Epitope recognized by anti-glomerular basement membrane (GBM) antibody in a patient with repeated relapse of anti-GBM disease.

The major epitopes recognized by autoantibodies in anti-glomerular basement membrane (GBM) disease are found in the α3-subunit non-collagenous domain of type IV collagen [α3(IV)NC1], which is present in the glomerular and alveolar basement membranes. These epitopes are structurally cryptic, owing to the hexamer formation of the non-collagenous domain of α3, α4, and α5 subunits and are expressed by the dissociation of the hexamer. Anti-GBM disease usually manifests as a single attack (SA), and we rarely see patients who repeatedly relapse. We recently treated a patient with anti-GBM disease who exhibited repeated relapse (RR). Here, we conducted immunohistochemistry of formalin-fixed paraffin-embedded normal kidney sections and immunoblotting using recombinant human α3(IV)NC1 to compare the epitopes recognized by anti-GBM antibodies in the RR patient and SA patients. Although a clear staining of GBM especially in the connecting basement membrane of Bowman's capsule was observed when IgGs of SA patients were used as primary antibodies, such staining was not obtained when IgG of the RR patient was employed. In immunoblotting of α3(IV)NC1 using the IgG of the RR patient as a primary antibody, an 18-kDa band was detected besides the 56.8-kDa band corresponding to the whole-size α3(IV)NC1. Whereas the 56.8-kDa band disappeared after digestion of the recombinant α3(IV)NC1 by protease, the 18-kDa band remained. Furthermore, the 18-kDa band was not detected by a commercially available anti-α3(IV)NC1 monoclonal antibody. These findings suggest that the IgG of the RR patient recognizes the epitope distinct from that recognized by the anti-α3(IV)NC1 monoclonal antibody.

CD8-positive T-cell lymphoproliferative disorder associated with Epstein-Barr virus-infected B-cells in a rheumatoid arthritis patient under methotrexate treatment.

We report a 48-year-old female who developed lymphoproliferative disorder (LPD) during treatment of rheumatoid arthritis (RA) with methotrexate (MTX). She presented with multiple tumors in the cervical lymph nodes (LNs), multiple lung shadows and round shadows in both kidneys with pancytopenia and a high CRP level. The LN showed CD8-positive T-cell LPD associated with Epstein-Barr (EB) virus-infected B-cells. Clonality assays for immunoglobulin (Ig) heavy chain and T-cell receptor gamma (TCRγ) were negative. The cessation of MTX without chemotherapy resulted in the complete disappearance of the tumors and abnormal clinical features. We compared this case with previously published ones and discuss the pathological findings, presuming that the proliferation of CD8 T-cells was a reactive manifestation to reactivated EB virus-infected B-cells.

Expression of matrix metalloproteinases 2 and 9 and tissue inhibitors of matrix metalloproteinases 2 and 1 in the glomeruli of human glomerular diseases: the results of studies using immunofluorescence, in situ hybridization, and immunoelectron microscopy.

BACKGROUND: It has been reported matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of matrix metalloproteinases (TIMPs), play important roles in the decomposition of the extracellular matrices of the glomerulus during the pathological processes in various glomerular diseases. Although the activity of these enzymes in cases of experimental glomerulonephritis has been described, the expression sites in the glomeruli of human renal diseases have been identified in only a few articles and remain controversial. METHODS: The expression of the gelatinase group of MMPs (MMP-2 and MMP-9) and their inhibitors (TIMP-2 and TIMP-1) were evaluated in 19 renal biopsies of several types of glomerular diseases by immunofluorescence (IF) labeling. In addition, several samples of immunoglobulin A nephropathy (IgAN) were also investigated by in situ hybridization (ISH) and immunoelectron microscopy (IEM). RESULTS: The expression of MMP-2 was observed in all the cases examined by IF and ISH. TIMP-2 expression varied from negative to positive among 11 cases of IgAN, but was negative in the cases with lupus nephritis (LN) (n = 3), membranoproliferative glomerulonephritis (MPGN) (n = 2), and post-streptococcal glomerulonephritis (n = 1). However, it was weakly positive in the cases of diabetic nephropathy (DMN) (n = 2). MMP-2 was mainly observed along glomerular capillary loops (GCLs) and Bowman's capsules, whereas TIMP-2 was found in the mesangial area. The expression of MMP-9 in cases of IgAN varied, and was local, not diffuse, if it was present. MMP-9 expression in cases of LN, MPGN, and DMN was diffuse, but the intensity of staining varied. MMP-9 was primarily expressed in the mesangium. TIMP-1 expression was negative in all cases except for those with IgAN. The localization of MMP-2 in patients with IgAN, which was investigated by IEM, was revealed to be mainly on the endothelial cell membranes of GCLs, podocyte membranes, the parietal cell membranes of Bowman's capsules, and some on the membranes of mesangial cells. CONCLUSION: The study results suggest that the expression levels and patterns of MMPs and TIMPs are generally similar in several types of glomerular diseases, even though each case has a somewhat different distribution and intensity of expression. When these enzymes were present, their main sites were as follows: MMP-2 was found along glomerular basement membrane, TIMP-2 was located in the acellular mesangial area, MMP-9 was seen in the mesangium, and TIMP-1 was hardly detected. MMP-2 expression is clearly demonstrated to exist at the above-described sites by IEM in patients with IgAN.

