Rheumatoid Arthritis: Masaki Y

Umehara H, Sawaki T, Kawanami T, Masaki Y, Fukushima T. · Division of Hematology and Immunology, Kanazawa Medical University. · Nippon Rinsho. · Pubmed #19280925 No free full text.

Abstract: Sjögren's syndrome (SS) is chronic autoimmune disease characterized by destructive lymphocyte infiltration of salivary and lacrimal glands, which results in dry eyes and dry mouth. Despite extensive study of the underlying cause of SS, the pathogenesis remains obscure. The Sjögren's International Collaborative Clinical Alliance (SICCA) by five Research Groups located in Argentina, China, Denmark, the United States and Japan, is the first registry and clinical data-specimen repository to establish the International Standard Criteria for diagnosing SS. Patients with SS have a relative increased risk for development of B cell lymphoma compared with other autoimmune rheumatic diseases. We discuss the possible mechanisms for lymphoma development. The topics concerning SS is IgG4-related lymphoproliferative diseases, such as Mikulicz's disease and autoimmune pancreatitis. Based on the analysis of patients registered from all over Japan, we propose a new clinical entity IgG4-positive multi-organ lymphoproliferative syndrome (IgG4+ MOLPS).

Dong L, Masaki Y, Takegami T, Jin ZX, Huang CR, Fukushima T, Sawaki T, Kawanami T, Saeki T, Kitagawa K, Sugai S, Okazaki T, Hirose Y, Umehara H. · Department of Hematology and Immunology, Kanazawa Medical University, Ishikawa, Japan. · Clin Exp Immunol. · Pubmed #17937678 links to  free full text

Abstract: The aim of this study was to clarify the nature of the clonal lymphocyte infiltration in Sjögren's syndrome (SS) patients associated with lymphoproliferative disorders. We examined B cell clonality in lymphoproliferative tissues from six primary SS patients associated with lymphoproliferative disorders or lymphoma by cloning and sequencing of the gene rearrangement of the immunoglobulin heavy chain complementarity determining region 3 (IgVH-CDR3). Three patients with sequential observation showed progressional clonal expansion with the presence of the same subclone in different tissues during the course of disease. Among them, one patient developed mucosa-associated lymphoid tissue (MALT) lymphoma in glandular parotid. The other three SS patients concomitant with malignant B cells lymphomas showed different clonal expansion of B cells between nodal sites and salivary glands. The cloanality analysis indicated that monoclonal B cell population could spread from one glandular site to another site during the course of SS, suggesting that the malignant clone may arise from the general abnormal microenvironment, not restricted to the glandular tissue, in some SS patients.

Umehara H, Tanaka M, Sawaki T, Jin ZX, Huang CR, Dong L, Kawanami T, Karasawa H, Masaki Y, Fukushima T, Hirose Y, Okazaki T. · Division of Hematology and Immunology, Department of Internal Medicine, Kanazawa Medical University, Daigaku, Uchinada-machi, Kahoku-gun, Ishikawa, 920-0293, Japan. · Mod Rheumatol. · Pubmed #16767549 No free full text.

Abstract: Leukocyte adhesion and trafficking at the endothelium requires both adhesion molecules and chemotactic factors. Fractalkine (CX3C) is a unique chemokine, and is expressed on tumor necrosis factor-alpha- and interleukin-1-activated endothelial cells (ECs). Fractalkine receptor, CX3CR1, is expressed on NK cells, monocytes, and some portion of CD4- and CD8-positive T cells. Interactions between fractalkine and CX3CR1 can mediate not only chemotaxis, but also cell adhesion in the absence of substrates for other adhesion molecules. Furthermore, fractalkine activates NK cells, leading to increased cytotoxicity and interferon-gamma production. Recently, accumulating evidence has shown that fractalkine is involved in the pathogenesis of rheumatoid arthritis and allied conditions. This review examines new concepts underlying fractalkine-mediated leukocyte migration and tissue damage, focusing primarily on the pathophysiological roles of fractalkine in rheumatic diseases.

