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Rheumatoid arthritis(RA)is one of the systemic autoimmune diseases characterized by progressive joint destruction with chronic synovitis. In the synovium, activated osteoclasts with plenty of inflammatory cytokines and metalloproteinases induce bone and cartilage destruction. Anti-cyclic citrullinated protein antibodies(ACPA)was recognized not only as a diagnostic marker but also as direct inducer of synovitis. In addition, environmental factors and background of daily life also contribute to the pathogenesis of RA, especially smoking and periodontitis are considered to be important factors for disease activities.

A 65-year-old woman with a 17-year history of polymyositis and 8-year history of rheumatoid arthritis who was treated with a low dose of prednisolone and tacrolimus (Tac) was admitted to our hospital because of general malaise and hypertension. Blood tests showed thrombocytopenia, hemolytic anemia with fragmented erythrocytes, and hypercreatinemia. Based on these clinical features, she was diagnosed with thrombotic micro-angiopathy (TMA). Thrombocytopenia and hemolytic anemia with fragmented erythrocytes improved with the discontinuation of Tac and plasma exchange; however, hypertension and renal dysfunction persisted. TMA due to calcineurin inhibitor (CNI) nephropathy was suspected based on the histopathological findings of renal biopsy. However, the condition was atypical of a CNI nephropathy because the trough level of Tac was lower than that reported previously and renal dysfunction persisted after drug discontinuation. She had mild sclerodactylia and Raynaud's symptoms, although the diagnostic criteria for systemic sclerosis (SSc) were not satisfied. Moreover, the patient tested positive for anti PL-7 antibody. The relationship between anti PL-7 antibody and pathogenesis of SSc has been reported. In this case, it was suspected that CNI nephropathy worsened because of the potential basic factors of SSc. These findings indicate that TMA may occur in patients testing positive for anti PL-7 antibody who are treated with Tac.

Anti-aminoacyl-tRNA synthetase (ARS) antibody is one of the myositis-specific autoantibodies to make a diagnosis of polymyositis (PM) and dermatomyositis (DM). Recently a new enzyme-linked immunosorbent assay (ELISA) kit of concurrently detected anti-ARS antibodies (anti-Jo-1, anti-PL-7, anti-PL-12, anti-EJ and anti-KS) have become to measure in the clinical setting. To evaluate the reliability of this ELISA kit, we measured anti-ARS antibodies in 75 PM and DM patients using by this ELISA assay and compared them with the results by RNA immunoprecipitation assay. Between the measurements of anti-PL-7, anti-PL-12, anti-EJ and anti-KS autoantibodies by ELISA assay and RNA-IP assay, the concordance rate of reproducibility is 95.1% and the positive agreement rate is 90.9% and negative agreement rate is 96.0% and kappa statistic is 0.841. Between the measurements of existing anti-Jo-1 antibody ELISA kit and anti-ARS antibody ELISA kit, the concordance rate of reproducibility is 96.9%, the positive agreement rate is 100%, negative agreement rate is 96.1% and kappa statistic is 0.909. The lung involvement in patients with PM and DM patients are positive of anti-ARS antibodies and anti-melanoma differentiation associated gene5 (MDA5) antibody at a rate around 70%. Then most life-threatening ILD with anti-MDA5 positive clinically amyopathic dermatomyositis patients could be highly guessed when anti-ARS antibodies are negative.

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.

There had been proved the efficacy of preventing bone destruction by using disease modifying anti-rheumatic drugs (DMARDS) such as methotrexate(MTX). A certain combination of DMARDS is more effective than treated alone. But the data about DMARDS combination therapy or DMARDS used mainly in Japan is not abundant, and there needed to establish the evidences of them.

Myositis is a heterogeneous group of systemic autoimmune disorders characterized by inflammation of skeletal muscle. Historically, myositis has been defined using clinical features including muscle weakness, skin disease, internal organ involvement, and an association with cancer in adults. From a clinicopathologic approach, myositis has been classified into pathologically distinct subsets, polymyositis, dermatomyositis(DM), necrotizing autoimmune myositis, amyopathic DM, and non-specific myositis. Although the characteristic pathological changes are believed to be important in pathological mechanisms of each subset of myositis, in clinical practices, the percentages of the patients with typical pathological findings are usually not high. On the other hand, with the recent discovery of new myositis-specific autoantibodies (MSAs), it has been revealed that around 60% of patients with IIMs have been shown to have a anti-myositis-specific autoantibody, including anti-synthetase, anti-Mi-2, anti-MDA5, anti-TIF1 and anti-SRP antibodies. Because of striking association between unique MSAs and distinct clinical phenotypes, these antibodies are thought to be important not only for classifications of IIMs, but also as factors involved in the mechanism underlying their pathogenesis. This review reports recent progress in understanding of pathological features of myositis with MSAs.

