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To optimize patient prognosis, patient needs, including unmet needs, should be adequately assessed. However, such needs are more challenging to report and, consequently, more likely to go unmet compared with the needs reported by physicians. We aimed to determine the appropriate direction of future research on unmet medical needs in rheumatic diseases in Japan by conducting a literature review. We searched PubMed and Web of Science using 23 terms linked to unmet medical needs for major rheumatic diseases in Japan. Further, we collected articles on health-related quality of life and investigated the scales used for assessment, as well as whether the terms "unmet needs" or "unmet medical needs" were used. We identified 949 papers on 10 diseases, including systemic lupus erythematosus, systemic sclerosis, dermatomyositis, juvenile idiopathic arthritis, adult-onset Still's disease, antiphospholipid syndrome, mixed connective tissue disease, Takayasu arteritis, Sjögren's syndrome, and Behçet's disease; 25 of the 949 papers were selected for full-text review. Fifteen articles on five diseases were related to health-related quality of life. The term "unmet needs" was used in only one article. Six out of 15 studies used the 36-item short form survey, whereas the scales used in other studies differed. The optimal treatment plan determined by a physician may not necessarily align with the best interests of the patient. In clinical research, cross sectional and standardized indicators of health-related quality of life should be employed along with highly discretionary questionnaires to assess and optimize resource allocation in healthcare and simultaneously achieve patient-desired outcomes. [ABSTRACT FROM AUTHOR]

Background: The risk and survival of patients with non-small cell lung cancer (NSCLC) with pre-existing autoimmune disorders (AIDs) receiving immune checkpoint blockade (ICB) therapy have not been clearly established., Patients and Methods: This multi-institutional, retrospective cohort study was conducted in collaboration with 20 centers in Japan., Results: In total, 229 patients with advanced or recurrent NSCLC and pre-existing AID, with or without ICB treatment from January 2010-February 2020, were included and analyzed. Among 69 patients who received ICB, 2 received two lines of ICBs with a total of 71 ICB treatments; 57 (80.3 %) and 14 (19.7 %) patients received ICB monotherapy and combination therapy, respectively. AID flares were observed in 18 patients (25.4 %, 95 % confidence interval [CI], 15.8-37.1 %) receiving ICB. AID exacerbations were more likely when NSCLC was diagnosed less than 1 year after the AID diagnosis (odds ratio 5.26 [95 % CI, 1.40-21.61]; P = 0.016). Immune-related adverse events were observed in 32 patients (45.1 %, 95 % CI, 33.2-57.3 %); 17 had grade 3 or higher. The safety profile of combination immunotherapy was not significantly different from that of the monotherapy. After inverse probability weighting, the use of ICB prolonged survival (hazard ratio 0.43 [95 % CI, 0.26-0.70]; P = 0.0006)., Conclusions: These findings revealed a novel risk factor for AID flares following ICB treatment, that is the diagnosis of NSCLC within 1 year of AID diagnosis, and showed that ICBs may improve survival in this population. These results support the utilization of ICB in patients with NSCLC and pre-existing AID., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Dr. Asao reported receiving personal fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, Merck Biopharma, MSD, Nippon Kayaku, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, and Takeda Pharmaceutical outside the submitted work. Dr. Shukuya reported receiving grants from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, MSD, and Novartis, outside the submitted work; and personal fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, MSD, Nippon Kayaku, Novartis, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, Takeda Pharmaceutical, outside the submitted work. Dr. Mouri reported receiving personal fees from Chugai Pharmaceutical and Eli Lilly, outside the submitted work. Dr. Tsukita reported receiving personal fees from AstraZeneca, Boehringer Ingelheim, Bristol-Meyers Squibb, Chugai Pharmaceutical, Daiichi-Sankyo, Eisai, Eli Lilly, MSD, and Taiho Pharmaceutical, outside the submitted work. Dr. Watanabe reported receiving grants from Nippon Kayaku outside the submitted work, personal fees from AstraZeneca, Bristol-Meyers Squibb, Celltrion, Chugai Pharmaceutical, Daiichi-Sankyo, Eli Lilly, Kyowa Kirin, MSD, Nippon Kayaku, Novartis, Ono Pharmaceutical, Taiho Pharmaceutical, Takeda Pharmaceutical, outside the submitted work. Dr. Morita reported receiving personal fees from Amgen, AstraZeneca, Bristol-Meyers Squibb, Chugai Pharmaceutical, Daiichi-Sankyo, Eli Lilly, MSD, Nippon Kayaku, Novartis, Pfizer, Taiho Pharmaceutical, Takeda Pharmaceutical, and ThermoFisher Scientific, outside the submitted work. Dr. Yoshioka reported receiving grants from AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Delta Fly Pharma, Janssen Pharmaceutical, MSD, and Novartis, outside the submitted work; and personal fees from AstraZeneca, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Kyowa Kirin, MSD, Nippon Kayaku, Nipro Pharma, Novartis, Ono Pharmaceutical, Otsuka Pharmaceutical, Pfizer, Taiho Pharmaceutical, outside the submitted work. Dr. Namba reported receiving personal fees from Chugai Pharmaceutical, Kyowa Kirin, MSD, and Taiho Pharmaceutical, outside the submitted work. Dr. Nakagawa reported receiving personal fees from AstraZeneca, Chugai Pharmaceutical, Eli Lilly Japan, Japan Blood Products Organization, MSD, Nippon Kayaku, Novartis Pharma, Ono Pharmaceutical, Pfizer Japan, and Taiho Pharmaceutical, outside the submitted work. Dr. Watanabe reported receiving grants from MSD, outside the submitted work. Dr. Kobayashi reported receiving personal fees from AstraZeneca and Takeda Pharmaceutical, outside the submitted work. Dr. Takahashi reports grant support from Asahi Kasei Pharma, Bayer, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, Eli-Lilly, Kyorin Pharmaceutical, Kyowa Kirin, Nippon Kayaku, Nippon Shinyaku, Nipro Pharma, Novartis, Ono Pharmaceutical, Pfizer, Sanofi, Shionogi, Takeda Pharmaceutical, Taiho Pharmaceutical, Teijin Pharma, and Tsumura, outside the submitted work; personal fees from Abbott Japan, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Janssen Pharmaceutical, Meiji Seika Pharma, Merck Biopharma, MSD, Kyorin Pharmaceutical, Nippon Kayaku, Novartis, Ono Pharmaceutical, Pfizer, Sumitomo Dainippon Pharma, Taiho Pharmaceutical, Takeda Pharmaceutical, ThermoFisher Scientific and Viatris, outside the submitted work.; and serving as a board member of director of the Japan Lung Cancer Society and The Japanese Respiratory Society. No other disclosures were reported., (Copyright © 2024. Published by Elsevier B.V.)