Sugai S, Masaki Y, Dong L. · Kanazawa Medical University. · Autoimmun Rev. · Pubmed #15309805 No free full text.

This publication has no abstract.

Masaki Y, Sugai S. · Kanazawa Medical University, Hematology and Immunology, Internal Medicine, 1-1 Daigaku, Uchinada, Hohoku-gum, Ishikawa, Japan. · Autoimmun Rev. · Pubmed #15110228 No free full text.

Abstract: Sjögren's syndrome (SS) is a chronic organ-specific autoimmune disease characterized by lymphocytic infiltration into the salivary and lacrimal glands. About half of primary SS patients develop systemic disorders. Primary SS can be divided into three stages according to the extent of organ damage and the course of the disease. In stage I, (approx. 45% of cases), patients have only sicca syndrome and do not experience any systemic involvement, even after 10 years. In stage II (approx. 50% of cases), patients experience lymphocytic organ damage, which may involve the pulmonary, renal, hepatic, hematologic, and/or dermatologic systems, among others. Finally, in stage III (approx. 5% of cases), patients develop malignant lymphomas. Lymphomas in salivary glands are thought to arise from lymphoepithelial lesions in which there are close interactions among epithelial cells, T cells, and B cells. The B cells in the lesions become activated through the interaction between CD40L and CD40. The progression from polyclonal lymphoproliferation to monoclonal lymphoproliferation, to mucosa-associated lymphoid tissue (MALT) lymphoma, and finally to high-grade malignant lymphoma is regarded as a multi-step process. Antigenic activation of B cells, together with oncogenic events, including p53 inactivation and bcl-2 activation, may play important roles in B cell monoclonal proliferation and malignant transformation. The rheumatoid factor clone is regarded as a candidate B cell clone that undergoes transformation.

Shimoyama K, Ogawa N, Sakai T, Sawaki T, Kawanami T, Karasawa H, Masaki Y, Tanaka M, Fukushima T, Hirose Y, Umehara H. · The third Department of Internal Medicine, Hamamatsu University School of Medicine. · Nihon Rinsho Meneki Gakkai Kaishi. · Pubmed #17984582 links to  free full text

Abstract: OBJECTIVE: To examine clinical significance of anti-cyclic citrullinated peptide antibody (anti-CCP antibody) in RA. METHODS: Hundred fifteen patients with polyarthralgia (89 females, 26 males) were recruited, and subjected for the study. We studied anti-CCP antibody, ESR, CRP, IgM-RF, IgG-RF, RAPA, MMP-3, CARF, C1q-IC, Stage, Class, Joint score, Sharp score, KL-6, SP-D, chest CT. RESULTS: Anti-CCP antibody test had high specificity (93.5%). In RA with positive anti-CCP antibody, Sharp score (10.9+/-22.4) was higher than those with negative anti-CCP (1.7+/-1.8), and may serve as a prognostic marker of joint destruction (P<0.05). Anti-CCP antibody in RA with interstitial pneumonia is higher (84.5+/-36.4 U/mL) than those without interstitial pneumonia (52.6+/-44.7 U/mL) (P<0.05). CONCLUSION: Anti-CCP antibody is useful for diagnosis of RA, and could be a specific marker of joint destruction. Further investigation is necessary to clarify the relation of anti-CCP antibody with organ involvement and activity of RA.

