Kimimasa Nakabayashi

Cutaneous polyarteritis nodosa: revisiting its definition and diagnostic criteria

Polyarteritis nodosa (PN) is a classical collagen disease with poor prognosis that demonstrates systemic necrotizing vasculitis of small and medium-sized arteries. Cutaneous symptoms are observed in 25–60% of PN patients. On other hand, cutaneous polyarteritis nodosa (CPN) is designated for the cutaneous limited form of PN and demonstrates benign prognosis. However, there has been much debate on whether or not CPN can progress to PN. Although CPN lesions are fundamentally limited to skin, some CPN cases show extracutaneous symptoms such as peripheral neuropathy and myalgia. According to PN diagnostic criteria, which were established by the Ministry of Health, Labour and Welfare of Japan, a disease with both cutaneous and at least one extracutaneous symptom with appropriate histopathological findings can be diagnosed as PN. The same is true according to diagnostic criteria established by the American College of Rheumatology. In addition, there are no specific diagnostic criteria for CPN. In this study, CPN cases were retrospectively collected from multiple Japanese clinics, and analyzed for detailed clinical and histopathological manifestations, in order to redefine the clinical entity of CPN and to propose appropriate diagnostic criteria for CPN and PN. According to the CPN description in Rook’s Textbook of Dermatology, we collected 22 cases with appropriate histopathological findings. Of the 22 cases, none progressed to PN or death during the follow-up period, 32% had peripheral neuropathy and 27% had myalgia. Regarding extracutaneous symptoms with CPN, 17 dermatological specialists in vasculitis sustained the opinion that CPN can be accompanied by peripheral neuropathy and myalgia but these symptoms are limited to the same area as skin lesions. Based on these results, we devised new drafts for CPN and PN diagnostic criteria. Our study shows the efficacy of these criteria and most dermatologists recognized that our new diagnostic criteria for CPN and PN are appropriate at the present time. In conclusion, this study suggests that CPN does not progress to PN, and introduces new drafts for CPN and PN diagnostic criteria.

Pulmonary artery involvement as first manifestation in three cases of Takayasu arteritis

Although the pulmonary artery is often involved in Takayasu arteritis, only a few cases have been reported in which pulmonary artery involvement occurred as the initial clinical manifestation. Based upon history, physical findings, laboratory data, and radiographic studies, we diagnosed Takayasu arteritis in three young females who had pulmonary artery occlusion without apparent lesions in the aortic arch and its main branches. Major symptoms and signs encountered were persistent mild or moderate chest pain, pleural effusion, and an episode of hemoptysis. Pulmonary artery occlusions were confirmed by angiography and perfusion studies. Steroid treatment relieved the symptoms in two cases, but the 3rd case required additional therapy with methotrexate for the suppression of disease activity. We emphasize the importance of considering Takayasu arteritis in cases with the above-mentioned signs and symptoms and pulmonary artery occlusion, despite the absence of aortic lesions.

Analysis of risk epitopes of anti-neutrophil antibody MPO-ANCA in vasculitis in Japanese population.

Autoantibodies to myeloperoxidase (MPO) are a subset of anti‐neutrophil cytoplasmic antibody (ANCA, MPO‐ANCA) detected in the sera of some patients with primary systemic vasculitis. The titer of MPO‐ANCA does not always reflect disease activity and this inconsistency may be attributable to differences in epitopic specificity by MPO‐ANCA among various patients with vasculitis. Epitope analysis may also explain the occurrence of MPO‐ANCA in different vasculitic syndromes. We screened the sera of 148 MPO‐ANCA positive patients from six vasculitic syndromes: rapidly progressive gromerulonephritis (RPGN), microscopic polyangiitis (MPA), idiopathic crescentic glomerulonephritis (I‐CrGN), classic polyangiitis nodosa (cPAN), Churg‐Strauss syndrome (CSS), Kawasaki disease (KD); and from patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). The sera were collected by the Intractable Vasculitis Research Project Group in Japan. No serum showed epitopes La and Lb of light chain of MPO, and sera with 68.6% of patients showed a positive reaction to one or more epitopes in heavy chain of MPO. Analysis of binding level showed that RPGN, I‐CrGN and MPA sera mainly reacted to the Ha epitope at the N‐termimus of the MPO heavy chain, CSS sera reacted to Ha and the Hf epitope close to the C‐terminus of the MPO heavy chain, KD reacted mainly to Hf, while SLE and RA sera reacted to all epitopes. These results suggest that MPO‐ANCA recognizing specific regions of the N‐terminus of the MPO H‐chain confer an increased risk of vasculitis RPGN, I‐CrGN, MPA and CSS. Furthermore, the epitopic specificity of MPO‐ANCA differentiates vasculitic from non‐vasculitic syndromes associated with MPO‐ANCA positivity and differentiates in the cirtain type of vasculitis from various vasculitic syndromes. In particular, vasculitic syndromes associated with kidney involvement had similar epitopic reactivity which suggests that this pattern confers an increased risk of vasculitis.

