A multicenter phase II prospective clinical trial of glucocorticoid for patients with untreated IgG4-related disease.

OBJECTIVE: Although glucocorticoids are effective for patients with IgG4-related disease, the treatment has not yet been standardized. Therefore, the treatment strategy should be established. PATIENTS AND METHODS: Patients who fulfilled the comprehensive diagnostic criteria for definite IgG4-related disease were started on prednisolone (0.6 mg/kg body weight) with the dose reduced every two weeks. The subsequent maintenance dose and need for prednisolone were determined for individual patients. The primary endpoint was the complete remission (CR) rate at one year. Secondary endpoints included overall response rate (ORR), the maintenance dose, the relapse rate, and adverse events. RESULTS: This study enrolled 61 patients. After clinicopathological review, three patients were excluded, and one, 13, and 44 patients were diagnosed with probable, possible, and definite IgG4-related disease, respectively. Of the 44 patients with definite IgG4-RD, 29 (65.9%) achieved CR, and the ORR was 93.2%. No patient was refractory to primary treatment. The most frequent adverse events were glucose intolerance. Six patients relapsed. CONCLUSIONS: Glucocorticoid treatment is usually effective for patients with IgG4-RD, and we should examine the possibility of other disorders when a patient is glucocorticoid refractory. Some patients are misdiagnosed, making central clinicopathological review of diagnosis very important in conducting clinical studies.

Clinicopathological characteristics of patients with IgG4-related tubulointerstitial nephritis.

IgG4-related disease is a recently recognized multi-organ disorder characterized by high levels of serum IgG4 and dense infiltration of IgG4-positive cells into several organs. Although the pancreas was the first organ recognized to be affected by IgG4-related disorder in the syndrome of autoimmune pancreatitis, we present here clinico-pathological features of 23 patients diagnosed as having renal parenchymal lesions. These injuries were associated with a high level of serum IgG4 and abundant IgG4-positive plasma cell infiltration into the renal interstitium with fibrosis. In all patients, tubulointerstitial nephritis was the major finding. Although 14 of the 23 patients did not have any pancreatic lesions, their clinicopathological features were quite uniform and similar to those shown in autoimmune pancreatitis. These included predominance in middle-aged to elderly men, frequent association with IgG4-related conditions in other organs, high levels of serum IgG and IgG4, a high frequency of hypocomplementemia, a high serum IgE level, a patchy and diffuse lesion distribution, a swirling fibrosis in the renal pathology, and a good response to corticosteroids. Thus, we suggest that renal parenchymal lesions actually develop in association with IgG4-related disease, for which we propose the term 'IgG4-related tubulointerstitial nephritis.'

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.

Clinical and pathological characteristics of Mikulicz's disease (IgG4-related plasmacytic exocrinopathy).

Mikulicz's disease (MD) has been considered part of primary Sjogren's syndrome (SS) since Morgan's report in 1953. MD represents a unique condition involving enlargement of the lacrimal and salivary glands, as is also seen in SS; however, MD is characterized by few autoimmune reaction and its good responsiveness to glucocorticoid. Recent reports have shown that the frequency of apoptosis in glands of MD patients is lower when compared with SS. This phenomenon reflects the histologically reversible gland secretion in MD. Elevated IgG4 concentrations in the serum and prominent infiltration by plasmacytes expressing IgG4 in the lacrimal and salivary glands have also been confirmed in MD. Plasma cells expressing IgG4 are also detected in lymph nodes and bone marrow. MD may be a systemic disease, rather than a lacrimal and salivary gland disease. We here propose the new entity "IgG4-related plasmacytic exocrinopathy" and expect future development with regard to its relationship with autoimmune pancreatitis, which similarly presents elevated serum IgG4 levels.

[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.

[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.

Lymphoproliferative disorders in Sjögren's syndrome.

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.

Epstein-Barr virus-associated anaplastic large cell variant of diffuse large B-cell-type non-Hodgkin's lymphoma with concurrent p53 protein expression.

In the new World Health Organization (WHO) classification of malignant lymphoma, anaplastic large cell lymphoma of B-cell phenotype is classified either as the anaplastic large cell variant of diffuse large B-cell lymphoma or as Hodgkin's lymphoma. A 71-year-old Japanese man developed fever and generalized lymphadenopathy. Biopsy of the right axillary node revealed morphology of malignant lymphoma in which large cells with abundant cytoplasm and pleomorphic nuclei were scattered among small lymphocytes. Immunostaining with various monoclonal antibodies revealed the large cells to be CD79+, CD20/L26+, CD45RO/UCHL-(1-), CD3-, CD10-, CD30+, NPM/ALK-, EMA-, CD15-, and bcl-(2-). Amplification of the J region of the immunoglobulin heavy chain by polymerase chain reaction revealed a single rearranged band. Therefore the diagnosis of anaplastic large cell variant of diffuse large B-cell lymphoma, stage IIIB, was made from the standpoint of the new WHO classification of malignant lymphoma. Biopsy led to findings of Epstein-Barr virus (EBV)-associated lymphoma with positive in situ hybridization results for EBV small RNAs, positive results of immunostaining with EBV latent membrane 1 antibody, and negative results of immunostaining with Epstein-Barr nuclear antigen 2. Results of immunostaining of the mass with p53 antibody also were positive for lymphoma cells. The findings in this case may suggest a close relationship between p53 expression and latent EBV infection.