Takayasu arteritis (TAK) is a systemic vasculitis affecting aorta and its large branches which were firstly reported from Japan. TAK develops mainly in young females and the number of patients with TAK in Japan is estimated about 6,000 to 10,000. This low prevalence has made genetic studies of TAK difficult to elucidate its genetic background. The HLA region, especially HLA-B locus, is the strongest susceptibility locus to TAK. The association between TAK and HLA-B*52:01 has been established beyond ethnicity. Recently, two different Japanese research groups identified HLA-B67:01, a relatively rare allele in East Asian population, as a novel susceptibility allele. At the same time, two amino acid variations, namely, histidine at position 171 and phenylalanine at position 67 were reported as susceptibility and protective variations, respectively. Since these positions of amino acid are in the peptide binding grooves of HLA-B protein, changes of peptide-binding in MHC class I seem to play a critical role on susceptibility to TAK. Furthermore, the importance of these two amino acid variations would explain the lack of susceptibility effect of HLA-B*51:01 to TAK, which shares most of amino acid sequences with HLA-B*52:01 except for two amino acids including the position 67.

In clinical practice of rheumatoid arthritis (RA), various kinds of laboratory tests are required for diagnosis, assessment of the disease activity, assessment of complications and risk factors before starting therapy, and assessment of adverse effects during the therapy. Anemia, thrombocytosis, and leukocytosis are common in active RA. During RA therapies, liver function tests (including ALT and AST) and renal function tests (including serum creatinine and urinalysis) should be performed. Anti-CCP antibody is an especially useful marker for diagnosis of RA, and the presence of the antibody has been included in ACR/EULAR 2010 RA classification criteria. Reactivation of hepatitis B virus (HBV) after immunosuppressive therapies is a potentially serious complication. HBc and/or HBs antibodies should be measured before starting the therapies even if HBs antigen is negative, and appropriate interventions including measurement of HBV-DNA and starting prophylaxis (entecavir is recommended) should be performed.

Anti-MDA5 antibody is one of the dermatomyositis-specific autoantibodies and anti-MDA5-potsitive patients show characteristic clinical features, such as hypomyositis, high prevalence of acute/subacute interstitial pneumonia (A/SIP) with poor prognosis, hyperferritinemia and elevated hepatobiliary enzyme. We found that serum IL-6, IL-18, M-CSF and IL-10 were significantly higher and serum IL-12 and IL-22 were significantly lower in anti-MDA5-positive patients than in anti-MDA5-negative patients before treatment. Taking together these serological findings, we hypothesized that monocyte and macrophage activation may underlie in the pathophysiology of anti-MDA5-positive patients. They rarely survive after they become to need oxygenation, and so need to be treated as soon as possible once the diagnosis has been made. Intensive regimen of combined immunosuppressive therapy (high-dose corticosteroids, oral cyclosporin and intravenous cyclophosphamide (IVCY, 900-1000 mg/m(2) in every other week)) improved the survival rate of anti-MDA5-positive patients. Especially, the serum ferritin levels tended to go down about 14 days after IVCY, suggesting that IVCY might be a key drug in the treatment of anti-MDA5-positive A/SIP patients.

IL-17 secreting helper CD4 T cells (Th17 cells) contribute to a variety of autoimmune diseases such as rheumatoid arthritis. IL-17 acts on neutrophils, macrophages, fibroblasts, or osteocalsts to mediate chronic inflammation and destroy the cartilage. Recently, studies of the spontaneous models of arthritis revealed that activation of innate immunity, such as Toll like receptors, C-type lectin receptors, complement, or ATP induce IL-6 or IL-23 production from macrophages or dendritic cells, which triggers the differentiation of Th17 cells and induces autoimmune arthritis. Although the role of Th17 cells in human rheumatoid arthritis is still controversial, activation of innate immunity and induction of Th17 cells should be associated with the induction of arthritis at least in a part of RA patients. These studies will help elucidate the mechanism of arthritis induction and discover the therapeutic method to prevent it.

Because of a paradigm shift in the therapeutic strategy of RA by biologics, the goal of RA therapy became not only the clinical remission, but also the imaging remission. From the results of randomized controlled clinical trials of disease modifying anti-rheumatic drugs (DMARDs), decreased radiographic progression has been documented. In particular, methotrexate (MTX) is described as "anchor drug" of RA therapy because inhibitory effects of MTX on radiographic progression are proved by many clinical trials. Although DMARDs can slow down the radiographic progression with the achievement of clinical remission in RA, some patients still have subclinical synovitis detected by imaging technique. Such subclinical inflammation may explain the observed discrepancy between disease activity and radiographic progression in RA during DMARD therapy.

