What is the cause of eosinophilia in patients with methotrexate toxicity?

Causes of Eosinophilia in Methotrexate Toxicity

Eosinophilia in methotrexate toxicity is primarily caused by a hypersensitivity reaction that manifests as an interface dermatitis with tissue eosinophilia, particularly in cases of acute mucocutaneous toxicity.

Mechanisms of Eosinophilia in Methotrexate Toxicity

Mucocutaneous Manifestations

• Methotrexate toxicity can present with interface dermatitis and numerous eosinophils in skin and mucosal lesions 1
• Histopathologic examination of affected tissue reveals psoriasiform epidermal hyperplasia with epidermal erosion, parakeratosis, and loss of the granular cell layer 2
• The underlying inflammatory infiltrate typically shows a band-like lymphoid pattern with interface dermatitis, dyskeratotic keratinocytes, and numerous eosinophils 2

Pulmonary Manifestations

• Peripheral eosinophilia has been reported in approximately one-third of cases with methotrexate-induced pneumonitis 3
• Pulmonary toxicity occurs in 0.5% to 14% of patients receiving low-dose methotrexate therapy 3
• Methotrexate-induced pulmonary fibrosis is the second most common cause of methotrexate-related death after myelosuppression 4

Risk Factors for Methotrexate Toxicity

Medication Interactions

• Drug interactions with methotrexate usually occur due to altered pharmacokinetic effects, such as displacement of protein binding and reduced renal elimination 5
• Concomitant use of NSAIDs can reduce renal elimination of methotrexate, leading to toxicity 5
• Antibiotics, particularly trimethoprim and sulfamethoxazole (co-trimoxazole), can result in bone marrow suppression when used with methotrexate 5

Patient-Related Factors

• Renal impairment significantly increases the risk of methotrexate toxicity, including pulmonary manifestations 4
• Advanced age is a risk factor for increased toxicity 4
• Pre-existing pulmonary disease increases the risk of pulmonary toxicity 4

Clinical Presentation of Methotrexate Toxicity with Eosinophilia

Skin and Mucosal Involvement

• Patients may present with blisters and erosions localized to psoriatic plaques, perineum, and oral mucosa 2
• Shallow circular cutaneous erosions can be found on chest, abdomen, and limbs 1
• These lesions often demonstrate interface dermatitis with eosinophilic infiltration on histopathology 1

Systemic Manifestations

• Pancytopenia and elevated liver function tests are common laboratory findings 1
• Patients may develop megaloblastic anemia 2
• Common toxicities include fatigue, anorexia, nausea, and stomatitis 5

Pulmonary Symptoms

• Dry, nonproductive cough is a common presenting symptom 4
• Reduced diffusion capacity on pulmonary function tests is a diagnostic finding 4
• Chest radiographs may show bilateral interstitial or mixed interstitial and alveolar infiltrates with a predilection for the lung bases 3

Management of Methotrexate Toxicity with Eosinophilia

Immediate Interventions

• Discontinuation of methotrexate is the first step in management 1
• Administration of leucovorin (folinic acid) can help reverse toxicity 1
• Hydration and urine alkalinization are frequently used treatments for methotrexate toxicity 6

Monitoring and Prevention

• Regular laboratory monitoring is essential to detect early signs of toxicity 5
• Baseline chest x-ray should be obtained for all patients starting methotrexate 4
• Folate supplementation may reduce some methotrexate toxicities 4

Clinical Pearls and Pitfalls

• The differential diagnosis of methotrexate-induced mucocutaneous lesions with eosinophilia may include lichen planus, lichenoid drug eruption, fixed drug eruption, or incipient pemphigus vulgaris 2
• Although pulmonary eosinophilia is common in methotrexate pneumonitis, some cases of methotrexate-induced pulmonary fibrosis may not show eosinophilia 7
• Methotrexate toxicity should be suspected in any patient on this medication who develops new mucocutaneous lesions or respiratory symptoms 4