Rheumatoid Arthritis: Japan

Yuasa H, Inoue K, Hayashi Y. · Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan. · J Pharm Sci. · Pubmed #18823045 No free full text.

Abstract: Proton-coupled folate transporter (PCFT) has recently been identified as the molecular entity of the carrier-mediated intestinal folate transport system. PCFT has been demonstrated to be most abundantly expressed in the upper small intestine, localizing at the brush border membrane of epithelial cells, transport folate and its analogs more efficiently at lower (acidic) pH by a H(+)-coupled cotransport mechanism, and have a high affinity for folate with a Michaelis constant (K(m)) of a few microM at pH 5.5 and somewhat lower affinities for reduced folates and methotrexate (MTX). A loss of PCFT function due to a homozygous mutation in its gene has been indicated to be responsible for hereditary folate malabsorption. Thus, PCFT has all the characteristics of the brush border H(+)-coupled cotransporter for folate and analogs, which has long been suggested to be present in the intestine. Furthermore, sulfasalazine was found to be a potent inhibitor of PCFT, suggesting that it is a risk factor that would cause malabsorption of folate and also MTX, when coadministered in the treatment of rheumatoid arthritis. Understanding the molecular and functional characteristics of PCFT should be important and helpful in exploring therapeutic strategies for folate malabsorption and in optimizing therapies using antifolate drugs.

Mori M, Naruto T, Imagawa T, Murata T, Takei S, Tomiita M, Itoh Y, Fujikawa S, Yokota S. · Department of Pediatrics, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan. · Mod Rheumatol. · Pubmed #18815725 links to  free full text

Abstract: Methotrexate (MTX), the primary treatment for the articular-type juvenile idiopathic arthritis (JIA), is effective and brings about radiological improvement. Patient compliance is good, and it is recognized that its known side effects, namely, disruption of liver function and induction of pulmonary lesions, are unlikely to be severe at the low MTX doses that are administered. In Japan, MTX was granted approval in 1999 by the then Ministry of Health and Welfare specifically for treating rheumatoid arthritis in adult patients, allowing it be generally used in medical institutions for patients having National Health Insurance. However, in the pediatric field, its use outside the indications has so far been unavoidable, and has been left to the discretion of the physician. Finally, at the present conference, expansion of the indications of MTX for JIA was approved in Japan. It is noteworthy that this expansion of indications was achieved without requiring clinical trials on children sponsored by the pharmaceutical company: it was achieved rather by collecting necessary information through ongoing efforts (including collection and analysis of information about approval status in foreign countries, adequate evidence from the literature, implementation of a clinical use survey in Japan, etc.). It also merits attention that the maximum dose (10 mg/m2) was set on the basis of pharmacokinetic data from children, rather than relying on the dosing method and dose for adults.

Amano H, Furuhata N, Tamura N, Tokano Y, Takasaki Y. · Department of Rheumatology and Internal Medicine, Juntendo University, Tokyo, Japan. · Lupus. · Pubmed #18755866 No free full text.

Abstract: We describe a female Japanese patient with concomitant hypocomplementemic urticarial vasculitis, Jaccoud's arthropathy and valvular heart disease. In 1996, she developed arthritis with swelling of both proximal interphalangeal joints and urticarial vasculitis on both arms that was resolved by administration of glucocorticoid (prednisolone 30 mg/day). Tests for antineutrophil cytoplasmic antibodies, antinuclear antibody and rheumatoid factor gave negative results. The findings of a skin biopsy examination were consistent with 'leukocytoclastic vasculitis'. During 10 years of observation, the patient manifested polyarthritis leading to progressive deformity of the joints of the hands and feet (without loss of cartilage or erosion of bone), persistent urticaria exacerbated by cold and accompanied by hypocomplementemia and progressive cardiac valvular disease with mitral valve regurgitation. There are only three reports described previously documenting five patients with this rare combination of manifestations.

Iwamoto T, Okamoto H, Toyama Y, Momohara S. · Institute of Rheumatology, Tokyo Women's Medical University, Japan. · FEBS J. · Pubmed #18662305 No free full text.