Aortic aneurysms in systemic lupus erythematosus: a meta-analysis of 35 cases in the literature and two different pathogeneses

BACKGROUND Aortic aneurysms including dissection are uncommon complications of systemic lupus erythematosus, but the incidence has been increasing with an improved prognosis for this disease. However, the mechanisms contributing to aneurysm formation in systemic lupus erythematosus have not been fully clarified. METHODS A meta-analysis of published cases was conducted to clarify the patient characteristics that may contribute to aneurysm formation in systemic lupus erythematosus. A search of relevant studies published over the past 40 years (1969-2008) was carried out in the publications on aortic aneurysms with systemic lupus erythematosus, and 35 cases were identified. The contributing factors to aneurysm formation as well as the patient prognosis were searched for sex, age, duration of corticosteroid treatment, aneurysm site (thoracic and/or abdominal), mortality, evidence of atherosclerotic involvement, and presence or absence of an operation, rupture, dissection, cystic medial degeneration, vasculitis, and hypertension. Each of these factors was assigned to each point score. Based on the point scores, a statistical analysis of rank correlation was thereafter performed. RESULTS The factors correlating with the presence of thoracic or abdominal lesions differed significantly. The presence of thoracic aneurysms correlated with dissection and cystic medial degeneration, whereas abdominal lesions correlated with the finding of atherosclerosis. Thoracic lesions showed a high rate of death, while abdominal lesions were associated with a relatively favorable prognosis. Abdominal lesions were related to the duration of steroid therapy. The other correlations among the various factors were also evaluated, with the finding of cystic medial degeneration associated with vasculitis. CONCLUSION Two principal patterns emerged from this analysis. One was the fatal nonatherosclerotic thoracic aneurysm which was associated with cystic medial degeneration and probably due to vasculitis. The other was atherosclerotic abdominal aneurysm which was complicated by long-term steroid treatment and it showed a relatively favorable prognosis.

Tubulointerstitial nephritis without glomerular lesions in three patients with myeloperoxidase-ANCA-associated vasculitis

BackgroundMyeloperoxidase–antineutrophil cytoplasmic antibody (MPO–ANCA)-associated vasculitis frequently induces crescentic glomerulonephritis. However, a few cases have so far been reported to have only tubulointerstitial (TI) nephritis without any apparent glomerular lesions. We recently treated three similar cases. Therefore, their pathological features as well as clinical manifestations were studied in detail.MethodsThe pathological study was performed with immunohistochemical staining using various antibodies to the vascular endothelial cell surface markers, von Willebrand factor, type IV collagen, cytokeratin, E-cadherin, and MPO in addition to the routine histochemical examination.ResultsThe study disclosed the loss of CD34 endothelial cell surface markers with and without the destruction of type IV collagen (capillary basement membrane) in the peritubular capillaries, even though the glomeruli showed good staining of these factors. Electron microscopy showed breaks in the capillary basement membrane. The loss of CD34 staining was associated with the infiltration of a few mononuclear cells and neutrophils in the lumen of peritubular capillaries and the surrounding interstitial tissues. The cytokeratin staining in the tubular epithelial cells was also diminished around these areas. Tubulitis was demonstrated with or without the destruction of the tubular basement membrane. The clinical manifestations of these three cases were only a few red blood cells and granular casts in the urinary sediment as well as slightly increased β2-microglobulin in the urine, but no proteinuria.ConclusionBased on these findings, the loss of CD34 vascular endothelial markers occurs in the early phase of the disease because of the MPO, which is presumed to have burst out from the infiltrated, activated neutrophils. This MPO, which releases proteolytic enzymes and radical oxygen species, acts on tissue destruction, namely the lysis of endothelial cell membranes as well as vascular basement membranes in the peritubular capillary. This mechanism eventually proceeds to the destruction of the peritubular capillary walls (vasculitis). This pathogenesis is thought to play an important role in the pathogenesis of TI nephritis, which is associated with MPO–ANCA vasculitis.

