Masaru Togashi

Up‐regulated expression of Toll‐like receptors mRNAs in peripheral blood mononuclear cells from patients with systemic lupus erythematosus

Recent studies in animal models for systemic lupus erythematosus (SLE) have shown that Toll‐like receptors (TLR‐7 and TLR‐9) and interferon (IFN)‐α are involved in the pathogenesis of murine lupus. Recent studies using flow cytometry have also shown increased expression of TLR‐9 in peripheral blood mononuclear cells (PBMCs) from SLE patients. In this study, we performed quantitative real‐time reverse transcription–polymerase chain reaction analyses of PBMCs from 21 SLE patients and 21 healthy subjects, to estimate TLR2, TLR3, TLR4, TLR5, TLR7, TLR8, TLR9, IFN‐α and LY6E (a type I IFN‐inducible gene) mRNA expression levels. Expression levels of TLR2, TLR7, TLR9, IFN‐α and LY6E mRNAs in SLE patients were significantly higher than those in healthy controls. Expression levels of TLR7 and TLR9 mRNAs correlated with that of IFN‐α mRNA in SLE patients. These results suggest that up‐regulated expression of TLR7 and TLR9 mRNAs together with increased expression of IFN‐α mRNA in PBMCs may also contribute to the pathogenesis of human lupus.

Monoclonal immunoglobulin deposition disease associated with membranous features

BACKGROUND Very few cases of non-organized and non-Randall-type monoclonal immunoglobulin deposition disease (MIDD) associated with membranous features have been reported. Information on clinicopathological features and prognosis in this entity is limited. METHODS We reviewed 5443 renal biopsies processed at our department, and identified three patients with MIDD associated with membranous features. We evaluated clinicopathological features and outcomes in these patients. RESULTS All patients had proteinuria, and one patient developed nephrotic syndrome. Renal insufficiency was not observed. Cryoglobulin or monoclonal protein in serum and urine was not detected. A renal biopsy showed thickening of the glomerular capillary walls and spike formation. Tubulointerstitial and vascular alterations were mild or absent. Immunofluorescence studies revealed granular IgG3-kappa deposits in two patients and IgG1-kappa deposits in one patient, along the glomerular capillary walls. Immunofluorescence studies using antibodies specific for gamma-heavy chain Fab containing C(H)1 domain, C(H)2 domain and C(H)3 domain did not show any apparent deletion. On confocal microscopy, glomerular colocalization of light and heavy chains was observed. Electron microscopy showed predominant subepithelial granular deposits without distinct ultrastructural organization. All patients were treated with steroids, and good effects were observed. A follow-up renal biopsy performed in one patient showed histological improvements. No patient developed myeloma or other haematological malignancy during the course of follow-up (mean 44 months). CONCLUSIONS MIDD associated with membranous features is an extremely rare but distinctive entity. Our study suggests glomerular deposition of a nondeleted whole immunoglobulin molecule. Patients with this entity appear to respond well to steroid therapy.

Clinicopathological features and prognosis in immunoglobulin light and heavy chain deposition disease.

BACKGROUND There are three subtypes of monoclonal immunoglobulin deposition disease: light chain deposition disease (LCDD), light and heavy chain deposition disease (LHCDD), and heavy chain deposition disease (HCDD). Although it has been considered that LHCDD is a variant of LCDD, information on clinicopathological features and prognosis in LHCDD is presently limited. METHODS We reviewed 5,443 renal biopsies, and evaluated clinicopathological features and outcomes in patients with LHCDD, in comparison with those in patients with LCDD and previously reported patients with HCDD. We also characterized paraprotein deposits in patients with LHCDD. RESULTS We identified 6 patients with LHCDD, 6 patients with LCDD, and 1 patient with HCDD. The most common clinicopathological findings in patients with LHCDD were proteinuria, renal insufficiency, and nodular sclerosing glomerulopathy. Three patients had IgG-k deposits and 3 patients had IgG-l deposits. Heavy chain subclass analysis performed in 4 patients showed IgG3 deposits in all patients. Dual immunostaining revealed glomerular colocalization of light and heavy chains. In contrast with LCDD, glomerular C3 and C1q deposits were common findings in LHCDD and HCDD. All patients with LHCDD were treated with steroids and cytotoxic agents, but no effect on proteinuria was observed. Three patients developed end-stage renal disease requiring hemodialysis. The underlying hematological disorders in LHCDD and HCDD were milder than in LCDD. Early renal survival and overall patient survival in our patients appeared to be better in LHCDD than in LCDD. CONCLUSIONS There are apparent differences in clinicopathological features and prognosis between LHCDD and LCDD. LHCDD is probably more similar to HCDD.