Ethnopharmacological Relevance: The herbal medicine designated Chai-Ling-Tang in China, Siryung-tang in South Korea, and Sairei-To (or Tsumura Saireito extract granules, TJ-114) in Japan is a complex polyherbal formulations with 12 plant components. It is used historically to treat Shaoyang syndrome, recorded in an ancient Chinese medical text "Treatise on Cold Damage Disorder" (Shanghan Lun). Chai-Ling-Tang formula combines two traditional Chinese herbal medicine prescriptions: Xiao-Chai-Hu-Tang and Wu-Ling-San (known as Sho-Saiko-To and Goreisan in Japan, and So Shi Ho Tang and Oreonsang in Korea, respectively). These traditional Chinese/Korean medicines and Kampo medicine have been used for more than 2000 years in East Asia, notably as regulators of body fluid homeostasis., Aim of the Study: This study aims to evaluate clinical uses, pharmacological effects and unwanted effects of Sairei-To through a narrative literature survey. The main active phytoconstituents and their mechanism of actions are also collated based on the literature., Methods: Several databases including SciFinder and PubMed were searched in sourcing information using keywords corresponding to the medicinal treatment names and the corresponding plants and phytochemicals. Relevant textbooks, reviews, and digital documents (mostly in English) were consulted to collate all available scientific literature and to provide a complete science-based survey of the topic., Results: Sairei-To derives from ten plants and two fungi. The three major components are Bupleuri radix (Saiko), Pinelliae rhizoma (Hange), and Alismatis rhizoma (Takusha). The rest includes the species Scutellariae radix, Zizyphi fructus, Ginseng radix, Glycyrrhizae radix, Zingiberis rhizoma, Cinnamomi cortex, Atractylodis lanceae rhizoma, Poria sclerotium, and Polyporus sclerotium. The therapeutic uses of Sairei-To are very diversified, ranging from the treatment of autoimmune diseases, intestinal inflammatory disorders, edema, intestinal and kidney diseases, cancers, inflammatory skin pathologies, and other conditions such as reproductive failure. Sairei-To is considered as a safe and efficient medication, with potential rare unwanted side effects, notably lung injuries (pneumonitis essentially). Marked anti-inflammatory and immune-modulatory effects of Sairei-To have been reported, generally associated to the action of saponins (saikosaponins, glycyrrhizin), terpenoids (alisols) and flavonoids (baicalin, oroxylin A)., Conclusion: Sairei-To is commonly used to treat inflammatory diseases and appears efficient to decrease the side effects of corticosteroids. Its immune-regulatory action is well recognized and exploited to treat certain skin lesions and chemotherapy-related toxic effects. The activity of the Sairei-To product relies on the synergistic action of its individual ingredients. Further studies are warranted to quantify the synergy of action inherent to this interesting botanical medication., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background and Objective: Immune checkpoint inhibitors (ICIs) such as programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitors have greatly improved cancer treatment. However, they are associated with immune-related adverse events, including autoimmune diseases (ADs) owing to their immune enhancement effect. As there are few comprehensive studies of ADs by ICIs, it is necessary to analyze the period information of drug-induced ADs. We also assumed that the temporal information may be useful to estimate the similarity of the pathogenic mechanism between spontaneous and ICI-induced ADs., Methods: A period analysis including the Weibull analysis was performed on ICI-induced ADs using the Japanese Adverse Drug Event Report (JADER) database. For evaluating the similarity of spontaneous and ICI-induced ADs, a hierarchical cluster analysis was conducted to compare the different onset-time ranges., Results: Type 1 diabetes mellitus, autoimmune colitis, and pemphigoid occurred earlier with CTLA-4 inhibitors (median: 46, 29.5 and 28 days, respectively) than with PD-1 inhibitors (> 130 days). Myasthenia gravis had a median time to onset of approximately 1 month, and the risk of onset would increase over time in ipilimumab combination therapy. This result reveals ADs that require attention. Using cluster analysis, we estimated six clusters with different patterns of onset times. Based on these results and a detailed previous research survey, the possible pathogenesis of drug-induced ADs was also discussed., Conclusions: This paper describes risk profiles with temporal information of ICI-induced ADs and proposes certain indicators for deciphering the mechanism of AD onset.