Epstein-Barr virus-associated B-cell type non-Hodgkin's lymphoma with concurrent p53 protein expression in a rheumatoid arthritis patient treated with methotrexate.

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.

Durable response but prolonged cytopenia after cladribine treatment in relapsed patients with indolent non-Hodgkin's lymphomas: results of a Japanese phase II study.

We conducted a phase II study to evaluate the efficacy and safety of cladribine (2-chlorodeoxyadenosine [2-CdA]) for patients with refractory or relapsed indolent B-cell lymphoma or mycosis fungoides. Forty-five patients were enrolled, and 43 patients, including 34 with follicular lymphoma, were eligible. 2-CdA was given by continuous intravenous infusion at a dose of 0.09 mg/kg daily for 7 consecutive days, and this schedule was repeated every 4 weeks up to a maximum of 6 cycles. The overall and complete response rates were 58.1% (25/43; 90% confidence interval, 44.5%-70.9%) and 14.0% (6/43), respectively. The disease progression-free proportions of all 43 eligible and all 25 responding patients at 2 years were 30.3% and 48.1%, respectively. Neutropenia and thrombocytopenia of grade 3 or 4 were observed in 53.3% and 37.8% of patients, respectively, with prolonged cytopenia observed in patients with increased numbers of treatment cycles. Nonhematologic toxicities of grade 3 or greater included diarrhea, arrhythmia, malaise, and gastrointestinal bleeding in 1 patient each, an increase in glutamic-pyruvic transaminase level in 2 patients, and infection in 5 patients. Two treatment-related deaths were observed. Four patients developed myelodysplastic syndrome (MDS) at 13 months to 2 years after completion of the 2-CdA treatments. 2-CdA is an active agent with acceptable toxicity for refractory or relapsed indolent lymphoma; however, prolonged myelosuppression and the potential development of MDS should be carefully monitored.

CT and MR findings of bilateral lacrimal gland enlargement in Sjögren syndrome.

Two women with primary Sjögren syndrome underwent computed tomography (CT) and magnetic resonance (MR) imaging because of bilateral lacrimal gland enlargement. Histopathologic confirmation was obtained in both patients. Of the four lacrimal glands, one had lymphoepithelial disease, two had pseudolymphoma and one had mucosa-associated lymphoid tissue (MALT) lymphoma, respectively. From the imaging findings, however, it was not possible to differentiate benign lymphoproliferative disorders and malignant lymphoma.

[Two cases of primary biliary cirrhosis accompanied with severe keratoconjunctivitis sicca due to Sjögren syndrome].

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.

['Reverse' variant of follicular lymphoma with monoclonality of the immunoglobulin heavy chain and T cell receptor gamma chain genes].

We report an unusual case of the 'reverse' variant of follicular lymphoma in which the nodules had central parts that stained dark and cuffs that stained pale. Because diagnosis was difficult relying only on formalin-fixed histopathology, we examined the cell surface markers and karyotype. The patient, a 65-year-old man, presented with multiple lymphadenopathy, low-grade fever, night sweats, anorexia, dry cough and sense of chest oppression. Cell surface marker analysis showed that pathologic lymphocytes were positive for CD 10, CD 19, CD 20, HLA-DR, IgM/IgD and kappa, and t (14; 18) (q 32; q 21) was detected by karyotypic analysis. The 'reverse' variant of follicular lymphoma, clinical stage IVB was diagnosed the rearrangement band was detected with PCR-based clonality analysis in not only the immunoglobulin heavy chain gene but also the T cell receptor gamma chain gene, thus confirming monoclonal proliferation of both B cells and T cells.

[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.

p38 mitogen-activated protein kinase and nuclear factor-κB facilitate CD40-mediated salivary epithelial cell death.