Predominant tubulointerstitial nephritis in a patient with systemic lupus erythematosus: phenotype of infiltrating cells.

A 63-year-old man with systemic lupus erythematosus developed tubular proteinuria. All subclasses of serum IgG increased, and the largest IgG subclass increase was IgG4. A renal biopsy showed lupus nephritis (Class II) with severe tubulointerstitial nephritis (so-called predominant tubulointerstitial lupus nephritis, an unusual form of lupus nephritis). Immunofluorescence microscopy revealed positive granular staining for IgG, C3 and C1q in the mesangium and peritubular interstitium, and along the tubular basement membranes (TBM). Electron microscopy also showed electron-dense deposits in the mesangium and TBM. Immunophenotyping of interstitial infiltrating cells disclosed a predominance of T cells. CD8-positive cytotoxic T cells infiltrated the peritubular interstitium, and some of these cells infiltrated the tubules. B cell-rich lymphoid follicles were also observed. IgG subclass analyses showed glomerular IgG1, IgG2 and IgG4 deposition, positive staining of IgG4 in the peritubular interstitium and along the TBM, and abundant IgG1-, IgG3- and IgG4-positive plasma cells in the interstitium. The patient responded well to moderate-dose steroid therapy. This is the first report of immunophenotyping of interstitial infiltrates in predominant tubulointerstitial lupus nephritis. The results suggest CD8-positive cytotoxic T cell-mediated tubular injury. Furthermore, immune complexes containing IgG4 might be one of etiologic factors.

Characteristics of proliferative glomerulo-nephritis with monoclonal IgG deposits associated with membranoproliferative features.

BACKGROUND Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) associated with membranoproliferative features is an extremely rare entity. Information on clinicopathological features and prognosis in this entity is limited. METHODS We reviewed 5,443 renal biopsies processed at our department, and identified 4 patients with PGNMID associated with membranoproliferative features. We evaluated clinicopathological features and outcomes in these patients, and characterized paraprotein deposits by immunofluorescence studies. RESULTS Three out of 4 patients had nephrotic syndrome with renal insufficiency at presentation. Cryoglobulin or monoclonal protein in serum and urine was not detected. Renal biopsy showed membranoproliferative features with or without nodular formation. Tubulointerstitial and vascular alterations were mild in three patients. All patients had glomerular IgG-kappa deposits. Heavy chain subclass analysis performed in 3 patients showed IgG3 deposits. Immunofluorescence studies using antibodies specific for gamma-heavy chain C(H)1, C(H)2, and C(H)3 domains and gamma3 hinge did not show any apparent deletion. Confocal microscopy revealed glomerular colocalization of light and heavy chains. On electron microscopy, granular deposits were predominantly mesangial and subendothelial. All patients were treated with steroids and cytotoxic agents, but no effect on proteinuria was observed. The renal outcome was progressive in all patients. Early death was observed in two elder patients. No patient had overt myeloma or lymphoma at presentation or over the course of follow-up (mean 43 months). CONCLUSIONS Our study suggests a predominance of IgG3-kappa glomerular deposits of nondeleted whole immunoglobulin molecules in PGNMID associated with membranoproliferative features. The clinical outcome in patients with this entity appears to be poor.

Effects of Denosumab on Bone Metabolic Markers and Bone Mineral Density in Patients Treated with Glucocorticoids

Objective We performed a prospective study to determine the efficacy and safety of denosumab on bone metabolic indices and bone mineral density (BMD) in 29 patients receiving long-term glucocorticoids (GCs) who had clinical risk factors for fracture. Methods Among these patients, 16 had systemic lupus erythematosus (SLE), 6 RA, 4 other autoimmune diseases, and 3 renal diseases. All patients received donosumab 60 mg at baseline and 6 months. Serum N-terminal cross-linked telopeptide of type I collagen (NTX) and bone-specific alkaline phosphatase (BAP) levels were measured as bone metabolic indices. BMD at the lumbar spine (LSBMD) and femoral neck (FNBMD) were measured using dual energy X-ray absorptiometry and expressed as a percentage of the young adult mean (%YAM). Results Denosumab therapy significantly reduced serum NTX and BAP levels from baseline after 12 months (from 19.2 to 13.9 nmol BCE/L; from 11.9 to 9.2 U/L, respectively). In 18 patients treated with bisphosphonates before the start of denosumab therapy, the improvements in the LSBMD and FNBMD values were 1.5%YAM/year and 1.1%YAM/year, respectively. The LSBMD and FNBMD values were both significantly higher 12 months after denosumab therapy (3.5%YAM/year and 3.0%YAM/year, respectively). The LSBMD gain was significantly higher after denosumab therapy than during bisphosphonate therapy. No fractures were observed in any patients during denosumab therapy. Conlusion Denosumab is effective and safe in preventing bone resorption and BMD loss in patients treated with long-term GCs for inflammatory diseases. This is the first study showing a significant increase in not only LSBMD but also FNBMD in GC-induced osteoporosis after denosumab therapy.

