Statement
Consensus statements for medical practice: Biological agents and lung disease [Abridged English translation by the Japanese Respiratory Society]

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Introduction

Biological agents that target and block the actions of cytokines or molecules that play major roles in inflammation have now been widely used in treatment settings of various immune-mediated inflammatory diseases. Biological agents have remarkable therapeutic effects in rheumatic diseases such as rheumatoid arthritis (RA), inflammatory bowel diseases such as Crohn׳s disease, and skin diseases such as psoriasis. However, various adverse events have also been documented through the post-marketing surveillance (PMS) of these agents. The most serious adverse event, in terms of frequency and severity, is infection. The cytokines and molecules targeted by these drugs have an important role in the protective immunity of the host; therefore, blocking the actions of these molecules can result in frequent infections.

The use of tumor necrosis factor (TNF) inhibitors resulted in the increased incidence of respiratory infections, including bacterial pneumonia, tuberculosis (TB), nontuberculous mycobacteriosis (NTM), and Pneumocystis pneumonia (PCP), causing an increase in patient mortality. Increased incidences of these infections were also observed in patients administered biologics with other modes of action, although the frequency was different. In addition to infection, non-infectious adverse events, particularly sub-acute to acute diffuse lung disease, are a serious complication of biological agents. In a multicenter study conducted in 2012 in Japan, 38 deaths were confirmed among 2697 RA patients who were administered a biological agent, and the cause of death in 47% of these patients was lung disease. Based on these findings, it is clear that pulmonary complications are now a major obstacle to successful treatment with biologics.

Because of the high incidence of adverse events associated with biological agents, the Japan College of Rheumatology has published and revised the usage guidelines for biological agents. However, when serious complications occur, the advice and cooperation of respiratory specialists are required. In June 2012, the Japanese Respiratory Society set up a special committee consisting of ten members to develop consensus statements for the use of biological agents. The group included six pneumology specialists, one individual from the Japanese Society for Tuberculosis, one individual from the Japanese Association for Infectious Diseases, and two individuals from the Japan College of Rheumatology. We discussed the challenges and best treatment practices of pulmonary complications under biologic treatment, and produced the present set of consensus statements for the use of biological agents.

The consensus statements presented here mainly focus on RA, but their basic principles can be applied to all medical fields where biological agents are used, including the fields of rheumatology, orthopedics, gastroenterology, and dermatology. It is our sincere hope that these statements will be helpful in a variety of areas related to the medical care of patients with immune-mediated inflammatory diseases.

Section snippets

Outline

Biological agents are preparations of recombinant proteins, such as monoclonal antibodies and fusion proteins, which are produced using various molecular biology and genetic engineering techniques. Table 1 shows the biological agents currently approved in Japan for autoimmune diseases, and Table 2 shows the indications of each agent.

Characteristics and efficacy of biological agents approved in Japan for autoimmune diseases

  • 1.

    TNF inhibitors

  • 1)

    Characteristics of TNF inhibitors

  • a.

    Infliximab(IFX)

    A chimeric monoclonal antibody that uses a murine amino acid sequence for the fragment antigen-binding

Bacterial infections

Q1. Which bacterial infections require particular attention in RA patients? Is pneumonia common in RA patients? Is there an increase in the frequency of pneumonia after initiation of treatment with biological agents?

A1: Attention should be paid to pneumonia, lung abscess, empyema, and acute exacerbation of BE [44]. A number of cohort studies have reported a higher incidence of pneumonia in RA patients compared with the general population [45]. In addition, an increased incidence of serious

Tuberculosis

Q1. Is TB common in RA patients?

A1. The risk of TB infections is high among RA patients. In the early 2000 s, just prior to the introduction of biological agents in Japan, the incidence rate of TB in Japanese RA patients was 0.08% [52]. This rate was 3.21-fold higher than the incidence of TB among the general population [52] suggesting a higher risk of TB infection in RA patients.