Abstract: Rheumatoid arthritis (RA) is a chronic symmetric polyarticular joint disease that primarily affects the small joints of the hands and feet. The inflammatory process is characterized by infiltration of inflammatory cells into the joints, leading to proliferation of synoviocytes and destruction of cartilage and bone. In RA synovial tissue, the infiltrating cells such as macrophages, T cells, B cells and dendritic cells play important role in the pathogenesis of RA. Migration of leukocytes into the synovium is a regulated multi-step process, involving interactions between leukocytes and endothelial cells, cellular adhesion molecules, as well as chemokines and chemokine receptors. Chemokines are small, chemoattractant cytokines which play key roles in the accumulation of inflammatory cells at the site of inflammation. It is known that synovial tissue and synovial fluid from RA patients contain increased concentrations of several chemokines, such as monocyte chemoattractant protein-4 (MCP-4)/CCL13, pulmonary and activation-regulated chemokine (PARC)/CCL18, monokine induced by interferon-gamma (Mig)/CXCL9, stromal cell-derived factor 1 (SDF-1)/CXCL12, monocyte chemotactic protein 1 (MCP-1)/CCL2, macrophage inflammatory protein 1alpha (MIP-1alpha)/CCL3, and Fractalkine/CXC3CL1. Therefore, chemokines and chemokine-receptors are considered to be important molecules in RA pathology.

Kobayashi S, Momohara S, Kamatani N, Okamoto H. · Institute of Rheumatology, Tokyo Women's Medical University, Japan. · FEBS J. · Pubmed #18662304 No free full text.

Abstract: Rheumatoid arthritis (RA) is a systemic, chronic inflammatory disease that affects 0.5-1% of the population. RA causes progressive joint destruction that leads to the restriction of activities of daily living and deterioration of quality of life. Although the pathogenesis of RA has not yet been fully elucidated, it is considered to be a complex, multifarious disease that is influenced by both genetic and environmental factors. Genetic influences that contribute to RA susceptibility have been demonstrated both in studies of twins and families, as well as in genome-wide linkage scans, and it is estimated that genetic factors are responsible for 50-60% of the risk of developing RA. Thus, environmental factors may explain the remaining risk of developing RA. A large variety of environmental factors such as infectious agents, smoking, sex hormones, pregnancy etc. have been extensively studied previously. Understanding of how these factors contribute to the development of RA may lead to the better understanding of pathogenesis of RA.

Okamoto H, Cujec TP, Yamanaka H, Kamatani N. · Institute of Rheumatology, Tokyo Women's Medical University, Japan. · FEBS J. · Pubmed #18662303 No free full text.

Abstract: Rheumatoid arthritis is a multifactorial disease characterized by chronic inflammation of the joints. Both genetic and environmental factors are involved in the pathogenesis leading to joint destruction and ultimately disability. In the inflamed RA joint the synovium is highly infiltrated by CD4+ T cells, B cells and macrophages, and the intimal lining becomes hyperplastic owing to the increased number of macrophage-like and fibroblast-like synoviocytes. This hyperplastic intimal synovial lining forms an aggressive front, called pannus, which invades cartilage and bone structures, leading to the destruction and compromised function of affected joints. This process is mediated by a number of cytokines (tumor necrosis factor-alpha, interleukin-1, interleukin-6, interleukin-17 interferon-gamma, etc.), chemokines (monocyte chemoattractant protein-1, monocyte chemoattractant protein-4 CCL18, etc.), cell adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, etc.) and matrix metalloproteinases. Expression of these molecules is controlled at the transcription level and activation of a limited number of transcription factors is involved in this process.

Kusunoki N, Yamazaki R, Kawai S. · Division of Rheumatology, Department of Internal Medicine, Toho University School of Medicine, 6-11-1 Omori-Nishi, Ota-ku, Tokyo, 143-8541, Japan. · Mod Rheumatol. · Pubmed #18642053 No free full text.

Abstract: Rheumatoid arthritis (RA) is a systemic inflammatory disease that mainly affects the articular synovial tissues. Although the etiology of RA has not yet been elucidated, physical and biochemical inhibition of synovial hyperplasia, which is the origin of articular destruction, may be an effective treatment for RA. Nonsteroidal anti-inflammatory drugs (NSAIDs) have long been used for the treatment of RA. The mechanism of action of NSAIDs generally involves the inhibition of cyclooxygenase (COX) at sites of inflammation. Thus, NSAIDs were not generally considered to have a so-called anti-rheumatic effect, including inhibition of progressive joint destruction and induction of remission. However, certain conventional NSAIDs and celecoxib, a selective COX-2 inhibitor, have been reported to inhibit synovial hyperplasia by inducing the apoptosis of human synovial fibroblasts. Therefore, it has been suggested that such NSAIDs may not only have an anti-inflammatory effect but also an anti-rheumatic effect. In this review, we summarize findings about the pro-apoptotic effect, in other words, anti-proliferative effect of NSAIDs on synovial fibroblasts from patients with RA.