Dong L, Masaki Y, Takegami T, Kawanami T, Itoh K, Jin ZX, Huang CR, Tong XP, Fukushima T, Tanaka M, Sawaki T, Sakai T, Sugai S, Okazaki T, Hirose Y, Umehara H. · Department of Hematology and Immunology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan. · Int Immunol. · Pubmed #17272286 links to  free full text

Abstract: Serum titers of antibody to Epstein-Barr virus (EBV) viral capsid antigen (VCA) have been positively correlated with malignancies of lymphoid proliferation, such as Burkitt's lymphoma and Hodgkin's lymphoma. We have constructed a phage display combinatorial antibody Fab library from a patient with marginal zone B cell lymphoma associated with Sjögren's syndrome and carrying high serum anti-EBV-VCA IgG titer. Fab fragments were selected by panning against EBV-VCA protein coated onto ELISA plates, and selected Fab clones were characterized by ELISA, western blotting (WB), indirect immunofluorescence assay and immunohistochemistry. We have established two Fab clones, Fab-aVCA1 and Fab-aVCA21, which specifically recognize EBV-VCA by ELISA and WB. Inhibition ELISA competition showed that both clones could significantly reduce the binding of specific anti-EBV-VCA mAb to its relevant proteins. Furthermore, these two Fab clones could localize VCA protein in the EBV-positive P3HR1 and Daudi cell lines, as well as in tissue samples from patients with EBV-infected lymphoid malignancies. These results indicate that our two Fab clones are novel human mAbs specific for EBV-VCA protein and may have potential benefits for development of novel diagnostic and therapeutic approaches in EBV-related lymphoid malignancies.

Ebata K, Masaki Y, Karasawa H, Okada J, Kim CG, Tsuka M, Ogawa N, Wano Y, Hirose Y, Sugai S. · Department of Hematology and Immunology, Kanazawa Medical University. · Nihon Rinsho Meneki Gakkai Kaishi. · Pubmed #16578967 No free full text.

Abstract: A 64-year-old female was admitted in May 1997, because of salivary gland swelling. Histology of the right parotid gland revealed malignant lymphoma, diffuse medium-sized B-cell type, and she was treated with local radiotherapy and chemotherapy. She was rehospitalized in April 1998, because of recurrence of lymphoma in the stomach and the sigmoid colon. She had splenomegaly and lymphadenopathy (neck and inguinal). Laboratory findings revealed marked elevation of rheumatoid factor and RNA of hepatitis C virus. A diagnosis of Sjogren's syndrome was made by dryness and the histological findings of labial biopsy. Marginal zone B-cell lymphoma mainly consisted of centrocyte-like cells and lymphoepithelial lesions, and CD 20 and IgM-kappa were positive with immunohistochemical staining. Lymphoma involved the gut and spleen. We discuss the correlation of malignant lymphoma with Sjogren's syndrome and HCV infection.

Ogawa N, Shimoyama K, Karasawa H, Fukushima T, Masaki Y, Wano Y, Hirose Y, Sugai S. · Division of Hematology & Immunology, Department of Internal Medicine, Kanazawa Medical University. · Nihon Rinsho Meneki Gakkai Kaishi. · Pubmed #15559322 links to  free full text

Abstract: To evaluate the efficacy and safety of cevimeline hydrochloride for the treatment of dry mouth in patients with Sjögren's syndrome (SS), eight SS patients received 30 mg of cevimeline twice or three times daily for 24 weeks. Six out of the eight patients had improvement in dry mouth. Five patients had more than 20% increase in saliva secretion. In the assessment of salivary gland scintigraphy, three patients showed improvement. There was a significant negative correlation between the improvement of saliva secretion and the severity of tissue damage assessed by MR sialography (r= - 0.754, p<0.05). One patient stopped cevimeline at 4 weeks because of headache and nausea. There was no significant change in laboratory data. Cevimeline is safe and effective medicine for dry mouth in patients with SS, in particular, with less severe salivary gland destruction.

Sakamoto A, Kitagawa K, Fujisawa A, Sugai S, Masaki Y. · Department of Ophthalmology, Kanazawa Medical University, 1-1 Daigaku, Uchinada-machi, Kahoku-gun, Ishikawa 920-0293, Japan. · Nippon Ganka Gakkai Zasshi. · Pubmed #12755067 No free full text.