It is well known that individuals positive for particular HLA-class II alleles show high risks for the development of Takayasu arteritis and other diseases caused by immunological disorders such as autoimmune diseases and allergies. HLA class II molecules present antigenic peptides to CD4+ T cells. Their extensive polymorphism affects the structures of peptides bound to HLA class II molecules to create individual differences in immune responses to antigenic peptides. To better understand the mechanisms for association between HLA class II alleles and susceptibility to autoimmune diseases, it is important to identify self-peptides presented by disease-susceptible HLA class II molecules and triggering disease-causative T cells. Many autoimmune diseases are observed in all ethnic groups, whereas the incidences of diseases, clinical manifestations and disease-susceptible HLA class II alleles are different among various ethnic groups for some autoimmune diseases. These phenomena suggest that differences in autoimmune self-peptide(s) in the context of disease-susceptible HLA class II molecules may cause these differences. Therefore, comparisons among disease-susceptible HLA class II alleles, autoimmune self-peptides and clinical manifestations of autoimmune diseases in different ethnic groups would be helpful in determining the pathogenesis of the diseases. In this paper, we describe our recent findings on: (1) the uniqueness of both clinical manifestations and HLA-linked genetic background of Asian-type (optico-spinal form) multiple sclerosis; (2) the structural characteristics of peptides bound to HLA-DQ molecules susceptible to insulin-dependent diabetes mellitus; (3) the identification of a disease-related autoantigenic peptide presented by disease-susceptible HLA-DQ molecules in Asians-specific infant onset myasthenia gravis; and (4) a manipulation of human T cell response by altered peptide ligands, as a possible candidate for new and antigen-specific immuno-suppressive therapy against autoimmune diseases.

Collagen disease is systemic autoimmune disease and consists of a lot of diseases with each clinical entity. for exact diagnosis, it is important to choose essential laboratory tests for the patient suspected of collagen disease in daily primary medical care. A guideline for the use of clinical laboratory tests for patients with collagen disease was proposed by the Japan Society of Clinical Pathology. This guideline was discussed repeatedly by subcommittee members of "the uses of clinical laboratory tests in daily primary medical care" and published on September of 1990. When the clinicians are suspected of the collagen disease from detailed history taking and physical examination, they must precisely interpret results of the essential laboratory tests. Urinalysis, hematology, ESR and CRP and Biochemistry show characteristic findings in the collagen disease, respectively. If further suspicion of the collagen disease is intensive, the clinicians proceed with the primary screening tests for collagen disease; rheumatoid factor, ANF, anti DNA antibody, LE test, STS and CH50. Finally, specific tests for each collagen disease are carried out to define the diagnosis; e.g. LE cell, anti-Sm antibody, IC, Coombs test and biopsy of kidney for SLE. This paper is presented on the intention of the guideline of clinical laboratory tests for the collagen disease and its issues. As it passed 4 years after published, this guideline should be more discussed and revised.