Ohori M. · Astellas Pharma Inc., Tsukuba, Ibaraki, Japan. · Drug News Perspect. · Pubmed #18596988 No free full text.

Abstract: Rheumatoid arthritis (RA), a chronic and systemic autoimmune disease that leads to progressive articular destruction, is evoked by the concerted action of RA-related cells, such as T cells, synovial fibroblasts and macrophages. Although anticytokine biologics block the intercellular signal transduction of these RA-related cells and thereby exert a strong ameliorative effect on RA, there still remains a significant percentage of nonresponsive patients. In addition to these biologics that disrupt specific intercellular signals, extracellular signal-regulated kinase (ERK) inhibitors, which are believed to target the intracellular signals common to the diverse RA-related cells, are also used as a treatment for RA patients, including those who are nonresponsive to the anticytokine therapies. Recently, potent and selective inhibitors for ERK with the co-crystal structures have been reported. FR180204, an ERK inhibitor, has been shown to be effective against mouse collagen-induced arthritis, a representative animal model of RA. This compound also suppresses the antigen-specific activation of T cells, which play a central role in the initiation and progress of the disease. Information obtained from the co-crystal structures would contribute to the improvement of the chemical characteristics. Thus, with the discovery of new potential chemical entities, ERK inhibitors may emerge as a new therapeutic approach for the treatment of RA.

Takei M, Kitamura N, Shiraiwa H, Inomata H, Nozaki T, Kuwana Y, Shiozaki M, Sawada S, Ishiwata T. · Division of Hematology and Rheumatology, Department of Medicine, Nihon University School of Medicine, Japan. · Nihon Rinsho Meneki Gakkai Kaishi. · Pubmed #18587224 links to  free full text

Abstract: Epstein-Barr virus (EBV) belong to herpes virus group. This virus is transmitted by human contact and cause primary infection and may exist even for years in a latent state in healthy individuals. This virus may be reactivated by the dysregulation of the host immune system or possibly by virus mutation. Here we have firstly demonstrated the host defense of EBV infection and association of EBV with rheumatoid synovitis, and then discussed our own ideas of the possible treatment in near future. The key points of this new therapy are SAP (signaling lymphocytic-activation molecule associated protein) or SH2D1A (Src homology 2 domain-containing protein). SAP (or SH2D1A), an adaptor-like molecule expressed in immune cells, is composed almost exclusively of a Src homology 2 (SH2) domain. In humans, SAP is mutated and either absent or non-functional in X-linked lymphoproliferative (XLP) syndrome (Duncan disease), a disease characterized by an inappropriate response to EBV infection. SAP is essential for late B cell help and the development of long-term humoral immunity. New approach to the therapeutic method for EBV might be opened by the regulation of this molecule (SAP).

Muramatsu K, Tanaka H, Taguchi T. · Department of Orthopedic Surgery, Yamaguchi University School of Medicine, Ube, Yamaguchi 755-8505, Japan. · Rheumatol Int. · Pubmed #18528693 No free full text.

Abstract: Although the clinical hallmark of rheumatoid arthritis (RA) involves inflammatory joint disease, extra-articular manifestations may be evident in 20% of patients. Among them neurologic features involving both the peripheral and central nervous system are one of the more common, but little has been noticed about it in clinic. The same mechanisms participating in joint destruction, synovial inflammation, and vasculitis contribute to the various RA neurological complications. In this article, we reviewed clinical outcomes of peripheral neuropathies of the upper extremity associated with RA and discussed the proper diagnosis and operative indication. Magnetic resonance imaging and electrophysiological examination are the best tools to lead the final diagnosis of nerve palsy secondary to RA synovial cyst. Such neuropathies require consideration in the differential diagnosis of wrist and hand disability. Surgical decompression is recommended at prompt timing if neurophysiologic studies demonstrate denervation or significant motor abnormalities, or sensory symptoms progress despite adequate medication.