Validation of the 2010 histopathological classification of ANCA-associated glomerulonephritis in a Japanese single-center cohort

Abstract Objectives. To validate the 2010 histopathological classification system of anti-neutrophil cytoplasmic antibodies (ANCA)-associated glomerulonephritis (GN) in a Japanese single-center cohort. Methods. We retrospectively studied 54 patients (28 renally limited pauci-immune GN, 25 microscopic polyangiitis, and one Churg–Strauss syndrome). Results. There were 17 patients with focal GN, eight patients with crescentic GN, 19 patients with mixed GN, and 10 patients with sclerotic GN. Detailed information regarding treatment was available in 39 patients. All these patients were treated with steroids with or without immunosuppressive agents. Hemodialysis was introduced in two patients with crescentic GN and three patients with sclerotic GN. During the follow-up period, 27 of 54 patients died. The major cause of death was pneumonia. Significant differences were observed in estimated glomerular filtration rate among patients with focal, crescentic, mixed, and sclerotic GN at entry and 1- and 5-year follow-up. Patients with focal GN had preserved renal function and favorable outcome. Conclusions. Our validation study suggests that the 2010 histopathological classification of ANCA-associated GN might aid in prognostication of patients at the time of diagnosis and in therapy selection.

IgA nephropathy associated with Castleman disease with cutaneous involvement.

A 35-year-old Japanese man developed systemic lymphadenopathy during the course of immunosuppressive therapy for IgA nephropathy associated with cutaneous nodules, polyclonal hypergammaglobulinemia, and persistent increased serum C-reactive protein of unknown cause. Lymph node examination showed the plasmacytic type of Castleman disease (CD). A skin biopsy showed specific pathologic findings of CD cutaneous involvement. Considering the involvement of interleukin-6 in CD, we treated the patient with humanized anti-interleukin-6 receptor antibody. Thereafter, his symptoms and abnormal laboratory findings were improved. Cutaneous CD has rarely been described in Asian population, and renal complications in CD are uncommon and heterogeneous. To our knowledge, this is the first case of IgA nephropathy associated with multicentric CD with cutaneous involvement.

Cutaneous polyarteritis nodosa in a patient with Crohn's disease

A 19-year-old Japanese woman with a 4-year history of Crohn’s disease (CD) developed high fever, polyarthralgia, and painful subcutaneous nodules of the legs. A skin biopsy showed panarteritis with fibrinoid necrosis in the deep dermis. Endoscopic examination showed aphthous lesions in the entire colon. She was diagnosed with cutaneous polyarteritis nodosa (PAN) associated with CD. Steroid therapy improved her symptoms. To our knowledge, this is the first Japanese case of cutaneous PAN associated with CD.

Serum interleukin 6 levels as a useful prognostic predictor of clinically amyopathic dermatomyositis with rapidly progressive interstitial lung disease

Abstract Objectives. Rapidly progressive interstitial lung disease (RP-ILD) is life-threatening in patients with clinically amyopathic dermatomyositis (CADM). Useful prognostic markers are necessary for treatment selection. This study aimed to investigate differences in clinical and laboratory characteristics between surviving and non-surviving patients. Methods. Twelve CADM patients with RP-ILD were enrolled. Six patients lived (Group A) and six patients died (Group B) after immunosuppressive treatment for RP-ILD. Clinical manifestations and laboratory data before treatment were compared between the two groups. Results. Among the clinical manifestations and laboratory data examined, serum interleukin 6 (IL-6) levels in Group B were significantly higher than those in Group A (mean ± SD 28.5 ± 21.0 vs. 7.2 ± 1.6 pg/mL; p = 0.009). Simple regression analysis showed that serum IL-6 was the only significant prognostic factor (p = 0.032). Kaplan–Meier estimates showed that the cumulative survival rate was significantly lower in patients with serum IL-6 levels of ≥ 9 pg/mL than in patients with those of < 9 pg/mL (p = 0.04). Conclusions. Serum IL-6 levels may predict the prognosis of CADM patients with RP-ILD. The intensity of immunosuppressive treatment can be decided according to serum IL-6 levels at an early phase of the disease.