StatementConsensus statements for medical practice: Biological agents and lung disease [Abridged English translation by the Japanese Respiratory Society]☆
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
References (95)
- et al.
Infliximab-induced nonspecific interstitial pneumonia
Am J Med Sci
(2012) - et al.
Bronchiectasis in rheumatoid arthritis: report of four cases and a review of the literature--implications for management with biologic response modifiers
Semin Arthritis Rheum
(2006) Biological agents and respiratory infections: causative mechanisms and practice management
Respir Investig
(2015)- et al.
Anti-tumor necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management
Lancet Infect Dis
(2003) - et al.
Pneumocystis jirovecii pneumonia in non-HIV-infected patients in the era of novel immunosuppressive therapies
J Infect Chemother
(2012) - et al.
Histopathologic pattern and clinical features of rheumatoid arthritis-associated interstitial lung disease
Chest
(2005) - et al.
Acute exacerbation of interstitial pneumonia associated with collagen vascular diseases
Respir Med
(2009) - et al.
Interstitial lung disease induced or exacerbated by TNF-targeted therapies: analysis of 122 cases
Semin Arthritis Rheum
(2011) - et al.
Pulmonary disorders induced by monoclonal antibodies in patients with rheumatologic autoimmune diseases
Am J Med
(2011) - et al.
Infliximab-induced nonspecific interstitial pneumonia
Am J Med Sci
(2012)
Tumor necrosis factor antagonist mechanisms of action: a comprehensive review
Pharmacol Ther
The Japanese experience with biologic therapies for rheumatoid arthritis
Nat Rev Rheumatol
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
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
Rheumatoid arthritis
Lancet
Phase II dose-response study of abatacept in Japanese patients with active rheumatoid arthritis with an inadequate response to methotrexate
Mod Rheumatol
Tolerability and efficacy of abatacept in Japanese patients with rheumatoid arthritis: a phase I study
Mod Rheumatol
Adverse effects of biologics: a network meta-analysis and Cochrane overview
Cochrane Database Syst Rev
Postmarketing surveillance of the safety profile of infliximab in 5000 Japanese patients with rheumatoid arthritis
Ann Rheum Dis
Postmarketing surveillance of the safety and effectiveness of etanercept in Japan
J Rheumatol
Safety and effectiveness of adalimumab in Japanese rheumatoid arthritis patients: postmarketing surveillance report of the first 3,000 patients
Mod Rheumatol
Postmarketing surveillance of tocilizumab for rheumatoid arthritis in Japan: interim analysis of 3881 patients
Ann Rheum Dis
Update on the Japanese guidelines for the use of infliximab and etanercept in rheumatoid arthritis
Mod Rheumatol
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
Malignancies associated with tumour necrosis factor inhibitors in registries and prospective observational studies: a systematic review and meta-analysis
Ann Rheum Dis
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
Developments in the scientific understanding of rheumatoid arthritis
Arthritis Res Ther
Airways abnormalities and rheumatoid arthritis-related autoantibodies in subjects without arthritis: early injury or initiating site of autoimmunity?
Arthritis Rheum
Cross-regulation of TNF and IFN-alpha in autoimmune diseases
Proc Natl Acad Sci USA
The mortality of rheumatoid arthritis
Arthritis Rheum
Prediction of long-term mortality in patients with rheumatoid arthritis according to simple questionnaire and joint count measures
Ann Intern Med
Treating rheumatoid arthritis to target: recommendations of an international task force
Ann Rheum Dis
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
Incidence and mortality of obstructive lung disease in rheumatoid arthritis: a population-based study
Arthritis Care Res
Comparison of pulmonary abnormalities on high-resolution computed tomography in patients with early versus longstanding rheumatoid arthritis
J Rheumatol
Mucosal inflammation in idiopathic bronchiectasis: cellular and molecular mechanisms
Eur Respir J
Immune mechanisms and the impact of the disrupted lung microbiome in chronic bacterial lung infection and bronchiectasis
Clin Exp Immunol
Bronchiectasis
Pulmonary function tests and high resolution computed tomography of the lungs in patients with rheumatoid arthritis
Ann Rheum Dis
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
Histopathological bronchial reconstruction of human bronchiolitis obliterans
Pathol Int
Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent
N Engl J Med
Role of tumour necrosis factor (TNF) in host defence against tuberculosis: implications for immunotherapies targeting TNF
Ann Rheum Dis
Tumor necrosis factor and its blockade in granulomatous infections: differential modes of action of infliximab and etanercept?
Clin Infect Dis
Reactivation of tuberculosis by tumor necrosis factor neutralization
Eur Cytokine Netw
Anti-TNF immunotherapy and tuberculosis reactivation: another mechanism revealed
J Clin Invest
The risk of tuberculosis related to tumour necrosis factor antagonist therapies: a TBNET consensus statement
Eur Respir J
Cited by (22)
2020 guide for the diagnosis and treatment of interstitial lung disease associated with connective tissue disease
2021, Respiratory InvestigationCitation Excerpt :However, it should be borne in mind that most immunosuppressants are known to cause a risk of drug-induced lung injury [221]. Furthermore, the diagnosis of drug-induced lung injury is difficult and many complex connections are involved in terms of the pathology, which may vary from simple allergic reactions to response to drug modifications for ILD-CTD (including the effects of newly started drugs as well as effects of discontinuing preceding drugs and CS reduction), and interactions between respiratory pathogens and the immune system [222]. Therefore, when administering immunosuppressants for ILD-CTD, every possibility should be considered.
Five-year point prevalence survey of healthcare-associated infections and antimicrobial use in a Japanese university hospital
2021, Infection Prevention in PracticeCitation Excerpt :Guidelines for Pneumocystis pneumonia prophylaxis in patients with HIV infection, haematopoietic cell transplant recipients, and solid organ recipients have been published [19–21]. Japanese guidelines are similar to these recommendations [22,23]. However, indications for Pneumocystis pneumonia prophylaxis in patients with immunosuppressants should be judged on a case-by-case basis [24].
Longitudinal changes in pulmonary function and respiratory impedance of rheumatoid arthritis
2019, Respiratory Physiology and NeurobiologyCitation Excerpt :RA-related pulmonary disorders, specifically interstitial pneumonia (IP) and airway abnormalities, are recognized as important extra-articular manifestations because they are responsible for a significant portion of the mortality (Tsuchiya et al., 2011; Nakamura et al., 2012; Assayag et al., 2014). Moreover, risks of complications of respiratory infection and drug-induced lung injury are increased in RA patients treated with disease-modifying antirheumatic drugs (DMARDs) (Tokuda et al., 2017). Importantly, the incidence of respiratory adverse events in RA patients with pre-existing respiratory involvement specifically IP and airway abnormalities is higher than that without respiratory involvement during biological DMARDs therapy (Curtis et al., 2015; Matsumoto et al., 2018).
Chest High-resolution Computed Tomography Findings in 601 Patients with Inflammatory Bowel Diseases
2018, Academic RadiologyCitation Excerpt :They concluded that early recognition and management of pulmonary manifestations is important to prevent significant morbidity and the development of destructive and irreversible changes in the airways (4). Several authors have recently recommended chest CT before the use of steroids, immunomodulators, or biological therapy in addition to early detection of pulmonary abnormalities (4,10). These therapies increase the risk of opportunistic infections and the risk of infection with intracellular pathogens, most notably tuberculosis (11–13).
- ☆
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.