Ishiguro T, Takayanagi N, Kurashima K, Matsushita A, Harasawa K, Yoneda K, Tsuchiya N, Miyahara Y, Yamaguchi S, Yano R, Tokunaga D, Saito H, Ubukata M, Yanagisawa T, Sugita Y, Kawabata Y. · Department of Respiratory Medicine, Saitama Cardiovascular and Respiratory Center, Kumagaya. · Intern Med. · Pubmed #18520114 links to  free full text

Abstract: This report describes a 65-year-old woman who developed granulomatous lesions consistent with sarcoidosis during etanercept therapy for rheumatoid arthritis. Hilar and mediastinal lymphadenopathy and multiple nodules in both lung fields developed 21 months after administration of etanercept. Noncaseating epithelioid cell granulomas consistent with sarcoidosis were detected in a lung biopsy specimen and in the parietal pleura obtained via thoracotomy. Diseases showing similar histologic changes were excluded, and a diagnosis of sarcoidosis was made. Etanercept was discontinued, which resulted in symptomatic relief, improvement of oxygenation and radiologic findings. There is substantial evidence of tumor necrosis factor-alpha involvement in the induction and maintenance of granuloma formation; however, we should keep in mind that granulomatous disease, such as sarcoidosis, can develop during treatment with a tumor necrosis factor-alpha blocking agent, such as etanercept.

Hayashi N, Nishimura K, Kumagai S. · Department of Clinical Laboratory, Kobe University Hospital, Kobe 650-0017. · Rinsho Byori. · Pubmed #18516964 No free full text.

Abstract: Rheumatoid factor (RF) has been commonly used as a biomarker of rheumatoid arthritis (RA). It is important to diagnose RA early and to prevent joint destruction before irreversible damage occurs. For this purpose, several new biomarkers, such as anti-cyclic citrullinated peptide antibody (anti-CCP) and matrix metalloproteinase-3 (MMP-3), have become available for both the diagnosis and prognosis of RA. RF showed a tolerable sensitivity of 68.5% for RA, but low specificity of 77.1% for patients with other rheumatic diseases. Anti-agalactosyl IgG antibodies (CARF) showed a slightly higher sensitivity of 73.9%, but specificity as low as that for RF. In contrast, anti-CCP demonstrated high sensitivity of 76.1% and marked specificity of 92.4% for patients with other rheumatic diseases. Anti-CCP was significantly superior to other biomarkers on receiver-operating characteristic curve (ROC) analysis. Moreover, meta-analysis revealed that the pooled sensitivity and specificity were 67% and 95% for anti-CCP, and 69% and 85% for RF, respectively, and that anti-CCP was more specific than RF for diagnosing RA. On the other hand, MMP-3 has been suggested to be a prognostic biomarker as well as an evaluative biomarker for RA. We next examined if the diagnostic accuracy of early RA is improved by combining these biomarkers. The specificity of RF was not as high as anti-CCP but rose to 92% when combined with MMP-3. Thus, we concluded that anti-CCP is superior to other biomarkers in terms of diagnostic accuracy, and that these combined assays are useful in the early diagnosis of RA.

Nagata S. · Department of Medical Science, Graduate School of Medicine, Kyoto University, Yoshida-Konoe, 606-8501 Kyoto, Japan. · Cytokine Growth Factor Rev. · Pubmed #18514017 No free full text.

Abstract: Macrophages phagocytose cells that die during programmed cell death and the nuclei that are expelled from erythroid precursor cells during erythropoiesis; subsequently, the ingested DNA is degraded in their lysosomes. A defect in this lysosomal DNA degradation activates the macrophages to produce cytokines such as IFNbeta and TNFalpha in a Toll-like receptor (TLR)-independent manner. IFNbeta thus produced in the mouse fetus induces the apoptosis of erythroid and lymphoid precursor cells, and kills the embryos. On the other hand, when the capacity for lysosomal DNA degradation is knocked out after birth, TNFalpha production increases in adulthood, causing chronic polyarthritis that resembles human rheumatoid arthritis. Here, I summarize recent findings on inflammatory diseases induced by such defects in DNA degradation.

Ogiwara Y, Mochizuki H, Morioka T, Sugihara T, Makino F, Takahashi H. · Division of Respiratory Medicine, Tokyo Metropolitan Geriatric Hospital, 35-2 Sakae-Cho, Itabashi-Ku, Tokyo, 177-0015, Japan. · Mod Rheumatol. · Pubmed #18504526 No free full text.

