Impact of biological treatment on left ventricular dysfunction determined by global circumferential, longitudinal and radial strain values using cardiac magnetic resonance imaging in patients with rheumatoid arthritis.

AIM: To evaluate left ventricular (LV) dysfunction in patients with rheumatoid arthritis (RA) and to determine the impact of biological treatment on LV function in these patients using global circumferential strain (GCS), global longitudinal strain (GLS) and global radial strain (GRS) values assessed by feature tracking cardiac magnetic resonance (FT-CMR) imaging. METHODS: Eighty patients with RA and 20 controls without cardiovascular disease underwent non-contrast CMR imaging. Patients with RA received conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or biologic DMARDs (bDMARDs). Global strains were calculated in 16 LV segments. RESULTS: No significant differences in cardiovascular risk factors were found between the RA group and controls. GCS was 21% lower in the RA group compared with controls (P < 0.001) and was 14% lower in the csDMARDs group compared with the bDMARDs group (P = 0.002), whereas, there was no significant difference in GLS and GRS between the RA group and the controls. In regard to strain rates, diastolic GCS and GRS rates were significantly lower in the RA group (P < 0.001, 0.011, respectively). In univariate analyses, GCS was significantly associated with the Simplified Disease Activity Index, bDMARDs, swollen joint count, anti-cyclic citrullinated peptides antibodies and matrix metalloproteinase-3, but in multivariable analysis, only bDMARDs was significantly associated with GCS (P = 0.021). CONCLUSION: Global circumferential strain, GLS and GRS assessed by FT-CMR can reveal subclinical LV dysfunction in patients with RA. Furthermore, they can be used to determine the normalization of LV regional dysfunction induced by bDMARDs possibly related to disease activity reduction.

Efficacy and safety of minodronic acid hydrate in patients with steroid-induced osteoporosis.

OBJECTIVES: Minodronic acid hydrate, an oral bisphosphonate, has a greater inhibitory effect on bone resorption than do other approved drugs; however, this has been studied only in patients with primary osteoporosis. Here, we administered minodronic acid hydrate to patients with steroid-induced osteoporosis who have been treated with steroids for rheumatoid arthritis or other collagen diseases, and the efficacy and safety of minodronic acid hydrate were prospectively investigated. METHODS: Twenty-five patients treated in our rheumatology clinic received minodronic acid hydrate 1 mg/day. The changes in bone mineral density (BMD) and bone turnover markers were investigated at 3 and 6 months, and adverse events, including the presence or absence of an incident osteoporotic fracture, were examined over a period of 6 months. RESULTS: Percent changes in BMD of the lumbar spine and femur significantly increased. The values of bone turnover markers significantly decreased. There were no patients with a radiographically apparent incident fracture. Adverse events included toothache for which the patient discontinued the treatment and three cases of gastrointestinal disorder that did not lead to discontinuation, and thus minodronic acid hydrate was well tolerated. CONCLUSIONS: Here, we show that minodronic acid hydrate is effectively and safely used for treatment of steroid-induced osteoporosis.

[Analysis of clinical significance of anti-cyclic citrullinated peptide antibody (anti-CCP antibody) in rheumatoid arthritis (RA)].

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.

Myelodysplastic syndrome complicated with inflammatory intestinal ulcers: significance of trisomy 8.

Three cases of myelodysplastic syndrome (MDS) complicated with inflammatory intestinal ulcers all had cytogenetic abnormalities with trisomy 8. The first two patients were diagnosed with intestinal Behçets disease and were successfully treated with salazosulphapiridine, and the third patient died after leukemic transformation. We review the reported cases of MDS complicated with Behçets disease. Most of these cases are Japanese, having intestinal involvement as well as cytogenetic abnormalities with trisomy 8. We discuss the significance of trisomy 8 in intestinal involvement in MDS.

Fractalkine in rheumatoid arthritis and allied conditions.

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.

A case of Mikulicz's disease complicated with interstitial nephritis successfully treated by high-dose corticosteroid.

A 40-year-old woman who had bilateral swelling in the eyelids and submandibular region was admitted. Clinical findings suggested she had primary Sjögren's syndrome. Laboratory data showed glucosuria, positive CRP (0.50 mg/dl), liver dysfunction (AST 53 U/l, ALT 101 U/l, gamma-GTP 241 U/l, ALP 914 U/l, LAP 496 U/l), hyperglycemia, hypergammaglobulinemia (IgG 3450 mg/dl, IgA 91 mg/dl, IgM 80 mg/dl), hypocomplementemia (C3 73 mg/dl, C4 2 mg/dl, CH50 < 19.0 U/ml), renal tubular dysfunction (urine N-acetyl-beta-D: -glucosaminidase 8.6 U/l, urine (beta2)-microglobulin 83 microg/l), and urinary concentration defect. Ammonium chloride loading test was normal. Gallium-67 scintigram indicated abnormal uptake in bilateral lacrimal glands, submandibular glands, and kidneys. A diagnosis of Mikulicz's disease and interstitial nephritis was made, since biopsy specimens of her lacrimal gland and minor salivary gland showed diffuse infiltration of lymphocytes. Renal biopsy specimens also showed severe interstitial infiltration of lymphocytes. Symptoms and laboratory data normalized in response to methylprednisolone pulse therapy and prednisolone 60 mg/day. This case of Mikulicz's disease complicated with interstitial nephritis was successfully treated by high-dose corticosteroid.