The majority of recent cases of TB in Japan develop through the reactivation of latent infection established at an

Conclusions

PCP in RA patients is likely to progress in severity, and diagnosis is often difficult. The risk of PCP during the administration of biological agents should be considered, and if there is even a slight suspicion of PCP, chest CT and/or serum β d-glucan measurements should be conducted. Furthermore, the establishment of guidelines for indications and treatment periods for preventative medication after PCP treatment or in high-risk patients is warranted.

Interstitial pneumonia

Q1. What is the frequency, classification, and clinical picture for interstitial pneumonia in RA?

A1-1 Epidemiology: The frequency of complications of interstitial pneumonia in RA (RA-IP) is reported to be approximately 20% based on a prospective study using HRCT [74]. Age, male gender, smoking, high titer of RF and high erythrocyte sedimentation rates have been cited as risk factors for interstitial pneumonia.

A1-2 Histologic classification: Histologically, RA-IP is often classified into

Conflict of interest

Hitoshi Tokuda has received speaker׳s honorarium from Mitsubishi Tanabe Pharma, and manuscript fees from Chugai Pharmaceutical Co. Masayoshi Harigai has received speaker׳s honorarium from Mitsubishi Tanabe Pharma, research funding from Takeda Pharmaceutical Co. Ltd., Eisai Co., Ltd., and is a member of endowed departments by Abbvie Japan Co., Ltd., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Co., Ono Pharmaceuticals, Santen Pharmaceutical

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References (95)

  • D. Tracey et al.

    Tumor necrosis factor antagonist mechanisms of action: a comprehensive review

    Pharmacol Ther

    (2008)
  • T. Takeuchi et al.

    The Japanese experience with biologic therapies for rheumatoid arthritis

    Nat Rev Rheumatol

    (2010)
  • N. Nishimoto 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

    (2009)
  • N. Nishimoto et al.

    Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomized controlled trial of tocilizumab

    Ann Rheum Dis

    (2007)
  • D.L. Scott et al.

    Rheumatoid arthritis

    Lancet

    (2010)
  • T. Takeuchi et al.

    Phase II dose-response study of abatacept in Japanese patients with active rheumatoid arthritis with an inadequate response to methotrexate

    Mod Rheumatol

    (2013)
  • T. Matsubara et al.

    Tolerability and efficacy of abatacept in Japanese patients with rheumatoid arthritis: a phase I study

    Mod Rheumatol

    (2013)
  • J.A. Singh et al.

    Adverse effects of biologics: a network meta-analysis and Cochrane overview

    Cochrane Database Syst Rev

    (2011)
  • T. Takeuchi et al.

    Postmarketing surveillance of the safety profile of infliximab in 5000 Japanese patients with rheumatoid arthritis

    Ann Rheum Dis

    (2008)
  • T. Koike et al.

    Postmarketing surveillance of the safety and effectiveness of etanercept in Japan

    J Rheumatol

    (2009)
  • T. Koike et al.

    Safety and effectiveness of adalimumab in Japanese rheumatoid arthritis patients: postmarketing surveillance report of the first 3,000 patients

    Mod Rheumatol

    (2012)
  • T. Koike et al.

    Postmarketing surveillance of tocilizumab for rheumatoid arthritis in Japan: interim analysis of 3881 patients

    Ann Rheum Dis

    (2011)
  • R. Koike et al.

    Update on the Japanese guidelines for the use of infliximab and etanercept in rheumatoid arthritis

    Mod Rheumatol

    (2007)
  • M. Harigai et al.

    Elevation of KL-6 serum levels in clinical trials of tumor necrosis factor inhibitors in patients with rheumatoid arthritis: a report from the Japan College of Rheumatology Ad Hoc Committee for Safety of Biological DMARDs

    Mod Rheumatol

    (2013)
  • X. Mariette et al.

