The treatment of autoimmune diseases, such as rheumatoid arthritis （RA）, has been transformed by the advent of molecular targeted drugs. In the past several years, therapeutic applications of molecular target medications have also started to be made for RA and other collagen illnesses. While existing therapeutic agents, such as steroids and immunosuppressive drugs, target nonspecifically, molecular target drugs exert their effects by inhibiting cytokines or cytokine signaling. However, enough patients have not obtained remission in RA and other collagen diseases, and the role of cytokines in pathogenesis remains unclear. Based on the findings of current investigations, we shall describe cytokines and chemokines in this article and how they relate to autoimmune illnesses. In particular, fractalkine/CX3CL1, the only CX3 chemokine, has been shown to be expressed in many autoimmune diseases and to be involved in their pathogenesis. Recent topics related to this topic include （1） the ADAM family and （2） post-translational modifications, which are believed to be involved in the soluble activation of the extracellular domain of cytokines and chemokines and in the activation of selectin family members as adhesion factors on the cell surface. Members of the ADAM family have correlated with disease activities in illnesses, including inflammatory muscle disorders and interstitial pneumonia, particularly RA, and to be expressed in pathological situations that cause inflammation and are connected to angiogenesis. Next-generation antibody drugs presently under development include glycosylated antibodies, bispecific antibodies, and small molecule antibodies. The role of cytokines in collagen diseases, such as RA, systemic lupus erythematosus （SLE）, inflammatory muscle diseases, and Sjögren’s syndrome, will be discussed, as well as new therapeutic agents in clinical practice. In recent years, the clinical use of molecular target medicines that target cytokines has increased, particularly in SLE. Additionally, a summary of the most recent findings from clinical studies on the interaction between cytokines and interferon will be provided.

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The prognosis of rheumatoid arthritis （RA） has improved drastically due to the introduction of highly effective biologic agents and innovative molecular targeted therapies such as Janus kinase inhibitors. However, some RA patients still experience symptoms even when treated with currently proposed therapies and management methods. This type of RA is known as difficult-to-treat RA （D2T RA）. D2T RA is categorized into three types: 1） RA that is complex to discern, 2） RA that is complex to treat with intensified therapy, and 3） RA that is refractory even with intensified therapy. The RA refractory for intensified therapy was further classified into five categories: （1） adverse drug events, （2） poor adherence, （3） inadequate drug management, （4） complications, and （5） economic factors. Furthermore, RA that is refractory despite the intensified treatment is classified into the following four categories: （1） classification of refractory RA, （2） differentiation between inflammatory and non-inflammatory RA, （3） response to inflammatory refractory RA, and （4） response to non-inflammatory refractory RA. Each of these complications and their present solutions are outlined in this study.

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Systemic lupus erythematosus （SLE） is a systemic autoimmune disease that affects multiple organs. The onset mechanism of SLE is thought to be caused by the combination of environmental and genetic factors due to disease susceptibility genes, as well as abnormalities of innate and acquired immunity. In recent years, we analyzed mitochondrial dysfunction and 27 types of immune cells extracted from the blood of patients with SLE and healthy subjects as a genetic factor and examined the expression patterns of disease-related genes. Some genes are involved in SLE and some in disease activity, and the members of both genes differ in many cells, suggesting that different pathological mechanisms are involved in SLE onset and exacerbation. Additionally, the involvement of innate immunity, such as type I interferon, has been emphasized and is attracting attention. Corticosteroids were traditionally used as SLE therapeutic agents, but in recent years, immunosuppressants, including biological agents, were rapidly developed and are being used in combination. The European College of Rheumatology recommended hydroxychloroquine administration for all patients. Mycophenolate mofetil has been proven the same as cyclophosphamide as a drug for inducing remission in lupus nephritis and is becoming the mainstream treatment. Additionally, biological agents, such as rituximab and belimumab, have been clinically applied as therapeutic agents that target the B cell system. Furthermore, the development and clinical trials of new drugs, such as voclosporin （an oral calcineurin inhibitor）, atacicept （neutralizing both B-cell-activating factor and a proliferation-inducing ligand）, iverdomide （cereblon regulator）, and Janus kinase inhibitors, are progressing, and treatment will continue to advance in the future.

