Methotrexate is commonly prescribed for autoimmune conditions but can rarely cause serious adverse effects [1]. Methotrexate toxicity is a rare cause of hypercalcaemia, particularly in patients with impaired renal function.
We present a case of severe hypercalcaemia secondary to methotrexate-induced granulomatous pneumonitis, a rare but significant adverse event. A 67-year-old man with rheumatoid arthritis and stage IV chronic kidney disease, on methotrexate therapy, presented with respiratory symptoms, cyclical fevers, and mood changes including mania. Investigations revealed severe PTH-independent hypercalcaemia (adjusted calcium 3.47 mmol/L), suppressed parathyroid hormone, and markedly elevated 1,25-dihydroxyvitamin D. Chest imaging showed bilateral pulmonary infiltrates. Extensive evaluation excluded malignancy, infection, and vasculitis. The diagnosis of methotrexate-induced granulomatous pneumonitis was made based on the modified Searles and McKendry criteria, including clinical, radiologic, and biochemical features.
Hypercalcaemia did not respond to initial treatment with intravenous rehydration, pamidronate, and calcitonin. Given the diagnostic uncertainty and the patient’s psychiatric comorbidities, corticosteroid use was initially deferred. Ultimately, a cautious trial of oral prednisolone 25 mg daily was initiated in conjunction with methotrexate cessation, resulting in rapid and sustained resolution of both hypercalcaemia and pneumonitis. The patient was transitioned to leflunomide for his rheumatoid arthritis and later recommenced on lithium with psychiatric support.
This case highlights the diagnostic complexity of unexplained hypercalcaemia in patients on methotrexate, particularly in the setting of chronic kidney disease. While rare, methotrexate-induced granulomatous pneumonitis should be considered in patients presenting with hypercalcemia, pulmonary infiltrates, and elevated 1,25-dihydroxyvitamin D [2]. Literature on this phenomenon remains limited, though similar clinical features and outcomes have been reported [3].
Clinicians should maintain a high index of suspicion for this under-recognised adverse drug reaction. Prompt recognition and treatment with corticosteroids – such as prednisolone – and methotrexate cessation are essential for recovery.