Rituximab-induced interstitial lung disease

Rituximab-induced interstitial lung disease (R-ILD) or rituximab pneumonitis is a rare non-infectious pulmonary side effect of the monoclonal CD20 antibody rituximab used in therapy for certain oncological/hematological and rheumatological disorders.

Epidemiology

Since solely based on casuistic reports, small series and two reviews ^4,5 the true incidence of this entity is unknown. However, with the number of case reports growing rapidly, it is very likely under-recognized ⁵.

Reports indicate a mean age of ~65 years (43–80) with male preponderance with a ratio of 2:1. The elderly appear more at risk.

Of today, the most common indication for rituximab is non-Hodgkin lymphomas, particularly diffuse large B-cell lymphoma.

Clinical presentation

It presents most frequently after a month, although it may present acutely (within hours) as well as chronically (within weeks/months). Importantly, ~20% of patients maybe totally asymptomatic.

The most common presenting symptoms include ^4,5,7:

• dyspnea (~75%)

• fever (~40%)

• cough (~30%), characteristically dry, non-productive

• fatigue

• rigors

• wheeze

• hemoptysis

• pleuritic chest pain

• skin rash

Possible signs comprise:

• hypoxemia

• restrictive pattern in pulmonary function tests

• diffuse inspiratory crackles

• digital clubbing

Pathology

As a human/mouse chimeric monoclonal antibody reacting specifically with the CD20 antigen expressed on >95% of normal and malignant B cell, rituximab induces complement-mediated and antibody-dependent cellular cytotoxicity. It revolutionised treatment of B-cell lymphomas at the end of 1990s and is currently being tried in other conditions, e.g. neuromyelitis optica.

Unfortunately, the pathophysiology behind rituximab-induced interstitial lung disease is not well understood. Although some pulmonary side effects were reported in phase II and phase III studies, severe and potentially fatal complications were not evident before widespread clinical use ^1,4-7.

The reported range of changes comprises ⁴:

• cryptogenic organizing pneumonia

• interstitial pneumonitis

• hypersensitivity pneumonitis

• idiopathic pulmonary fibrosis

• alveolar-interstitial pneumonitis

• diffuse alveolar damage

• usual interstitial pneumonia

• lymphocytic interstitial pneumonitis

• desquamative interstitial pneumonia

Radiographic features

Imaging abnormalities may precede the onset of symptoms.

Plain radiograph

Diffuse bilateral lung infiltrates.

CT

CT and especially HRCT almost invariably depict ground glass opacities with additional findings in some cases:

• alveolitis

• pulmonary fibrosis

• alveolar hemorrhage

• pleural effusions

• consolidation

Nuclear medicine

Findings in CT part as described above, typically FDG-avid, indicative of neutrophil activation. FDG-PET/CT may be preferable ^4,6 and advantageous also because of its recommendation in clinical routine for staging and treatment assessment in most lymphomas.

Treatment and prognosis

Although spontaneous recovery is possible and treatment with corticosteroids usually leads to a rapid improvement (~70%), rituximab-induced interstitial lung disease may be fatal in ~20% of cases.  The withdrawal of the drug may be the safest way of treatment ^3,4.

Differential diagnosis

Differential diagnoses include pulmonary infections or other forms of interstitial lung disease ⁸. Bronchoalveolar lavage and transbronchial or open lung biopsy (video-assisted thoracoscopic (VATS)) may aid in establishing diagnosis and subtype.

Practical points

• rituximab-induced interstitial lung disease should be considered in any patient developing respiratory symptoms or new radiographic changes while receiving rituximab

See also

• drug-induced lung disease