Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) in Ophthalmology

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Article initiated by:

Samir Cayenne

All contributors:

Andrew Go Lee, MD, Clement Anozie, Saif Aldeen Alryalat, MD, Samir Cayenne, Rahul Nanduri, Beck Burgelin, Nagham Al-Zubidi, MD, Aroucha Vickers, DO, Osama Al Deyabat, MBBS

Assigned editor:

Osama Al Deyabat, MBBS

Review:

Assigned status Update Pending

 by Osama Al Deyabat, MBBS on May 12, 2023.

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Contributing Editors:	add

Introduction

Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) is an uncommon, adverse cutaneous reaction associated with certain medications, including broad spectrum antibiotics and cephalosporins. The criteria for diagnosing SDRIFE encompass the following elements: initial or repeated exposure to a systemic drug, manifestation of erythema in the gluteal or perianal region and/or V-shaped erythema in the inguinal area, engagement of at least one additional intertriginous site, symmetry in the affected regions, and the absence of systemic toxicity. Few studies have assessed its occurrence with drugs commonly used in ophthalmologic practice, and poses a significant clinical challenge as it has potential to impact the balance between pharmacological therapeutic value and adverse outcome.

Epidemiology

SDRIFE (previously known as drug-related “baboon syndrome”) is rare, with over 100 cases reported in literature since its first description in 1984. The reaction can be seen in patients of any age, with reported cases in patients as young as 18 months of age to 84 years, however, cases with children are rarer. Literature includes reports of SDRIFE in both genders, but adverse reaction prevalence is found higher in males with roughly a 3:1 male/female ratio.

Etiology and Risk Factors

The etiology of SDRIFE is predominantly linked to the use of antibiotics, particularly beta lactams such as amoxicillin. However, incidence of SDRIFE has also been noted in non-beta lactams, including but not limited to clindamycin, cotrimoxazole, and valacyclovir. SDRIFE is able to affect individuals of all ages, with a higher incidence in males.

Pathophysiology

SDRIFE is attributed to a delayed type IV hypersensitivity reaction. The rapid onset of the rash in SDRIFE can be attributed to the direct binding of the drug to T-cell receptors. Histological examinations of SDRIFE cases have revealed dermal infiltration characterized by CD3+ and CD4+ T cells, accompanied by an expansion of CD26 P-selectin. This protein, typically involved in recruiting memory or effector type 1 helper T cells to inflammatory sites, exhibits increased presence in the endothelial and keratinocyte layers. Histopathological findings in SDRIFE can vary, ranging from a superficial perivascular inflammatory infiltrate composed of lymphocytes and eosinophils, to subcorneal pustules, vacuolar changes, hydropic degeneration in the basal cell layer, and the formation of subepidermal bullae with necrotic keratinocytes.[] Following metabolism in the liver, acetazolamide is converted into its metabolites and acts as a hapten, triggering an immune response led by T cells, resulting in a cutaneous reaction. While still not completely understood, the immune reaction migrates to the skin in intertriginous and flexural regions, namely the axilla, gluteal cleft, antecubital and popliteal fossae.

Clinical Presentation

SDRIFE presents with a distinct clinical picture following drug treatment. Proposed diagnostic criteria includes a history of recent drug intake, sharply demarcated erythema of the gluteal/perianal region or V-shaped erythema of the inner thighs, involvement of at least one great flexure, symmetry, and absence of systemic organ involvement. Combination of ophthalmological and dermatological manifestations will point to adverse drug reaction, the result being colloquially described as “baboon syndrome” given the location of a red rash in the gluteal and perianal region.

Application in Ophthalmology

Adverse skin reactions have been noted to present itself in ophthalmology treatment, including epidermal necrolysis, lichenoid drug eruption and contact dermatitis. Common treatments like acetazolamide has particularly been noted to cause maculopapular eruptions, posing a significant challenge for ophthalmologists in first line treatments of ocular disease such as idiopathic intracranial hypertension (IIH). In addition to SDRIFEs prevalence in general antibiotic use that can be administered in ophthalmology during ocular infection, SDRIFE may manifest itself as an adverse outcome in other commonly prescribed ophthalmologic medications.

Management

Treatment of SDRIFE involves the management of both the cutaneous reaction, as well as the underlying cause, often resulting in assessment of the continued use of the medication at hand. Clinicians must perform a risk-benefit analysis based on the severity of the skin reaction against the therapeutic benefit provided by the drug in question. Consultation with dermatology is recommended for differential diagnosis and treatment.

Substitution with Other Medications

If the risk-benefit analysis demonstrates that immediate discontinuation of a drug is necessary, other medications should be considered. However, treatment decisions should be individualized, considering patient-specific factors and the overall risk-benefit profile of each medication. While potentially less effective, other medications can prove to be overall more beneficial to the patient’s health in the long-term. Furthermore, non-pharmacological approaches can be considered to mitigate ophthalmological manifestations of disease, such as diet, weight loss, and aerobic exercise. A multidisciplinary approach should be used when designing a management plan and assess the patient's health status or any comorbidities that can lead to other potential complications from alternative therapies.

Consultation with Dermatology

Concurrent with immediate discontinuation of the medication, dermatological evaluation is recommended to assess severity and to treat existing damage caused by SDRIFE. Treatment includes corticosteroids and antihistamines such as levocetirizine and methylprednisolone. Such treatments alleviate itching and redness symptoms and will vary based on the existing severity.

Rechallenge Consideration

Monitoring the efficacy of discontinuation of the drug in question, one may consider a rechallenge under closely monitored supervision. Gradual dosage increases can be administered while simultaneously monitoring the signs of skin rash along with symptoms of ocular disease, such as intraocular pressure and changes in fundoscopic examination.

Prognosis

The prognosis of SDRIFE is generally favorable following discontinuation of the causing agent. Continued monitoring by a clinician is imperative to examine resolution of skin redness, and typically the rash resolves itself within days to weeks following treatment. Prognosis can vary individually as other factors such as genetic predisposition and comorbidities influence severity of disease and rate of recovery. Close consultation between ophthalmology and dermatology is recommended for optimal recovery of adverse reactions aligned with the ocular pathology in question. Ophthalmologists should be aware of the potential complications of medications which they prescribe including acetazolamide for idiopathic intracranial hypertension (IIH). The development of SDRIFE should prompt dermatology consultation and discontinuation of the drug.