Hiroshi Tsukamoto

Serum progranulin levels are elevated in patients with systemic lupus erythematosus, reflecting disease activity

IntroductionProgranulin (PGRN) is the precursor of granulin (GRN), a soluble cofactor for toll-like receptor 9 (TLR9) signaling evoked by oligonucleotide (CpG)-DNA. Because TLR9 signaling plays an important role in systemic lupus erythematosus (SLE), we investigated whether PGRN is involved in the pathogenesis of SLE.MethodsWe measured concentrations of serum PGRN and interleukin-6 (IL-6) with enzyme-linked immunosorbent assay (ELISA) in patients with SLE (n = 68) and in healthy controls (n = 60). We assessed the correlation between the serum PGRN levels and established disease-activity indexes. The sera from the patients with high PGRN titers (>80 ng/ml) at the initial evaluation were reevaluated after the disease was ameliorated by treatment. We also measured the IL-6 concentration secreted by peripheral blood mononuclear cells (PBMCs) incubated with (a) oligonucleotide (CpG-B) in the presence or absence of recombinant human PGRN (rhPGRN); and (b) lupus sera in the presence or absence of a neutralizing anti-PGRN antibody.ResultsSerum PGRN levels were significantly higher in SLE patients than healthy controls. Their levels were significantly associated with activity of clinical symptoms. They also significantly correlated with values of clinical parameters, including the SLE Disease Activity Index and anti-double-stranded DNA antibody titers, and inversely with CH50, C3, and C4 levels. Moreover, serum PGRN levels significantly decreased after successful treatment of SLE. The rhPGRN significantly upregulated the production of IL-6 by PBMCs stimulated with CpG-B. Patients sera stimulated production of IL-6 from PBMCs, which was significantly impaired by neutralization of PGRN. The serum PGRN levels significantly correlated with the serum IL-6 levels.ConclusionsSerum PGRN could be a useful biomarker for disease activity of SLE. PGRN may be involved in the pathogenesis of SLE partly by enhancing the TLR9 signaling.

The Cytotoxic Effects of Certolizumab Pegol and Golimumab Mediated by Transmembrane Tumor Necrosis Factor α

Background:Anti–tumor necrosis factor &agr; (anti-TNF-&agr;) agents have been successfully applied for the treatment of rheumatoid arthritis, Crohns disease, and other chronic inflammatory diseases. Not only the neutralization of soluble TNF-&agr; but also the effect on transmembrane TNF-&agr; is important mechanisms of action of anti-TNF-&agr; agents. This study investigated the cytotoxic effects of new anti-TNF-&agr; agents, certolizumab pegol and golimumab, which are mediated by transmembrane TNF-&agr;. Methods:Transmembrane TNF-&agr;–expressing Jurkat T cells that did not express TNF receptors were used. The binding ability of each anti-TNF-&agr; agent to transmembrane TNF-&agr;, antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, and the apoptotic effect were examined. Results:Certolizumab pegol and golimumab bound to transmembrane TNF-&agr;. Golimumab induced antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity, which was comparable to infliximab and adalimumab. However, certolizumab pegol did not induce antibody-dependent cell-mediated cytotoxicity or complement-dependent cytotoxicity. Certolizumab pegol directly induced nonapoptotic cell death in transmembrane TNF-&agr;–expressing cells. Golimumab induced a weaker apoptotic effect than infliximab and adalimumab. Conclusions:The cytotoxic effects of anti-TNF-&agr; agents on TNF-&agr;–expressing cells are considered to be associated with the clinical effect of these agents on granulomatous diseases. The direct cytotoxic effect of certolizumab pegol on TNF-&agr;–producing cells may contribute to its clinical efficacy in Crohns disease. Golimumab may be less effective for granulomatous diseases.

Analysis of immune reconstitution after autologous CD34+ stem/progenitor cell transplantation for systemic sclerosis: predominant reconstitution of Th1 CD4+ T cells

