A 42-year-old woman with rheumatoid arthritis returns to the clinic for follow-up. The patient reports improvement in joint pain after methotrexate therapy was begun 6 months ago. Over the past 2 months, she has felt increasingly winded, causing her to stop jogging. She has a nonproductive cough and low-grade fevers. She has no other medical conditions and is a lifelong nonsmoker. Temperature is 37.5 C (99.5 F), blood pressure is 120/70 mm Hg, pulse is 88/min, and respirations are 18/min. Oxygen saturation is 89% on room air at rest. Jugular venous pressure is normal. Lung auscultation reveals fine bibasilar inspiratory crackles. Heart sounds are normal. Musculoskeletal examination shows mild interphalangeal synovitis. High-resolution CT scan of the chest reveals patchy areas of consolidation and reticular thickening. A respiratory sample obtained by bronchoscopy yields lymphocyte-predominant fluid negative for bacterial, viral, and fungal pathogens. Which of the following is the best next step in management of this patient?
Methotrexate-induced lung injury | |
Pathogenesis |
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Clinical |
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BAL = bronchoalveolar lavage; GGO = ground-glass opacities; MTX = methotrexate; PFTs = pulmonary function tests. | |
This patient taking methotrexate (MTX) for rheumatoid arthritis (RA) now has exertional dyspnea, hypoxemia, and pulmonary infiltrates with potential fibrosis (ie, reticular thickening). Microbiologic workup is negative for infection. In this context, methotrexate lung toxicity (aka MTX pneumonitis) becomes the primary diagnostic consideration.
MTX lung injury is an idiosyncratic (ie, not dose dependent) reaction. The mechanism is akin to hypersensitivity pneumonitis, with granulomatous lymphocytic lung inflammation. It manifests with often overlapping patterns, including acute inflammatory pneumonitis (ground glass), organizing pneumonia (consolidations), and rapidly progressive pulmonary fibrosis (reticulation, honeycomb changes).
There is no specific diagnostic test for MTX pneumonitis. Infection must be excluded first, often through bronchoalveolar lavage (BAL). Empiric antimicrobials are often administered while awaiting culture data. BAL fluid typically demonstrates lymphocytic pleocytosis, a finding consistent with hypersensitivity. A provisional diagnosis is made when an MTX cessation trial leads to clinical improvement. Systemic corticosteroids are sometimes indicated if respiratory status does not improve with MTX cessation.
(Choice B) Pulmonary sarcoidosis (which is sometimes treated with MTX) can present with dyspnea, mixed consolidative and fibrotic infiltrates, and lymphocytic BAL. However, sarcoidosis usually features hilar adenopathy and peribronchovascular nodules. Serum ACE levels may track with disease severity but are neither sensitive nor specific for diagnosis.
(Choice C) Allergic bronchopulmonary aspergillosis, associated with elevated IgE, can present with low-grade fever and persistent cough. However, underlying asthma, bronchiectasis, and thick, mucinous sputum would be expected.
(Choice D) Lung biopsy, a last resort in the diagnosis of interstitial lung disease, is reserved for rare occasions when noninvasive studies are inconclusive (eg, atypical imaging features, non-improvement or deterioration despite MTX cessation). This patient has a classic presentation of MTX pneumonitis based on history (exposure time frame) and chest imaging, so monitoring clinical response after drug cessation is diagnostic. Therefore, lung biopsy is not immediately required.
(Choice E) Antifibrotic agents (eg, pirfenidone) are used for idiopathic pulmonary fibrosis, which is characterized by fibrotic interstitial pneumonia (ie, predominant honeycombing without consolidations) without an underlying autoimmune disorder (ie, no RA). They have no established role in MTX pneumonitis, in which drug cessation quells the hypersensitivity response, leading to spontaneous resolution.
Educational objective:
Methotrexate (MTX) pneumonitis is an idiosyncratic lung toxicity sharing similar pathogenesis to hypersensitivity pneumonitis. Evaluation for pulmonary infection is obligatory. MTX cessation is both diagnostic and therapeutic.