Severity-based treatment for Japanese patients with MPO-ANCA-associated vasculitis: the JMAAV study.

We (JMAAV [Japanese patients with MPO-ANCA-associated vasculitis] Study Group) performed a prospective, open-label, multi-center trial to evaluate the usefulness of severity-based treatment in Japanese patients with myeloperoxidase-anti-neutrophil cytoplasmic antibodies (MPO-ANCA)-associated vasculitis. Patients with MPO-ANCA-associated vasculitis received a severity-based regimen according to the appropriate protocol: low-dose corticosteroid and, if necessary, cyclophosphamide or azathioprine in patients with mild form; high-dose corticosteroid and cyclophosphamide in those with severe form; and the severe-form regimen plus plasmapheresis in those with the most severe form. We followed up the patients for 18 months. The primary end points were the induction of remission, death, and end-stage renal disease (ESRD). Fifty-two patients were registered, and 48 patients were enrolled in this study (mild form, n = 23; severe form, n = 23; most severe form, n = 2). Among the 47 patients who received the predefined therapies, 42 achieved remission within 6 months, 5 died, and 1 developed ESRD. Disease flared up in 8 of the 42 patients with remission during the 18-month follow-up period. The JMAAV trial is the first prospective trial for MPO-ANCA-associated vasculitis to be performed in Japan. The remission and death rates were comparable to those in several previous clinical trials performed in western counties. The regimen employed in this trial was tailor-made based on patients' disease severity and disease type, and it seems that standardization can be consistent with treatment choices made according to severity.

Increased concentrations of antibody against heat shock protein in patients with myeloperoxidase anti-neutrophil cytoplasmic autoantibody positive microscopic polyangiitis.

To determine serum antibody against human and bacterial heat shock protein (HSP) 60/70 in myeloperoxidase (MPO)-specific anti-neutrophil cytoplasmic autoantibody (ANCA) positive microscopic polyangiitis (MPA), 58 patients with MPO-ANCA positive MPA, 48 with RA (rheumatoid arthritis) and 40 with SLE (systemic lupus erythematosus) were studied. Serum antibodies against HSP (human HSP 70, human HSP 60, Mycobacterium HSP 70, and Escherichia coli HSP 60) were measured by sandwich ELISA. The frequency of anti-human HSP 60/70 antibody positive patients was significantly greater in MPO-ANCA positive MPA than SLE and healthy controls. Anti-human HSP 60/70 antibody titers in patients with MPO-ANCA positive MPA were significantly higher than those of healthy controls; anti-bacterial HSP 60/70 antibody titers were also higher. There was a significant correlation between titers of anti-human HSP 70 antibody and anti-Mycobacterium HSP 70 antibody. A correlation was also found between titers of anti-human HSP 70 antibody and anti-human HSP 60 antibody. Anti-human and bacterial HSP 60/70 antibody titers changed in parallel with disease activity in patients with antibody positive MPA. The anti-HSP antibody titer was also increased in patients with RA and SLE. These results suggest that an immunological background via anti-HSP 60/70 antibodies might be associated with pathogenesis in MPO-ANCA positive MPA.

Dual myeloperoxidase-antineutrophil cytoplasmic antibody- and antiglomerular basement membrane antibody-positive cases associated with prior pulmonary fibrosis: a report of four cases.

