiotics (the most common cause of AGEP), but may take longer to develop after other medications – between 7 and 12 days (1). Clinically AGEP is characterised by a subcorneal pustular dermatosis, extending centrifugally from the torso onto the upper limbs. It is associated with malaise, fever and neutrophilia at the outset. The eruption typically resolves spontaneously without treatment, although re‐exposure may lead to more severe disease evolving into erythroderma. Causality can be hard to prove without re‐exposure, although patch testing can occasionally be associated with further AGEP and is not without its risks (2). Thus where there is a temporal relationship between exposure and symptoms, with supportive histological findings, any new medications should be suspected and avoided if possible.

CASE REPORT

We present a case of AGEP in a 90‐year old lady following an intravitreal injection of 0·5 mg Ranibizumab (Lucentis^®), a monoclonal antibody vascular endothelial growth factor (VEGF) inhibitor. Four days after her first intravitreal injection of Ranibizumab for age‐related ‘wet’ macular degeneration, the patient experienced malaise and developed an erythematous eruption on the upper thighs. The eruption continued to progress despite treatment with topical corticosteroids (0·1% betamethasone valerate, initiated immediately after the rash appeared) and oral corticosteroids (20 mg prednisolone, started 2 weeks after onset). After 3 weeks the patient had a florid erythematous rash involving the torso and limbs, with characteristic fine epidermal desquamation and small pustules at the leading edge (Figure 1). With the exception of Ranibizumab, there had been no additions or changes to her regular medications (quinine bisulphate, ascorbic acid, omeprazole, alendronic acid, ferrous sulphate, simvastatin, aspirin, paracetamol, fentanyl transdermal patch, dorolamide and timolol eye drops (2% + 0·5%) and Travoprost eye drops) over the preceding 2 months, no recent systemic infection and no history or family history of psoriasis. Examination did not show maceration of the toe webs, and skin scrapings of the eruption were negative by microscopy and mycological culture. Histology showed spongiosis with subcorneal microabcesses along the epidermis, with exocytosis of neutrophils and scattered apoptotic keratinocytes. The papillary dermis contained a perivascular mixed inflammatory infiltrate with predominantly lymphocytes and neutrophils with small numbers of eosinophils. There were no features of vasculitis (Figure 2) and PAS stain was negative. The rash resolved spontaneously 6 weeks after the initial appearance.

Figure 1.

Week 3 after intravitreal injection of Ranibizumab. Dramatic erythematous skin eruption characterised by superficial exfoliation progressing along a boarder studded with epidermal pustules.

Figure 2.

Histology showing spongiosis with subcorneal microabcesses along the epidermis, with exocytosis of neutrophils and scattered apoptotic keratinocytes.

DISCUSSION

Ranibizumab is a monoclonal antibody fragment derived from Bevacizumab, and by blocking VEGF works as an angiogenesis inhibitor, reducing choroidal neovascularisation and disease progression (3). Ranibizumab is licensed for treatment of age‐related macular degeneration and is injected intravitreally, typically every 1–3 months. Approximately 0–5% of individuals have circulating antibodies against Ranibizumab, rising to a maximum of 8% in those treated with the drug. Even after intravitreal injection, human studies have shown that serum concentrations up to 1·5 ng/ml are reached, with a half life of 9 days (4). Other VEGF inhibitors, such as bevacizumab (Avastin^®), sunitinib (Sutent^®) and sorafenib (Nexavar^®) are given parenterally for a variety of cancers, and are associated with numerous cutaneous side effects, such as pyoderma gangrenosum, hand‐foot syndrome, skin discolouration and stomatitis (5). Imatinab, an inhibitor of Bcr/Abl tyrosine kinase activity which indirectly inhibits VEGF (6), has been reported as causing AGEP (7). We believe that this case represents the first description of AGEP caused by intravitreal Ranibizumab.