Journal of Clinical Pharmacy and Therapeutics, 2015, 40, 249–250

doi: 10.1111/jcpt.12252

Commentary

TNF-a antagonist may not be suitable for severe rituximab-induced interstitial lung disease J. Tan MD and X. Ni MD Department of Hematology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China

Received 25 November 2014, Accepted 2 February 2015

Keywords: interstitial lung disease, rituximab, TNF-a

of the condition has led to an increase in the number of cases.1 As previously reviewed by Wagner,2 the onset of the disease is typically weeks to months after the start of treatment. Fever, dry cough and progressive hypoxaemia are frequently presented in R-ILD. Symptoms are more frequently acute, but can be more insidious in the onset. Although the elderly are at greatest risk of R-ILD, severely affected children have also been reported.5 Computed tomographies often show diffuse bilateral interstitial infiltrations. In some cases, alveolitis, pulmonary fibrosis, alveolar haemorrhage, pleural effusions and consolidation were also described.2 Lung biopsies predominantly revealed alveolar damage and interstitial fibrosis.2 Sedimentation rates or C-reactive protein and selected cytokines are elevated in patients tested for signs of systemic inflammation. The diagnosis for R-ILD is mainly based on the characteristic diffuse interstitial infiltrations, lack of obvious clinical evidence of microbial infections and negative response to antibiotics. Once R-ILD is suspected, discontinuation of rituximab containing therapy and treatment with glucocorticoids improve the prognosis for most patients. However, some patients do not respond to glucocorticoids, even with high-dose glucocorticoids.1–3,5 R-ILD may occur in patients already receiving concomitant rituximab and glucocorticoids.5 Therefore, therapeutic approaches other than glucocorticoids are required. The pathogenesis of R-ILD is still unclear. TNF-a has been postulated as the main component in the pathogenesis of the condition because of its proinflammatory effects.6,7 Increased TNFa level was observed after rituximab infusion.3,8 What’s more, case reports also suggest a possible improvement in autoimmune disease associated interstitial lung disease after anti-TNF-a treatment.9 On the basis of such evidence, TNF-a has been suggested as a potential target in severe R-ILD. The TNF-a antagonist etanercept was used to treat a case of severe R-ILD but with no favourable outcome.3 TNF-a level has been reported to be higher after etanercept intervention.3 We believe that not only rituximab but also etanercept contributed to the elevation of TNF-a level. Many studies have shown elevation of biologically active TNF-a after etanercept treatment in different types of disease.10–12 Delayed use of TNF-a antagonist and inadequate dosage were suggested as reasons for the unfavourable outcome in that case. Interpretation of etanercept-induced TNF-a elevation has been reviewed by Kast.13 Briefly, TNF-a mediates its action through 2 outer cell-membrane receptors, TNF-R1 and TNF-R2. TNF-R1 signalling results in cell apoptosis pathways, and TNF-R2 triggers antiapoptotic pathways. Soluble TNF preferentially binds TNF-R1 over TNF-R2, and the transmembrane form of TNF stimulates TNF-R1 and TNF-R2 equally. Etanercept binds mainly to soluble

