Anti-TNF therapy has improved outcomes in rheumatoid arthritis (RA), but has also been associated with serious respiratory adverse events (SRAEs)
Biologic therapy might cause SRAEs by inducing idiosyncratic reactions, accelerating pre-existing ILD, modifying ILD into a more injurious phenotype or increasing susceptibility to infection
The risks associated with anti-TNF therapy in patients with RA-associated ILD (RA-ILD) remain uncertain; whether other biologic agents are safer is also still unclear
Given this uncertainty, careful assessment of patients before treatment and strict subsequent monitoring is required, particularly in patients at high risk of ILD progression, regardless of chosen treatment
We need to move towards a better understanding of the natural history of RA-ILD and the roles of new therapies in the management of this disease, which requires well-conducted research
Interstitial lung disease (ILD) is a common extra-articular manifestation associated with increased morbidity and mortality in patients with rheumatoid arthritis (RA). Early case reports of serious respiratory adverse events (SRAEs) following treatment with anti-TNF agents have led to concerns about biologic therapy in patients with RA-associated ILD (RA-ILD), and a tendency for biologic agents targeting factors other than TNF to be prescribed in such patients. At present, the appropriateness of such decisions is not clear. Given that the therapeutic goal for RA is remission, clinicians increasingly face the challenge of choosing the optimal biologic agent in patients with RA-ILD and uncontrolled joint disease. However, no evidence-based guidelines exist to guide physicians in deciding whether to commence biologic therapy in this setting, or in selecting which drug is most appropriate. Herein, we review the evidence for the comparative pulmonary safety of anti-TNF agents and non-TNF-targeting biologic agents in RA-ILD. In addition, we propose a framework for assessment of baseline disease severity to guide treatment decisions, and for monitoring during therapy. Because of substantial gaps in the available evidence, we also describe a research agenda aimed at obtaining data that will help inform future clinical practice.
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Ostor, A. J. et al. Pulmonary complications of infliximab therapy in patients with rheumatoid arthritis. J. Rheumatol. 33, 622–628 (2006).
Castelino, F. V. & Varga, J. Interstitial lung disease in connective tissue diseases: evolving concepts of pathogenesis and management. Arthritis Res. Ther. 12, 213 (2010).
Turesson, C., O'Fallon, W. M., Crowson, C. S., Gabriel, S. E. & Matteson, E. L. Extra-articular disease manifestations in rheumatoid arthritis: incidence trends and risk factors over 46 years. Ann. Rheum. Dis. 62, 722–727 (2003).
Peno-Green, L., Lluberas, G., Kingsley, T. & Brantley, S. Lung injury linked to etanercept therapy. Chest 122, 1858–1860 (2002).
Liote, H., Liote, F., Seroussi, B., Mayaud, C. & Cadranel, J. Rituximab-induced lung disease: a systematic literature review. Eur. Respir. J. 35, 681–687 (2010).
O'Connor, M. B., Abdullah, M. F., O'Donovan, N. & Phelan, M. J. Rituximab-induced pulmonary disease. Rheumatol. Int. 32, 2955–2956 (2012).
Wada, T. et al. A case of rheumatoid arthritis complicated with deteriorated interstitial pneumonia after the administration of abatacept [Japanese]. Nihon Rinsho Meneki Gakkai Kaishi. 35, 433–438 (2012).
Ikegawa, K., Hanaoka, M., Ushiki, A., Yamamoto, H. & Kubo, K. A case of organizing pneumonia induced by tocilizumab. Intern. Med. 50, 2191–2193 (2011).
Kawashiri, S. Y., Kawakami, A., Sakamoto, N., Ishimatsu, Y. & Eguchi, K. A fatal case of acute exacerbation of interstitial lung disease in a patient with rheumatoid arthritis during treatment with tocilizumab. Rheumatol. Int. 32, 4023–4026 (2012).
Wendling, D. et al. Exacerbation of combined pulmonary fibrosis and emphysema syndrome during tocilizumab therapy for rheumatoid arthritis. Joint Bone Spine http://dx.doi.org/10.1016/j.jbspin.2013.03.009.
Thrall, R. S., Vogel, S. N., Evans, R. & Shultz, L. D. Role of tumor necrosis factor-α in the spontaneous development of pulmonary fibrosis in viable motheaten mutant mice. Am. J. Pathol. 151, 1303–1310 (1997).