Abstract: We report a case of bucillamine-induced interstitial pneumonia accompanied by severe hypoxemia in an 83-year-old woman who had rheumatoid arthritis. Respiratory failure worsened even after withdrawal of bucillamine and administration of high-dose corticosteroids, and mechanical ventilation was required. A review of 15 cases with bucillamine-induced pulmonary injury suggests that advanced age may be associated with the development of severe interstitial pneumonia. Bucillamine can cause corticosteroid-resistant and life-threatening lung injury, especially in the elderly.

Okamoto H. · Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan. · IUBMB Life. · Pubmed #18484089 No free full text.

Abstract: Vitamin K2 [menaquinone-4 (MK-4)] has been reported to induce apoptosis in hepatocellular carcinoma, leukemia, and MDS cell lines. The effects of MK-4 on the development of arthritis have never been addressed so far. In this study, we investigated the effect of MK-4 upon the proliferation of rheumatoid synovial cells and the development of arthritis in collagen-induced arthritis (CIA). We analyzed the effect of MK-4 on the proliferation of fibroblast-like synoviocytes (FLSs) using the 3-(4,5-demethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The proapoptotic effect of MK-4 upon FLS was investigated with annexin V staining and DNA fragmentation and caspase 3/7 assays. Moreover, we analyzed the effect of MK-4 on the development of CIA in female dark agouti rats. Our results indicated that MK-4 inhibited the proliferation of FLS and the development of CIA in a dose-dependent manner. We concluded that MK-4 may represent a new agent for the treatment of RA in the setting of combination therapy with other disease-modifying antirheumatic drugs.

Uchida K. · Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan. · Mol Cells. · Pubmed #18483467 No free full text.

Abstract: Several lines of evidence indicate that the oxidative modification of protein and the subsequent accumulation of the modified proteins have been found in cells during aging, oxidative stress, and in various pathological states including premature diseases, muscular dystrophy, rheumatoid arthritis, and atherosclerosis. The important agents that give rise to the modification of a protein may be represented by reactive aldehydic intermediates, such as ketoaldehydes, 2-alkenals and 4-hydroxy-2-alkenals. These reactive aldehydes are considered important mediators of cell damage due to their ability to covalently modify biomolecules, which can disrupt important cellular functions and can cause mutations. Furthermore, the adduction of aldehydes to apolipoprotein B in low-density lipoproteins (LDL) has been strongly implicated in the mechanism by which LDL is converted to an atherogenic form that is taken up by macrophages, leading to the formation of foam cells. During the search for an endogenous inducer of cyclooxygenase-2 (COX-2), an inducible isoform responsible for high levels of prostaglandin production during inflammation and immune responses, 4-hydroxy-2-noennal (HNE), one of the most representative lipid peroxidation product, has been identified as the potential inducer of COX-2. In addition, the following study on the molecular mechanism of the COX-2 induction by HNE has unequivocally established that a serum component, which is eventually identified to be denatured LDL, is essential for COX-2 induction. Here I review current understanding of the mechanisms by which HNE in cooperation with the serum component activates gene expression of COX-2.

Okamoto H, Hoshi D, Kiire A, Yamanaka H, Kamatani N. · Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan. · Inflamm Allergy Drug Targets. · Pubmed #18473901 No free full text.

Abstract: Rheumatoid arthritis (RA) is a multifactorial disease characterized by chronic inflammation of the joints. Both genetic and environmental factors are involved in the pathogenesis of joint destruction and disability. In the inflamed RA joint, the synovium is highly infiltrated by CD4+ T cells, B cells, and macrophages. Furthermore, the intimal lining becomes hyperplastic due to the increased numbers of macrophage-like and fibroblast-like synoviocytes. This hyperplastic intimal synovial lining forms an aggressive front, called pannus, which invades cartilage and bone structures, leading to compromised function and/or destruction of affected joints. RA pathology is mediated by a number of cytokines (TNF-alpha, IL-1, IL-6, IL-17, IFN gamma, etc.), chemokines (MCP-1, MCP-4, CCL18, etc.), cell adhesion molecules (ICAM-1, VCAM-1, etc.) and matrix metalloproteinases. Currently, treatment strategies targeted against TNF-alpha, IL-1 and IL-6 are available. In this review, we will summarize the use of biologics, the pros and cons of the use of biologics, and discuss on the potential molecular targets of RA.