Abstract: BACKGROUND: Primary biliary cirrhosis(PBC) is occasionally associated with Sjögren syndrome and results in liver cirrhosis. It occurs particularly in women, middle-aged or older, and is characterized by the presence of anti-mitochondrial antibody (AMA). We diagnosed PBC in 2 patients with severe keratoconjunctivitis sicca (KCS). CASE 1: A 45-year-old woman was diagnosed with PBC. A test for the presence of AMA was positive and liver dysfunction was detected. Tests for the presence of anti-SSA antibody and anti-SSB antibody were also positive. Signs of severe sicca syndrome observed in the oral cavity and in the eyes were compatible with signs of Sjögren syndrome. Furthermore, superior limbic keratoconjunctivitis was also observed. CASE 2: A 57-year-old woman was diagnosed with PBC and Sjögren syndrome. She also had thyroiditis and severe KCS. Tests for the presence of AMA, anti-SSA antibody, and anti-SSB antibody were positive. In both cases, eye drops were not effective as a treatment for the KCS, but lacrimal punctal occlusion with cauterization was effective. CONCLUSION: PBC should be looked on as a disease that may possibly promote severe KCS.

Ogawa N, Shimoyama K, Kawabata H, Masaki Y, Wano Y, Sugai S. · Division of Hematology and Immunology, Department of Internal Medicine, Kanazawa Medical University, Kahokugun, Ishikawa. · Ryumachi. · Pubmed #12692986 No free full text.

Abstract: OBJECTIVE: To elucidate the clinical significance of serum KL-6 and SP-D for the diagnosis and treatment of interstitial lung disease in connective tissue disorders. METHODS: 139 patients with various connective tissue disorders were subjected for the study, which included 46 cases of rheumatoid arthritis, 43 cases of Sjögren's syndrome, 16 cases of SLE, 10 cases of systemic sclerosis, 9 cases of polymyositis/dermatomyositis, 6 cases of vasculitis syndrome, 5 cases of Behçet's disease and 4 cases of MCTD. Serum levels of KL-6 and SP-D were determined by enzyme-immunoassay. The sensitivity, specificity and accuracy of serum KL-6 and SP-D for the diagnosis of interstitial lung disease were compared with serum LDH. The relationship of serum KL-6 and SP-D levels with high resolution CT (HRCT) of the lung and Gallium scintigraphy findings was analyzed. In some cases, serum levels of the two markers were determined monthly in the course of the disease. RESULTS: When the serum levels of KL-6 and SP-D were measured simultaneously, the sensitivity to diagnose interstitial lung disease was 67.7%, the specificity was 98.1%, and the accuracy was 91.4%, while those of serum LDH were 45.2%, 88.9%, 79.1% respectively. In the patients with interstitial lung disease, those who had elevated serum levels of both KL-6 and SP-D showed parenchymal collapse opacity-dominant pattern in HRCT. On the other hand, the patients with interstitial lung disease who had normal levels of serum KL-6 and SP-D or had elevation either in KL-6 or SP-D levels showed ground glass opacity-dominant pattern in HRCT. There was no significant correlation between serum marker levels and Gallium scintigraphy findings. When serum KL-6 and SP-D were measured monthly, the levels of both markers changed more specifically and sensitively to the lung disease activity compared with serum LDH. CONCLUSIONS: Serum KL-6 and SP-D are more specific and useful markers for the diagnosis and evaluation of interstitial lung disease compared with serum LDH in connective tissue disorders.

Sugai S, Masaki Y. · No affiliation provided · Nippon Naika Gakkai Zasshi. · Pubmed #12373887 No free full text.

This publication has no abstract.

Hirose Y, Masaki Y, Okada J, Kim CG, Kawabata H, Ogawa N, Wano Y, Sugai S. · Department of Internal Medicine, Kanazawa Medical University, Ishikawa, Japan. · Int J Hematol. · Pubmed #12041674 No free full text.

