Nationwide epidemiological survey of polyarteritis nodosa in Japan in 2020.

Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis that predominantly affects medium-sized arteries. With advances in our understanding of the pathogenesis and classification of vasculitis, PAN and microscopic polyangiitis (MPA), a disease of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV), were separated from the group of diseases previously diagnosed as periarteritis nodosa (PN) at the Chapel Hill Consensus Conference (CHCC) in 1994 (1).

Survey of Japanese nephrologists' use of clinical practice guidelines for rapidly progressive glomerulonephritis.

BACKGROUND: The guidelines in Japan for the treatment of rapidly progressive glomerulonephritis (RPGN) have been revised; the latest update was released in 2020. We investigated the actual usage of the new guidelines in Japan. METHODS: We distributed a survey electronically to board-certified nephrologists throughout Japan from December 15, 2021 to January 31, 2022. The survey focused on anti-neutrophil cytoplasmic antibody (ANCA)-associated RPGN and anti-glomerular basement membrane (GBM)-antibody RPGN, plus the treatment strategies and infection-prevention measures used. RESULTS: The survey was completed by 155 certified nephrologists from medical facilities across Japan. Their responses regarding treatment procedures revealed that ANCA-associated RPGN was treated with immunosuppressants and/or biologics by 58.1% of the survey respondents, and with plasma exchange (PE) in combination with corticosteroids by 21.3%. Regarding anti-GBM-antibody RPGN, 78.1% of the respondents used corticosteroids in combination with PE (63.2%), cyclophosphamide (CY) (23.9%), or rituximab (RTX) (8.4%), suggesting a discrepancy between clinical practice and the actual use of the guidelines. Trimethoprim-sulfamethoxazole was prescribed as prophylaxis by 94.8% of the respondents, reflecting the widespread recognition of the need to prevent infectious disease in patients with RPGN. CONCLUSIONS: The survey responses revealed how Japan's new RPGN guidelines are used in actual clinical practice. Our findings will contribute to the guidelines' dissemination and implementation.

Two distinct subsets of LDGs (low density granulocytes) in ANCA-associated vasculitis.

OBJECTIVES AND METHODS: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is an autoimmune disorder that causes vasculitis in small blood vessels throughout the body. Low-density granulocytes (LDGs) in autoimmune diseases, such as SLE and AAV, might play a critical role in the pathogenesis of these diseases. Here, we aimed to determine the characteristics of LDGs in patients with AAV. We assessed the number of whole white blood cells, neutrophil extracellular traps (NETs) productivity, proportion of cell surface markers (e.g. CD10), responses to immunosuppressants, and proteomics of LDGs in patients with AAV. RESULTS: We found more LDGs in peripheral blood mononuclear cells (PBMCs) of patients with AAV than PBMCs of healthy controls (HCs) and confirmed that these LDGs in AAV produced more NETs than normal density granulocytes (NDGs) in HCs. We identified CD10-positive LDGs with mature neutrophil features and CD10-negative LDGs with immature granulocyte properties; the proportion of the two LDG types decreased and increased, respectively, in the patients during treatment. Proteomic analysis revealed that the two LDG groups shared protein expression that differed from those of NDGs. CONCLUSION: We identified distinct CD10-positive and CD10-negative LDGs in patients with AAV. The roles of these LDGs in AAV pathology will require further investigation.

MPO-ANCA-positive Microscopic Polyangiitis Following COVID-19 Infection.

Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is a systemic disease that causes vasculitis in various organs. Although the cause of the onset is unknown, infection has been reported to be a causative factor. The subsequent cytokine storm triggered by the immune response against SARS-CoV-2 infection has been reported to lead to symptoms being more severe. We herein report our experience with the onset of AAV following COVID-19 infection. We also report the course of anti-SARS-CoV-2 serum antibody titers following induction therapy, which suggests that vaccination and education concerning standard precautions are necessary in patients who require immunosuppressive therapy, even after COVID-19 infection.

Clinical features of psoriatic arthritis.