Adachi Y, Yoshio-Hoshino N, Nishimoto N. · Laboratory of Immune Regulation, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan. · Curr Pharm Des. · Pubmed #18473869 No free full text.

Abstract: After three decades from the development of the hybridoma technology, a monoclonal antibody-based therapy targeting the inflammatory cytokine has been established as an ultimate treatment for chronic inflammatory diseases. Interleukine-6 (IL-6) is one of the inflammatory cytokines playing a pivotal role in these conditions, and strategies targeting IL-6 signal show promise in the treatment of chronic inflammatory diseases such as rheumatoid arthritis, juvenile idiopathic arthritis, and Crohn's disease. Although many groups have been exploring the approach to block the IL-6 signal, tocilizumab, a humanized monoclonal antibody of the IL-6 receptor, has been the most intensively studied agent for clinical use. Clinical trials regarding chronic inflammatory diseases described above have demonstrated efficacy of tocilizumab, however, this treatment has limitations in terms of economic costs and ease of administration, and further advances are necessary to expand the concept of IL-6-specific therapeutics. In this review, we discuss targeting IL-6 in a rational drug design and present the various strategies to achieve this.

Shibuya M. · Department of Molecular Oncology, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan. · BMB Rep. · Pubmed #18452647 links to  free full text

Abstract: Angiogenesis, the formation of blood vessels, is essential for preparing a closed circulatory system in the body, and for supplying oxygen and nutrition to tissues. Major diseases such as cancer, rheumatoid arthritis, and atherosclerosis include pathological angiogenesis in their malignant processes, suggesting anti-angiogenic therapy to be a new strategy for suppression of diseases. However, until the 1970s, the molecular basis of angiogenesis was largely unknown. In recent decades, extensive studies have revealed a variety of angiogenic factors and their receptors, including vascular endothelial growth factor (VEGF)-VEGFRs, Angiopoietin-Tie, Ephrin-EphRs and Delta-Notch to be the major regulators of angiogenesis in vertebrates. VEGF and its receptors play a central role in physiological as well as pathological angiogenesis, and functional inhibitors of VEGF and VEGFRs such as anti-VEGF neutralizing antibody and small molecules that block the tyrosine kinase activity of VEGFRs have recently been approved for use to treat patients with colorectal, lung, renal and liver cancers. These drugs have opened a novel field of cancer therapy, i.e. anti-angiogenesis therapy. However, as yet they cannot completely cure patients, and cancer cells could become resistant to these drugs. Thus, it is important to understand further the molecular mechanisms underlying not only VEGF-VEGFR signaling but also the VEGF-independent regulation of angiogenesis, and to learn how to improve anti-angiogenesis therapy.

Yoshizaki K. · Health Care Center, Osaka University. · Nihon Rinsho Meneki Gakkai Kaishi. · Pubmed #18446013 links to  free full text

Abstract: Every clinician knows the elevation of acute phase proteins at the inflammatory status, but nobody knows the CRP or SAA induction mechanism on inflammation, in which a lot of cytokines or chemokines are activated. Induction mechanism of CRP and SAA is analyzed based on the result of the normalization of serum CRP or SAA in rheumatoid arthritis by the IL-6 blocking therapy with a humanized anti IL-6 receptor antibody. Ultimately, IL-6 is a pivotal cytokine among IL-6, IL-1 and TNF-a in induction of CRP and SAA in hepatocyte. Furthermore, activation of STAT3, a transcriptional factor under IL-6 signal transduction pathway, is critical on the expression of these mRNAs. Based on this mechanism, the depression of CRP and SAA induction could be explained by the IL-6 blockage both in vitro and in vivo. Therefore, IL-6 blocking therapy may elucidate the pathogenic significance of IL-6 in chronic inflammatory disease.

Yokota S. · Department of Pediatrics, Yokohama City University School of Medicine. · Nihon Rinsho Meneki Gakkai Kaishi. · Pubmed #18446012 links to  free full text

Abstract: Systemic-onset juvenile idiopathic arthritis (JIA) is a subtype of chronic childhood arthritis of unknown cause, manifested by spiking fever, erythematous rash, arthritis, pericarditis, and hepatosplenomegaly. It has been believed a disease developed due to an excessive production of pro-inflammatory cytokines, especially interleukin (IL)-6. We organized trials of a new biologic response modifier, Toclizimuab, anti-IL-6 receptor monoclonal antibody, to patients with systemic-onset JIA. Tocilizumab directs to solely IL-6 receptor, and is called as a one-point hit drug. We successfully administered Tocilizumab to stabilize the inflammation, and inflammatory symptoms and signs of the patients were abruptly gone. Previously, corticosteroids were the only life-saving drugs, but we proved Tocilizumab will be the possible alternative for treating these children. Basic science will help us to save the children, and clinical science also will promote the basic science in turn.

