(Overview)
In response to the rapid rise of social interest, the importance of medical care throughout lifelong, including the development of transitional medical care, has been reviewed. In addition, since 2015, the intractable disease policy in Ministry of Health, Labour and Welfare has been enriched as a national policy. However, the university courses in Japan have not successfully departed from the traditional framework of internal medicine and pediatrics so far. Especially in intractable immune diseases, pediatric rheumatology has developed mainly in a limited number of university hospitals, but rather than integrating with internal medicine, the stable succession of this field has even become a challenge. In addition, there is a shortage of providers who can treat pediatric patients with primary immunodeficiency after they reach adulthood. Therefore, the cooperation between the Departments of Pediatrics and Rheumatology is essential in dealing with autoimmune diseases complicated by primary immunodeficiency.
　Therefore, it is now required to establish a system for seamless research and education on intractable immune diseases such as rheumatic diseases from children to adults, succeeding the pediatric rheumatology in Japan. In response to this demand, the Lifelong Intractable Immunological Diseases Lecture (hereafter referred to as "this course") was established as a donation course at the Graduate School of Medical and Dental Sciences of our university in April, 2016. With the cooperation of the Departments of Rheumatology and Pediatrics, under the concept of "There is no framework of pediatrics/internal medicine in intractable diseases," we are confident that the new course has become a pioneer in the reform and enhancement of medical care and academics for all intractable diseases by building a research and educational system for intractable immune diseases, which could not be achieved in the existing courses. Thanks to these efforts, the "transitional medicine" research being conducted in this course has become widely accepted by society and is now being taken up as part of national policy. By renewing this course, we need and have an obligation to respond to the needs of society. Finally, we have been planning to renew the course with the aim of further pursuing and expanding the course to meet the needs for the medical care of autoimmune diseases complicated with PID and transitional care for PID patients diagnosed in childhood, while applying the achievements made so far in actual clinical practice.

(Research activities)
1) Establishment of a research and educational system through cooperation between the Departments of Pediatrics and Rheumatology
　This course clarifies the differences and similarities of rheumatic diseases between children and adults and develops and embodies a universal approach to "countermeasures for intractable diseases throughout life course". Although various treatment strategies have been proposed for rheumatic diseases, no detailed strategy that takes into account patient background, especially age, has yet been proposed. Especially in the transitional phase from pediatric to adult, there may be many transition-specific problems such as changes in the department/physician in charge from pediatrics to internal medicine and changes in the required amount of medication due to changes in drug metabolism and physique.
　In addition, we will continue to propose treatment strategies that consider the needs and issues of those who wish to have children and are restricted from various treatments, such as with methotrexate, and the elderly, for whom complications and compliance may be a concern.

2) Construction and analysis of a database for pediatric rheumatic diseases and comparative study with adult cases
　With this course playing a central role, we aim to complete the construction of a nationwide database on pediatric rheumatic diseases, which has not yet been developed in Japan.
　In particular, for juvenile idiopathic arthritis (JIA), we aim to enroll 500 cases and monitor their long-term course through continuous observation, in cooperation with the Pediatric Rheumatology Association of Japan, in a design linked to the existing adult rheumatoid arthritis (RA) database: National Database of Rheumatic Disease by iR-net in Japan (NinJa). We will grasp the current status and extract problems in JIA, establish evaluation indices that can be commonly used in JIA and RA, and examine the validity of existing RA disease activity indices in JIA. Since approximately 30% of patients with joint-type JIA, including those with severely active disease in childhood, are drug-free, we will analyze these cases to determine the possibility of drug-free diseases in adult patients. Adult-onset Still's disease has been considered to be the adult onset of systemic JIA, but differences exist. In systemic JIA, on the other hand, genetic abnormalities are now considered to be the underlying cause. In this course, we will perform the pathological analysis of various types of JIA as well as adult-onset Still's disease and RA using cohort studies, systematic genetic analysis, and microbiome analysis in order to redefine these diseases.
In other rheumatic diseases, polymyositis and dermatomyositis, especially dermatomyositis, have two peaks of onset in childhood and adulthood, and there are also differences in symptoms such as cutaneous calcification, drawing attention to the dissimilarities in the pathophysiology. Cohort studies in Japan have been conducted independently in children and adults for the purpose of certification for "designated intractable diseases" and "specific pediatric chronic diseases" by the Ministry of Health, Labour and Welfare. Internationally, Euromyositis is constructing a multinational database. In this course, we will construct a database of patients from childhood to adulthood that will be linked to international databases to clarify the current situation of the medical care of patients with myositis in Japan.