BACKGROUND: Both myeloperoxidase-associated antineutrophil cytoplasmic antibody (MPO-ANCA) and antiglomerular basement membrane antibody (anti-GBM Ab) positivity have been demonstrated in patients with rapidly progressive glomerulonephritis (RPGN), either with or without pulmonary hemorrhage; however, the implications of these antibodies in such patients have not yet been elucidated. The cases with dual positive antibodies were studied clinically, serologically, and pathologically, and the implications of antibodies are discussed here. PATIENTS AND METHODS: Four patients with prior pulmonary fibrosis, who subsequently developed RPGN and pulmonary hemorrhage, were studied clinically, serologically, and pathologically. The clinical data were reviewed extensively and the dual positive antibodies were detected by enzyme-linked immunosorbent assays. Pathological studies were performed with a renal biopsy in one patient, a gastric biopsy in another patient, and autopsy materials in the remaining 2 patients. RESULTS: All 4 patients had prior pulmonary fibrosis before the symptoms of RPGN when the dual positivity of MPO-ANCA and anti-GBM Ab was detected. Three cases were accompanied by pulmonary hemorrhage around the time of RPGN whereas the remaining case demonstrated pulmonary hemorrhage a few years later. Renal tissue specimens in 3 cases showed circumferential crescents and linear immunoglobulin G deposits along the glomerular capillary loops in glomeruli. Two autopsy specimens revealed vasculitis of the small arteries and arterioles of the kidney, and one of them showed similar vasculitic findings in both the gastrointestinal tract walls and the adipose tissues of the adrenal glands. Additionally, a case with pulmonary hemorrhage occurring after remission was associated with re-elevated MPO-ANCA levels but without anti-GBM Ab positivity. A gastric biopsy was unremarkable and non-contributory for the diagnosis, but this case showed vasculitic symptoms of peripheral neuritis and retinal hemorrhage. Taken together, all 4 cases demonstrated prior pulmonary fibrosis and dual positivity of MPO-ANCA as well as anti-GBM Abs at the time of RPGN, and were associated with either pulmonary hemorrhage or its occurrence thereafter. CONCLUSION: Four cases that showed prior pulmonary fibrosis as well as subsequent RPGN and pulmonary hemorrhage were both MPO-ANCA- and anti-GBM Ab-positive at the time of RPGN. The glomeruli disclosed features compatible with anti-GBM Ab disease, but the clinical and pathological vasculitic manifestations, including prior pulmonary fibrosis that might be an early manifestation of ANCA disease, suggested the occurrence of MPO-ANCA-associated vasculitis. Furthermore, 1 case subsequently showed repetitive pulmonary hemorrhage with re-elevated MPO-ANCA positivity but without anti-GBM Ab positivity, and this event was possibly due to MPO-ANCA-associated alveolar capillaritis. As anti-GBM Ab disease is generally thought not to manifest the clinical and pathological features of vasculitis excluding the kidney, MPO-ANCA might be a key factor regarding the occurrence of this dual positive disease.

Anti-glomerular basement membrane (anti-GBM) disease accompanied by vasculitis that was not positive for antineutrophil cytoplasmic antibodies to myeloperoxidase and proteinase 3: a report of two cases and the incidence of anti-GBM disease at one institution.

BACKGROUND: Anti-glomerular basement membrane (anti-GBM) disease is thought to be distinct from vasculitis. In contrast, there have been several papers suggesting the presence of angiitis in cases that were positive for anti-GBM antibody (Ab), as well as for either myeloperoxidase (MPO)- or proteinase 3 (PR3)-anti-neutrophil cytoplasmic antibody (ANCA) (Group I). We experienced four patients who had anti-GBM Abs, but not MPO- and PR3-ANCA (Group II), and two of these patients were found to have vasculitis. Therefore, we performed an in-depth study on these two patients. METHODS: The patients with anti-GBM disease were isolated from 578 cases whose renal tissues were examined, and they were categorized into two groups. We have already published the data about Group I. We then proceeded to study two vasculitic patients in Group II clinically, pathologically, and serologically. The anti-GBM Ab and ANCA levels were detected by enzyme-linked immunosorbent assays. Renal specimens were studied by routine staining as well as immunohistochemical investigations of CD31 and type IV collagen. RESULTS: The total number of patients with anti-GBM disease was 7 (7/578 = 1.2%), with 3 patients belonging to Group I and 4 patients belonging to Group II. Two patients in Group II were diagnosed to have vasculitis, but the remaining 2 patients did not. One vasculitic patient was complicated by pulmonary hemorrhage, while the other vasculitic patient displayed peripheral neuropathy as well as a small cavity lesion in the lung. The latter patient was found to be positive for perinuclear (p)-ANCA, but not for any other ANCA subsets. The renal pathology in the two vasculitic patients showed crescentic glomerulonephritis (CSGN) and immunoglobulin (Ig) G linear deposits along the glomerular capillary loops. The former patient showed fibrinoid angiitis in an afferent arteriole as well as peritubular capillaritis. The latter patient demonstrated peritubular capillaritis. These peritubular capillaritides were diagnosed by the loss of CD31 and type IV collagen staining, the blurred appearance of peritubular capillary walls by periodic acid-Schiff staining, and the pericapillary infiltration of inflammatory cells. CONCLUSION: The incidence of anti-GBM disease was very low, and our patients were categorized into two groups (Groups I and II) based on whether or not they were positive for MPO- or PR3-ANCA. Two patients in Group II were found to have vasculitis. According to our results, we concluded that the anti-GBM disease of Group II could also be associated with vasculitis.