Matsushita S, Higashi T. · Department of Allergy and Immunology, Faculty of Medicine, Saitama Medical University, Saitama, Japan. · Allergol Int. · Pubmed #18427166 No free full text.

Abstract: Immunomodulators such as lipopolysaccharides (LPS) and forskolin change the nature of dendritic cells (DCs) to induce Th1 and Th2 cells, respectively, thereby designated Th1 or Th2 adjuvants. Recent studies showed that Th17-inducing activity can be carried by certain polysaccharides such as beta-glucan derived from Candia albicans. Such activities can be scrutinized by using MLR, cAMP and possibly, differential expression of Notch ligand isoforms. In this review article, we also introduce an effective method to establish human Th17 cell clones and a transcriptome analysis using human Th subpopulations. In vivo relevance to human Th17 responses is discussed.

Sato K. · Department of Rheumatology and Applied Immunology, Faculty of Medicine, Saitama Medical University, Saitama, Japan. · Allergol Int. · Pubmed #18427163 No free full text.

Abstract: Rheumatoid arthritis is a chronic disease that affects multiple joints. It is considered to be an autoimmune disease in which a T helper (Th)-1 type response has been implicated to play an important pathogenetic role. As osteoclasts, cells that resorb bone, play a crucial part in the bone destruction that occurs in RA, we and others have investigated the pathophysiology of these cells. The findings that interferon (IFN)-gamma strongly inhibits osteoclastogenesis and that interleukin (IL)-17 has the ability to enhance osteoclast differentiation have cast doubt on the hypothesis that RA is a Th1 disease. In this review, I describe the relationship between Th cells, the so-called "commander" of the immune response, and RA, mainly from the viewpoint of the environments Th cells create for the excessive differentiation and function of osteoclasts, resulting in the destruction of bone.

Ishii M, Saeki Y. · Department of Rheumatology and Clinical Research, NHO National Osaka Minami Medical Center, 2-1 Kidohigashimachi, Kawachinagano, Osaka, Japan. · Mod Rheumatol. · Pubmed #18425565 No free full text.

Abstract: Osteoclasts are bone-resorbing multinuclear polykaryon that are essential for bone remodeling and are formed through cell fusion of mononuclear macrophage/monocyte-lineage hematopoietic precursors. In arthritic joints, a large number of activated osteoclasts can be detected, which are suggested to be causative of bone erosion in rheumatoid arthritis. It has been fully established that osteoclastogenesis is critically regulated by several key essential factors, such as M-CSF and RANKL. However, regarding their most characteristic property, i.e., cell fusion to form giant polykaryons, there are still miscellaneous questions to be clarified, although several molecules have been shown to be critically involved in this process. Here we review the latest knowledge about osteoclastogenic cell fusion and novel concepts underlying the characteristic phenomenon. Because cell fusion is a genuine property of mature osteoclasts, modulating this process will become a promising therapeutic tool for bone resorptive disorders in the future.

Neo M. · Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. · Mod Rheumatol. · Pubmed #18414784 No free full text.

Abstract: The cervical spine, especially the upper cervical spine, is a common focus of destruction by rheumatoid arthritis (RA). Because of its potentially debilitating and life-threatening sequelae, cervical spine involvement remains a priority in the diagnosis and treatment of RA. Many studies show that early surgical intervention gives a more satisfactory outcome. Surgery aims to establish spinal stability and to prevent neurological deterioration and injury to the spinal cord, leading to improved neurological function. The recent sophisticated screw-rod-plate technique allows one to obtain a solid fixation of the upper cervical spine with a high possibility of bone union even in RA patients. Although surgery of the occipitoatlantoaxial region is a challenge with many possibilities of serious complications, recent advances in the surgical technique, complete understanding of the anatomy, and precise preoperative evaluation have decreased complication rates. Early consultation with a specialized spine surgeon is mandatory once cervical involvement is suspected in an RA patient because once the patient becomes myelopathic, the rate of long-term mortality increases and the chance of neurological recovery decreases.