3) Epidemiological studies on pediatric patients with rheumatic diseases in Japan and database studies for proper evaluation and formulation of evidence-based diagnostic criteria and severity classifications
　In this course, we will initiate the "epidemiological studies on pediatric and adult patients in transitional phase of rheumatic diseases in Japan and database studies for proper evaluation and formulation of evidence-based diagnostic criteria and severity classifications", especially for pediatric rheumatic diseases, as a joint research project with the Pediatric Rheumatology Association of Japan, Research Group for "Research contributing to the proper use of biological agents and other drugs based on patient stratification in rheumatic diseases centering on JIA in the transition phase" (Principal Investigator: Masaaki Mori), Ministry of Health, Labour and Welfare Scientific Research Project on Intractable Diseases (Policy Research Project on Allergic and Immunological Diseases, etc.). We will utilize the NinJa system described above in 2) to make clinical use of data from the disease registry system of the Pediatric Rheumatology Association of Japan, as well as data on pediatric chronic diseases and designated intractable diseases. In particular, we will prioritize epidemiological studies on patients receiving biological agents for JIA, the most common pediatric rheumatic disease, and continue to evaluate their efficacy and safety in Japan. In juvenile dermatomyositis, the diagnostic criteria for inflammatory muscle diseases proposed by the International Myositis Classification Criteria Project (IMCCP) have been validated in a multicenter survey of a population of Japanese pediatric patients with dermatomyositis, and it is now at the stage of reporting its results to the world.

4) Elucidation of the pathophysiology of all intractable immune diseases observed in children and adults by whole exome sequencing, next-generation sequence analysis, and immunomarker research using the Bioresource Research Center
　In this course, we will utilize the Bioresource Research Center, which has the latest technologies such as whole exome sequencing, next-generation sequence analysis, and immunomarker research, to elucidate the pathophysiology of all intractable immune diseases (primary immunodeficiency, autoinflammatory diseases, rheumatic diseases, and vasculitis syndrome) in children and adults and to perform comprehensive analysis of childhood-onset cases, cases transitioning from childhood to adulthood, and adult-onset cases. More than 300 responsible genes have been identified in primary immunodeficiency, and genetic abnormalities have also been identified mainly in disease symptoms such as systemic lupus erythematosus (SLE) symptoms, arthritis, and vasculitis. Based on these findings, we will conduct research that sheds light on the genetic background and expression modifications in rheumatic diseases in adults. In addition, we will make efforts to develop and introduce advanced early diagnostic methods, such as neonatal mass screening for primary immunodeficiency, and examine their relevance to rheumatic diseases in adulthood. Expected applications of the research results include: 1) determination of the efficacy of cytokine inhibitors for JIA; 2) determination of the efficacy of anti-IL-1β monoclonal antibody therapy for "cryopyrin-associated periodic syndrome with a background of genetic mutation"; 3) establishment of universal early diagnosis based on the cause and onset mechanism of hypercytokinemia; 4) analysis of the involvement of immunodeficiency genes in adult patients with rheumatic diseases; and 5) efficacy of IVIg in autoimmune diseases with a background of immunodeficiency.

5) Implementation of transitional care for patients with primary immunodeficiency and medical care for complicated autoimmune phenomena and autoimmune diseases
Most primary immunodeficiency occurs in children and often requires continuous replacement therapy with immunoglobulin products, however, there is a shortage of providers who can continue to treat these patients after they reach adulthood. Furthermore, primary immunodeficiency and complicated autoimmune phenomena and autoimmune diseases found in adulthood are not rare, and a cross-departmental system of medical care is required. Our institution is actively involved in the transitional care of patients with primary immunodeficiency, and we will take advantage of being able to provide seamless care between the Departments of Pediatrics and Rheumatology to meet these unmet needs.

(Educational activities)
Fostering a “hybrid physician” who can provide consistent medical care from children to adults
　The clinical system so far has been separated for children and adults. From the perspective of patients, many feel confused and anxious about the change of the department in charge and the attending physician once they reach a certain age when they grow up despite the same disease. The adult physicians also often struggle with how those patients have progressed the diseases, what problems or worries of patients have had other than medical concerns while growing up, and whether those patients in carry-over case can be treated in the same manner as adults. For this purpose, this course plays a central role in providing an educational system for fostering "hybrid physicians" who are specialists in rheumatism treatment, are well familiar with treatment for both children and adults, and transcend the boundaries between children and adults.

(Education policy)
In this course, with the cooperation of Department of Rhewumatology and Pediatrics, we will promote the integration of research, education, and clinical systems for intractable immune diseases throughout the life of patients, and further aim to be a pioneer of renovation and enhancement of medical treatment and academics for intractable diseases. And this course is intending to foster pediatricians and adult physicians who can solve various problems for patients in the transition from childhood to adulthood and from adulthood to the elderly.

(Clinical features)
The Lifelong Intractable Immunological Diseases Lecture, “is a unique university course that cannot be found elsewhere in the world, which aims to integrate research, education, and treatment systems for "immune intractable diseases", such as collagen and rheumatic diseases, for a lifetime from children to adults and the elderly”. This course in our University has assessed various problems for patients with intractable diseases in the transitional phase from pediatric to adult or adult to elderly, which have not been solved by conventional medical system of Pediatrics and Internal medicine.