Ortiz, L. A. et al. Expression of TNF and the necessity of TNF receptors in bleomycin-induced lung injury in mice. Exp. Lung. Res. 24, 721–743 (1998).
Piguet, P. F., Ribaux, C., Karpuz, V., Grau, G. E. & Kapanci, Y. Expression and localization of tumor necrosis factor- α and its mRNA in idiopathic pulmonary fibrosis. Am. J. Pathol. 143, 651–655 (1993).
Kapanci, Y., Desmouliere, A., Pache, J. C., Redard, M. & Gabbiani, G. Cytoskeletal protein modulation in pulmonary alveolar myofibroblasts during idiopathic pulmonary fibrosis. Possible role of transforming growth factor β and tumor necrosis factor α. Am. J. Respir. Crit. Care Med. 152, 2163–2169 (1995).
Raghu, G. et al. Treatment of idiopathic pulmonary fibrosis with etanercept: an exploratory, placebo-controlled trial. Am. J. Respir. Crit. Care Med. 178, 948–955 (2008).
US National Library of Medicine. ClinicalTrials.gov [online], (2013).
Winthrop, K. L. Infections and biologic therapy in rheumatoid arthritis: our changing understanding of risk and prevention. Rheum. Dis. Clin. North Am. 38, 727–745 (2012).
Lipsky, P. E. et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N. Engl. J. Med. 343, 1594–1602 (2000).
Klareskog, L. et al. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet 363, 675–681 (2004).
Weinblatt, M. E. et al. Adalimumab, a fully human anti-tumor necrosis factor α monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum. 48, 35–45 (2003).
Maini, R. N. et al. Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate. Arthritis Rheum. 50, 1051–1065 (2004).
van Vollenhoven, R. F. et al. Addition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in patients with early rheumatoid arthritis (Swefot trial): 1-year results of a randomised trial. Lancet 374, 459–466 (2009).
van der Heijde, D. et al. Comparison of etanercept and methotrexate, alone and combined, in the treatment of rheumatoid arthritis: two-year clinical and radiographic results from the TEMPO study, a double-blind, randomized trial. Arthritis Rheum 54, 1063–1074 (2006).
Breedveld, F. C. et al. The PREMIER study: A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum. 54, 26–37 (2006).
Burmester, G. R. et al. Adalimumab alone and in combination with disease-modifying antirheumatic drugs for the treatment of rheumatoid arthritis in clinical practice: the Research in Active Rheumatoid Arthritis (ReAct) trial. Ann. Rheum. Dis. 66, 732–739 (2007).
Ostor, A. J., Crisp, A. J., Somerville, M. F. & Scott, D. G. Fatal exacerbation of rheumatoid arthritis associated fibrosing alveolitis in patients given infliximab. BMJ 329, 1266 (2004).
Antoniou, K. M. et al. Infliximab therapy in pulmonary fibrosis associated with collagen vascular disease. Clin. Exp. Rheumatol. 25, 23–28 (2007).
Vassallo, R., Matteson, E. & Thomas, C. F., Jr. Clinical response of rheumatoid arthritis-associated pulmonary fibrosis to tumor necrosis factor-α inhibition. Chest 122, 1093–1096 (2002).
Bargagli, E., Galeazzi, M. & Rottoli, P. Infliximab treatment in a patient with rheumatoid arthritis and pulmonary fibrosis. Eur. Respir. J. 24, 708 (2004).
Perez-Alvarez, R. et al. Interstitial lung disease induced or exacerbated by TNF-targeted therapies: analysis of 122 cases. Semin. Arthritis Rheum. 41, 256–264 (2011).
Dascalu, C., Mrejen-Shakin, K. & Bandagi, S. Adalimumab-induced acute pneumonitis in a patient with rheumatoid arthritis. J. Clin. Rheumatol. 16, 172–174 (2010).
Yamazaki, H., Isogai, S., Sakurai, T. & Nagasaka, K. A case of adalimumab-associated interstitial pneumonia with rheumatoid arthritis. Mod. Rheumatol. 20, 518–521 (2010).
Cho, S. K., Oh, I. H., Park, C. K., Bae, S. C. & Sung, Y. K. Etanercept induced organizing pneumonia in a patient with rheumatoid arthritis. Rheumatol. Int. 32, 1055–1057 (2012).