Information about several papers discussed at the Post-International Investigate Dermatology (IID) International Meeting on Autoimmune Bullous Diseases held in Tokyo, Japan is presented. Among the papers discussed during the meeting were the desmosome dynamics in health and disease, the mysterious target antigens in autoimmune bullous diseases, and the mouse model for pemphigus and pemphigoid. An overview on how the sessions was conducted is also presented.

von Willebrand factor (VWF) forms high-molecular-weight multimers and plays an essential role in hemostasis, and thus its deficiency leads to bleeding symptoms. Acquired von Willebrand syndrome (AVWS) is rare, but potentially underdiagnosed, and develops in various underlying disorders. AVWS caused by anti-VWF autoantibodies is a rare subcategory of AVWS that can also be referred to as autoimmune VWF deficiency (AiVWFD). We performed a search of patients with autoimmune coagulation factor deficiencies in our nationwide survey in Japan. Among these, suspected cases of AiVWFD were extremely few, with only 11 case consultations in the last 10 years. Of these, three and five were respectively positive for anti-VWF autoantibodies (anti-VWF-Ab) and VWF inhibitor (VWF-inh). We also performed an extensive literature search of other cases from Japan, and in total, 40 cases were finally identified to have AiVWFD, with mean age of 55.0 years. Most underlying disorders were lympho- or myeloproliferative diseases, followed by autoimmune diseases. The major bleeding sites were subcutaneous and mucosal, the bleeding severity was moderate, and there were no hemorrhagic deaths. Bleeding time was prolonged; factor VIII activity, VWF antigen, and VWF activity were decreased, and high-molecular-weight VWF multimers were absent or decreased. These are similar to the common abnormal laboratory findings observed among general AVWS cases. Hemostatic therapy often involved VWF concentrates and vasopressin, and antibody eradication therapy often included corticosteroids and achieved remission. Notably, of all cases, 68% had anti-VWF-Abs, and 83% of anti-VWF-Ab-positive patients were also VWF-inh positive. To accumulate precise clinical information on AiVWFD, it is necessary to verify and improve the measurement methods for both anti-VWF-Ab and anti-VWF-inh. These findings from Japan should be confirmed in other geographic localities. [ABSTRACT FROM AUTHOR]

Background: Allergen immunotherapy (AIT) is the only treatment that has modified the natural history of allergic diseases. However, since its overall effect on the immune system has not been elucidated, AIT is either absolutely or relatively contraindicated in patients with rheumatic autoimmune diseases (RADs). Therefore, there have been no long-term observations of patients with RADs receiving AIT; thus, the effectiveness and safety of AIT in these patients remain unclear. Methods: This was a single-center retrospective observational study. RAD patients receiving AIT for allergic rhinitis at our institution were selected. Changes in the activity of RAD patients were investigated for 2 years from baseline, including those who discontinued AIT. The effectiveness of AIT was also investigated using the Japan Allergic Rhinitis Standard Quality of Life Questionnaire. Results: Thirteen patients with RADs were enrolled in the study. All patients received sublingual immunotherapy, of which four discontinued AIT owing to adverse events. Among all patients, the symptoms of RADs in three patients worsened during the observation period; however, none of them were causally related to AIT. Most of the adverse events associated with AIT were mild, in which only one patient required drug intervention due to worsening rhinitis symptoms. In the nine patients who were able to continue AIT, their eye and nasal symptom scores showed a significant improvement from 1.67 (1.5–2.0) at baseline to 0.67 (0–1.17) in the 2nd year of treatment (p = 0.0141). Conclusions: AIT is a safe and effective treatment modality for patients with allergic rhinitis complicated by RADs. [ABSTRACT FROM AUTHOR]

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy (GFAP-A) is a type of autoimmune corticosteroid-responsive meningoencephalitis that occurs with or without myelitis. Movement disorders have been reported in GFAP-A patients but have not been characterized. In this study, we examined the characteristics of movement disorders in GFAP-A patients. We retrospectively reviewed clinical data from 87 consecutive patients with GFAP-A attending Gifu University Hospital in Japan. We compared the demographics, clinical features, cerebrospinal fluid characteristics, and neuroimaging findings from patients with and without movement disorders. Seventy-four patients (85%) had movement disorders, including ataxia (49%), tremor (45%), myoclonus (37%), dyskinesia (2%), opsoclonus (2%), rigidity (2%), myokymia (1%), and choreoathetosis (1%). GFAP-A patients with movement disorders were significantly older than those without. Movement disorders are therefore common in GFAP-A patients, and the main types of movement disorders observed in this population were ataxia, tremor, and myoclonus. These abnormal movements can serve as clinical features that facilitate the early diagnosis of GFAP-A. Elderly GFAP-A patients are more likely to have movement disorder complications than younger patients. [ABSTRACT FROM AUTHOR]

