Cutaneous Cell-Mediated Delayed Hypersensitivity to Intravitreal Bevacizumab

Abstract

The literature contains few reports describing autoimmune reactions to intravitreal bevacizumab and no Type-IV delayed hypersensitivity reactions. This was unexpected, as administration of intravenous bevacizumab has frequently caused dermatologic side-effects. This difference was likely attributable in part to the minimum 300-times difference between intravitreal versus intravenous dosing. Here, we present a case of a 52-year-old male who was treated with plaque brachytherapy for a subfoveal choroidal melanoma. The patient was treated with intravitreal bevacizumab for macular edema, retinal detachment and to delay radiation retinopathy. Following his eighth injection, the patient experienced pruritus, rashes, and progressive exacerbations associated with subsequent injections. Cessation of bevacizumab with or without medication (e.g., oral steroid, antihistamine) resulted in complete remission. Switching to periodic intravitreal aflibercept resulted in no additional cutaneous reactions. Physicians administering intravitreal bevacizumab should be aware of this potential systemic side-effect. Its delayed time course facilitates identification and, thus, treatment to resolution.

Introduction

Systemic anti-vascular endothelial growth factor (VEGF) bevacizumab (Avastin, Genentech, San Francisco, CA, USA) has been used for treating brain, colon, breast, and kidney malignancies. Associated allergic reactions have been reported following intravenous administration ranging from nonspecific morbilliform rashes to exfoliative dermatitis (Type-IVb and IVc hypersensitivity reactions).[1]

In contrast, a significantly lower dose of bevacizumab (typically 1.25 mg) has been employed in the vitreous humor to suppress macular edema associated with several pathologies. Although bevacizumab has not been approved by the Food and Drug Administration for ocular indications, many large trials have proven its efficacy. While one center has seen no significant cutaneous reactions during 10-years of treatment follow-up, several centers have implicated it as a source of cutaneous eruptions, including cutaneous lupus erythematosus, pityriasis rubra pilaris-like eruption, eczematous pruritic plaques and papules, and acneiform lesions.[2,3,4,5,6]

Herein, we describe a novel case in which a patient developed a morbilliform exanthema, temporally related and cumulatively increasing with periodic bevacizumab injections for radiation retinopathy.

Case Report

A 52-year-old Caucasian male was referred for the evaluation of a biopsy-proven spindle B, Subfoveal, American Joint Committee on Cancer T2-sized choroidal melanoma in his right eye. On initial presentation, his visual acuities were 20/20 OU, his anterior segments were quiet, and he was taking no systemic medications. Palladium-103 ophthalmic plaque brachytherapy was employed to destroy the melanoma. Macular edema due to his subfoveal melanoma, retinal detachment, and postradiation retinopathy were treated with intravitreal bevacizumab (2.5 mg), administered every 4 weeks.[6]

The bevacizumab used in treatment was supplied by Besse Medical (West Chester, OH, USA) and was drawn into syringes by Leiter's Compounding Laboratory (San Jose, CA, USA). It was stored at a temperature of 2°C–8°C (36°–46° Fahrenheit) and was taken from the refrigerator immediately before each injection. The patient was prepared with ophthalmic lidocaine gel (Akten, Akorn, Lake Forest, Illinois, USA) and Betadine^® (Alcon, Fort Worth, Texas, USA) before each injection.

While our patient received a total of 10 injections of bevacizumab, 3 days following the eighth injection, he began to experience generalized pruritus. This gradually resolved over 3 weeks. After his ninth injection, the pruritus returned, worsened and a rash appeared on his chest wall. This cutaneous rash was morbilliform (elevated 2–10 mm in diameter, red lesions with areas of confluence). Like the first incidence of pruritus, the rash appeared 3 days after the bevacizumab injection. This rash and pruritus again resolved gradually over 3 weeks. However, after the tenth injection, a more severe and widely distributed dermatological reaction erupted with moderate-to-severe erythematous maculopapular eruptions on the chest, abdomen [Figure 1a], shoulders [Figure 1b] and anterior thighs [Figure 1c]. The eye showed no symptoms of ocular inflammation.

Figure 1.

