It is known that prognosis of pulmonary hypertension (PH), especially connective tissue disease related PH (CTD-PH), is serious. CTD-PH is caused by not only pulmonary arterial hypertension, but also interstitial pneumonitis, hypoxia, chronic thromboembolism of pulmonary artery, or left heart diseases. Recently, prognosis of PH is improved by progress of diagnostic measures including echocardiography and development of effective vasodilators. However, early diagnosis of PH is necessary for further improvement of the prognosis. Previous reports have shown that diffusion lung capacity for carbon monoxide (DLco) is reduced in the early phase of PH, and we have shown that serum lactate dehydrogenase level is also elevated in this phase. Furthermore, we have been studying significance of stress echocardiography. Therefore, if reduced DLco or LDH elevation are recognized, follow up of laboratory data such as blood levels of KL-6, NT-proBNP, D-dimer, echocardiography, high resolution CT of the lung, in addition to clinical findings are important for prediction of PH.

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  Synovial tissues of patients with rheumatoid arthritis (RA) include factors regulating bone resorption, such as receptor activator NF-κB ligand (RANKL), TNF-α, IL-6, IL-17, and IFN-γ. However, in addition to these cytokines, other factors expressed in synovial tissues may play a role in regulating bone resorption. In 2009, we demonstrated that novel peptides from T-cell leukemia translocation-associated gene (TCTA) protein expressed in synovial tissues from patients with RA inhibit human osteoclastogenesis, preventing cellular fusion via the interaction between TCTA protein and a putative counterpart molecule. Only a few studies on the role of TCTA protein have been reported, including our report published in 2009. In the current review paper, we summarized papers on TCTA protein before 2009 and our recent findings.

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  Animal models of human diseases are very useful to better understand their pathomechanism and to develop new therapies. However, due to the differences among different species, it is sometimes difficult to reproduce reliable diseases phenotype in animals. Bullous pemphigoid is the most common autoimmune blistering skin disease, in which circulating IgG autoantibodies directed against type XVII collagen (COL17) leads to skin blister formation. Interestingly, due to significant interspecies differences in its amino acid sequences in major pathogenic epitope on COL17, passive transfer of auto-antibodies (Abs) from patients with bullous pemphigoid into mice failed to induce blister formation. To overcome this species' differences, we have recently established a novel molecular method “humanization of autoantigen” by genetic manipulation. Using COL17-humanized mice, we have established 2 different mouse models of bullous pemphigoid. One is by injecting human auto-Abs from bullous pemphigoid patients into the neonatal COL17-humanized mice. Another model was induced by mouse Abs to human COL17 passively transferred from mother via placenta and milk into the neonatal COL17-humanized mice. “Humanization of autoantigen” is a novel and potential method to produce animal models for autoimmune diseases.

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  Since Hamano et al. have first reported serum IgG4 elevation in sclerosing pancreatitis in 2001, various systemic disorders have been reported to be related to elavated IgG4, and many names have been proposed from the point of view of the systemic condition. Despite similarities in the organs damaged in IgG4-related Mikulicz's disease and Sjögren's syndrome, there are marked clinical and pathological differences between the two entities. IgG4-related Mikulicz's disease and Küttner's tumor are related diseases and complete differentiation is very difficult. The majority of cases diagnosed with autoimmune pancreatitis in Japan are IgG4-related sclerosing pancreatitis, and it should be recognized that this is distinct from the western type. There is a likelihood that cases once diagnose as Castleman's disease that showed good responsiveness to glucocorticoid treatment may have been IgG4-related lymphadenopathy, and should be re-assessed in light of recent findings. Diagnosis of IgG4-related disease is defined by both 1) Elevated serum IgG4 (>135 mg/dl) and 2) Histopathological features including lymphocyte and IgG4⁺ plasma cell infiltration (IgG4⁺ plasma cells/IgG⁺ plasma cells >50% on a highly-magnified slide checked in five points), however differential diagnosis from other distinct disorders, such as sarcoidosis, Castleman's disease, Wegener's granulomatosis, lymphoma, cancer, and other existing conditions is necessary. To avoid diagnostic confusion, simpler and more scientific names should be used where disease-specific pathogenesis or markers have been ascertained.

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  These days, rheumatoid arthritis (RA) is reported to be subclassified into two subsets by anti-citrullinated peptide antibody (ACPA) positivity. Clinically, ACPA positive RA tends to develop more severe arthritis than ACPA negative RA. In addition, a lot of reported susceptibility genes to RA (ie. HLA-DRB1^*04, PTPN22, TRAF1/C5, CTLA4) are found to be associated only with ACPA positive RA but not with ACPA negative RA. It is getting clear that HLA-DRB1^*04, which was believed to be primarily associated with RA, is not a primary risk factor but ACPA is. Then, a hypothesis for the disease mechanism of ACPA positive RA is set as follows; citrullination possibly due to smoking, etc, provokes ACPA production in individuals who have susceptibility alleles of genes including HLA, followed by joint inflammation in autoantibody-dependent manner. The search for susceptibility genes for ACPA negative RA is slowly progressing, but only a few genes are so far reported: HLA-DRB1^*03 for Caucasian, HLA-DRB1^*09 for Japanese, IRF5 and STAT4. When we investigate the disease mechanisms of RA, we should manage independently the two disease subsets : ACPA positive and ACPA negative RA.