Horai, Y. et al. Eternacept for the treatment of patients with rheumatoid arthritis and concurrent interstitial lung disease. J. Clin. Pharm. Ther. 37, 117–121 (2012).
Sakaida, H., Komase, Y. & Takemura, T. Organizing pneumonia in a patient with rheumatoid arthritis treated with etanercept. Mod. Rheumatol. 20, 611–616 (2010).
Yokoyama, T. et al. A case of etanercept-induced pneumonitis [Japanese]. Nihon Kokyuki Gakkai Zasshi 47, 870–874 (2009).
Hadjinicolaou, A. V. et al. Non-infectious pulmonary complications of newer biological agents for rheumatic diseases—a systematic literature review. Rheumatology (Oxford) 50, 2297–2305 (2011).
Pearce, F., Johnson, S. R. & Courtney, P. Interstitial lung disease following certolizumab pegol. Rheumatology (Oxford) 51, 578–580 (2012).
Millar, A., McKew, J. & Taggart, A. Fatal fibrosing alveolitis with certolizumab. Rheumatology (Oxford) 51, 953–955 (2012).
Glaspole, I. N., Hoy, R. F. & Ryan, P. F. A case of certolizumab-induced interstitial lung disease in a patient with rheumatoid arthritis. Rheumatology (Oxford) 52, 2302–2304 (2013).
Lager, J., Hilberg, O., Lokke, A. & Bendstrup, E. Severe interstitial lung disease following treatment with certolizumab pegol: a case report. Eur. Respir. Rev. 22, 414–416 (2013).
Wolfe, F., Caplan, L. & Michaud, K. Rheumatoid arthritis treatment and the risk of severe interstitial lung disease. Scand. J. Rheumatol. 36, 172–178 (2007).
Herrinton, L. J. et al. Association between anti-TNF-α therapy and interstitial lung disease. Pharmacoepidemiol. Drug Saf. 22, 394–402 (2013).
Dixon, W. G., Hyrich, K. L., Watson, K. D., Lunt, M. & Symmons, D. P. Influence of anti-TNF therapy on mortality in patients with rheumatoid arthritis-associated interstitial lung disease: results from the British Society for Rheumatology Biologics Register. Ann. Rheum. Dis. 69, 1086–1091 (2010).
Kim, Y. J. et al. Mortality in patients with rheumatoid arthritis-associated interstitial lung disease treated with an anti-tumour necrosis factor agent [abstract 0210]. Ann. Rheum. Dis. 72 (Suppl. 3), 444 (2013).
US Food and Drug Administration. Therapeutic Biological Products Approvals [online], (2003).
US Food and Drug Administration. Rituximab for moderate to severe rheumatoid arthritis [online], (2006).
European Medicines Agency. Mabthera: procedural steps taken and scientific information after authorisation [online], (2013).
Haraoui, B., Bokarewa, M., Kallmeyer, I. & Bykerk, V. P. Safety and effectiveness of rituximab in patients with rheumatoid arthritis following an inadequate response to 1 prior tumor necrosis factor inhibitor: the RESET Trial. J. Rheumatol. 38, 2548–2556 (2011).
Emery, P. et al. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis Rheum. 54, 1390–1400 (2006).
Emery, P. et al. Efficacy and safety of different doses and retreatment of rituximab: a randomised, placebo-controlled trial in patients who are biological naive with active rheumatoid arthritis and an inadequate response to methotrexate (Study Evaluating Rituximab's Efficacy in MTX Inadequate Responders (SERENE)). Ann. Rheum. Dis. 69, 1629–1935 (2010).
Mease, P. J. et al. Efficacy and safety of retreatment in patients with rheumatoid arthritis with previous inadequate response to tumor necrosis factor inhibitors: results from the SUNRISE trial. J. Rheumatol. 37, 917–927 (2010).
Edwards, J. C. et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N. Engl. J. Med. 350, 2572–2581 (2004).
Hadjinicolaou, A. V., Nisar, M. K., Parfrey, H., Chilvers, E. R. & Ostor, A. J. Non-infectious pulmonary toxicity of rituximab: a systematic review. Rheumatology (Oxford) 51, 653–662 (2012).
Keir, G. J. et al. Severe interstitial lung disease in connective tissue disease: rituximab as rescue therapy. Eur. Respir. J. 40, 641–648 (2012).