Coagulation factor V (or FV for the purpose of medical safety) is an essential cofactor of coagulation factor X in the common pathway of coagulation; severe FV deficiency leads to a bleeding tendency. Although both congenital and acquired FV deficiencies are widely recognized, FV deficiency also presents as an autoimmune disorder. A nationwide survey on autoimmune coagulation factor deficiencies (AiCFDs) conducted in Japan by our Japanese Collaborative Research Group identified 24 new patients with autoimmune FV deficiency (AiFVD) in the past 5 years. Furthermore, our extensive literature search confirmed that 177 AiFVD cases have been reported in previous articles published from Japan. Patients with AiFVD in Japan were predominantly men, with age similar to those with other AiCFDs. AiFVD was confirmed as a relatively mild type of bleeding diathesis, associated with lower mortality rate than that for AiFVD and other AiCFDs reported in previous studies. Patients with AiFVD had variable FV inhibitor titers and both neutralizing anti-FV autoantibodies and nonneutralizing counterparts. Although spontaneous resolution occurs in some patients, timely initiation of hemostatic and immunosuppressive therapies helps arrest the bleeding and eliminate anti-FV antibodies, resulting in a high cumulative recovery rate. Immunological anti-FV antibody detection is recommended to avoid missing AiFVD cases for the presence of nonneutralizing anti-FV autoantibodies. Further investigation is necessary to clarify the long-term prognosis and optimal management of AiFVD. [ABSTRACT FROM AUTHOR]

Prednisolone (PSL), a type of corticosteroid used to treat autoimmune diseases, can increase the risk of infection and osteoporosis. Saireito (114), a Kampo medicine, has an immunosuppressive effect; with its use, the dose of steroids can be reduced. However, its mechanism when used with PSL is still unclear. We used peripheral blood mononuclear cells (PBMCs) from healthy adults to examine the effect of 114 and PSL treatment on PBMC proliferation, T-cell subsets, and cytokine production. PBMCs were cotreated with concanavalin A and 300 μM 114 (either Tsumura & Co. (TJ) or Kracie Holdings (KR)) and 0.0001–1.0 μM PSL for 96 h to create the T-cell mitogen. We then measured the PBMC proliferation; ratio of CD4+ T cells, CD8+ T cells, and T-follicular helper (Tfh) cells; and concentration of cytokines (TNF, IFN-γ, IL-6, IL-10, IL-17A, and IL-21). The proliferation of PBMCs was dose dependently suppressed in both the PSL and PSL + 114 groups (p < 0. 05). Combination therapy increased the IC50 in the PSL group (0.0947 μM) by 2.02 and 1.64-fold in the PSL + TJ114 and PSL + KR114 groups, respectively. Both the PSL + 114 groups had an increased ratio of CD4+ T cells compared to the PSL group, with no effect on the ratio of CD8+ T and Tfh cells. Furthermore, the PSL + 114 groups showed increased IL-6 and IL-10 compared to the PSL monotherapy group, although the difference was not significant. There was no significant difference in the TNF, IFN-γ, IL-17A, and IL-21 concentrations between the PSL and PSL + 114 groups. The elevated IC50 with 114 cotreatment suggests diminished immunosuppressive action. Moreover, increased cytokine production by Th2 with 114 cotreatment suggests a restoration of T-cell balance in Th1-mediated autoimmune diseases. However, increased IL-6 suggests potential exacerbation of IL-6-mediated diseases, such as rheumatoid arthritis. Therefore, it is necessary to monitor these clinical parameters when using 114 in combination with PSL. [ABSTRACT FROM AUTHOR]

Autoimmune thyroid diseases (AITDs), including Graves' disease (GD) and Hashimoto's thyroiditis (HT), are caused by immune response to self-thyroid antigens and affect approximately 2-5% of the general population. Genetic susceptibility in combination with external factors, such as smoking, viral/bacterial infection, and chemicals, is believed to initiate the autoimmune response against thyroid antigens. Abundant epidemiological data, including family and twin studies, point to a strong genetic influence on the development of AITDs. Various techniques have been employed to identify genes contributing to the etiology of AITDs, including candidate gene analysis and whole genome screening. These studies have enabled the identification of several loci (genetic regions) that are linked to AITDs, and, in some of these loci, putative AITD susceptibility genes have been identified. Some of these genes/loci are unique to GD and HT and some are common to both diseases, indicating that there is a shared genetic susceptibility to GD and HT. Known AITD-susceptibility genes are classified into three groups: HLA genes, non-HLA immune-regulatory genes (e.g., CTLA-4, PTPN22, and CD40), and thyroid-specific genes (e.g., TSHR and Tg). In this paper, we will summarize the latest findings on AITD susceptibility genes in Japanese. [ABSTRACT FROM AUTHOR]

