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.
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.
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
- pleuritic chest pain
- skin rash
Possible signs comprise:
- restrictive pattern in pulmonary function tests
- diffuse inspiratory crackles
- digital clubbing
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 1990´s 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
Radiological abnormalities may precede the onset of symptoms.
Diffuse bilateral lung infiltrates.
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%), R-ILD may be fatal in ~20% of cases. The withdrawal of the drug may be the safest way of treatment 3,4.
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.
- R-ILD should be considered in any patient developing respiratory symptoms or new radiographic changes while receiving rituximab
- 1. Wagner SA, Mehta AC, Laber DA. Rituximab-induced interstitial lung disease. Am. J. Hematol. 2007;82 (10): 916-9. doi:10.1002/ajh.20910 - Pubmed citation
- 2. Baldo BA. Adverse events to monoclonal antibodies used for cancer therapy: Focus on hypersensitivity responses. Oncoimmunology. 2014;2 (10): e26333. doi:10.4161/onci.26333 - Free text at pubmed - Pubmed citation
- 3. Farnam K, Chang C, Teuber S et-al. Nonallergic drug hypersensitivity reactions. Int. Arch. Allergy Immunol. 2012;159 (4): 327-45. doi:10.1159/000339690 - Pubmed citation
- 4. Hadjinicolaou AV, Nisar MK, Parfrey H et-al. Non-infectious pulmonary toxicity of rituximab: a systematic review. Rheumatology (Oxford). 2012;51 (4): 653-62. doi:10.1093/rheumatology/ker290 - Pubmed citation
- 5. Lioté H, Lioté F, Séroussi B et-al. Rituximab-induced lung disease: A systematic literature review. Eur. Respir. J. 2010;35 (3): 681-7. doi:10.1183/09031936.00080209 - Pubmed citation
- 6. Nieuwenhuizen L, Verzijlbergen FJ, Wiltink E et-al. A possible role of 18F-FDG positron-emission tomography scanning in the early detection of rituximab-induced pneumonitis in patients with non-Hodgkin's lymphoma. Haematologica. 2008;93 (8): 1267-9. doi:10.3324/haematol.12802 - Pubmed citation
- 7. Lim KH, Yoon HI, Kang YA et-al. Severe pulmonary adverse effects in lymphoma patients treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen plus rituximab. Korean J. Intern. Med. 2010;25 (1): 86-92. doi:10.3904/kjim.2010.25.1.86 - Free text at pubmed - Pubmed citation
- 8. Meyer KC. Diagnosis and management of interstitial lung disease. Transl Respir Med. 2014;2 (1): 4. doi:10.1186/2213-0802-2-4 - Free text at pubmed - Pubmed citation
- 9. Naqibullah M, Shaker SB, Bach KS, Bendstrup E. Rituximab-induced interstitial lung disease: five case reports. (2015) European clinical respiratory journal. doi:10.3402/ecrj.v2.27178 - Pubmed