Expression of MMP-9 in mesangial cells and its changes in anti-GBM glomerulonephritis in WKY rats

BackgroundMatrix metalloproteinase (MMP)-9, a member of the MMP family with specificity towards type IV collagen, is implicated in the turnover of the extracellular matrix in the kidney. To elucidate its physiological and pathophysiological significance, we examined the expression and localization of MMP-9 in the normal kidney and the changes in these features during the course of anti-glomerular basement membrane (GBM) glomerulonephritis induced in WKY rats, along with the changes in these features of tissue inhibitor of metalloproteinase 1 (TIMP-1) and MMP-2.MethodsThe expression of MMP-9, TIMP-1 and MMP-2 mRNA was quantified by ribonuclease protection assay, and the gelatinolytic activities of MMP-9 and MMP-2 were evaluated by gelatin zymography. The localization of MMP-9 was visualized by immunohistochemistry and immunofluorescence microscopy.ResultsThe ribonuclease protection assay indicated the almost exclusive expression of MMP-9 mRNA in the glomerulus of normal kidneys. Immunohistochemistry and double-label immunofluorescence microscopy showed that MMP-9 was localized in the mesangial cells. During the course of anti-GBM glomerulonephritis, the expression of MMP-9 mRNA in glomeruli increased on day 1, peaked on days 3 to 7, and then decreased on day 14. The change in MMP-9 mRNA expression was accompanied by parallel changes in the gelatinolytic activity of the active form of MMP-9, TIMP-1 mRNA expression, and MMP-9 immunoreactivity in mesangial cells. In contrast, glomerular MMP-2 mRNA expression and its activity increased after the decline of MMP-9.ConclusionsMMP-9 mRNA was predominantly expressed in the glomerulus in normal rat kidneys and MMP-9 was present in the mesangium. The MMP-9 mRNA expression increased in the glomerulus 3 to 7 days after the induction of anti-GBM glomerulonephritis in WKY rats, in parallel with the development of abnormal glomerular histology and injury, suggesting a role of MMP-9 in proteolysis of the GBM during glomerulonephritis. MMP-2 may participate in the later phase of the nephritis.

Aortitis syndrome associated with positive perinuclear antineutrophil cytoplasmic antibody: report of three cases

We recently experienced three cases of aortitis syndrome that were associated with perinuclear antineutrophil cytoplasmic antibody (ANCA). In the three cases, roentgenographic examination revealed the typical appearance of stenosis or occlusive subclavian arteries. In addition, two cases showed a thickened thoracic aorta wall and the remaining case had irregular stenosis of both common iliac arteries. All three cases had persistently increased ESR and CRP over the years. These findings suggested the diagnosis of aortitis syndrome. ANCA tests were performed because of rapidly progressive glomerulonephritis symptoms in two patients and marked excretion of beta(2)-microglobulin in urine in one patient. The test showed P-ANCA in all three patients, with two patients identified as anti-MPO antibody and the third patient as non-MPO antibody. The implication of ANCA in the pathogenesis of aortitis syndrome is presumed to be: ANCA, which plays an important role in the pathogenesis of small vessel vasculitis, induces vasculitis of the vasa vasorum in the aorta or main branches (or both) and this pathologic process results in the pathogenesis of aortitis syndrome.