OBJECTIVEnThe aim of this study is to evaluate the mechanism of long-term effect of autologous haematopoietic stem cell transplantation (ASCT) in treatment of SSc.nnnMETHODSnEleven patients (three males and eight females) with SSc were enrolled. Blood mononuclear cells were harvested after mobilization treatment with CYC and G-CSF. CD34+ haematopoietic stem/progenitor cell fractions were purified and cryopreserved. Patients were transplanted with > 2u2009×u200910(6)/kg autologous CD34+ cells after high-dose CYC (50 mg/kg for 4 days) conditioning. Immune reconstitution was evaluated serially by analysing lymphocyte subpopulations for 36 months.nnnRESULTSnProgressive improvement of skin sclerosis has been observed for 3 years in most of the patients. The serum level of anti-Scl-70, an auto-antibody specific to SSc, was progressively decreased after ASCT. Improvement of skin sclerosis was significantly associated with the change in the serum anti-Scl-70 level after ASCT at 36 months. Serum levels of KL-6 and surfactant protein D, indicators for interstitial pneumonia activity, were also significantly decreased. The number of CD8+ T cells immediately recovered within a month after ASCT, while the number of CD4+ T cells remained low for >36 months post-transplant. The majority of CD4+ cells were memory but not naïve T cells, and regulatory CD4+ T cells were not recovered. Th1/Th2 ratio was significantly increased after ASCT.nnnCONCLUSIONSnASCT with purified CD34+ cells was effective in controlling the disease activity of SSc. Th1/Th2 ratio was significantly increased for at least 3 years after ASCT.

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.

Association of hepatitis B with antirheumatic drugs: a case–control study

BackgroundThough concern of hepatitis B virus (HBV) reactivation by antirheumatic agents has limited therapeutic opportunities in HBV-infected rheumatoid arthritis (RA) patients, the relative risks (RR) among such agents have not been clarified.ObjectiveWe compared the reporting of antirheumatic-agent-associated hepatitis B.PatientsWe assessed 92 hepatitis B cases and 98,069 controls from a population of 98,161 RA patients registered into the US Food and Drug Administration’s (FDA’s) adverse event database between 2004 and 2010.MeasurementsA reporting odds ratio (ROR), a signal suggesting a risk for hepatitis B among antirheumatic agents, was measured.ResultsTreatment with corticosteroids [ROR 2.3 (95xa0% confidence interval 1.3–4.0)], methotrexate [4.9 (3.9–6.0)], rituximab [7.2 (5.3–9.9)], tacrolimus [4.2 (1.5–11.9)], or reporting from Japan [2.2 (1.1–4.2)] were associated with higher signal, whereas adalimumab had a lower ROR [0.2 (0.1–0.4)].LimitationsThere are known limitations of spontaneous reporting, such as underreporting, the Weber effect, reporting bias, indication bias, and limited clinical information such as HBV status.ConclusionsAdalimumab’s low reporting rate is most likely be due to notoriety. However, the possibility that adalimumab might suppress reactivation of HBV cannot be denied. Until the possibility is clarified in well-designed clinical studies, physicians should use adalimumab cautiously in patients with HBV.

Hereditary angioedema in Japan: Genetic analysis of 13 unrelated cases

Introduction:The molecular bases and clinical features of hereditary angioedema (HAE) have not been systematically documented in Japan or in other Asian countries. Thus, the authors researched the genetic and clinical characteristics of Japanese patients with HAE. Methods:The authors analyzed the CIINH gene for mutations in 13 unrelated Japanese patients with HAE by means of the polymerase chain reaction and nucleotide sequencing. In addition, the authors searched the literature from January 1969 to October 2010 on Japanese patients with HAE. Results:Seven of the mutations found were novel, including 4 missense mutations (8728T>G, 8831C>A, 16661T>G and 16885C>A), 2 frameshift mutations (2281_2350del70, 14158delT) and 1 large deletion (at least 1 kb-length deletion including exon 4), whereas 6 mutations had previously been reported in European populations. Conclusions:The genetic and clinical characteristics in Japanese patients with HAE may be similar to those in Western patients although our sample size is small and the authors identified 7 novel mutations.

Reduced carotid intima–media thickness in systemic lupus erythematosus patients treated with cyclosporine A

Abstract Background Patients with systemic lupus erythematosus (SLE) are at risk of atherosclerosis. An increased carotid intima–media thickness (IMT) is considered to be a marker of early atherosclerosis. Objective To determine influential factors for increased carotid IMT in SLE patients. Methods We evaluated the impact of conventional risk factors for atherosclerosis on carotid IMT in 427 healthy controls and of clinical factors on carotid IMT in 94 SLE patients. Carotid IMT was measured by using a newly developed computer-automated system. Unconditional logistic regression was used to assess the adjusted odds ratios (ORs) and 95 % confidence intervals (95 % CI). Results Multivariate-adjusted mean carotid IMT (mm) was significantly reduced in SLE patients (0.51, 95 % CI = 0.36–0.66) compared to healthy controls (0.55, 95 % CI = 0.40–0.70) (P = 0.003). The SLE Disease Activity Index (SLEDAI) was associated with carotid IMT in a dose-dependent manner (Ptrend = 0.041). The current use of cyclosporine A (adjusted OR = 0.02, 95 % CI = 0.01–0.40, P = 0.011) and a history of steroid pulse therapy (adjusted OR = 0.01, 95 % CI = 0.01–0.25, P = 0.006) were significantly associated with a decreased risk of increased carotid IMT. Conclusions Our findings suggest that the current use of cyclosporine A can protect against increased carotid IMT, leading to a decreased risk of arteriosclerosis. Future studies with a larger sample size need to confirm that this association holds longitudinally.