    Malignancies associated with tumour necrosis factor inhibitors in registries and prospective observational studies: a systematic review and meta-analysis

    Ann Rheum Dis

    (2011)
  • M. Harigai et al.

    Risk for malignancy in rheumatoid arthritis patients treated with biological disease-modifying antirheumatic drugs compared to the general population: a nationwide cohort study in Japan

    Mod Rheumatol

    (2016)
  • C.M. Weyand et al.

    Developments in the scientific understanding of rheumatoid arthritis

    Arthritis Res Ther

    (2009)
  • M.K. Demoruelle et al.

    Airways abnormalities and rheumatoid arthritis-related autoantibodies in subjects without arthritis: early injury or initiating site of autoimmunity?

    Arthritis Rheum

    (2012)
  • A.K. Palucka et al.

    Cross-regulation of TNF and IFN-alpha in autoimmune diseases

    Proc Natl Acad Sci USA

    (2005)
  • F. Wolfe et al.

    The mortality of rheumatoid arthritis

    Arthritis Rheum

    (1994)
  • T. Pincus et al.

    Prediction of long-term mortality in patients with rheumatoid arthritis according to simple questionnaire and joint count measures

    Ann Intern Med

    (1994)
  • J.S. Smolen et al.

    Treating rheumatoid arthritis to target: recommendations of an international task force

    Ann Rheum Dis

    (2010)
  • J.A. Singh et al.

    2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis

    Arthritis Care Res

    (2012)
  • C. Nannini et al.

    Incidence and mortality of obstructive lung disease in rheumatoid arthritis: a population-based study

    Arthritis Care Res

    (2013)
  • S. Mori et al.

    Comparison of pulmonary abnormalities on high-resolution computed tomography in patients with early versus longstanding rheumatoid arthritis

    J Rheumatol

    (2008)
  • S. Fuschillo et al.

    Mucosal inflammation in idiopathic bronchiectasis: cellular and molecular mechanisms

    Eur Respir J

    (2008)
  • R.J. Boyton et al.

    Immune mechanisms and the impact of the disrupted lung microbiome in chronic bacterial lung infection and bronchiectasis

    Clin Exp Immunol

    (2012)
  • D.P. Naidich

    Bronchiectasis

  • B. Cortet et al.

    Pulmonary function tests and high resolution computed tomography of the lungs in patients with rheumatoid arthritis

    Ann Rheum Dis

    (1997)
  • S. Mori et al.

    Radiological features and therapeutic responses of pulmonary nontuberculous mycobacterial disease in rheumatoid arthritis patients receiving biological agents: a retrospective, multicenter study in Japan

    Mod Rheumatol

    (2012)
  • K. Sugino et al.

    Histopathological bronchial reconstruction of human bronchiolitis obliterans

    Pathol Int

    (2011)
  • J. Keane et al.

    Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent

    N Engl J Med

    (2001)
  • S. Ehlers

    Role of tumour necrosis factor (TNF) in host defence against tuberculosis: implications for immunotherapies targeting TNF

    Ann Rheum Dis

    (2003)
  • S. Ehlers

    Tumor necrosis factor and its blockade in granulomatous infections: differential modes of action of infliximab and etanercept?

    Clin Infect Dis

    (2005)
  • M. Jacobs et al.

    Reactivation of tuberculosis by tumor necrosis factor neutralization

    Eur Cytokine Netw

    (2007)
  • E.A. Miller et al.

    Anti-TNF immunotherapy and tuberculosis reactivation: another mechanism revealed

    J Clin Invest

    (2009)
  • I. Solovic et al.

    The risk of tuberculosis related to tumour necrosis factor antagonist therapies: a TBNET consensus statement

    Eur Respir J

    (2010)
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    This article is based on an abridged edition of consensus statements first published as Consensus Statements for Medical Practice-Biological Agents and Lung Disease by the Japanese Respiratory Society in Japanese in February 2014.

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