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Inhibitors on Lung Lesions With Rheumatoid Arthritis
National Institute for Environmental Studies, Tsukuba-City, Japan Kyoto Prefectural University of Medicine, Kyoto-City, Japan
Correspondence to: Ken-ichiro Inoue, MD, Department of Internal Medicine, Naka Central Hospital, 1733-1, Iida, Naka-cho, Naka-gun, Ibaraki, 311-0134, Japan; e-mail: keni{at}kk.iij4u.or.jp
To the Editor:
Recently in CHEST, Vassallo and colleagues1
(September 2002) reported on a 71-year-old man with a 3-year history of rheumatoid arthritis (RA) whose damaged pulmonary function, associated with RA, was ameliorated by treatment with the tumor necrosis factor (TNF)-
inhibitor infliximab. More recently, Peno-Green and coworkers2
(November 2002) reported the first case of lung injury to occur while the patient was receiving etanercept. Although the molecular players in RA are still poorly understood, representative proinflammatory cytokines, such as TNF- and interleukin (IL)-1, have proven to be major contributors to this disease. However, there are few studies elucidating the role of TNF- in the pulmonary lesions of RA. The contrary effects of TNF- inhibitors on the pulmonary lesions of RA in the published case reports in CHEST might have depended on the severity of the disease affecting the lung parenchyma.
Over a decade ago, Gosset et al3
elucidated the roles of the release of TNF- and IL-1 from alveolar macrophages in patients with RA and compared the contributions of these proinflammatory cytokines between RA patients who had or did not have lung involvement. In the study, Gosset et al3
showed that the spontaneous production of TNF- was significantly increased in RA patients with or without pulmonary manifestations compared with production in control subjects, but patients with interstitial lung disease had a markedly increased rate of local immune complex reactions to albumin in BAL fluid compared with patients without lung disease. However, Elias4
claimed that the interaction of TNF with IL-1 or interferon-
modulated fibroblast proliferation. Therefore, TNF- inhibition may alter the interaction, resulting in an increased proinflammatory effect for IL-1 or interferon- in the patient reported by Peno-Green et al.2
The histopathologic findings of the patient by Peno-Green et al2
also require some discussion. Transbronchial lung biopsy specimens obtained from the patient demonstrated noncaseating granulomas, and Mycobacterium avium-intracellulare complex was isolated in the BAL fluid specimens. A pivotal role for TNF- in the defense against mycobacteria has been implicated, and causative mechanisms of anti-TNF- agents have been reported to impair the tuberculosis immune response.5
Transgenic mice lacking TNF receptors developed lethal mycobacterial infections due to widespread inflammatory cell apoptosis within disintegrating granulomas, which was mediated by an excess of T cells.6
Granuloma formation may be elicited through the reduced immunity to mycobacteria, which is caused by TNF- blocking.
Additionally, we would like to introduce an interesting study by Campbell et al.7
The investigators examined the direct role of TNF in two representative animal models of arthritis using TNF-deficient (Tnf-/-) mice. Two RA models (ie, collagen-induced arthritis and acute monoarticular arthritis) in Tnf-/- mice generally had some reduction in the clinical parameters and histology when compared with those in wild-type mice, but some mice exhibited severe disease. Campbell and colleagues7
concluded that TNF is important but not essential for these types of inflammatory arthritis. This excellent work illustrates that TNF- inhibition may be harmful as well as beneficial for RA patients.
The further accumulation of similar case reports is needed to clarify the contribution of TNF- inhibitors on RA patients.
References
inhibition. Chest 122,1093-1096 secretion by alveolar macrophages from patients with rheumatoid arthritis. Am Rev Respir Dis 1991;143,593-597[ISI][Medline]
Mayo Clinic, Rochester, MN
Correspondence to: Charles F. Thomas, Jr., MD, FCCP, Mayo Clinic, 200 First St SW, Rochester, MN 55905
To the Editor:
Peno-Green et al1
reported an individual with rheumatoid arthritis who acquired worsening lung infiltrates while receiving infliximab therapy. Transbronchoscopic lung biopsy demonstrated granulomas, and subsequent cultures on the BAL fluid grew Mycobacterium avium-intracellulare complex (MAC). Withdrawal of infliximab therapy together with the addition of prednisone resulted in rapid clinical improvement. The case reported by Peno-Green et al1
emphasizes the possibility that certain infectious organisms (such as MAC) that are usually kept in control by the normal immune system, may flourish when tumor necrosis factor (TNF)- is neutralized. Thus, rather than contradicting our report of potential benefit associated with TNF- inhibition in the course of lung fibrosis associated with rheumatoid arthritis,2
the report by Peno-Green et al1
emphasizes the need for clinicians to be aware of the increased predisposition of infliximab-treated individuals to mycobacterial (and fungal) infection.3
4
Numerous reports3
5
6
7
have cited the potential for reactivation of mycobacterial and fungal infection in patients receiving infliximab, mandating appropriate tuberculosis screening prior to drug initiation. The US Food and Drug Administration has received a total of 117 cases of infliximab-associated tuberculosis through November 30, 2001. This concern has resulted in the package insert of the product including a warning about the risk of tuberculosis and the need to screen patients for tuberculosis before treatment with infliximab is initiated. The specific role of TNF- in the pathogenesis of rheumatoid arthritis associated lung fibrosis is yet to be determined. In addition to the study by Gosset et al,8
there are numerous animal studies implicating TNF- as an important factor in the pathogenesis of lung fibrosis. TNF- receptor knockout mice are resistant to the development of lung fibrosis induced by inhaled asbestos, silica, and bleomycin, supporting the concept that signaling through TNF- receptors is fundamental to the development of lung injury and fibrosis in these animal models.9
10
Furthermore, treatment of mice with antagonistic TNF- antibodies11
or a human recombinant soluble TNF- receptor (TNF antagonist)12
reduced fibrosis induced by bleomycin in mice.
Lung fibrosis is a devastating clinical problem with limited treatment options. Considering the substantial data supporting a role for TNF- in mediating lung injury and fibrosis in animal models, we believe that infliximab and other inhibitors of TNF- signaling merit consideration for the management of lung fibrosis associated with rheumatoid arthritis. However, clinicians must be vigilant about associated risks of infection and appropriate measures undertaken to minimize this risk. Finally, although it is possible that more case reports may provide some additional insight, the contribution of TNF- inhibition in the course of lung fibrosis associated with rheumatoid arthritis can only be firmly established by prospective randomized trials. In view of the lack of proven therapies for lung fibrosis, the demonstrated efficacy of TNF- inhibitors for the joint manifestations of rheumatoid arthritis, and the data from animal studies, we believe that a prospective clinical trial with the primary aim of establishing the effect of TNF- inhibition on the course of lung fibrosis in rheumatoid arthritis is reasonable.
References
inhibition. Chest 2002;122,1093-1096
neutralizing agent. N Engl J Med 2001;345,1098-1104 secretion by alveolar macrophages from patients with rheumatoid arthritis. Am Rev Respir Dis 1991;143,593-597[ISI][Medline]
receptor mRNA after silica and bleomycin exposure and protection from lung injury in double receptor knockout mice. Am J Respir Cell Mol Biol 1999;20,825-833 receptor knockout mice. J Environ Pathol Toxicol Oncol 2001;20,97-108[Medline]
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