External Photographs. (a) The skin over the abdomen reveals a maculopapular drug-related exanthema. (b) The right upper back reveals a multifocal papular drug-related exanthema. (c) The right anterior leg reveals a multifocal maculopapular drug-related exanthema

The time course and presentation of this patient's rashes were consistent with a delayed sensitivity drug reaction to bevacizumab. Therefore, a short course of oral prednisone (Actavis Pharma, Parsippany, NJ, USA) and nonsedating antihistamines (levocetirizine dihydrochloride, Chattem Inc, Chattanooga, TN, USA) was prescribed. The patient was switched to monthly aflibercept (Eylea, Regeneron, Tarrytown, NY, USA) for radiation retinopathy prophylaxis. Subsequent visits revealed gradual resolution of the rash and no new cutaneous eruptions.

Discussion

Intravenous systemic bevacizumab treatment of colorectal cancer and breast cancer was frequently associated with cutaneous side effects following the standard treatment dosage of 5–15 mg/kg of bevacizumab. In contrast, skin reactions are rarely noted after low-dose bevacizumab (1.25–2.5 mg) administered into the vitreous. It was reasonable to assume this difference may be related to the lower dosages required for intravitreal therapy (rather than the route of administration). Our literature review found 5 reports of skin reactions after intravitreal injection of bevacizumab from 2009 to 2016.[2,3,4,5] These cases revealed 4 skin pathologies: Cutaneous lupus erythematosus, pityriasis rubra pilaris-like eruption, eczematous pruritic plaques and papules, and acneiform lesions.

Our patient's cutaneous rash was a delayed maculopapular rash with excoriation, erythema, and edema, classically seen with a Type IVb or IVc hypersensitivity drug reaction. The cutaneous manifestations of the first and second hypersensitivity reactions were noted to subside without prednisone or antihistamine intervention. However, each outbreak became more intense, leading to the patient's third outbreak being so extensive that prednisone and antihistamines were employed to treat the condition. Progressively worsening reactions following recurring intravitreal injections are consistent with Type IV, T-cell mediated hyper-responsiveness. At this point, the bevacizumab was switched to aflibercept, after which his outbreaks ceased, proving that bevacizumab was the etiologic agent. The delayed appearance of symptoms, the clinical course, along with the efficacy of oral steroids, also all support the diagnosis of a delayed-type hypersensitivity reaction to bevacizumab. In addition, we note that the same lidocaine anesthetic and Betadine® antisepsis was used before both bevacizumab and aflibercept. Therefore, these drugs cannot be implicated as causing his Type IV reaction.

Studies have shown that bevacizumab has an intravitreal half-life of 9.8 days, and a systemic half-life of 18.7 days, based on intravitreal injection of 1.25 mg.[7] A substantive systemic accumulation of bevacizumab occurs following successive monthly doses.[7] The patient received 8 total doses of bevacizumab at 4-week intervals before the first symptom of pruritus. Therefore, the delayed event course further supports the diagnosis of delayed hypersensitivity to intravitreal bevacizumab, based on its known pharmacokinetic properties.

Our patient's rash was widely distributed, as expected in Type IV drug-related hypersensitivity reactions. Lesions were concentrated at the apices of the shoulders (bilaterally) and extended into the anterior surfaces of the upper legs [Figure 1]. This distribution of skin lesions was unique, being more widely distributed than previous reports where cutaneous reactions to bevacizumab were limited to the scalp and hairline.[3,5]

All reported rashes associated with intravitreal bevacizumab have been resolved after discontinuation of the drug.[2,3,4,5] Similarly, once our patient's bevacizumab was replaced by aflibercept therapy, he had no further cutaneous reactions over 9 months. Physicians administering intravitreal bevacizumab should be aware of this potential cutaneous side effect, its delayed initial presentation, increasing intensity, response to anti-inflammatory medication and its resolution after cessation of bevacizumab.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Supported by The Eye Cancer Foundation, Inc. (https://eyecancercure.com). Dr. Finger has been awarded and holds US Patent # US 7,553,486 B2, issued Jun 30, 2009 “Anti-VEGF therapy for radiation induced vasculopathy.”

Conflicts of interest

There are no conflicts of interest.