Noriyoshi Ogawa

Primary Sjogren's syndrome in men.

OBJECTIVE--To describe the clinical expression of primary Sjögrens syndrome (SS) in men, focusing on extraglandular manifestations (EGM) and serological markers of disease. METHODS--In a cross sectional and comparative study, adult men with primary SS were identified from a cohort study on SS, and 26 age matched adult women with primary SS were selected as a control group. All patients met the European classification criteria for SS. They were compared for demographic, clinical and laboratory findings. RESULTS--Thirteen men with primary SS were identified. Mean age at onset was 39 (SEM 4) years and mean duration of disease was 7.8 (1) years. Sicca complex or parotitis was the presenting feature in eight patients (61.5%), and an EGM in five (38.5%). During the course of the disease, EGM were present in 12 patients (92%), polyarthralgias and lymphopenia being the most frequent (38.5% each). Rheumatoid factor was positive in 73% of patients, antinuclear antibodies in 85%, anti-(SS-A) in 62%, and anti-(SS-B) in 46%. No statistical differences in the frequency of EGM or in the presence of autoantibodies were observed between men and women. However, men patients were more likely to have EGM. CONCLUSION--Primary SS in men is an uncommon condition with clinical and serological characteristics similar to those observed in women. Sex hormones may be incriminated in the pathogenesis of SS. However, it remains poorly understood whether sex hormones play a major role in the severity of disease and have any importance with regard to treatment.

Activation of the Interferon Pathway in Peripheral Blood of Patients with Sjögren’s Syndrome

Objective. DNA microarray analysis and quantitative real-time polymerase chain reaction (PCR) were performed to identify key target genes in peripheral blood from patients with Sjögren’s syndrome (SS). Methods. DNA microarray analysis was performed in 19 patients with SS (all women) and 10 healthy controls (5 men and 5 women) using a low-density DNA microarray system with 778 genes. For confirmation, the expression of upregulated genes was analyzed by quantitative real-time PCR in another 37 SS patients (35 women and 2 men) and 9 healthy controls (8 women and 1 man). Relationships between gene signatures and various clinical measures, such as disease duration, symptoms and signs, complications, immunological findings, and salivary and lacrimal functions, were analyzed. Results. Interferon-α (IFN-α)-inducible protein 27 (IFI27) showed the most significant difference between SS patients and controls in the microarray screening. We performed quantitative RT-PCR for IFI27. IFI27 gene expression level was increased in patients with SS compared with controls (p < 0.01) by real-time PCR, supporting our observations from the microarray data. The level of IFI27 was significantly correlated with serum IgG levels (r = 0.462, p < 0.01) and ß2-microglobulin (r = 0.385, p < 0.05), soluble interleukin 2 receptor (r = 0.473, p < 0.01), erythrocyte sedimentation rate (r = 0.333, p < 0.05), and antinuclear antibody titer (speckled pattern; r = 0.445, p < 0.01). Conclusion. Our results suggest that upregulation of IFN-inducible genes in SS patients is a systemic phenomenon, and IFN may play an important role in the pathogenesis of SS. The expression level of IFI27 could be an effective and specific biomarker associated with SS.

Abnormal production of B cell growth factor in patients with systemic lupus erythematosus.

In order to clarify the role of B cell growth factor (BCGF) in the pathogenesis of systemic lupus erythematosus(SLE), BCGF production by peripheral blood mononuclear cells(PBMC) and T cells was studied using a new bioassay for BCGF activity. For this purpose, we established an Epstein‐Barr (EB) virus‐transformed B cell line KS‐3.F10 that proliferates only in response to two B cell‐specific BCGF, low‐mol. wt BCGF (LMW‐BCGF) and high‐mol. wt BCGF (HMW‐BCGF). PBMC from active SLE patients produced less BCGF when stimulated with phytohaemagglutinin (PHA) compared with controls. The decreased BCGF production by PHA‐stimulated PBMC from active SLE reverted to control values when SLE became inactive. However, PHA‐stimulated T cells from active SLE patients produced more BCGF compared with controls, whereas those from inactive SLE showed normal BCGF production. Spontaneous BCGF production by T cells was not observed in active SLE patients. These findings suggest that decreased BCGF production by SLE PBMC is due to excessive BCGF consumption by B cells in vitro and that SLE T cells produce large amounts of BCGF with appropriate immune stimuli in vitro to promote polyclonal B cell activation.

