IgG4-related disease is a chronic and fibroinflammatory disorder, which is characterized with elevated levels of serum IgG4, and prominent infiltration of IgG4-bearing plasma cells in the involved organs. It often affects with lacrimal glands, salivary glands, pancreas, kidneys, lungs, and retroperitoneal cavity. Now, the first line of the induction therapy for IgG4-related disease is glucocorticoid, but almost patients need the maintenance treatment and experience the relapse. It is recently reported that biologic agents, including rituximab and abatacept, are effective for the relapse of IgG4-related disease. It is clear that the tapering effect of glucocorticoid is better than conventional oral immunosuppressants. We can use it in safely if we choose the appropriate cases. The investigator-initiated trial of rituximab for IgG4-related disease is scheduled in Japan. This article reviews the new strategies for the treatment of IgG4-related disease with our data of SMART registry, and discuss the problems of each biologic agents for IgG4-related disease.
ANCA-associated vasculitis is characterized by the presence of anti-neutrophil cytoplasmic antibody (ANCA) in the serum. ANCA is a pathogenic autoantibody as well as the disease marker. It has been realized that ANCA-cytokine sequence is involved in the pathogenesis of ANCA-associated vasculitis. Recent studies have revealed that neutrophil extracellular traps induced by ANCA are also involved in the pathogenesis. In this study, we review the roles of neutrophils, eosinophils, macrophages/dendritic cells, complements, B cells/plasma cells, T cells, and cytokines/chemokines/cell growth factors in the pathogenesis of ANCA-associated vasculitis.
Since the general population is ageing, the number and the mean age of elderly patients of rheumatoid arthritis (RA) have increased. Elderly RA is classified into two clinical subsets, younger onset elderly RA (YORA) and elderly-onset RA (EORA). In the past literature, onset after 60 years of age is mainly adopted as the classical definition of EORA. Elderly-YORA patients, in addition to disease-modifying antirheumatic drugs, sometimes need analgestics, joint surgery and rehabilitation taking into account their bone destruction and their activities of daily living. Early phase EORA patients should be treated using the treat-to-target strategy, although low disease activity is the realistic goal due to their co-morbidities, patient factors and drug-related risks. Methotrexate (MTX) is the anchor drug in the treatment of EORA. It should be started at low dose (2-4 mg/day) and if tolerated, the dosage is carefully increased. In the case of renal dysfunction or dementia, and MTX is intolerable, biologics monotherapy could be a choice of treatment. Tapering of glucocorticoid, as far as possible, is needed because it is one of the risk factors of infection. Treatment of super-aged RA patients is a future agenda.
Recent researches are revealing the importance of a new subset of memory T cells called resident memory T cells (TRMs). Once they enter the tissues according to their tissue-homing receptors, TRMs do not go back to circulation and stay in the same tissues for a long time. These T cells are defined as expressing CD69 and/or CD103, and are known to show strong effector functions. It is considered that TRMs have an important role against infection in barrier tissues such as GI tract, skin, respiratory system and reproductive tract. Furthermore, recent reports indicate their roles in organ-specific chronic inflammatory disorders, autoimmune disorders and tumor immunology even in non-barrier tissues such as central nerve system, lymphatic tissue, liver, kidney, pancreas and joint. Here in this session, the author organized what have been known about TRM both in mouse and human, including the development, functional activities and relation of TRM to disease manifestation, for the detailed understanding of this fraction.
Juvenile idiopathic arthritis, JIA, is a novel rheumatic disease in childhood introduced by the International League of Associations for Rheumatology. It is defined as a chronic, inflammatory disorder of unknown etiology, which is classified into seven categories; systemic-onset type, persistent and extended oligoarthritis, polyarthritis with rheumatoid factor negative, polyarthritis with rheumatoid factor positive, psoriatic arthritis, enthesitis-related arthritis and undifferentiated arthritis. As each category of JIA has different features in clinical phenotypes, precise subtyping is required for research and management. However, some modifications to the criteria might be helpful for getting better answers in diagnosis because of ethnical difference in prevalence and subtype distribution. Actually in Japanese population, a unique subset “B27-negative polyenthesitis” termed by Shichikawa should be included in enthesitis-related arthritis of JIA as a different type of enthesitis from B27-positive counterpart of spondyloarthritis in adulthood. Deep insights into the classification criteria will be needed for the better understanding of JIA.