Objectives: Gonadotoxic therapies, mainly cyclophosphamide, are used for the treatment of various systemic autoimmune diseases. In Japan, the number of patients who undergo gonadotoxic therapy for autoimmune diseases, fertility preservation procedures performed in these patients, and problems associated with performing such procedures have not been reported. This study was performed to address these issues. Methods: A questionnaire was sent to Certified Educational Facilities of the Japanese Society of Rheumatology, and a single rheumatologist at each center completed the questionnaire. Results: A total of 63 facilities completed the questionnaire. Between April 2014 and March 2019, a total of 1302 men and premenopausal women had received gonadotoxic therapies for systemic autoimmune disease. Nearly half of the respondents reported that gonadotropin releasing hormone analog therapy was available in their area. However, the availability of other fertility preservation procedures was limited, and the number of patients undergoing fertility preservation procedures was limited. 85.7% of the respondents responded that measures to preserve fertility in patients receiving gonadotoxic therapies for autoimmune diseases were inadequate. Conclusions: A substantial number of patients are receiving gonadotoxic therapies for the treatment of autoimmune diseases in Japan, and those patients may not be receiving adequate care regarding their fertility. [ABSTRACT FROM AUTHOR]

Background: Clinical outcomes in neuromyelitis optica spectrum disorders (NMOSD) vary across different regions. Objective: To describe clinical profiles in Japanese and German NMOSD patients. Methods: Medical records of aquaporin-4-immunoglobulin G (AQP4-IgG) positive NMOSD patients from Japan (n = 54) and Germany (n = 38) were retrospectively analyzed. Results: The disability status was similar between both cohorts, although Japanese patients had a longer disease duration (13.3 ± 11.1 vs. 8.1 ± 6.9 years, p = 0.018) but similar relapse rates. Optic neuritis and myelitis were the most frequent attacks in both cohorts. Brain attacks occurred more frequently in Japanese patients (40.7% vs. 15.8%, p = 0.020). The time from disease onset (median [interquartile range] 2.3 [0.3-10.1] vs. 0.6 [0.2-1.9] years, p = 0.009) and the number of attacks (2.5 [1-7] vs. 2 [1-3], p = 0.047) until start of the first immunotherapy were higher in the Japanese cohort. Rituximab was the most common drug in the German cohort (52.6%) and not given in the Japanese cohort (p < 0.001), where oral prednisolone was the most common drug (92.6% vs. 15.8%, p < 0.001). The frequency of autoimmune comorbidities was higher in the German cohort (39.5% vs. 18.5%, p = 0.047). Conclusion: Compared with Japanese NMOSD patients, German patients presented with similar disability despite shorter disease duration and earlier and more frequent immunosuppressive therapy. [ABSTRACT FROM AUTHOR]

Background: An administrative database covering a whole population such as the national database in Japan may be used to estimate the nationwide prevalence of diseases including rheumatoid arthritis (RA) when a well-validated definition of the disease is available. In Japan, the record linkage between the administrative database and medical charts in hospitals is strictly prohibited. A "hospital-based" validation study is one of few possible validation studies where claims kept inside the study hospital are rearranged into the database structure.Methods: We selected random samples of 19,734 patients from approximately 1.6 million patients who received medical care between February 2018 and January 2019 in one of the 64 hospitals of the Tokushukai Medical Group. We excluded patients whose observation period was less than 365 days and identified 334 patients who met the definition of "possible cases of RA" whose medical charts were then independently evaluated by two rheumatologists. In a sensitivity analysis, we assessed bias due to misclassifying some patients with RA who did not meet the definition of "possible cases of RA" as a patient with no RA.Results: The kappa coefficient between the two rheumatologists was 0.80. The prevalence of RA in the study population was estimated to be 0.56%. We found that [condition code of RA] and ([any disease-modifying antirheumatic drug] or [oral corticosteroid with no systemic autoimmune diseases (other than RA) and no polymyalgia rheumatica]) had a relatively high sensitivity (approximately 73%) and a high positive predictive value (approximately 80%). In a sensitivity analysis, we found that when some patients with RA who did not meet the definition of "possible cases of RA" were misclassified as a patient with no RA, then this would lead to underestimation of the prevalence of the definition-positive patients and the adjusted prevalence.Conclusions: We recommend using the claims-based definition of RA (found in the current validation study) to estimate the prevalence of RA in Japan. We also suggest estimating the adjusted prevalence using the quantitative bias analysis method, since the prevalence of the disease in the "hospital-based" validation study is different from that in the administrative database.Trial Registration: The current study is not a clinical trial and hence not subject to trial registration. [ABSTRACT FROM AUTHOR]

