Severe Cutaneous Adverse Reactions



Severe Cutaneous Adverse Reactions


Elisa M. Schunkert

Andrew C. Walls



Severe cutaneous adverse reactions (SCARs) to drugs include several potentially lifethreatening conditions, such as:



  • SJS/TEN (Stevens-Johnson syndrome/toxic epidermal necrolysis)


  • SJS/TEN-like hypersensitivity reaction or SJS/TEN mimics


  • DRESS (drug reaction with eosinophilia and systemic symptoms)


  • AGEP (acute generalized exanthematous pustulosis)

The majority of these processes are thought to be severe allergic reactions that are T-cell-mediated, delayed-type drug hypersensitivity reactions, which can occur in response to a wide spectrum of medications. SJS-TEN mimics may involve alternative pathophysiologic pathways, though the morphologic clinical outcome remains similar. The increasing utilization of targeted anticancer medications and immunotherapies has led to an increase in the incidence and diversity of SCARs alongside their expanding role in oncology.


SJS/TEN AND SJS/TEN MIMICS

SJS/TEN is a serious mucocutaneous condition characterized by prodromal fever and skin pain succeeded by target lesions, blistering, and sloughing of the epidermis with involvement of at least two mucosal sites (oral, ocular, urogenital). Typically, 7 to 21 days after initial drug exposure, lesions appear on the trunk, palms, and soles with subsequent spread to the face and extremities. The initial morphology may be somewhat nonspecific and mimic that of a typical drug exanthem; however, over days, characteristic findings appear, including dusky/purple targetoid macules, epidermal detachment (may be elucidated by the Nikolsky sign), and mucosal involvement (Figures 21.1 and 21.2). Initial mucosal involvement may be described as pain or foreign body sensation without obvious visual abnormality; however, these symptoms are never part of a typical morbilliform drug exanthem and should be regarded with a high degree of suspicion and closely monitored for emerging SJS/TEN. Importantly, and an increasing challenge in oncodermatology, patients may present with bullous or erosive lichenoid or autoimmune blistering disorders in the setting of checkpoint blockade. Both may present with mucosal involvement; lichenoid processes commonly affect the oral mucosa. Thus, multidisciplinary evaluation, consideration of lesion morphology, timing and pace of presentation, and careful consideration of biopsy findings are critical.












Classically, the involved body surface area defines true SJS (<10%), SJS/TEN overlap (10%-30%), or TEN (>30%). Skin biopsy demonstrates pauci-immune epidermal necrosis and detachment.1


Drug Culprits

Both oncologic (Table 21.1) and nononcologic supportive medications may be implicated in the development of SJS/TEN and no specific test exists to determine the culprit. Timing and clinical suspicion is paramount to determining the causal agent and distinguishing if
the reaction was due to oncologic therapy or a supportive medication. Traditional nononcologic medications most commonly associated with SJS/TEN are as follows:



  • Antibiotics—most commonly sulfamethoxazole/trimethoprim


  • Allopurinol


  • Anticonvulsants


Differential Diagnosis for a Patient Presenting with Blistering Skin +/− Mucositis



  • Paraneoplastic Pemphigus (PNP): A paraneoplastic autoimmune bullous disease with skin and mucosal involvement. May be clinically identical to SJS/TEN; however, a skin biopsy for H&E and direct immunofluorescence will help distinguish between the two. Moreover, PNP would be characterized by a chronic course with relapses and a culprit medication is often difficult to identify. Most commonly associated malignancies are non-Hodgkin lymphomas, chronic lymphocytic leukemia, and Castleman disease; however, many diverse malignancies have been reported.


  • Toxic Medication Accumulation: Seen with cytotoxic chemotherapies when supratherapeutic medication accumulation occurs through lack of excretion due to renal or hepatic insufficiency, genetic enzyme deficiency resulting in decreased metabolism of the medication, or iatrogenic overdose. Skin blistering and mucositis may occur due to direct toxic effects from the medication rather than an immune-mediated process as is seen in true SJS/TEN. Specific examples of these include the following:



    • □ Methotrexate-induced epidermal necrolysis: Toxic accumulation of methotrexate (MTX) results in diffuse skin sloughing and mucositis. Risk factors are absence of folate supplementation, impaired kidney function, and older age.2



      • Leukopenia and pancytopenia are rare findings in SJS/TEN and point toward MTX-induced bone marrow suppression


      • Skin biopsy may help to differentiate the two, however, imperfectly as significant histological overlap exists


      • First-line therapy includes prompt leucovorin rescue.


    • □ 5-fluorouracil (5-FU)-toxicity due to dihydropyrimidine dehydrogenase (DPD) deficiency: Prevalent in 3% to 5% of the population. Presents with fevers, severe erythematous rashes, oral mucositis, diarrhea, neurological abnormalities, leucopenia, and thrombocytopenia often within ˜1 week of treatment onset. Management includes 5-FU discontinuation, evaluation of DPD levels via reverse transcription quantitative polymerase chain reaction, supportive care, and potentially hemodialysis.3


  • Severe Intertriginous Eruptions: Cytotoxic therapy may cause local erosions due to excreted drug in intertriginous areas, which may be due to direct toxic effects or local allergic contact dermatitis. These drug classes may also induce mucositis as a direct toxic effect. The clinical presentation of both skin and mucosal lesions is most helpful in clarifying this diagnosis.


  • Erythema Multiforme: Presents with true target lesions (three zones of color). The center of these lesions may develop small vesicles or bullae, but extensive skin sloughing

    is not seen and overall body surface area is <10%. Mucosal involvement is common. Common triggers include prior mycoplasma infection or herpes simplex virus.







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Nov 1, 2025 | Posted by in ONCOLOGY | Comments Off on Severe Cutaneous Adverse Reactions

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