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Polymyositis （PM） and dermatomyositis （DM） are often complicated by interstitial lung disease （ILD）. In recent years, the clinical course was found to differ depending on the type of myositis-related autoantibodies. Anti-aminoacyl tRNA synthetases （ARS） antibodies are autoantibodies that present with clinical manifestations called anti-ARS antibody syndromes, such as myositis, fever, polyarthritis, interstitial pneumonia, Raynaud’s phenomenon, and mechanic’s hands. High-resolution computed tomography and pathological findings often show a nonspecific interstitial pneumonia pattern but some cases are accompanied by infiltrative opacities. Currently, eight types of anti-ARS antibodies have been identified with different phenotypes depending on the type. Anti-melanoma differentiation-associated gene 5 （MDA5） antibody is an autoantibody whose corresponding antigen is a protein called MDA5 which is involved in defense against infection. Muscle symptoms are limited in patients positive for this antibody, but they show a pattern of diffuse alveolar damage on imaging for several days. It frequently complicates rapidly progressing ILD leading to respiratory failure over several weeks. The treatment algorithm regarding ILD, which will merge with PM/DM in 2020, is proposed in the “Diagnosis and treatment guidelines for interstitial lung diseases associated with connective tissue disease,” which was jointly created by the Japanese Respiratory Society and the Japanese Society of Rheumatology. Triple therapy with high-dose prednisone, including steroid pulse therapy, a calcineurin inhibitor, and intermittent high-dose cyclophosphamide, was recommended from the beginning, especially for patients positive for the anti-MDA5 antibody. In recent years, new treatment methods, such as plasma exchange therapy, have been used in cases where even these three-drug combination therapies were ineffective.

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Rheumatoid arthritis （RA） is an autoimmune disease characterized by polyarthritis, which is prevalent in women of childbearing age. Recent advances in therapeutic agents have made it possible to achieve early remission of the disease and the treatment aims to maintain remission while preserving the patient’s quality of life. Thus, if a young female patient desires to become pregnant, it is essential to continue treatment with drugs that allow pregnancy and lactation. First, the mutual effects of rheumatoid arthritis and pregnancy must be identified. The high disease activity decreases fertility and increases the risk of obstetric complications. While it was believed that RA generally improves with pregnancy, it has been demonstrated that improvement during pregnancy is inhibited if the patient becomes pregnant while in a state of high disease activity. Thus, to prevent joint destruction and enable a good pregnancy outcome, it is important to conceive while RA is stable and to stabilize the RA activity during pregnancy. The use of MTX （methotrexate）, the anchor drug for RA, is contraindicated during pregnancy and lactation, requiring the withdrawal of at least one menstrual cycle before pregnancy. If arthritis flares up or is predicted to flare up after discontinuation of MTX, suitable intervention with medications that are known to have a high safety profile is recommended. Therefore, use of medications during pregnancy and lactation can be very uncomfortable for the patient; hence, it is essential to offer an adequate explanation and obtain consent for treatment. To achieve the best result in complicated pregnancies, it is crucial to provide preconception care and planned pregnancy prior to conception, in addition to intensive care with other departments and multidisciplinary care during the pregnancy and the postpartum period.

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Osteoarthritis （OA） is the most common joint disease associated with articular cartilage destruction. Matrix metalloproteinase-13 （MMP-13） and a disintegrin and thrombospondin motif-5 （ADAMTS-5）, which are enzymes that degrade the extracellular matrix, promote OA pathogenesis. We have recently shown that hydrogen peroxide-inducible clone-5 （Hic-5）, a mechanical stress-responsive adaptor molecule, promotes OA by inducing the expression of MMP-13 and ADAMTS-5 in chondrocytes in response to proinflammatory cytokines and mechanical stress. In this review, we discuss the potential of Hic-5 to be a therapeutic target for OA and the relevance of the focal adhesion molecules vinculin and talin to OA using single-cell data.