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  A 23-year-old Japanese woman was diagnosed with lupus nephritis on May 2007. The patient was prescribed 30 mg/day of prednisolone, but developed a pulmonary abscess and was admitted to Sapporo Medical University Hospital in March 2008. Antibiotics improved the symptoms. We prescribed trimethoprim-sulfamethoxazole as prophylaxis for pneumocystis pneumonia; however, the patient developed fever and thrombocytopenia with hyperferritinemia after a week of this prophylaxis. We considered that she was developing hemophagocytic syndrome, and administered methylprednisolone pulse therapy. The clinical findings soon improved. However, when the prophylaxis was restarted, the patient developed fever, headache, and anaphylaxis the same day. Symptomatic therapy resolved these symptoms after three days, but they recurred on recommencing trimethoprim-sulfamethoxazole. Analysis of the cerebrospinal fluid revealed aseptic meningitis. These episodes were thought to be induced by trimethoprim-sulfamethoxazole. As trimethoprim-sulfamethoxazole is frequently used as prophylaxis for pneumocystis infection in immunosuppressed patients, clinicians should be vigilant regarding the complications of this treatment, particularly the rare occurrence of aseptic meningitis and anaphylaxis.

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  <PURPOSE> To examine therapeutic effect of leukocytapheresis (LCAP) for rheumatoid arthritis (RA) resistant to various treatments. <METHOD> Thirteen patients with RA (mean age : 60.8±11.4, male : female=5 : 8), ① who were resistant to disease-modifying anti-rheumatic drugs (DMARDs) and biologics, or ② who failed with those medicines because of side effects or complications. We performed LCAP, which was carried out once a week for a total of five sessions, with a throughput of about 0.1 L/kg. Before and after LCAP, we evaluated the effect of LCAP therapy. <RESULT> DAS28 (CRP) score was 5.70±1.12 before LCAP, 4.57±1.19 (P<0.05) just after the final LCAP and 4.83±1.35 (P<0.05) about 4weeks after LCAP. DAS28 score decreased in all patients after LCAP. No serious adverse events were observed except temporary anemia. <CONCLUSION> LCAP therapy may be useful and safe for patients with RA resistant to conventional medication. Patients who show good clinical response by LCAP needs to be clarified.

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  A 62-year-old male was admitted to a local hospital due to a clouding of consciousness in October 2006. On admission, his renal function was observed to have severely deteriorated, which is thought to cause disturbance of consciousness. Laboratory data showed blood urea nitrogen to be 160 mg/dl and the serum creatinine level was 25 mg/dl and, as a result, continuous hemodiafiltration (CHDF) was started. Although his general condition improved, his renal function did not recover. Therefore, regular hemodialysis was started in December 2006. The cause of renal dysfunction was uncertain, because MPO-ANCA was negative, and a renal biopsy could not be done due to the lack of a clear corticomedullary border in his kidneys. In January 2008, he was diagnosed to have microscopic polyangiitis (MPA) because of hemoptysis, elevated serum CRP levels and a positive finding for MPO-ANCA (408.0 EU). An alveolar hemorrhage was also ascertained in a broncoscopic examination. Steroid pulse therapy and intravenous pulse therapy of cyclophosphamide were thus started. The patient's clinical symptoms thereafter significantly improved and his MPO-ANCA level became normalized. This is a rare case characterized by a late appearance of MPO-ANCA, which occurred after more than one year after the onset of renal failure in MPA.

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  We report a case of Chlamydia-associated arthritis in a 40-year-old man. The patient experienced four episodes of Chlamydia trachomatis urtethritis within a few years. During the present episode, polyarthritis developed a few days after Chlamydia trachomatis urethritis was noted. The patient was diagnosed as having Chlamydia-associated arthritis. Loxoprofen sodium and azithromycin were started. Antibiotics induced clinical improvement of urethritis, although arthritis persisted for 3 months. HLA-B27 was negative, but both HLA-B35 and B40 were positive. Thus, we speculate that positivity for both HLA-B35 and HLA-B40 contributed to the persistence of arthritis in this case. During the course, the levels of Th1, Th17 and regulatory T cells in the peripheral blood were increased on flowcytometry. Thus, we speculate that Th17 may play, at least in part, an important role of the pathogenesis in this case.

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