Abstract: A Japanese male patient received various medications for his long-standing rheumatoid arthritis (stage IV, class II). He developed a mass on the right anterior chest wall after being treated with methotrexate (MTX) for 4 months. A biopsy of the mass showed it to be Epstein Barr virus (EBV)-associated lymphoma of B-cell phenotype stage IE (bulky mass), with positive EBV-encoded small RNAs (EBERs) in situ hybridization, EBV latent membrane protein-1 (LMP-1) negative, EB nuclear antigen-2 (ERNA-2) negative, CD20/L26 (+), CD45RO/UCHL-1 (-). A single band of the joined termini of the EBV genome was demonstrated in DNA extracted from the mass, suggesting a clonal disorder of the mass. Immunostaining of the mass with p53 antibody was also positive. With discontinuation of MTX and administration of chemotherapy, the tumor disappeared but recurred after 3 months. This case suggests that concordant p53 expression and latent EBV infection may play an important role in the pathogenesis of lymphomas arising in patients with rheumatoid arthritis who are immunosuppressed with MTX.

Fukumura A, Ogawa N, Simoyama K, Karasawa H, Okada J, Kim CG, Kawabata H, Masaki Y, Wano Y, Sugai S. · Division of Hematology and Immunology, Department of Internal Medicine, Kanazawa Medical University, Kahokugun, Ishikawa. · Ryumachi. · Pubmed #11296454 No free full text.

Abstract: We report a case of 55 year-old woman with six year history of Sjögren's syndrome developed fatal rapidly progressive interstitial pneumonia. She had been well until February 1999. She developed swelling and erythematous lesions in the cheek and hands in spring 1999. She was admitted to our hospital for investigations of skin lesions in May 1999. Physical examination on admission revealed small hemorrhagic lesions in the nailfold. Serum CK level was slightly elevated. Electromyogram and MRI suggested mild myositis in the proximal upper extremities. She was suspected to have dermatomyositis along with Sjögren's syndrome. Prednisolone 10 mg/day had been given for her skin problems since March 1999. Suddenly, dyspnea on exertion was appeared on 34th day of admission. Chest X-ray film showed an acute worsening of interstitial pneumonia. Methylprednisolone pulse therapy (1000 mg for 3 days) and cyclophosphamide pulse therapy (500 mg for a day) were started, and she was subsequently treated with 60 mg/day of prednisolone and 250 mg/day of Cyclosporin A. However, interstitial pneumonia did not respond to the treatment, and pneumomediastinum and pneumothorax have developed. She died of respiratory failure on 55th day. We consider that most likely explanation for fatal interstitial pneumonia is concomitantly occurred dermatomyositis.

Cui G, Sugai S, Ogawa Y, Takeshita S, Masaki Y. · Division of Hematology & Immunology, Department of Internal Medicine, Kanazawa Medical University. · Nihon Rinsho Meneki Gakkai Kaishi. · Pubmed #11126657 No free full text.

