[Jpn. J. Clin. Immunol., 34(5) 426 (2011)]

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[Jpn. J. Clin. Immunol., 34(6) 485 (2011)]

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  Ulcerative colitis (UC) and Crohn's disease (CD) is an inflammatory bowel disease of unknown aetiology characterized by periods of remission and acute episodes of relapse with severe inflammation in the colonic mucosa. Conventional treatments for UC and CD include 5-aminosalicylate, corticosteroid, elemental dietary treatment, corticosteroid, and thiopurine (azathioprine). Recently, new immunomodulators and anti-TNFa agents, such as tacrolimus, infliximab, and adalimumab have been developed and these treatments are available to be treated for patients with refractory UC and CD. Conventional step-up treatment has been replaced by top-down treatment using biologics. Infliximab and adalimumab induce not only clinical remission but also improve relapse rates and surgical rates. Endoscopic mucosal healing predicts short- and long-prognosis for both of these diseases, thus recent treatment strategy should be aimed for endoscopic remission. Although biologics is useful for patients with UC/CD, secondary loss of responses (LOR) for biologics has been partly observed in CD patients. Measuring anti-infliximab antibodies and concentration of infliximab trough level may help considering treatment strategy for patients with LOR.

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  Atopic dermatitis (AD) is a common, chronically relapsing skin disease. It is very difficult to treat severe type AD by steroid ointment. We therefore hypothesized that synthetic double-stranded DNA with a high affinity for Signal Transducers and Activators of Transcription 6 (STAT6) could be introduced in vivo as a decoy cis elements to bind the transcriptional factor and to block the gene activation of contributing the onset and progression of AD, thus providing effective therapy for AD. Treatment by the transfection of STAT6 decoy oligodeoxynucleotides (ODN), but not scrambled decoy ODN in the AD model mice, had a significantly inhibitory effect on not only STAT6 binding to nuclei but also on the third phase response. A histological analysis revealed that both edema and the infiltration of eosinophils and degranulated mast cells significantly decreased in STAT6 decoy ODN transfected mice. We herein report the first successful in vivo transfer of STAT6 decoy ODN to reduce the third phase reaction in AD model mice, thereby providing a new therapeutic strategy for atopic dermatitis. We also introduce another NF-kB Decoy Oligodeoxynucleotides therapy or STAT6siRNA therapy for allergic diseases.

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  Treatment of rheumatoid arthritis (RA) has dramatically developed with the use of biologics targeting inflammatory cytokines. However, expense and parenteral use can cause issues in the initiation and continuation of the treatment. Therefore a new orally available anti-rheumatic drug has been long-awaited. Recently, small-molecule compounds targeting Janus kinase (JAK) has shown clinical efficacy similar to biologics in clinical trials for active RA. Among the JAK-inhibitors, new drug application for tofacitinib is concurrently under review in western and asian countries and is highly expected to become a new anti-rheumatic drug in the near future. In order to evaluate the mode of action, we utilized peripheral blood and synovium from RA patients. Proliferation and cytokine production of CD4+ T cell was prominently reduced and subsequently inhibited cartilage destruction by the synovium. Our result is in line with the inhibitory effect of tofacitinib on joint destruction in RA patients those who were treated with tofacitinib. Therefore, further clinical efficacy is expected in the in the long-term treatment with tofacitinib.

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  Recently, a lot of new anti-cancer agents have come to the cancer treatment scene. The development of monoclonal antibodies like rituximab, trastuzumab, cetuximab, and bevacizumab are symbolic of the new era, and their effect on the various cancers is remarkable. They have occupied essential position in the cancer treatment as a first-line therapy or as an adjuvant therapy.
  In Japan, the approval of drugs which are not only anti-cancer agent but also any other drugs don't have been quick for long ago. So when we treat the cancer patient with their new agent, there is the limitation in the way to use them. But we should not only submit to this situation, as a member of worker in Japanese medical academic, clinical, industrial situation should progress the research and development and clinical study of the new anti-cancer agent including monoclonal antibody.

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  Neuromyelitis optica (NMO) or Devic's disease is an inflammatory neurologic disease characterized by severe optic neuritis and transverse myelitis. Other features of NMO include female preponderance, higher onset age, severe functional disability, longitudinally extensive spinal cord lesions (longer than 3 vertebral segments), and oligoclonal IgG bands negativity. Brain lesions are not uncommon in NMO. The relation between NMO and multiple sclerosis (MS) has long been a matter of controversy, but since the discovery of anti-aquaporin 4 (AQP4) antibody (NMO-IgG), an NMO-specific autoantibody, the clinical, MRI, and laboratory features that distinguish NMO from MS have been clarified. Anti-AQP4 antibody binds to the extracellular domain of AQP4, which is highly expressed in endfeet of astrocytes. Recent neuropathological studies, analysis of CSF-GFAP levels during relapse and experimental studies strongly suggest that NMO is an anti-AQP4 antibody-mediated astrocytopathic disease and that T cell-mediated CNS inflammation is necessary to develop NMO. Also, IL-6 is remarkably elevated in the CSF and appears to regulate plasmablasts to produce anti-AQP4 antibody. Therefore, from the therapeutic point of view, depletion of anti-AQP4 antibody, suppression of T cell response to trigger relapse and anti-IL-6 therapy seem to be pivotal. High-dose intravenous methylprednisolone is the first-line therapy for acute exacerbations of NMO. But plasma exchange should be started soon if corticosteroid is not efficacious. If untreated, AQP4 antibody-positive patients are highly likely to experience relapses within a year. Thus, immunosuppressive therapy (corticosteroids, immunosuppressants, rituximab) should be initiated without delay. Preliminary results suggest that eculizumab, an anti-C5 monoclonal antibody, can also prevent relapse in NMO, Meanwhile, interferon-beta, a first-line disease modifying drug of MS, is not effective in NMO. Symptomatic therapy for pain, paresthesia, spasticity, dysuria and constipation which commonly occur in the chronic stage of NMO is also important to improve patients' quality of life.