In recent years, novel immunosuppressive drugs applies to various autoimmune diseases and the evidences increase. Since immunosuppressive drugs inhibit nonselectively the whole immune system, there are possibilities that infection may be induced by decreasing the immunity against pathological agents and malignancy may develop by suppressing immune surveillance. In order to use the immunosuppressants safely and effectively, we should obey the indication and dosage, and be familiar with the side effects. It is also important to take informed consent from patients after explaining the benefit and risk. Therefore, the doctors who are going to use immunosuppressive drugs must know well about the indication, the side effects, the metabolism and the action mechanisms of those drugs.

Autoantibodies against various cellular components are found in sera from patients with connective tissue diseases. These autoantibodies have been demonstrated to be associated with certain diseases and clinical manifestations, and give us useful information for clinical practice. The development of new technologies for detecting autoantibodies have been able to identify a hundred of autoantibodies and their target autoantigens. They are mostly intracellular enzymes and regulatory factors necessary for important biological function involved in gene replication, repair, transcription, RNA processing and protein translation. The studies of fine structures and functions of target autoantigens have given us important suggestions to understand the mechanisms of autoantibody production and etiology of autoimmune diseases. Most autoantibodies found in systemic autoimmune diseases have been thought to be rather "reporters" of diseases and innocent from direct pathogenic effects. However, certain autoantibodies are supposed to have some pathogenic effect in certain conditions such as anti-SS-A/Ro antibodies and neonatal lupus, although the mechanism is still not clarified. We found that anti-U1RNP antibodies are more concentrated in cerebrospinal fluids than in sera of MCTD patients with aseptic meningitis, suggesting a possible role of the autoantibodies in the development of CNS disease.

Many autoantibodies associated with nucleic acids are found in autoimmune diseases, and are important for analyzing pathophysiologic mechanisms. Toll-like receptors (TLRs) are receptor molecules for innate immunity and some of them recognize nucleic acids. Nucleic acids in autoantigens may stimulate TLR and activate antigen presenting cells as adjuvants. The Wa antigen was found as a transfer RNA (tRNA)-binding protein by RNA immunoprecipitation and identified as NEFA/Nucleobindin-2. Although the function of NEFA/Nucleobindin-2 is still not clear, it may be involved in secretion of proteins along with calcium metabolism and in protein translation by tRNA-binding ability.

Some patients with rheumatoid arthritis (RA) suffer from disease that is refractory to both conventional therapy and newer biological agents such as tumor necrosis factor (TNF) inhibitors. In recent years, there has been growing interest in, and enhanced understanding of, the contribution of B cells to the immunopathogenesis of RA. Rituximab (RTX), a chimeric monoclonal antibody against CD20 that effectively depletes B cells in peripheral blood, has been licensed for the treatment of malignant lymphoma for almost 10 years. Efficacy of rituximab in RA has already been demonstrated in randomized control trials, and US Food and Drug Administration has approved the combination of RTX with methotrexate for use in patients with RA, who have had an inadequate response to one or more TNF antagonist therapies. The long-term efficacy, especially about joint damage, and long-term safety need to be further investigated.

The patient is a 56-year-old Japanese woman who suffered from breast cancer and ovarian cancer at intervals of 6 years, and was also complicated by two episodes of dermatomyositis, each of which occurred simultaneously with each of two cancers. When she was 51 years old, she developed dermatomyositis for the first time 6 months after the resection of breast cancer, whose histological type was tubular adenocarcinoma. The dermatomyositis remitted without oral corticosteroids in 2 months, and the remission had continued for 6 years. However, at the age of 56, dermatomyositis abruptly recurred with a pruritic generalized rash, Gottron's papules and elevated serum CK levels. Examination for malignancy revealed an ovarian tumor, which was diagnosed as serous papillaly adenocarcinoma, and the surgery was performed. After the resection of the ovarian cancer, skin rash was improved dramatically and CK levels were normalized again without oral corticosteroids. Since there were no evidences of recurrence of the breast cancer, it was considered that each episode of dermatomyositis was associated with each of the cancers, respectively. We report this rare and interesting case to consider the etiology of cancer-associated myositis as a paraneoplastic syndrome, since the two cancers have different histological types.

Recently identified autoantibodies in rheumatoid arthritis are targeting autoantigen molecules, such as calpastatin, a novel form of soluble gp130, and follistatin-related protein, that appear to play a role in protecting effects in joint inflammation. These autoantibodies inhibit the function of target molecules and may be involved in the pathogenic mechanisms by upregulating inflammation and joint destruction. Another autoantibody targets filaggrin, a citullurinated protein distributed in keratinated epithelia. Although the pathogenic effect of anti-filaggrin antibody is not elucidated, this autoantibody has a potentiality of a new diagnostic marker of RA because of its high sensitivity and specificity.