Evaluation of the extent of ground-glass opacity on high-resolution CT in patients with interstitial pneumonia associated with systemic sclerosis: Comparison between quantitative and qualitative analysis

AIMnTo verify whether quantitative analysis of the extent of ground-glass opacity (GGO) on high-resolution computed tomography (HRCT) could show a stronger correlation with the therapeutic response of interstitial pneumonia (IP) associated with systemic sclerosis (SSc) compared with qualitative analysis.nnnMATERIALS AND METHODSnSeventeen patients with IP associated with SSc received autologous peripheral blood stem cell transplantation (auto-PBSCT) and were followed up using HRCT and pulmonary function tests. Two thoracic radiologists assessed the extent of GGO on HRCT using a workstation. Therapeutic effect was assessed using the change of vital capacity (VC) and diffusing capacity of the lung for carbon monoxide (DLco) before and 12 months after PBSCT. Interobserver agreement was assessed using Spearmans rank correlation coefficient and the Bland-Altman method. Correlation with the therapeutic response between quantitative and qualitative analysis was assessed with Pearsons correlation coefficients.nnnRESULTSnSpearmans rank correlation coefficient showed good agreement, but Bland-Altman plots showed that proportional error could be suspected. Quantitative analysis showed stronger correlation than the qualitative analysis based on the relationships between the change in extent of GGO and VC, and change in extent of GGO and DLco.nnnCONCLUSIONnQuantitative analysis of the change in extent of GGO showed stronger correlation with the therapeutic response of IP with SSc after auto-PBSCT than with the qualitative analysis.

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) in Japan : a review of the literature

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is a dominantly inherited autoinflammatory syndrome that is characterized by recurrent episodes of fever attacks associated with rashes, abdominal pain, myalgia, conjunctivitis, chest pain, and arthralgia. Some patients have severe abdominal pain leading to abdominal surgery. Most reported cases of TRAPS involve patients of European ancestry, but there have been nine reports of patients with TRAPS in Japan. Here, we review these nine case reports. Reported TNFRSF1A gene mutations in these nine index patients were C70S, T61I, C70G, C30Y, C30R, N101K, and N25D. Fever (100xa0%) was seen in all 23 cases. Most patients developed rash (erythema) (84.6xa0%) and arthralgia (73.3xa0%), and half suffered from myalgia (54.5xa0%) and abdominal pain (50.0xa0%). Although one-half of the patients suffered from abdominal pain, none underwent surgery. In contrast, only a small percentage of patients suffered from chest pain (20.0xa0%), conjunctivitis (20.0xa0%), and headache (10.0xa0%). Almost all cases (95.7xa0%) concerned patients whose relatives suffered from periodic fever. These findings suggest that the clinical features of Japanese TRAPS patients may be milder than those of patients in Western countries.

CIN85 is required for Cbl-mediated regulation of antigen receptor signaling in human B cells.

The aberrant regulation of B-cell receptor (BCR) signaling allows unwanted B cells to persist, thereby potentially leading to autoimmunity and B-cell malignancies. Casitas B-lineage lymphoma (Cbl) proteins suppress BCR signaling; however, the molecular mechanisms that control Cbl function in human B cells remain unclear. Here, we demonstrate that CIN85 (c-Cbl interacting protein of 85 kDa) is constitutively associated with c-Cbl, Cbl-b, and B-cell linker in B cells. Experiments using CIN85-overexpressing and CIN85-knockdown B-cell lines revealed that CIN85 increased c-Cbl phosphorylation and inhibited BCR-induced calcium flux and phosphorylation of Syk and PLCγ2, whereas it did not affect BCR internalization. The Syk phosphorylation in CIN85-overexpressing and CIN85-knockdown cells was inversely correlated with the ubiquitination and degradation of Syk. Moreover, CIN85 knockdown in primary B cells enhanced BCR-induced survival and growth, and increased the expression of BcLxL, A1, cyclin D2, and myc. Following the stimulation of BCR and Toll-like receptor 9, B-cell differentiation- associated molecules were up-regulated in CIN85-knockdown cells. Together, these results suggest that CIN85 is required for Cbl-mediated regulation of BCR signaling and for downstream events such as survival, growth, and differentiation of human B cells.