Matteson, E. L. et al. Open-label, pilot study of the safety and clinical effects of rituximab in patients with rheumatoid arthritis-associated interstitial pneumonia. Open J. Rheumatol. Autoimmune Dis. 2, 53–58 (2012).
Becerra, E. & Leandro, M. J. Safety and efficacy of rituximab in patients with rheumatoid arthritis and lung involvement [abstract 502]. Arthritis Rheum. 64 (Suppl. S10), S220 (2012).
Dass, S. et al. Safety of rituximab in patients with rheumatoid arthritis and concomitant lung disease [abstract 205]. Rheumatology (Oxford) 50 (Suppl. 3), iii121 (2011).
Weinblatt, M. E. et al. Safety of abatacept administered intravenously in treatment of rheumatoid arthritis: integrated analyses of up to 8 years of treatment from the Abatacept Clinical Trial Program. J. Rheumatol. 40, 787–797 (2013).
US Food and Drug Administration. Abatacept for moderate to severe rheumatoid arthritis [online], (2005).
Nishimoto, N. et al. Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum. 50, 1761–1769 (2004).
Smolen, J. S. et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet 371, 987–997 (2008).
Nishimoto, N. et al. Study of active controlled tocilizumab monotherapy for rheumatoid arthritis patients with an inadequate response to methotrexate (SATORI): significant reduction in disease activity and serum vascular endothelial growth factor by IL-6 receptor inhibition therapy. Mod. Rheumatol. 19, 12–19 (2009).
Gabay, C. et al. Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial. Lancet 318, 1541–1550 (2013).
US Food and Drug Administration. Tocilizumab for moderate to severe rheumatoid arthritis [online], (2009).
European Medicines Agency. RoActemra, tocilizumab: authorisation details 16/01/2009 [online], (2009).
Periodic Safety Update Report 1053705 (Roche Products Limited, 2012).
Yamanaka, H. et al. Efficacy and tolerability of tocilizumab in rheumatoid arthritis patients seen in daily clinical practice in Japan: results from a retrospective study (REACTION study). Mod. Rheumatol. 21, 122–133 (2011).
Mohr, M. & Jacobi, A. M. Interstitial lung disease in rheumatoid arthritis: response to IL-6R blockade. Scand. J. Rheumatol. 40, 400–401 (2011).
Koike, T. et al. Postmarketing surveillance of tocilizumab for rheumatoid arthritis in Japan: interim analysis of 3881 patients. Ann. Rheum. Dis. 70, 2148–2151 (2011).
Smolen, J. S., van der Heijde, D., Machold, K. P., Aletaha, D. & Landewe, R. Proposal for a new nomenclature of disease-modifying antirheumatic drugs. Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis-2013-204317.
US Food and Drug Administration. Xeljanz (Tofacinitib) approval for moderate to severe rheumatoid arthritis [online], (2012).
van Vollenhoven, R. F. et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N. Engl. J. Med. 367, 508–519 (2012).
Fleischmann, R. et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N. Engl. J. Med. 367, 495–507 (2012).
Stenton, C. The MRC breathlessness scale. Occup. Med. (Lond.) 58, 226–227 (2008).
Danoff, S. K., Terry, P. B. & Horton, M. R. A clinician's guide to the diagnosis and treatment of interstitial lung diseases. South. Med. J. 100, 579–587 (2007).
Egan, J. J., Martinez, F. J., Wells, A. U. & Williams, T. Lung function estimates in idiopathic pulmonary fibrosis: the potential for a simple classification. Thorax 60, 270–273 (2005).
Ley, B. et al. A multidimensional index and staging system for idiopathic pulmonary fibrosis. Ann. Intern. Med. 156, 684–691 (2012).
Latsi, P. I. et al. Fibrotic idiopathic interstitial pneumonia: the prognostic value of longitudinal functional trends. Am. J. Respir. Crit. Care Med. 168, 531–537 (2003).
Raghu, G. et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am. J. Respir. Crit. Care Med. 183, 788–824 (2011).
Hamblin, M. J. & Horton, M. R. Rheumatoid arthritis-associated interstitial lung disease: diagnostic dilemma. Pulm. Med. 2011, 872120 (2011).
Flaherty, K. R. et al. Radiological versus histological diagnosis in UIP and NSIP: survival implications. Thorax 58, 143–148 (2003).
Kim, E. J. et al. Usual interstitial pneumonia in rheumatoid arthritis-associated interstitial lung disease. Eur. Respir. J. 35, 1322–1328 (2010).