Objective: To externally validate the performance of the new European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria set for idiopathic inflammatory myopathies (IIM) with a Japanese cohort.Methods: This study included 420 IIM and 402 non-IIM cases. Probability of having IIM in each patient was calculated using the collected data set. The cut-off probability was set at 55%, as recommended by EULAR/ACR. Patients classified as IIM by the criteria were further subclassified with classification trees.Results: When the probability cut-off was set at 55%, the sensitivity/specificity of the new criteria to diagnose IIM were 89.3%/91.0% in the total cohort, 88.1%/95.1% without muscle biopsy data and 90.4%/65.5% with biopsy data. The cohort included 12 overlap syndrome patients with biopsy data, who were included as non-IIM cases in accordance with traditional Japanese methods. When they were included in the IIM cases, the specificity in patients with biopsy increased to 74.4%. The sensitivity/specificity of the new criteria to diagnose polymyositis/dermatomyositis (PM/DM) plus juvenile and amyopathic DM in the Japanese cohort was 87.4%/92.4%, which were greater than those of the Tanimoto's criteria revised to enable classification of amyopathic DM (ADM) (71.2%/87.8%) and were comparable with those of Bohan & Peter's criteria to diagnose those diseases except for ADM (88.4%/88.3%).Conclusions: Our study externally validated high specificity of the new criteria for the first time, although with several limitations, including low percentage of child patients. The new criteria have higher sensitivity and/or specificity in classification of PM/DM than the previously reported criteria, demonstrating its usefulness for interethnic patients. [ABSTRACT FROM AUTHOR]

Background: This study was performed to determine the clinical features and outcomes of childhood-onset anti-neutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV), particularly microscopic polyangiitis (MPA). Methods: A retrospective Japanese multicenter study was performed in patients diagnosed with AAV before 16 years of age. Results: Of 49 patients with AAV, 36 were female. The diagnoses were as follows: MPA (n = 38, 78%), granulomatosis with polyangiitis (GPA; n = 9, 18%), eosinophilic granulomatosis with polyangiitis (EGPA; n = 1, 2%), and other (n = 1, 2%). The median age at onset was 10.7 years, and median time to diagnosis was 2.0 months. Twenty-seven (55%) patients were identified through a school urinary screening program. Initial symptoms included fever and fatigue (45%), and renal (71%), pulmonary (29%), ocular (20%), and mucocutaneous involvement (22%). Although 27 (55%) patients achieved remission and none had died at the last follow-up, at least one recurrence occurred in 13 (48%) patients after a median of 48 months and was more common in patients with GPA (P < 0.01). After a median follow-up of 43 months, seven (14%) patients (all with MPA) progressed to end-stage renal disease (ESRD). Conclusions: Childhood-onset AAV has an estimated prevalence of 3.41–4.28 per million children and is characterized by female predominance and high frequency of detection in school urinary screening programs. More than 10% of patients with childhood-onset AAV still progress to ESRD without achieving remission. Histological chronicity is a factor associated with ESRD. [ABSTRACT FROM AUTHOR]

Conclusion: This study demonstrated that the common immunological mechanism, which involves aberration of immunoglobulin and T-cell distribution in histologically distinctive tonsils, may be associated with the pathogenesis of tonsillar focal infection. Objectives: Tonsillar focal infection comprises a group of relatively common diseases combined with chronic tonsillar infection, is associated with unusual immune responses in tonsils, and may cause lesions in another distant target organ. This study aimed to investigate the distribution of inflammatory T cells and T-cell regulatory elements, such as programmed cell death-1 (PD-1) and Fork head box protein 3 (Foxp3), immunoglobulin production, and histological characteristics in tonsils from patients with tonsillar focal infection. Methods: Immunohistochemistry and reverse transcription-polymerase chain reaction (PCR) were used to compare the expression of CD8+ T cells, immunoglobulins, and cytokines associated with immunoglobulin production in the tonsils of patients with IgA nephropathy (IgAN), palmoplantar pustulosis (PPP), rheumatoid arthritis (RA), and chronic tonsillitis. Results: The overexpression of CD8+ T cells combined with decreased expression of Foxp3 and PD-1 and the aberration of immunoglobulin production, which may be due to the elevated expression of activation-induced deaminase (AID), B-cell-activating factor of the TNF family (BAFF), supporting isotype switching, and B-cell survival in the histologically distinctive tonsils. [ABSTRACT FROM AUTHOR]

Background and purpose The differences in the characteristics of thymus histology, coexisting autoimmune diseases and related autoantibodies between anti-muscle-specific receptor tyrosine kinase ( Mu SK)-antibody ( Ab)-positive myasthenia gravis ( MG) patients, and anti-acetylcholine receptor ( ACh R)- Ab-positive MG patients are not clearly defined. Methods The types of thymus histology, coexisting autoimmune diseases and associated Abs in 83 Mu SK- Ab-positive patients nationwide were investigated and were compared with those in ACh R- Ab-positive patients followed at our institute ( n = 83). As for the autoantibodies associated with thymoma, titin Abs were measured. Results Thymoma was not present in any of the Mu SK- Ab-positive patients but presented in 21 patients (25.3%) amongst the ACh R- Ab-positive patients. Titin Abs were absent in Mu SK- Ab-positive patients but positive in 25 (30.1%) of the ACh R- Ab-positive patients. Concomitant autoimmune diseases were present in eight Mu SK- Ab-positive patients (9.6%) amongst whom Hashimoto's thyroiditis and rheumatoid arthritis predominated, whereas 22 ACh R- Ab-positive patients (26.5%) had one or more concomitant autoimmune diseases of which Graves' disease predominated. Conclusions Differences in frequency of thymoma and thymic hyperplasia, coexisting autoimmune diseases and autoantibody positivity between Mu SK- Ab-positive and ACh R- Ab-positive MG were indicated, suggesting that, in contrast with ACh R- Ab-positive MG, thymus does not seem to be involved in the pathogenic mechanisms of Mu SK- Ab-positive MG. [ABSTRACT FROM AUTHOR]