Identification of MPO-positive capillaries of the pleura by immunohistochemistry in MPO-ANCA associated vasculitis.

We present a case of a middle-aged woman with myeloperoxidase anti-neutrophil cytoplasmic autoantibody (MPO-ANCA)-associated vasculitis that demonstrated immunohistochemically positive MPO capillaries of the pleura. The patient initially presented with proteinuria and microscopic hematuria at the age of 38. Acute progressive glomerulonephritis and pulmonary hemorrhage occurred 4 years later, and a high serum titer of MPO-ANCA was detected therefore a diagnosis of microscopic polyangiitis was made. Steroid-pulse therapy was performed and the pulmonary shadow improved, but the renal failure did not improve, thus, hemodialysis was initiated. Thereafter, an 18-year asymptomatic phase followed, but high serum levels of MPO-ANCA persisted during this period. Chronic pulmonary hemorrhage was discovered at the age of 60, and video-assisted thoracoscopic surgery was performed. Resected tissue revealed diffuse aloveolar hemorrhage accompanied by marked hemosiderin deposition, whereas MPO-immunopositive capillaries were identified only in the pleura. To our knowledge, this is the first report demonstrating MPO-positive capillaries in a disease other than glomerulonephritis. Judging from this unique case, MPO-positive endothelial cells may appear only during the hyperacute stage before hemorrhage, and may diminish thereafter, thus, may be associated with the trigger of microscopic polyangiitis.

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

BACKGROUND: Myeloperoxidase-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. METHODS: The 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. RESULTS: The 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 beta2-microglobulin in the urine, but no proteinuria. CONCLUSION: Based 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.

[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.

Multiple aortic aneurysms complicated by a rupture in the systemic lupus erythematosus: a case report.

We report the case of a 61-year-old female who suffered from systemic lupus erythematosus (SLE) and died of a ruptured abdominal aortic aneurysm (AA). She was diagnosed to have SLE at 39 years of age, and was administrated steroids and prostaglandin E(2). From 52 years of age, AA, peripheral arterial occlusion, and multiple organ infarctions appeared repeatedly. At 59 years of age, she was found to be affected by antiphospholipid antibody syndrome (APS). In the following year, expansion of an abdominal AA was identified, but she was given only conservative treatment. In the next year, sudden epigastralgia and dyspnea occurred, and she died. An autopsy revealed multiple AAs up to 11 cm in diameter, one of which showed ruptures, forming a retroperitoneal hematoma. Marked atherosclerosis of the aorta was noted, and she also had aortic dissection accompanied by cystic medial necrosis (CMN). An old myocardial infarction and brain infarction were also confirmed. Although SLE with APS is common, a complication of the disease by CMN, multiple AAs, or ruptured AA has been described in several cases to date. Regarding the etiology of this complicated presentation, we presume synergistic involvement of various factors, such as atherosclerosis and CMN associated with SLE, thrombosis due to APS, and prolonged steroid therapy.

Azurocidin-specific-ANCA-related idiopathic necrotizing crescentic glomerulonephritis.

