Orelabrutinib-induced severe exfoliative dermatitis

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A man in his 60s presented with widespread erythema and exfoliative scaling, affecting over 90% of his body surface area, accompanied by fever and severe itching (visual analogue scale score: 8/10) for 10 days. Physical examination revealed erythroderma with lamellar desquamation, palmoplantar keratoderma, and fissuring of the skin folds [Figure 1]. No mucosal involvement or lymphadenopathy was observed. The patient had initiated orelabrutinib a day prior to the onset of skin lesions for lymph node recurrence of marginal-zone B-cell lymphoma. There was no history of other medications or food allergies, or prior atopic dermatitis, eczema, or other skin conditions. A skin biopsy from the right arm demonstrated eosinophilic infiltration with spongiosis, consistent with drug-induced subacute dermatitis [Figure 2]. Laboratory findings included leucocytosis (11.82×10⁹/L), eosinophilia (8.2%), and elevated C-reactive protein (20.28 mg/L). No abnormalities were detected in other routine serum laboratory tests, such as liver enzymes. Based on the patient’s medication history, a diagnosis of drug-induced exfoliative dermatitis was established. Orelabrutinib was immediately discontinued. Treatment comprised systemic methylprednisolone (40 mg daily, tapered gradually) alongside supportive measures such as emollients, wet wraps, and antipruritic agent (Gabapentin 20mg, Chlorphenamine 4mg daily). After 11 days of treatment, the patient achieved complete clinical remission [Figure 3], with no recurrence during a 5-month follow-up.

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Figure 1:

The skin lesion appeared as widespread erythema and exfoliative scaling affecting over 90% of the body surface area.

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Figure 2:

Biopsy showing eosinophilic infiltration with visible spongiosis (red dashed circles)​ consistent with drug-induced subacute dermatitis (Haematoxylin & eosin, 400x).

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Figure 3:

Significant improvement after 11 days.

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Exfoliative dermatitis, or erythroderma, is an inflammatory disorder characterised by extensive erythema and moderate to severe scaling, affecting nearly the entire body surface. This condition can be life-threatening due to its metabolic burden and complications.^1,2 A detailed patient history should be taken to identify potential precipitating factors, including medication, infections, ultraviolet exposure, congenital disorders, neoplasia, and other causes. The onset of the lesion occurred shortly after administration of the medication. Elevated eosinophils in the patient’s blood routine examination, eosinophilic infiltration of the lesion, rapid improvement of skin lesions following discontinuation of orelabrutinib and initiation of systemic corticosteroids, collectively supported the conclusion that the erythroderma in this case was drug-induced.

Drug‐induced erythroderma is often caused by anticonvulsants, antibiotics, and topical preparations.¹ The chronological history, including clinical improvement after drug discontinuation, is key to identifying the causative agent. Previous studies have reported dermatological toxicities associated with Bruton’s tyrosine kinase (BTK) inhibitors, but these primarily manifest as mild, self-limiting, nonspecific lesions such as petechiae, bruising, skin infections, folliculitis, or other rashes.³ Orelabrutinib, a new generation oral small-molecule BTK inhibitor, provides more selective and sustained BTK inhibition compared to earlier generations.⁴ Its enhanced specificity reduces off-target effects, resulting in fewer adverse reactions, making it a promising therapeutic option with improved safety and tolerability. According to previous reports, the incidence of rash as a treatment-emergent adverse event in patients treated with orelabrutinib was 15.8%.⁵ However, to the best of our knowledge, exfoliative dermatitis due to orelabrutinib has never been reported. In this patient, the temporal association between orelabrutinib initiation and the onset of severe exfoliative dermatitis strongly suggested drug-induced toxicity. The pathogenesis of drug-induced exfoliative dermatitis likely involves both immune-mediated and direct toxic mechanisms. Inhibition of BTK by orelabrutinib may disrupt immune homeostasis, leading to cutaneous inflammation, cytokine dysregulation, and immune complex deposition. Genetic predispositions related to drug metabolism or immune function could further contribute to susceptibility.^3,5

Discontinuation of the suspected drug immediately is important, with systemic corticosteroids recommended for severe cases. Hospitalisation may be necessary for supportive care. Prognosis depends on aetiology and response to treatment, though most patients improve after withdrawal of the offending agent.

This report describes the first documented case of severe exfoliative dermatitis attributed to orelabrutinib, highlighting the importance of recognising rare but serious dermatologic adverse events. Elucidating the pathophysiology of such reactions is critical for optimising treatment strategies and ensuring patient safety, particularly as targeted therapies gain broader use.