Psoriatic arthritis (PsA) is associated with decreased quality of life. As delayed diagnosis may lead to progressive joint destruction and long-term disability, the key clinical features of PsA should be recognizable to a wide range of clinicians to facilitate early diagnosis. In addition to assessment and identification of skin and nail lesions, which occur in up to 85% of those with musculoskeletal manifestations, clinicians should be aware of both the peripheral and axial manifestations of musculoskeletal disease reviewed here. Peripheral joint diseases include polyarticular, oligoarticular, distal, and arthritis mutilans subtypes, and cognizance of these patterns of disease, as well as periarticular manifestations, including dactylitis and enthesitis, is useful for swift diagnosis of PsA. Axial psoriatic arthritis (axial PsA), also known as the spondylitis subtype, may be limited to the spine and sacroiliac joints, but may also affect peripheral structures. Meticulous history-taking and physical examination and familiarity with appropriate imaging studies are often necessary to distinguish axial-PsA from other differential diagnoses. Swift diagnosis and treatment are necessary to both control PsA disease and mitigate the risks of the many associate comorbidities that may accompany it.

Elevated fecal calprotectin and lactoferrin associated with small intestinal lesions in patients with Behçet disease.

BACKGROUND AND AIMS: Small intestinal lesions in patients with Behçet disease (BD) have a risk of perforation and hemorrhage requiring surgery. However, no screening strategy for such lesions has been established. We investigated small intestinal lesions in BD patients with video capsule endoscopy (VCE) and analyzed clinical characteristics to identify noninvasive biomarkers of such lesions. METHODS: This study included 33 BD patients who underwent VCE (PillCam® SB3) at our institution from June 2016 to January 2019. Clinical characteristics, including age, sex, disease duration, body mass index, gastrointestinal symptoms, eye involvement, and blood examinations, were obtained from the medical records of 27 of the 33 patients. Fecal immunochemical tests for hemoglobin, fecal calprotectin (FC), and fecal lactoferrin (FL) were measured. VCE findings of 145 healthy Japanese individuals from a previous report were used as controls. RESULTS: Two intestinal BD patients were included in the 27 patients. We observed that BD patients exhibit more small intestinal lesions compared with healthy individuals, including erosions, ulcers, and total lesions (erosions or ulcers). FC and FL levels were significantly higher in patients with versus without small intestinal lesions (P = 0.034 and P = 0.046, respectively). Receiver operating characteristic analyses demonstrated that FC (cutoff value = 119 µg/g) and FL (cutoff value = 17 µg/g) were biomarkers for small intestinal lesions in patients with BD. CONCLUSION: The present study using VCE showed that patients with BD had more small intestinal lesions than healthy individuals. FC and FL could be useful for screening BD patients who may have small intestinal lesions.

Systematic review and meta-analysis for 2017 clinical practice guidelines of the Japan research committee of the ministry of health, labour, and welfare for intractable vasculitis for the management of ANCA-associated vasculitis.

OBJECTIVES: To provide evidence for the revision of clinical practice guideline (CPG) for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) by the Japan Research Committee for Intractable Vasculitis. METHODS: PubMed, CENTRAL, and the Japan Medical Abstracts Society were searched for articles published between January 1994 and January 2015 to conduct systematic review (SR), and the quality of evidence was assessed with GRADE approach. RESULTS: Nine randomized controlled trials (RCTs) and two non-RCTs were adopted for remission induction therapy, three RCTs and two non-RCTs for plasma exchange, and five RCTs and one non-RCT for remission maintenance therapy. A significant difference was found in efficacy and safety for the following comparisons. In the non-RCT adopted for remission induction therapy, glucocorticoid (GC) + cyclophosphamide (CY) was significantly superior to GC monotherapy regarding remission. GC + intravenous CY for remission induction therapy was superior to GC + oral CY regarding death at one year, serious adverse events, and serious infection. Concomitant use of plasma exchange for remission induction therapy of AAV with severe renal dysfunction reduced risk of end-stage renal disease versus non-users at month 3. CONCLUSION: This SR provided necessary evidence for developing CPG for the management of ANCA-associated vasculitis.

The role of myeloperoxidase and myeloperoxidase-antineutrophil cytoplasmic antibodies (MPO-ANCAs) in the pathogenesis of human MPO-ANCA-associated glomerulonephritis.

It is well known that antineutrophil cytoplasmic antibodies (ANCAs) are pathogenic and have a diagnostic value for ANCA-associated vasculitis. We demonstrated that a rise in myeloperoxidase (MPO)-ANCA titers during remission is often predictive of a future relapse in MPO-ANCA-associated vasculitis. Pathological examination of renal biopsies indicated that not only MPO-ANCAs, but also extracellular MPO, an in situ immune complex composed of MPO and MPO antibodies, may play important roles in the pathogenesis of glomerular capillary injury in MPO-ANCA-associated vasculitis.