An 80-year-old woman who had rapidly progressive glomerulonephritis unaccompanied by systemic vasculitis is described. On renal biopsy, she showed necrotizing crescentic glomerulonephritis by light microscopy and pauci-immune glomerular lesions by immunofluorescent study. No dense deposits were present on electronmicroscopic study. On serum examination, indirect immunofluorescent study showed perinuclear pattern antineutrophil cytoplasmic antibody (ANCA), but myeloperoxidase-ANCA and proteinase 3-ANCA were both negative. Her serum reacted only to azurocidin excluding other ANCA antigens: bactericidal permeability-increasing protein, cathepsin G, elastase, lactoferrin, or lysozyme. Serum creatinine level decreased, and C-reactive protein turned negative after steroid therapy. Azurocidin-ANCA also turned negative. It is suggested that azurocidin-ANCA might have been related to the inflammatory process of pauci-immune necrotizing crescentic glomerulonephritis in this patient.

[Secondary nephrotic syndrome due to collagen disease and vasculitis].

The most frequent and representative nephrotic syndrome associated with collagen disease is encountered in patients suffering from lupus nephritis. Lupus nephritis is a glomerulonephritis, which discloses various localizations of immune complexes in the endothelium, mesangium and subepithelium. In addition, vasculitides complicated by nephrotic syndrome also show the deposition of immune complexes in their glomeruli, such as Henoch-Schönlein nephritis and cryoglobulinemic nephritis. The pathogenetic mechanisms of these nephrotic syndromes are explained as follows. The depositions of immune complexes in glomeruli causes proteinuria through a variety of mechanisms. Namely, subendothelial and mesangial immune deposits give capillary and mesangial injuries as well as inflammation that are mediated through activation of complements and cytokines, and subsequently leads to nephrotic-range proteinuria and impairment of renal function. On the other hand, subepithelial and intramembranous deposits disrupt the regulated arrangement of epithelial cells and slit diaphragms, and then disturb the slit diaphragms. The eventual dysfunction of slit diaphragms accordingly progresses to massive proteinuria even without capillary injury. Therefore, nephrotic syndrome associated with collagen disease or vasculitis is usually observed in lupus nephritis or vasculitis related to immune complex depositions, but is not observed in non-immune complex glomerulopathy or vasculopathy.

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.

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.

Classification of clinical subtypes, patient survival, kidney prognosis, and relapse in patients with MPO-ANCA-associated vasculitis: a single-center experience.

Myeloperoxidase-type antineutrophil cytoplasmic antibody (MPO-ANCA)-associated vasculitis may manifest various organ symptoms. Treatment allows recovery from early, but severe, organ involvement. However, the relationship between the initial organ involvement and the eventual clinical course has not been studied in this disease. Therefore, the current study evaluated 30 patients who were hospitalized and then categorized into ten clinical subtypes based on organ involvement. The relationship of these subtypes to development of clinical features, patient survival, kidney prognosis, and relapse were evaluated over an average observation period of 4.3 years. During this study, the most common clinical features were lung and kidney involvement. Twenty-one patients already manifested clinical features around the time of admission and did not commonly present new symptoms as long as they were receiving the treatment for vasculitis. In contrast, as far as pulmonary involvement type at the initial time was concerned and in those not being treated for vasculitis, 7 of the 12 patients progressed to pulmo-renal involvement and 5 of them went onto renal failure. Progression to renal failure also occurred frequently in patients with pulmo-renal type manifesting at the initial time. Thirteen patients died, including three patients due to vasculitis of systemic type, seven due to infections, and three due to malignancy. Death due to vasculitis occurred in the early phase of treatment and was associated with either pulmonary hemorrhage or gastrointestinal bleeding. Infectious death occurred throughout the entire course of treatment, mostly in patients with pulmo-renal or pulmonary type, and tended to be associated with opportunistic organisms. Death with malignancy was observed after several years of treatment. Regarding renal prognosis, ten patients underwent hemodialysis. At initiation of hemodialysis, nine patients had pulmo-renal type and only one had renal type. A relapse was observed in ten patients, mainly in patients with pulmo-renal or pulmonary type, and it occurred after about 2.7 years, even with treatment. Such relapses manifested in a similar manner to their initial clinical subtypes. These results suggest that pulmo-renal type as well as pulmonary type have a high chance to progress to renal failure or systemic type, and they were fairly commonly associated with vasculitic or infectious death. Therefore, classification of clinical subtypes at the initial time and on admission is meaningful to some extent for predicting patient survival, kidney prognosis, and relapse, in addition to indicating the appropriate treatment regimen.