SUMMARY What is known and Objective: Rituximab-induced interstitial lung disease (R-ILD) has aroused more concern in recent years. Anti-TNF-a treatment has been suggested for the treatment of severe R-ILD, due to the plausible suggestion that its pathogenesis is related to TNF-a. This commentary aimed to comment on the role of TNF-a antagonists in R-ILD. Comment: Although most R-ILD patients respond well to glucocorticoids, other treatment options are needed for patients who are refractory to conventional treatment. Contrary to expectations, the TNF-a antagonist etanercept brought no benefit in R-ILD. Moreover, TNF-a-targeted therapies were reported to induce or exacerbate interstitial lung disease. What is new and conclusion: The role of TNF-a in the pathogenesis of R-ILD is still unclear due to limited studies on its aetiology. Use of TNF-a antagonists in R-ILD is still speculative, as clinical trials do not support its efficacy. What’s more, TNF-a antagonists may themselves induce interstitial lung disease with poor prognosis. WHAT IS KNOWN AND OBJECTIVE Rituximab is a chimeric anti-CD20 monoclonal antibody. It is being increasingly used in CD20+ non-Hodgkin’s lymphoma and some autoimmune diseases for which it shows good efficacy and tolerability. There are increasing reports indicating that rituximab may induce lung disease (R-ILD).1 R-ILD appears to be rare but is potentially fatal in a fraction of patients, who do not respond to glucocorticoids. Treatment for such severe R-ILD is still challenging. As tumour necrosis factor-a (TNF-a) is believed to be the main inflammatory factor participating in R-ILD, anti-TNF-a therapy has been suggested for severe R-ILD.2,3 Our objective was to comment on the role of TNF-a antagonists in R-ILD. COMMENT Rituximab-induced interstitial lung disease is rare, with and estimated incidence of 001%.4 A systematic review revealed a rate of occurrence ranging from 37% to 10%.1 Increasing usage of rituximab in a variety of patients and clinicians’ better awareness Correspondence: J. Tan, Department of Hematology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China 637000. Tel.: +86 817 2262405; +86 817 2262405; fax: +86 817 2262856; e-mail: [email protected]

© 2015 John Wiley & Sons Ltd

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be associated with ILD.15,16 It is worth noting that TNF-a antagonist-induced interstitial lung disease has a poor prognosis, with an overall mortality rate of around on third. Therefore, TNF-a antagonists are not recommended in patients with pre-existing interstitial lung disease.15,16

TNF-a, preventing it from binding to TNF receptors. Blocking of TNF-R1 by etanercept may lead to TNF signalling being skewed from TNF-R1 towards TNF-R2, and therefore increased antiapoptosis signalling. TNF-R2 signalling tends to activate nuclear factor kappa B-regulated genes such as that encoding TNF itself, the synthesis of which is then upregulated. TNF-a has been postulated as the main component in the pathogenesis of interstitial lung disease.7 However, antifibrotic effects of TNF-a have also been identified.14 TNF-a-/- mice developed an accelerated form of bleomycin-induced pulmonary fibrosis, thereby demonstrating that TNF-a plays an important role in limiting pulmonary inflammation.14 Although TNF-a inhibitors have been suggested as a potential therapy for interstitial lung disease, the increasing number of cases of interstitial lung disease triggered or exacerbated by TNF-a-targeted therapies is a concern.15 A variety of TNF-a antagonists including etanercept, infliximab, adalimumab and golimumab have been reported to

WHAT IS NEW AND CONCLUSIONS R-ILD is rare but is potentially fatal. The use of anti-TNF-a treatment for severe R-ILD is still speculative, given that the role of TNF-a in its pathogenesis is still unclear. TNF-a antagonist may not be suitable for treating severe R-ILD. COMPETING INTERESTS The authors declare that they have no competing interests.

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12. Suffredini AF, Reda D, Banks SM, Tropea M, Agosti JM, Miller R. Effects of recombinant dimeric TNF receptor on human inflammatory responses following intravenous endotoxin administration. J Immunol, 1995;155:5038–5045. 13. Kast RE. Evidence of a mechanism by which etanercept increased TNF-alpha in multiple myeloma: new insights into the biology of TNF-alpha giving new treatment opportunities–the role of bupropion. Leuk Res, 2005;29:1459–1463. 14. Kuroki M, Noguchi Y, Shimono M et al. Repression of bleomycin-induced pneumopathy by TNF. J Immunol, 2003;170:567– 574. 15. Perez-Alvarez R, Perez-de-Lis M, DiazLagares C et al. Interstitial lung disease induced or exacerbated by TNF-targeted therapies: analysis of 122 cases. Semin Arthritis Rheum, 2011;41:256–264. 16. Hadjinicolaou AV, Nisar MK, Bhagat S, Parfrey H, Chilvers ER, Ostor AJ. Noninfectious pulmonary complications of newer biological agents for rheumatic diseases–a systematic literature review. Rheumatology (Oxford), 2011;50:2297–2305.

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TNF-α antagonist may not be suitable for severe rituximab-induced interstitial lung disease.

Rituximab-induced interstitial lung disease (R-ILD) has aroused more concern in recent years. Anti-TNF-α treatment has been suggested for the treatmen...
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