Urinary pseudouridine in patients with lymphoma: comparison with other clinical parameters.

BACKGROUND: Some patients with malignant lymphoma do not manifest superficial lymphadenopathy. In such cases, clinical parameters that indicate the number of tumor cells are important for the assessment of tumor growth and choice of proper treatment. We evaluated urinary pseudouridine (U-PU) as an indicator of the growth of malignant lymphoma by comparing its levels with serum concentrations of other clinical parameters in patients with various lymphomas at various stages. METHODS: Urine was obtained from 67 patients with lymphoma. U-PU was assayed by recombinant Fab-based inhibition ELISA. Serum soluble IL2 receptor (sIL2R), serum deoxythymidine kinase (dTK), serum beta-2 microglobulin (beta2MG) and serum lactate dehydrogenase (LDH) were also assayed. RESULTS: U-PU concentrations showed good correlations with serum concentrations of beta2MG, LDH, sIL2R and dTK. The level of U-PU was higher in stage IV than in stages I (P=0.023), II (P=0.006) and III (P=0.036). CONCLUSION: U-PU concentration correlates with the clinical stage of lymphoma and is a useful tool to assess the growth of lymphoma.

Association of Epstein-Barr virus with human immunodeficiency virus-negative peripheral T-cell lymphomas in Japan.

The association of Epstein-Barr virus (EBV) with human immunodeficiency virus-negative T-cell lymphoma was examined in 68 patients using the polymerase chain reaction (PCR) with DNA obtained from formalin-fixed paraffin-embedded tissues and an in situ hybridization technique. EBV-encoded RNA (EBER) was detected in 43 of 68 cases (63%) of peripheral T-cell lymphoma: in 100% (11 of 11 cases) of NK/T-cell lymphomas, 70% (14 of 20 cases) of angioimmunoblastic T-cell lymphomas (AILT) and 49% (18 of 37 cases) of other types of peripheral T-cell lymphoma. A positive band was also detected at high incidence (36 of 65 cases; 55%) in a PCR analysis using primers to detect the Bam HI-W fragment of EBV. In the immunohistochemical analysis using a monoclonal antibody to latent membrane protein 1 (LMP-1) of EBV, one of the EBV-encoded latent gene products, LMP-1, was found to be expressed in 13 of 64 cases (20%), but EBNA-2 was not expressed in all the cases examined (0 of 59 cases; 0%). The 5-yr survival rate was 28% for peripheral T-cell lymphomas overall, 0% for NK/T-cell lymphomas, 38% for AILTs and 28% for other types of peripheral T-cell lymphoma. The difference in the overall survival rate between NK/T-cell lymphoma and non-NK/T-cell lymphoma was significant (P = 0.0498 by Log-rank test). Among peripheral T-cell lymphoma patients overall, the group severely infected with EBV (EBER-ISH ++) had a lower 5-yr survival rate (8%) than the group slightly (EBER-ISH +) or not infected (38%; P = 0.0013).

[Successful treatment with etoposide by oral administration for recurrence of gastric diffuse large B-cell lymphoma after surgical resection--a case report].

A 64-year-old woman, who had been treated for gastric diffuse large B-cell lymphoma (DLBCL) by total gastrectomy and received 3 courses of CHOP therapy at 61 years of age, was diagnosed with recurrence of DLBCL in the small intestine. After the small intestinal tumor was resected, multiple metastases were found in the liver. Because intensive chemotherapy was difficult for her poor performance status, 50 mg of etoposide daily by oral was administered for 21 consecutive days. After one course of chemotherapy, liver metastases and lymph node swelling almost disappeared without severe adverse effects, and after five courses she achieved complete remission. Though DLBCL invaded the central nervous system, the abdominal regions had been free from recurrence for 12 months. This case report suggests that oral etoposide therapy is useful for gastrointestinal DLBCL which has metastasized to the liver.

Incidence of diffuse large B-cell lymphoma of germinal center B-cell origin in whole diffuse large B-cell lymphoma: tissue fluorescence in situ hybridization using t(14;18) compared with immunohistochemistry.