OBJECTIVE: Our previous studies indicated that CD40-mediated Fas-dependent apoptosis is important for the glandular destruction of Sjögren's syndrome (SS), although other immune and nonimmune mechanisms are also involved in exocrine dysfunction. We investigated the roles of p38 mitogen-activated protein kinase (p38MAPK) and nuclear factor-κB (NF-κB) in salivary epithelial cell death in SS. METHODS: Expression of p38, phosphorylated p38 (pp38), and IκB-α was examined by Western blotting upon CD40 ligation. Activity of NF-κB induced by anti-CD40 monoclonal antibody (mAb) was examined by electrophoretic mobility shift assay (EMSA) and Western blotting. Expression of Fas was analyzed by flow cytometry and Western blotting with or without the p38-specific inhibitor SB203580 or the NF-κB-specific inhibitor caffeic acid phenethyl ester (CAPE). Induction of apoptosis in salivary epithelial cells was examined by DNA fragmentation and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay. Expression of phosphorylated p38MAPK and NF-κB was measured by immunohistochemistry. RESULTS: pp38MAPK and NF-κB p65 were predominantly expressed in the ductal and acinar epithelium adjacent to lymphoid infiltrates of SS salivary gland by immunohistochemistry. CD40 ligation strongly enhanced p38MAPK and NF-κB activity by EMSA and Western blotting in cultured salivary epithelial cells. Treatment of cells with anti-CD40 mAb resulted in significantly upregulated Fas expression and induction of Fas-dependent apoptosis. Inhibition of p38MAPK and NF-κB activity by SB203580 and/or CAPE reduced Fas expression and apoptosis in salivary epithelial cells, establishing p38MAPK and NF-κB as proapoptotic factors in this context. CONCLUSION: CD40 ligation plays an important role in activation of p38MAPK, NF-κB, and Fas molecules to initiate proapoptotic signaling. p38MAPK and NF-κB collaborate in regulation of proapoptotic signaling in CD40-mediated Fas-dependent apoptosis in salivary epithelial cells.

Primary Sjögren's syndrome as a systemic disease: a study of participants enrolled in an international Sjögren's syndrome registry.

OBJECTIVE: To study the prevalence of extraglandular manifestations in primary Sjögren's syndrome (SS) among participants enrolled in the Sjögren's International Collaborative Clinical Alliance (SICCA) Registry. METHODS: A total of 1,927 participants in the SICCA registry were studied, including 886 participants who met the 2002 American-European Consensus Group (AECG) criteria for primary SS, 830 "intermediate" cases who had some objective findings of primary SS but did not meet AECG criteria, and 211 control individuals. We studied the prevalence of immunologic and hematologic laboratory abnormalities, specific rheumatologic examination findings, and physician-confirmed thyroid, liver, and kidney disease, as well as lymphoma among SICCA participants. RESULTS: Laboratory abnormalities, including hematologic abnormalities, hypergammaglobulinemia, and hypocomplementemia, frequently occurred among primary SS cases and were more common among the intermediate cases than among control participants. Cutaneous vasculitis and lymphadenopathy were also more common among primary SS cases. In contrast, the frequency of physician-confirmed diagnoses of thyroid, liver, and kidney disease and lymphoma was low and only primary biliary cirrhosis was associated with primary SS case status. Rheumatologic and neurologic symptoms were common among all SICCA participants, regardless of case status. CONCLUSION: Data from the international SICCA registry support the systemic nature of primary SS, manifested primarily in terms of specific immunologic and hematologic abnormalities. The occurrence of other systemic disorders among this cohort is relatively uncommon. Previously reported associations may be more specific to select patient subgroups, such as those referred for evaluation of certain neurologic, rheumatologic, or other systemic manifestations.

Cutoff Values of Serum IgG4 and Histopathological IgG4+ Plasma Cells for Diagnosis of Patients with IgG4-Related Disease.

IgG4-related disease is a new disease classification established in Japan in the 21st century. Patients with IgG4-related disease display hyper-IgG4-gammaglobulinemia, massive infiltration of IgG4+ plasma cells into tissue, and good response to glucocorticoids. Since IgG4 overexpression is also observed in other disorders, it is necessary to diagnose IgG4-related disease carefully and correctly. We therefore sought to determine cutoff values for serum IgG4 and IgG4/IgG and for IgG4+/IgG+ plasma cells in tissue diagnostic of IgG4-related disease. Patients and Methods. We retrospectively analyzed serum IgG4 concentrations and IgG4/IgG ratio and IgG4+/IgG+ plasma cell ratio in tissues of 132 patients with IgG4-related disease and 48 patients with other disorders. Result. Serum IgG4 >135 mg/dl demonstrated a sensitivity of 97.0% and a specificity of 79.6% in diagnosing IgG4-related disease, and serum IgG4/IgG ratios >8% had a sensitivity and specificity of 95.5% and 87.5%, respectively. IgG4+cell/IgG+ cell ratio in tissues >40% had a sensitivity and specificity of 94.4% and 85.7%, respectively. However, the number of IgG4+ cells was reduced in severely fibrotic parts of tissues. Conclusion. Although a recent unanimous consensus of all relevant researchers in Japan recently established the diagnostic criteria for IgG4-related disease, findings such as ours indicate that further discussion is needed.