The article presents abstracts on medical topics of Great Britain which include autoimmune disease mediated by the IgG4 diseases found pancreatitis, the results of IgG4 positive hepatic inflammatory in Japan and the prediction of cirrhosis in patients suffering from acute kidney injury.

Background: Primary biliary cirrhosis (PBC) is regarded as an autoimmune liver disease and familial clustering of PBC could represent some genetic predisposition to the disease.Aims: To elucidate the genetic background of PBC by investigating familial cases of PBC.Methods: Familial cases were picked out from 171 PBC patients who enrolled in this study. We analyzed them and their family members, and compared them clinically and immunogenetically to non-familial cases.Results: Out of 171 PBC patients, ten (5.8%) were identified as familial PBC in five families. The clinical features of familial PBC were almost comparable to those of non-familial PBC. The distribution of human leukocyte antigens (HLA)-A, -B and -DR in familial PBC showed no specificity. Two new PBC patients were identified in one family in addition to the two originally enrolled PBC patients, resulting in four patients with PBC within the same family. The two new PBC patients had an identical HLA haplotype. On the other hand, one HLA-identical sister of a PBC patient in another family did not develop PBC.Conclusions: Primary biliary cirrhosis can exhibit familial clustering without any HLA predisposition, however, a survey of families for PBC could be useful for identifying new patients with PBC in the asymptomatic stage for earlier diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Type 1 diabetes is a multifactorial disease which results from a T-cell-mediated autoimmune destruction of the pancreatic beta cells in genetically predisposed individuals. The risk for individuals of developing type 1 diabetes varies remarkably according to country of residence and race. Japan has one of the lowest incidence rates of type 1 diabetes in the world, and recognises at least three subtypes of the condition: acute-onset (‘classical’), slow-onset, and fulminant type 1 diabetes. The incidence rate of type 1 diabetes in children aged 0–14 years in Japan increased over the period from 1973–1992, but remained constant over the last decade, averaging 2.37 cases per 100,000 persons per year; the incidence does not appear to have increased in older age groups. Although there are few reports regarding the incidence and prevalence of type 1 diabetes in adult-onset patients, it appears that the prevalence of type 1 diabetes in adults is more than twice that in childhood-onset patients and that two-thirds of them have a slow-onset form of type 1 diabetes. Differences and similarities in the association of MHC and non-MHC genes with type 1 diabetes are observed in Japan and in countries with Caucasoid populations. Highly susceptible class II HLA haplotypes identified in patients of Caucasoid origin are rarely seen in Japanese patients, whereas protective haplotypes are universal. Non-MHC genes associated with susceptibility to type 1 diabetes in both Japanese and Caucasoid patients include polymorphisms in the insulin gene, the cytotoxic T-lymphocyte antigen 4 ( CTLA4) gene, the interleukin-18 ( IL18) gene and the major histocompatibility complex class I chain-related gene A ( MICA) gene. Fulminant type 1 diabetes is a unique subtype of type 1 diabetes that accounts for about 20% of acute-onset type 1 diabetes, and is seen mainly in adults. The challenge for the future is to investigate the underlying pathogenesis of beta cell destruction, including the genetic or environmental factors that may modify the form of onset for each subtype of Japanese type 1 diabetes. [ABSTRACT FROM AUTHOR]

Unlabelled: Tumour necrosis factor receptor-associated periodic syndrome (TRAPS) is a dominantly inherited disorder characterised by recurrent episodes of sustained fever. Here we report a case of TRAPS with a novel TNFRSF1A mutation, C70S, in a Japanese family. The mutation disrupts one of the three disulphide bonds in cysteine-rich domain 2 of TNF receptor 1, similar to the reported mutations of the same cysteine residue (C70R, C70Y). This is the first confirmed case of TRAPS in an eastern Asian population. The patient's asymptomatic sister as well as their mother with mild symptoms had the same mutation.Conclusion: Although tumour necrosis factor receptor-associated periodic syndrome has been reported mainly in families of northern European ancestry, our case suggests the need to include it in the differential diagnosis of patients with recurrent fever even in ethnic groups in which no case has been documented. [ABSTRACT FROM AUTHOR]