Diffuse large B-cell lymphoma (DLBCL) can be divided into prognostically important categories such as germinal center B (GCB)-like and non-GCB-like groups. The t(14;18)(q32;q21) translocation defines a unique subset of DLBCL cases with a GCB gene expression profile. Two-color fluorescence in situ hybridization (FISH) analysis was applied to detect t(14;18) (q32;q21) in the nuclei of paraffin-embedded tissue sections from 61 patients with de novo DLBCL. Nine (15%) of 61 cases had a positive pattern. Fifty-seven cases were subclassified in an immunohistochemical study with anti-CD10, anti-bcl-6, and anti-MUM1 antibodies. In this classification, 21 cases (37%) were placed in the GCB group, and 36 (63%) were placed in the non-GCB group. There was a discrepancy between t(14;18) occurrence and bcl-2 protein expression. Bcl-2 protein expression was positive in 40 (67%) of 60 cases. The expression of bcl-2 protein in the GCB and non-GCB groups was not significantly different: 15 (71%) of 21 cases in the GCB group and 24 (67%) of 36 cases in the non-GCB group tested positive. We found no difference between the FISH-positive and FISH-negative groups in overall survival time (P = .6019, log-rank test). The overall survival rates of GCB and non-GCB groups did not differ significantly by immunohistochemical classification (P = .5399, log-rank test). Overall survival was significantly longer in the group with a low International Prognostic Index (IPI) score than in the group with a high IPI score (P = .0002, log-rank test). Our results suggest that immunohistochemical study and cytogenetic study with t(14;18) FISH cannot predict the clinical outcomes of DLBCL patients. A study with a larger number of patients may show a difference in clinical outcomes between FISH-positive and FISH-negative groups and between GCB and non-GCB groups.

[Successful salvage therapy of continuous low-dose irinotecan for a patient with relapsed and refractory diffuse large B-cell lymphoma].

A 46-year-old man with relapsed and refractory diffuse large B-cell lymphoma after salvage therapy (EPOCH and ESHAP regimens) was treated with continuous low-dose CPT-11 (irinotecan hydrochloride) at 30 mg/day (20 mg/m2/day) for three consecutive days every week. The patient's general condition and both LDH and CRP, tumor related markers, improved dramatically. Complete remission was achieved after a 10-week cycle of therapy without severe adverse effects. Unfortunately, the lymphoma relapsed after allogeneic hematopoietic stem cell transplantation, low-dose CPT-11 therapy was used again to palliate tumor symptoms for 12 months. This therapy may be a useful salvage and palliative chemotherapy for relapsed and refractory lymphoma.

[Clinical significance of cevimeline hydrochloride in the treatment of dry mouth in patients with Sjögren's syndrome].

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.

Epstein-Barr virus-associated composite lymphoma composed of peripheral T-cell lymphoma and an anaplastic variant of a diffuse large B-cell type of non-Hodgkin's lymphoma and strongly expressing p53 protein.

We report a case of composite lymphoma consisting of peripheral T-cell lymphoma and an anaplastic variant of diffuse large B-cell lymphoma (DLBCL) and associated with Epstein-Barr virus (EBV) infection and strong p53 expression. A 65-year-old Japanese woman developed fever and generalized lymphadenopathy. A biopsy of the cervical node revealed the morphology of malignant lymphoma with 2 kinds of lymphoma coexisting in 1 lymph node. One lymphoma type consisted of immunoblastic large cells with the T-cell marker phenotype CD3+, CD45RO/UCHL-1+, CD20/L26-, CD79-, CD10-, CD30-, and CD15-; the other type consisted of large cells with abundant cytoplasm and pleomorphic nuclei with the marker phenotype CD79+, CD20/L26+, CD45RO/UCHL-1-, CD3-, CD10-, CD30+, NPM/ALK-, and CD15-. Therefore, the diagnosis was composite lymphoma of peripheral T-cell lymphoma and an anaplastic variant of DLBCL, stage IVB, because the patient had bone marrow involvement with peripheral T-cell lymphoma. The biopsy led to findings of latent type II EBV-associated lymphoma in both the peripheral T-cell lymphoma and the anaplastic variant of DLBCL as the result of positive signals for EBV small RNAs by in situ hybridization, positive immunostaining results for EBV latent membrane protein 1 antibody, and negative immunostaining results for EBV nuclear antigen 2. Immunostaining of the mass with p53 antibody also yielded positive results for both types of lymphoma cells. This case suggests that the immunocompromised state of this patient with EBV-related peripheral T-cell lymphoma allowed the emergence of an EBV-related anaplastic variant of DLBCL and suggests a close relationship between p53 expression and latent EBV infection.