Review
Japanese guideline for the treatment of idiopathic pulmonary fibrosis

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Abstract

Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology which accounts for a large proportion of cases of idiopathic interstitial pneumonia. It has a very poor prognosis with a 5-year survival rate of 30% or below, and so far there has been no guideline in Japan offering an established effective therapy based on evidence. In addition to the establishment of basic therapies, there is also an urgent need to establish therapies to deal with complications, as death occurs in many cases due to acute exacerbation or comorbid lung cancer. It was therefore decided to formulate a guideline in order to promote evidence-based clinical practice, to further improve the quality of medical treatment in the clinical setting, and to allow the benefits to be enjoyed by the public.

Introduction

In recent years, there has been a worldwide move toward measures to standardize clinical practice in the treatment of diseases. As idiopathic pulmonary fibrosis (IPF) is the form of idiopathic interstitial pneumonias (IIPs) with the poorest prognosis and an intractable condition, recent years have seen many drugs put forward as candidates in clinical trials for assessment of their efficacy and safety. Back in 2000, a consensus statement on IPF treatment was formulated by bodies chiefly in Europe and North America [1]. Subsequently a number of scientifically based randomized controlled trials (RCT) were planned and carried out, which resulted in the accumulation of evidence-based medicine (EBM) in literatures. It was on the basis of these results that the first EBM guideline was created in 2011 [2].

In Japan, the Manual for the Diagnosis and Treatment of Idiopathic Interstitial Pneumonias was issued in 2004 [3] with the aim of establishing consistency with the European and North American consensus statement. The end of 2008 brought a world-first development with the marketing of the antifibrotic agent pirfenidone. To coincide with the 2011 issue of the EBM guideline, its content was incorporated in the Manual for the Diagnosis and Treatment of Idiopathic Interstitial Pneumonias (revised 2nd edition) published in the same year. Between 2012 and the end of 2014 the results of further international clinical trials have been reported, leading to the revision of the European and North American EBM guideline on IPF treatment in 2015 [4].

Building on this background situation toward the issue of a scientifically based guideline for Japan, the present guideline was formulated on the basis of clinical trial results from Japan and overseas and Japanese post-marketing surveillance data. The main aim of the present guideline is to outline practically effective therapies and measures for patients based on appropriate diagnosis of IPF. However, the present guideline is designed strictly to give recommendations of various strengths in accordance with the GRADE system and does not limit the discretion of the treating physician based on assessment of patient benefit. We also wish to make clear that it is not intended as supporting material for decisions in medical disputes or medical-related litigation. When non-standard therapies or measures are introduced, the patient should be given an adequate explanation and a relevant entry should be made in the medical notes.

The use of the present guideline is not limited to physicians specializing in the diagnosis and treatment of respiratory diseases, but is also aimed at non-specialist doctors, medical treatment staff, patients, and their families.

A clinical practice guideline that can be used with confidence is defined as ‘a document including recommendations which is intended to optimize patient care and is based on systematic review of the evidence and an assessment of the benefits and harms of a number of treatment options.’ Meanwhile, the website of the Minds Guideline Center, which promotes evidence-based medical information as one of the functions of the Japan Council for Quality Health Care, states that ‘a clinical practice guideline is a document including scientifically based and systematically formulated recommendations which is created for the purpose of supporting patients and medical professionals and which can be used as one basis for judgment when making decisions in the clinical setting.’ It further states that ‘a clinical practice guideline does not negate the experience of medical professionals, and as the guideline content refers to clinical practice in general, it may not necessarily be applicable depending on the individual patient׳s condition.’ It thus remains of prime importance that the final judgment in the clinical setting is made by the treating physician in discussion with the patient.

Section snippets

Committee composition

The IPF treatment guideline is a guideline specifically addressing treatment and management which was created with the collaboration of the Japanese Respiratory Society (JRS) under the leadership of the Ministry of Health, Labour and Welfare, the Study Group on Diffuse Pulmonary Disorders, Scientific Research/Research on Intractable Diseases. Hitherto in Japan, the document used to support decision-making at the frontline of clinical practice for IPF and other idiopathic interstitial pneumonias

The GRADE system and self-assessment

Quality of evidence and terminology used for the recommendation show Table 1 and Table 2. In this clinical practice guideline formulated using the GRADE system, self-assessment shows in Table 3. Since its presentation in 2004, the GRADE system has benefited from the accumulation of experience and discussion by many relevant practitioners around the world, which has contributed to growing methodological refinement and the consolidation of its core elements. At present, the resulting insights can

Recommendations for specific treatment questions

Fig. 1 shows clinical questions for treatment of IPF.

Clinical Question 1: Should patients with IPF be treated with corticosteroid monotherapy?

We recommend strongly that patients with IPF in the chronic phase should not be treated with corticosteroid monotherapy.

Conclusions

Since its presentation in 2004, the GRADE system has benefited from the accumulation of experience and discussion by many relevant practitioners around the world, which has contributed to growing methodological refinement and the consolidation of its core elements. At present, the resulting insights can be expressed in the seven criteria outlined above. The GRADE working group regards these as essential requirements, but as stated in Criterion 4, the formulation of evidence profiles in a fixed

Future directions

The existing evidence on IPF is characterized by the very small number of RCTs available and by the resulting necessity to turn to observational study. In the systematic review for the formulation of the present guideline, difficulties were consequently encountered in both the integration of RCT findings and in the assessment of the quality of the observational study. In frequent instances, the specialists disagreed among themselves as to the interpretation and evaluation of the individual

Revision schedule

It is planned to revise the present guideline every 4–5 years in response to the results of new clinical trials, etc. However, in the case of important findings, consideration will be given as necessary to bringing forward the revision date or undertaking partial revision.

Funding

The formulation of the present guideline was funded exclusively with survey and research grants from the Ministry of Health, Labour and Welfare, the Study Group on Diffuse Pulmonary Disorders, Scientific Research/Research on Intractable Diseases.

Conflict of interest

In line with the Japanese Respiratory Society׳s conflict of interest policy, which is based on the Policy of Conflict of Interest in Clinical Research adopted jointly by the Japan Society of Internal Medicine and other scientific societies, all 34 committee members were requested to declare conflict of interest status with respect to economic relationships with enterprises involved in IPF or related diseases in accordance with the criteria listed below.

  • (1)

    Any service as officer, advisor, etc., to

Acknowledgments

The authors are grateful to external assessment committee members (Shoji Kudoh: The Research Institute of Tuberculosis, Japan Anti-tuberculosis Association, Yukihiko Sugiyama: Japan Association for Development of Community Medicine, Nerima-Hikarigaoka Hospital, Toshihiro Nukiwa: Japan Anti-Tuberculosis Association, Research Institute of Tuberculosis), and collaborators (Takekazu Iwata: Chiba University, Graduate School of Medicine, Department of General Thoracic Surgery, Ryo Ko: Juntendo

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