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  Purpose: We classified underlying diseases presenting as inflammation of unknown origin in division of rheumatic diseases. On the other hand, patients with malignant lymphoma (ML) varying in cause and symptoms are often admitted to our Rheumatology Division as cases of malignant disease presenting with fever of unknown origin.
  Patients and Methods: Clinical records over 5 years were reviewed for 246 cases of undiagnosed inflammatory diseases at hospitalization.
  Results: The 246 patients included 76 patients with infection, 116 with rheumatic disease, 8 with solid cancer, 9 with drug-induced fever, 10 with other disorders, and 27 with suspected ML. Of theses, malignant lymphoma (ML) was diagnosed in 20 patients (5 Mature T-cell and NK-cell neoplasms, 3 Hodgkin lymphomas, and 12 Mature B cell neoplasms including 5 Intravascular large B-cell lymphoma (IVLBCL)). The reasons for hospitalization were underlying collagen disease in 6 patients, medical workup for fever of unknown origin in 8 patients, and symptoms suggestive of collagen disease in 6. Nearly all of these patients presented with fever and other B symptoms, frequently with concurrent hypoxemia and hemophagocytic syndrome in IVLBCL. For diagnostic purposes, biopsy sites were determined by 18fluorodexyglucose-positron emission tomography and computed tomography (FDG-PET/CT) in 13 patients, and findings on random skin biopsies were diagnostic in 3 of 5 patients with IVLBCL. Laboratory data on patients with B-cell lymphoma or peripheral T-cell lymphoma revealed tendencies for thrombocytopenia, elevated serum LDH, and increased soluble interleukin-2 receptor (sIL-2R). High serum ferritin values were more frequent in IVLBCL than in other B-cell lymphomas.
  Conclusion: ML ranked first among causes of inflammation of unknown origin at the division of Rheumatic Diseases, and FDG-PET/CT proved to be useful for biopsy site selection. IVLBCL was not uncommon, and our results show the usefulness of clinical features and random skin biopsies for rapid diagnosis.

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  A 73-years-old man, who was a farmer, developed fever, fatigue, and muscle weakness. His serum creatine kinase (CK) level was found to be high. Computed tomography showed the presence of bibasilar subpleural interstitial infiltrates. He was therefore clinically given a diagnosis of polymyositis. After high-dose glucocorticoid (GC) and GC-pulse therapies were started, his symptoms improved, and the CK level decreased. The patient's son was 44-years-old. He moved back into his parent's home, quit his corporate job and started working in the agricultural field. He then developed fever, myalgia, and muscle weakness. His serum CK level was high. Therefore, he also was given a diagnosis of polymyositis. After high-dose GC and immunosuppressive therapies were stared, his symptoms improved and CK level decreased. Polymyositis may be triggered by specific environmental exposures in genetically susceptible individuals. The son developed the disease immediately after he moved into his parent's home and changed his profession to farming which was same as his father's profession. Moreover, the father and his son may have had common genetic factors. We believe that some environmental factors triggered the onset of polymyositis in the father and his son.

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  A girl, 7 years of age, was reported who had been suffered from migratory arthralgia, bone pain and erythematous rash. She had increased inflammatory markers such as C-reactive protein, erythrocyte sedimentation rate, and mild anemia for more than 6 months. In the beginning, she was suspected of having either juvenile idiopathic arthritis or chronic recurrent multifocal osteomyelitis. However, after about 6 months, there were abrupt increases of LDH in serum titers and blast cells were also revealed by bone marrow examination.
  Upon these findings, she was diagnosed with acute lymphocytic leukemia. Since bone pain and arthralgia bone pain and arthralgia are both indicative of numerous inflammatory disorders such as infectious myelitis, juvenile chronic arthritis, childhood leukemia and malignancies, and auto-inflammatory bone diseases, especially chronic recurrent multifocal osteomyelitis, it is difficult to accurately diagnose right away. For now, these aforementioned inflammatory responses are the sole key findings for clinical investigations. Other than that, there are not enough reports yet to help diagnose incases similar to this. Therefore, it is difficult to differentiate between the disorders above even after blood tests, Ga-scincigraphy, and imaging examinations.
  Moreover, in the case of childhood leukemia, it was difficult to differentiate these diseases by routine X-ray surveys in the general pediatric fields. The reasons are because there are only a few descriptions on X-ray bone examinations on findings of X-ray bone investigations, and both are usually non-specific.
  However, according to the pediatric radiology specialists, of which there are only a few in Japan, the imaging results show somewhat abnormal findings could be spotted from the early stage. Through this present case, it is suggested to us that it is important to consult the pediatric radiology specialists in order to speed up the diagnostic process. Furthermore, the accumulation of radiological findings of leukemia in children with bone pain and arthralgia will attribute to an early diagnosis and lead to the resolution of pathogenesis of leukemia.

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