Immunopathologic co-localization of MPO, IgG, and C3 in glomeruli in human MPO-ANCA-associated glomerulonephritis.

Myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA)- associated glomerulonephritis (GN) is characterized by pauci-immune necrotizing glomerulonephritis(NGN). Although it has been thought that MPO-ANCA is involved in the pathogenesis of capillary injuries in NGN via activation of neutrophils, recent studies suggest a possible role of other factors such as immunoglobulins precipitated on the glomeruli. Here we performed a pathological study investigating a relationship of deposition of MPO, IgG, complements with regard to MPO-positive cells and glomerular capillaries in human MPO-ANCA-associated GN. Renal specimen including 317 glomeruli obtained from 20 patients with MPOANCA- associated GN were analyzed. All of the specimens showed significant focal segmental deposition of IgG. There was a significant glomerular infiltration of MPO-positive cells along with deposition of extracellular MPO in the active lesions of segmental and global NCG, with CD34 staining being decreased in the adjacent areas. IgG deposits were almost colocalized with C3 and partly with MPO, which are also associated with a decrease in CD34 staining, suggesting that immune complex formation and the resultant capillary injuries. Actually occurred, the colocalization of MPO, IgG and C3 was seen only in the glomerular lesions with low severity and activity. These results suggest that not only MPO itself released from the neutrophils but also immune complexes composed of MPO and anti-MPO antibody may play some pathogenetic roles for the glomerular injuries especially in the early phase of human MPO-ANCA-associated GN.

AP-VAS 2012 case report: MPO-ANCA-negative relapse of MPO-ANCA-associated vasculitis.

A 79-year-old female was admitted to our hospital with fever, proteinuria, hematuria, high levels of C-reactive protein (CRP), and high titer of myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA). Our diagnosis was microscopic polyangiitis (MPA) and she was treated with steroid pulse therapy. Clinical remission was induced; however, the disease relapsed with saddle nose and necrotizing vasculitis of the nasal cavity mucosa 1 year later. Although there was no elevation of the MPO-ANCA titer, we diagnosed the patient with relapse of MPO-ANCA-positive granulomatosis with polyangiitis (GPA). Remission was induced again with steroids and azathioprine. It has been reported that the number of MPO-ANCA-positive patients in Asian countries is relatively higher than in Western countries. We checked 29 GPA patients in our hospital and 9 patients (31.0 %) were MPO-ANCA-positive. In addition, it is not rare that an ANCA-associated vasculitis (AAV) patient who has been in remission with negative ANCA relapses without any elevation of ANCA titer. We checked the transition of ANCA titer of 24 AAV patients in our hospital who relapsed and 6 patients (25 %) relapsed without any elevation of ANCA titer. We should be careful for a relapse, even if the ANCA titer remains negative. It is also possible that ANCA had been changed so as not to be detected by the same enzyme-linked immunosorbent assay (ELISA) kit. Thus, it is also important to change the detection system if clinical symptoms are worsened while ANCA is still negative.

The effect of water loading on the urinary ratio of cortisone to cortisol in healthy subjects and a new approach to the evaluation of the ratio as an index for in vivo human 11ß-hydroxysteroid dehydrogenase 2 activity.

Factors that give rise to a large variation in the urinary ratio of free cortisone to cortisol (UFE/UFF) were investigated to accurately estimate 11ß-hydroxysteroid dehydrogenase 2 (11ß-HSD2) activity in humans in vivo. A water loading test was first carried out in two healthy subjects to examine the effect of water intake or urine volume on the urinary ratio of free cortisone to cortisol (UFE/UFF). The ratio was found to increase by water loading. We also examined urinary concentrations and amounts of cortisol, cortisone, creatinine, Na(+), K(+), and Cl(-), and urine volume, as possible factors affecting the urinary ratio (UFE/UFF), in 60 urine samples obtained from 15 healthy volunteers. Among these factors tested, the urinary concentration of cortisol was most highly correlated with the UFE/UFF ratio (r=-0.858), indicating that the in vivo activity of 11ß-HSD2 (UFE/UFF) should fluctuate with the changes of the urinary concentration of cortisol. Based on the findings, we proposed a new estimation method of in vivo activity of 11ß-HSD2 in humans, using the UFE/UFF ratio correlated with the urinary concentration of cortisol (UFE/UFF-cortisol concentration). Taking into consideration the intra-individual variabilities in the urinary concentration of cortisol, there were no significant within-day variations in 11ß-HSD2 activity. The findings indicate that 11ß-HSD2 activities can be accurately evaluated by simply measuring free cortisol and cortisone concentrations in spot urine samples. Furthermore, administrations of glycyrrhetinic acid in three healthy volunteers were performed to confirm the usefulness of the present assessment for the activity of 11ß-HSD2.