Wells, A. U. & Hogaboam, C. M. Update in diffuse parenchymal lung disease 2007. Am. J. Respir. Crit. Care Med. 177, 580–584 (2008).
Goh, N. S. et al. Interstitial lung disease in systemic sclerosis: a simple staging system. Am. J. Respir. Crit. Care Med. 177, 1248–1254 (2008).
Sathi, N., Urwin, T., Desmond, S. & Dawson, J. K. Patients with limited rheumatoid arthritis-related interstitial lung disease have a better prognosis than those with extensive disease. Rheumatology (Oxford) 50, 620 (2011).
Mann, D. L. et al. Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation 109, 1594–1602 (2004).
Kwon, H. J., Cote, T. R., Cuffe, M. S., Kramer, J. M. & Braun, M. M. Case reports of heart failure after therapy with a tumor necrosis factor antagonist. Ann. Intern. Med. 138, 807–811 (2003).
Saketkoo, L. A. et al. Developing an index for disease activity and therapeutic response in connective tissue disease related interstitial lung disease: results from a Delphi exercise: delivering a consensus on domains. Arthritis Rheum. 64, 1713 (2012).
Cottin, V., Capron, F., Grenier, P. & Cordier, J. F. Diffuse idiopathic interstitial pneumonias. International multidisciplinary consensus classification by the American Thoracic Society and the European Respiratory Society, principal clinico-pathological entities, and diagnosis [French]. Rev. Mal. Respir. 21, 299–318 (2004).
Collard, H. R. et al. Changes in clinical and physiologic variables predict survival in idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 168, 538–542 (2003).
Bottomley, A., Jones, D. & Claassens, L. Patient-reported outcomes: assessment and current perspectives of the guidelines of the Food and Drug Administration and the reflection paper of the European Medicines Agency. Eur. J. Cancer. 45, 347–353 (2009).
Speight, J. & Barendse, S. M. FDA guidance on patient reported outcomes. BMJ 340, c2921 (2010).
Pope, J. Measures of systemic sclerosis (scleroderma): Health Assessment Questionnaire (HAQ) and Scleroderma HAQ (SHAQ), physician- and patient-rated global assessments, Symptom Burden Index (SBI), University of California, Los Angeles, Scleroderma Clinical Trials Consortium Gastrointestinal Scale (UCLA SCTC GIT) 2.0, Baseline Dyspnea Index (BDI) and Transition Dyspnea Index (TDI) (Mahler's Index), Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR), and Raynaud's Condition Score (RCS). Arthritis Care Res. (Hoboken) 63, S98–S111 (2011).
Minnock, P., Kirwan, J. & Bresnihan, B. Fatigue is a reliable, sensitive and unique outcome measure in rheumatoid arthritis. Rheumatology (Oxford) 48, 1533–1536 (2009).
Boers, M., Brooks, P., Strand, C. V. & Tugwell, P. The OMERACT filter for outcome measures in rheumatology. J. Rheumatol. 25, 198–199 (1998).
Makol, A., Wright, K. & Matteson, E. L. Safe use of antirheumatic agents in patients with comorbidities. Rheum. Dis. Clin. North Am. 38, 771–793 (2012).
Zink, A. et al. European biologicals registers: methodology, selected results and perspectives. Ann. Rheum. Dis. 68, 1240–1246 (2009).
The authors thank J. Ryu for reviewing the draft manuscript before submission. M. Jani is a Medical Research Council (MRC) Clinical Training Fellow supported by the North West England MRC Fellowship Scheme in Clinical Pharmacology and Therapeutics, which is funded by the MRC (grant number G1000417/94,909), with additional financial support from ICON, GSK, AstraZeneca and the Medical Evaluation Unit. W. G. Dixon acknowledges research funding from the MRC (Clinician Scientist Fellowship; G0902272).
M. Jani has received reimbursement for attending symposia from UCB and Pfizer. N. Hirani has received reimbursement for attending symposia from Boehringer-Ingelheim and has received research funding from the AstraZeneca. E. L. Matteson and W. G. Dixon declare no competing interests.
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Jani, M., Hirani, N., Matteson, E. et al. The safety of biologic therapies in RA-associated interstitial lung disease. Nat Rev Rheumatol 10, 284–294 (2014). https://doi.org/10.1038/nrrheum.2013.197
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