Longterm Safety and Efficacy of Subcutaneous Tocilizumab Monotherapy: Results from the 2-year Open-label Extension of the MUSASHI Study

Objective. To evaluate the longterm safety and efficacy of subcutaneous tocilizumab (TCZ-SC) as monotherapy in patients with rheumatoid arthritis (RA). Methods. Of 346 patients who received 24 weeks of double-blind treatment with either TCZ-SC monotherapy, 162 mg every 2 weeks (q2w); or intravenous TCZ (TCZ-IV) monotherapy, 8 mg/kg every 4 weeks; 319 patients continued to receive TCZ-SC q2w in the 84-week open-label extension (OLE) of the MUSASHI study (JAPICCTI-101117). Efficacy, safety, and immunogenicity were evaluated for all patients treated with TCZ during 108 weeks. Results. The proportions of patients who achieved American College of Rheumatology 20/50/70 responses, low disease activity [28-joint Disease Activity Score (DAS28) ≤ 3.2], or remission (DAS28 < 2.6) at Week 24 were maintained until Week 108. The incidences of adverse events and serious adverse events were 498.3 and 16.9 per 100 patient-years (PY), respectively. The overall safety of TCZ-SC monotherapy was similar to that of TCZ-IV monotherapy. Rates of injection site reactions (ISR) through 108 weeks remained similar to rates through 24 weeks. ISR were mild and did not cause any patient withdrawals. No serious hypersensitivity events (including anaphylactic reactions) occurred. Anti-TCZ antibodies were present in 2.1% of patients treated with TCZ-SC monotherapy. Conclusion. TCZ-SC monotherapy maintained a favorable safety profile and consistent efficacy throughout the 108-week study. Like TCZ-IV, TCZ-SC could provide an additional treatment option for patients with RA.

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.

Effective plasma concentrations of mycophenolic acid and its glucuronide in systemic lupus erythematosus patients in the remission‐maintenance phase

What is known and Objective:  Mycophenolate mofetil (MMF) has been reported recently to be effective in the treatment of systemic lupus erythematosus (SLE). The therapeutic range of mycophenolic acid (MPA) in SLE in the remission‐maintenance phase remains to be clarified. The aim of this study was to evaluate the therapeutic efficacy of MMF and predose plasma concentrations of MPA and its phenolic glucuronide (MPAG) in patients with SLE in the remission‐maintenance phase.

ABCB1 genetic variant and its associated tacrolimus pharmacokinetics affect renal function in patients with rheumatoid arthritis.

BACKGROUND This study aimed to evaluate the blood exposure of and clinical responses to tacrolimus based on genetic variants of CYP3A5 and ABCB1 in patients with rheumatoid arthritis. METHODS Seventy rheumatoid arthritis patients treated with oral tacrolimus once daily were enrolled. Blood concentrations of tacrolimus and its major metabolite 13-O-demethylate at 12h after dosing were determined. The relationships between the tacrolimus pharmacokinetics and efficacy, renal function, and CYP3A5 and ABCB1 genotypes were evaluated. RESULTS Dose-normalized blood concentration of tacrolimus was significantly higher in the CYP3A5*3/*3 group than in the *1 allele carrier group. A lower metabolic ratio of 13-O-demethylate to tacrolimus was observed in the CYP3A5*3/*3 group. The ABCB1 3435TT group had higher dose-normalized blood concentrations of tacrolimus and 13-O-demethylate. The blood tacrolimus concentration was inversely correlated with the estimated glomerular filtration rate (eGFR). ABCB1 C3435T but not CYP3A5 genotype had decreased eGFR. Patients lacking the CYP3A5*3 allele had a higher incidence of tacrolimus withdrawal. CONCLUSION CYP3A5*3 increased the blood exposure of tacrolimus through its metabolic reduction. ABCB1 C3435T led to a higher blood exposure of tacrolimus and its major metabolite. The ABCB1 genetic variant and its associated tacrolimus pharmacokinetics affected renal function in rheumatoid arthritis patients.