Matrix metalloproteinase-2, matrix metalloproteinase-9, and tissue inhibitor of metalloproteinase-1 in the peripheral blood of patients with various glomerular diseases and their implication in pathogenetic lesions: study based on an enzyme-linked assay and immunohistochemical staining

BackgroundVarious glomerular diseases progress to end-stage renal failure due to an accumulation of the mesangial matrix (MM) and a thickening of the glomerular basement membrane (GBM). Both the MM and GBM are consistently metabolized through the synthesis and destruction of the matrix. Such synthesis is influenced by transforming growth factor-β (TGF-β) and other factors, whereas the destruction is presumed to be mediated by both matrix metalloproteinases (MMPs) and inhibitors of matrix metalloproteinases (TIMPs). Based on such evidence, we tried to detect MMP-2, MMP-9, and TIMP-1 in the peripheral blood of patients with various glomerular diseases.MethodsSerum was used to detect MMP-2 and TIMP-1, while plasma was used to detect MMP-9. These enzymes were detected using an enzyme-linked assay.ResultsThe findings showed an increased level of MMP-2 in patients with a alteration of GBM, typically membranous nephropathy (MN), regardless of the differences in their etiological processes. In contrast, MMP-9 did not show a strong association with any specific glomerular abnormalities. However, it mainly tended to increase in patients with MM accumulation. In addition, the localization of MMP-2, MMP-9, and TGF-β1 was studied using immunohistochemical staining. MMP-2 was demonstrated to exist in the glomerular capillary loop (GCL) as well as in the mesangial cells and the mesangial matrix. MMP-9 was found to exist in mesangial cells and the matrix, GCL, infiltrated neutrophils, and some tubular epithelial cells. Positive staining for TGF-β1 in GCL was found to be associated with an increased level of MMP-2 in patients with MN, whereas in MM such positive staining was not necessarily associated with an increased level of MMP-9.ConclusionsThese results therefore suggest that MMP-2 plays an important role in the degradation of GBM, while MMP-9 only moderately affects the degradation of MM.

Increased release of myeloperoxidase in vitro from neutrophils of patients with myeloperoxidase-specific anti-neutrophil cytoplasmic antibody (MPO-ANCA) related glomerulonephritis

Summary: In order to elucidate the role of neutrophils in the pathogenesis of MPO‐specific anti‐neutrophil cytoplasmic antibody (MPO‐ANCA) related glomerulonephritis (GN), MPO release, beta‐glucuronidase (BGL) release, superoxide anion (O2−) production from the neutrophils of patients with MPO‐ANCA related GN were measured. the effect of plasma on MPO release from neutrophils was also studied in patients with MPO‐ANCA related GN. Neutrophils and plasma were obtained from patients with MPO‐ANCA related GN, GN unrelated to MPO‐ANCA and healthy controls. MPO release from the neutrophils of patients with MPO‐ANCA related GN was higher than that of controls significantly. This was also higher than that in patients with GN unrelated to MPG‐ANCA, but this was not statistically significant. Superoxide anion production from neutrophils of patients with MPO‐ANCA related GN was significantly higher than that in patients with GN unrelated MPO‐ANCA, However, BGL release was not significantly different among three groups. Furthermore, MPO release and O2− production increased in parallel with clinical activity of MPO‐ANCA related GN. Neutrophils of patients with MPO‐ANCA related GN showed to be significantly more sensitive to FMLP on MPO release than those in the other two groups. However, plasma from MPO‐ANCA related GN increased the sensitivity to FMLP on MPO release, but not BGL release, in neutrophils obtained from healthy controls, whereas it suppressed MPO release from neutrophils with MPO‐ANCA related GN. This suggests that in patients with MPO‐ANCA related GN MPO can be highly released from activated neutrophils and that the plasma of patients with MPO‐ANCA contains factor(s) which modulate reactivity of neutrophils.

Tubulointerstitial immune complex nephritis in a patient with systemic lupus erythematosus: role of peritubular capillaritis with immune complex deposits in the pathogenesis of the tubulointerstitial nephritis

The correct name of the fourth author should be given as Yoshihiro Arimura, not Yoshiro Arimura.