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Recently, the noninvasive estimation of periodontal disease severity using mouth smells has gained attention. In this study, Fourier transform infrared spectroscopy （FTIR） was employed to examine the exhaled breath of patients with periodontal disease at the time of periodontal pocket assessment. The outcomes were then compared in terms of probing pocket depth （PPD）, the total number of bacteria in the periodontal pocket （logarithm）, and the percentage of bleeding on probing （BOP） to examine their relationship with periodontal disease. Thirty-one patients in total were divided into three groups according to the classification of periodontitis: 5 with PPD ＜ 4mm as the slight periodontitis health group （SLP group）, 16 with 4mm ≦ PPD ＜ 6mm as the moderate periodontitis group （MOP group）, and 10 with PPD ≧ 6mm as the severe periodontitis group （SEP group）. We analyzed the relationship between PPD and total bacterial count determined by the periodontal disease bacterial test kit （BML, Tokyo）. Therefore, the total bacterial count was considerably associated with PPD, with significant differences between the SLP group （3.3±0.6） and the MOP group （4.3±0.9） （P＝0.037）, and also between the SLP group and the SEP group （4.9±0.6） （P＝0.0021）. Regarding the relationship between total bacterial count and the three items of FTIR analysis （Regions 1/2） and BOP, there was a significant correlation between total bacterial count and FTIR analysis values （P＝0.0171, R2＝0.181）. In addition, in the FTIR analysis values between the three PPD groups, there was a discernible difference between the SLP group （0.164±0.00774） and the SEP group （0.119±0.0275） （P＝0.0273）. These results indicate the possibility of identifying a periodontal disease from exhaled breath. Furthermore, a further increase in sensitivity and specificity can be expected in this FTIR breath analysis by way of multidimensional evaluation utilizing infrared absorbance spectroscopy.

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It has been established that autonomic nervous function and physical function can deteriorate in orthostatic dysregulation （OD） as physical strength decreases due to decreased daily life activities. The resulting deconditioning and symptoms are exacerbated. This study examined the relationship between OD pathophysiology and grip strength to elucidate the risk of deconditioning formation. This study included 51 patients （14.7 years ± 1.1 standard deviation ［SD］）, who diagnosed with OD at A Clinic from June to December 2019. The grip strength of the participants was evaluated. The relationship between OD diagnosis, degree of obesity, questionnaire for triage and assessment with 30 items （QTA30）, and grip strength was determined. Moreover, statistical analysis was performed using IBM’s Statistical Package for the Social Sciences version 22.0. The average SD score for grip strength was −0.8. The physical severity included severe at 64.7％, moderate at 9.8％, mild at 9.8％, judgment pending at 15.7％, and obesity at −8.9％ ± 11.7％. Furthermore, the ratio of areas requiring special attention at QTA30 total score included somatic symptoms at 90.2％, depressive symptoms at 66.7％, self-efficacy at 58.8％, anxiety symptoms at 80.4％, and family function at 25.5％. The grip strength also correlated with obesity （r＝0.407, p＝0.004）, QTA30 total score （r＝−0.486, p＜0.001）, physical symptoms （r＝−0.480, p＜0.001）, depressive symptoms （r＝−0.402, p＝0.003）, and anxiety symptoms （r＝−0.412, p＝0.003）. Moreover, the grip strength in the severe group was lower than the mild group （p＝0.024）. The statistical significance was set at P-values of ＜0.05. Patients with OD with low obesity, high physical severity, high QTA30 total scores, and physical, depressive, and anxiety symptoms were more likely to have decreased physical strength. Thus, grip strength measurement is useful in understanding deconditioning in patients with OD and supporting physical strength.

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Here, we present the first case in Japan of pediatric multisystem inflammatory syndrome in children （MIS-C） with asymptomatic coronavirus disease 2019 （COVID-19）. The patient had negative polymerase chain reaction （PCR） results and severe acute respiratory syndrome coronavirus 2 antigen but positive N antibody. The patient was a 5-year-old girl who was diagnosed with Kawasaki disease. However, 1 month prior to hospitalization, she had come in close contact with a COVID-19-infected person, but she was asymptomatic and had a negative result of one PCR test. During hospitalization, hypotension, restlessness, and abnormal behavior were observed. As the SARS-CoV-2 N antibody test result was positive, we made a diagnosis of MIS-C. Since the COVID-19 outbreak in 2019, it has been assumed that COVID-19 infection in children is often asymptomatic or mild. In the future, asymptomatic infections are expected to increase with viral mutation. Kawasaki disease is a highly prevalent disease in Japan, and the number of cases with MIS-C differential diagnosis is expected to increase in the future. As the complications and long-term prognosis of MIS-C are different from those of Kawasaki disease, the possibility of MIS-C in close contacts suffering from Kawasaki disease, even if asymptomatic, should be considered. It is necessary for individuals involved in the treatment of children as well as those who work with Kawasaki disease patients to have sufficient knowledge about MIS-C. Furthermore, it will be very important for the future of pediatric medicine to accumulate more cases in Japan and elucidate the prognosis of MIS-C.

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