A novel method predicting clinical response using only background clinical data in RA patients before treatment with infliximab.

Abstract Objectives: The aim of the present study was to generate a novel method for predicting the clinical response to infliximab (IFX), using a machine-learning algorithm with only clinical data obtained before the treatment in rheumatoid arthritis (RA) patients. Methods: We obtained 32 variables out of the clinical data on the patients from two independent hospitals. Next, we selected both clinical parameters and machine-learning algorithms and decided the candidates of prediction method. These candidates were verified by clinical variables on different patients from two other hospitals. Finally, we decided the prediction method to achieve the highest score. Results: The combination of multilayer perceptron algorithm (neural network) and nine clinical parameters shows the best accuracy performance. This method could predict the good or moderate response to IFX with 92% accuracy. The sensitivity of this method was 96.7%, while the specificity was 75%. Conclusions: We have developed a novel method for predicting the clinical response using only background clinical data in RA patients before treatment with IFX. Our method for predicting the response to IFX in RA patients may have advantages over the other previous methods in several points including easy usability, cost-effectiveness and accuracy.

難治性関節リウマチ（RA）に対する白血球除去療法（LCAP）の臨床的有用性の検討

PURPOSE To examine therapeutic effect of leukocytapheresis (LCAP) for rheumatoid arthritis (RA) resistant to various treatments. METHOD Thirteen patients with RA (mean age : 60.8+/-11.4, male : female=5 : 8), 1 who were resistant to disease-modifying anti-rheumatic drugs (DMARDs) and biologics, or 2 who failed with those medicines because of side effects or complications. We performed LCAP, which was carried out once a week for a total of five sessions, with a throughput of about 0.1 L/kg. Before and after LCAP, we evaluated the effect of LCAP therapy. RESULT DAS28 (CRP) score was 5.70+/-1.12 before LCAP, 4.57+/-1.19 (P<0.05) just after the final LCAP and 4.83+/-1.35 (P<0.05) about 4 weeks after LCAP. DAS28 score decreased in all patients after LCAP. No serious adverse events were observed except temporary anemia. CONCLUSION LCAP therapy may be useful and safe for patients with RA resistant to conventional medication. Patients who show good clinical response by LCAP needs to be clarified.

Activation-induced cell death of peripheral blood T lymphocytes in patients with primary Sjögren’s syndrome

Activation-induced cell death (AICD) in T lymphocytes is important for the maintenance of peripheral tolerance. We studied AICD of peripheral blood T cells from patients with primary Sjögren’s syndrome (SS). AICD was induced in mitogen-activated T cellsin vitro using mAb to CD3 or Fas (CD95). Cell death and proliferation, Fas and Fas ligand (FasL) expression, and soluble Fas and soluble FasL production were measured. Surface phenotypes and cytokine production of AICD-surviving cells and effects of cytokines on AICD were examined. Anti-CD3 mAb induced cell death is SS and normal T cells in the presence of exogenous interleukin (IL)-2. In the absence of IL-2 anti-CD3 mAb induced cell proliferation in SS and normal T cells. There was no significant difference in Fas/FasL expression and sFas/sFasL production between SS patients and normals. AICD-surviving cells consisted of more CD4+ T cells and less CD8+ T cells in SS compared to normals. AICD-surviving cells produced abundant interferon-γ and little IL-4. There was no significant difference in the effects of cytokines on AICD between SS patients and normals. These findings suggest that IL-2 is a critical factor for AICD. AICD works almost normally in SS T cells when sufficient IL-2 is present prior to T cell receptor re-stimulation.