The intestinal epithelium constitutes a physical barrier between inner and outer side of our body. It also functions as a “hub” which connects factors that determine the development of inflammatory bowel disease, such as microbiota, susceptibility genes, and host immune response. Accordingly, recent studies have implicated and further featured the role of intestinal epithelial cell dysfunction in the pathophysiology of inflammatory bowel disease. For example, mucin producing goblet cells are usually “depleted” in ulcerative colitis patients. Studies have shown that those goblet cells exhibit various immune-regulatory functions in addition to mucin production, such as antigen presentation or cytokine production. Paneth cells are another key cell lineage that has been deeply implicated in the pathophysiology of Crohn's disease. Several susceptibility genes for Crohn's disease may lead to impairment of anti-bacterial peptide production and secretion by Paneth cells. Also, other susceptibility genes may determine the survival of Paneth cells, which leads to reduced Paneth cell function in the patient small intestinal mucosa. Further studies may reveal other unexpected roles of the intestinal epithelium in the pathophysiology of inflammatory bowel disease, and may help to develop alternative therapies targeted to intestinal epithelial cell functions.
Kawasaki disease (KD) is an acute systemic vasculitis presenting as an infantile febrile disease. In Japan, the widespread cedar plantation commenced in 1945 has been correlated with the increased incidences of both KD and allergic rhinitis (pollinosis) since the early 1960s. We previously showed that KD was a pollen-induced, delayed-type hypersensitivity that displays biphasic peaks in both summer and winter. KD incidences decrease suddenly around February, particularly after influenza epidemics. Here we investigated the reason for a drastic decrease in KD onsets directly before spring pollen release following rapid increase after autumn pollen release leading to the biphasic pattern. We separately analyzed weekly incidences of KD and influenza in Tokyo (1987-2010) and Kanagawa (1991-2002). Repeated measures for the analysis of variance followed by Bonferroni's multiple comparison tests were performed to compare KD incidence over 3 consecutive weeks, including the weeks when the mean KD prevalence showed the steepest decrease. Next, the week with peak influenza incidence was reset for each year. KD incidence over 3 consecutive weeks, including the new origin week (adjusted week 0), was similarly analyzed. In Tokyo and Kanagawa, KD incidence significantly decreased only after resetting the influenza peak time. These findings suggested that influenza epidemics suppressed KD onset.
A 48-year-old woman had suffered from a fever and general fatigue, and visited the other hospital for fever elevation in November 2013, at which time interstitial lung disease was revealed. In January 2014, she experienced an eruption in the hand and developed peripheral blood flow damage. Under a diagnosis of adult Still's disease, the patient was administered 0.5 mg of betamethasone as well as cyclosporin at 75 mg/day. In November 2014, general fatigue, fever, and headache were noted, while MRI revealed an enlarged hypophysis and laboratory findings were positive for the anti-pituitary cell antibody, thus a diagnosis of autoimmune hypophysitis was made. Although disease activity was low, she requested hospitalization and was admitted by the Division of Endocrinology and Metabolism at our hospital in May 2015, though only observed. Fever developed again, along with interstitial lung disease, Raynaud's phenomenon, and pain in the crural area again, and we considered the possibility of another disease. After stopping administration of betamethasone and cyclosporin, we made a diagnosis of anti-aminoacyl tRNA synthetase antibody syndrome, and administered methylprednisolone at 500 mg for 3 days as well as prednisolone at 35 mg/day following steroid pulse therapy. Although her condition soon improved, fever, muscle pain, and pancytopenia returned after 3 days. Bone marrow findings revealed the existence of hemophagocytosis, for which we again gave methylprednisolone at 500 mg for 3 days and cyclosporin at 125 mg/day. Thereafter, the patient recovered and was discharged from the hospital.