Abstract: OBJECTIVE: The most important diagnostic criterion in Sjögren's syndrome (SS) is considered to be the histologic focus score of the labial salivary glands. The focus score is defined as the number of lymphocytic foci per 4 mm2 of the salivary gland according to the criterion of Chisholm & Mason. On the other hand, in the criteria of the Sjögren's Disease Research Committee of the Ministry of Health and Welfare in Japan it is defined as the number of lymphocytic foci per a lobule of the salivary gland. By setting the limited criteria for SS on the basis of objective signs of both dry eyes and dry mouth, we compared the usefulness of these two diagnostic criteria for the diagnosis of SS in terms of the sensitivity, the specificity and laboratory data. METHODS: The biopsy of labial salivary glands was performed in 245 patients (230 females and 15 males, with a mean age of 54.9 years) who were suspected of SS in our hospital during the time between 1975 and 1996. Labial salivary glands were histologically assessed and the focus score was calculated according to the criterion of Chisholm & Mason and to that of the Sjögren's Disease Research Committee, respectively. RESULTS: The average area per a lobule of the salivary gland was 0.70 mm2. According to the limited criteria for SS, the Japanese histologic diagnostic criteria showed a higher specificity (93.3%) and a lower sensitivity (23.5%). The sensitivity of the criterion of Chisholm & Mason was 72.1%, and the specificity was 80.0%. The margin of the lobule was sometimes difficult to be identified because of the fatty change and fibrosis in some salivary glands. CONCLUSIONS: By comparing the two different histologic criteria using our limited criteria, it was better to use the histologic criterion of Chisholm & Mason as a criterion for the diagnosis of SS than that of the Sjogren's Disease Research Committee of the Ministry of Health and Welfare in Japan in terms of the sensitivity, the specificity and laboratory data.

Ditzel HJ, Masaki Y, Nielsen H, Farnaes L, Burton DR. · Departments of Immunology and Molecular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA. · Proc Natl Acad Sci U S A. · Pubmed #10922075 links to  free full text

Abstract: An increasing number of studies suggest the importance of antibodies in the pathogenesis of most systemic and organ-specific autoimmune diseases, although there is considerable controversy over the precise role of the autoantibodies involved. In humans, a major obstacle to progress is the identification and cloning of the relevant autoantibodies and autoantigens. Here, an approach based on the sequential use of antibody phage display and antigen expression libraries is developed and applied to a donor suffering from rheumatoid arthritis (RA), splenomegaly, and peripheral destruction of neutrophils leading to neutropenia (Felty's syndrome). An antibody phage display library was constructed from bone marrow from the donor and a high-affinity human mAb, ANA15, selected by panning against fresh neutrophils and independently by panning against a fixed cell line. The antibody showed strong staining of neutrophils and a number of cell lines. Probing of a lambdagt11 expression library from an induced myelomonocytic cell line with the mAb ANA15 identified the eukaryotic elongation factor 1A-1 (eEF1A-1) as a novel autoantigen. The specificity of ANA15 was confirmed by reactivity with both purified and recombinant eEF1A-1. Screening of a large panel of sera revealed that 66% of patients with Felty's syndrome had elevated levels of anti-eEF1A-1 antibodies. The cloning of this antibody-antigen pair should permit rational evaluation of any pathogenicity resulting from the interaction and its significance in neutropenia.

Hirose Y, Sugai S, Masaki Y, Ogawa Y, Takeshita S, Kin C, Ogawa N. · Department of Internal Medicine, Kanazawa Medical University, Ishikawa, Japan. · Int J Hematol. · Pubmed #10222656 No free full text.

Abstract: The association of Epstein-Barr virus (EBV) with Sjögren's syndrome (SS) is controversial. Reports suggest there is an increased risk of developing lymphoid malignancy in SS. Among our 425 cases of SS, 17 cases of malignant lymphoma (4%), 16 cases of non-Hodgkin's lymphoma (NHL), and 1 case of Hodgkin's disease were found. We looked for an association between EBV and 14 cases of NHL, 13 cases of B-cell lymphoma, and 1 case of T-cell lymphoma in which tissue specimens were available. Epstein-Barr virus-encoded RNA in situ hybridization study and polymerase chain reaction (PCR) study using primers to detect the Bam HI W fragment of EBV with DNA extracts were positive in 2 NHLs: 1 diffuse, large B-cell-type lymphoma, 1 out of 13 cases (8%) of B-cell lymphoma, and 1 angioimmunoblastic T-cell lymphoma with dysproteinemia. In the Bam HI W PCR study of DNA obtained from the labial small salivary glands of 55 cases with SS, 3 cases (5%) were positive. These 3 cases were not associated with malignant lymphoma. Our study revealed that EBV association in SS did not lead to an increased occurrence.