[Case of MPO-ANCA-associated vasculitis with membranous nephropathy].

We experienced a rare case of membranous glomerulopathy(MN) with myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA)-associated glomerulonephritis. A 79-year-old woman was admitted to our hospital because of pyrexia, microscopic hematuria, massive proteinuria and positive MPO-ANCA on June, 2007. We diagnosed her as MPO-ANCA-associated vasculitis accompanied by nephrotic syndrome. Intravenous methylprednisolone sodium succinate (500 mg/day for three days)therapy and oral prednisolone (40 mg/day) improved her fever, hematuria, serum CRP and MPO-ANCA titer. Renal biopsy was performed and light microscopic examination of a renal biopsy specimen containing 21 glomeruli revealed global sclerosis in 3 and thickened basement membrane in 18 of the glomeruli. Fibrocellular crescents were found in 2 and segmental necrosis in 1. Immunofluorescence microscopy showed granular staining with IgG and C3 along the capillary walls. Electron microscopic examination disclosed subepithelial dense deposits in the thickened glomerular basement membrane. To investigate the pathogenesis of MN, IgG subclass was examined by means of immunofluorescence microscopy. IgG1 and IgG4 were deposited on the glomerular capillary walls, which suggested secondary MN. However, this patient refused to take any medicines and had no disease such as infection or cancer which cause secondary MN. MPO staining was performed to investigate the relation of MPO-anti-MPO antibody immune complex in the pathogenesis of MN. The results showed only a few MPO-positive cells in the glomeruli and MPO stains on the glomerular capillary walls near the MPO-positive cells. These findings suggested that the patient had MPO-ANCA-associated glomerulonephritis superimposed on idiopathic MN. In the case of nephrotic syndrome with MPO-ANCA, we should consider the coexistence of other types of glomerulonephritis, especially MN.

[MPO-positive cells and extracellular MPO in the glomeruli of MPO-ANCA-associated glomerulonephritis].

BACKGROUND: MPO-ANCA (myeloperoxidase anti-neutrophil cytoplasmic antibody) is closely related to the pathogenesis of MPO-ANCA-associated glomerulonephritis through MPO-positive cells and MPO-positive cell activation. Activated MPO-positive cells, including neutrophils and monocytes, cause glomerular capillary injury via enzyme release, such as MPO. We evaluated glomerular MPO-positive cell infiltration, extracellular MPO localization and glomerular endothelial cell injury in MPO-ANCA-associated glomerulonephritis. METHODS: Renal specimens including 282 glomeruli obtained from 19 patients with MPO-ANCA-associated glomerulonephritis were analyzed. Enzyme-labeled antibody assay and immunofluorescence staining of MPO and CD34 were employed. MPO-staining was used to detect MPO-positive cells and extracellular MPO and CD34-staining was used to define glomerular endothelial cell injury. The number of MPO-positive cell infiltrations, and localization of MPO and CD34-staining areas were scored in each glomerulus. These scores were compared with the glomerular damage grading used by PAS and PAM staining. RESULTS: 1) MPO-positive cells increased in number in correlation with the grade of acute glomerular injury. 2) Extracellular MPO were present close to the MPO-positive cells, along the glomerular capillary walls. 3) The CD34-staining area on the glomerular capillary wall decreased, in parallel with the acute glomerular injury grading. 4) MPO depositions along the glomerular capillary wall were shown to be associated with decreased staining of CD34, with immunofluorescence staining on the same glomerular section. 5) Several glomeruli with minor abnormalities showed focal MPO-positive cell infiltration associated with the presence of MPO along the glomerular capillary wall. CONCLUSION: These results suggest that MPO-positive cells and extracellular MPO play important roles in the pathogenesis of glomerular capillary injury from the early stage of MPO-ANCA-associated glomerulonephritis.