Survey of Japanese dermatological vasculitis specialists on cases of cutaneous arteritis (cutaneous polyarteritis nodosa).

We developed a questionnaire to examine the findings of cutaneous arteritis among dermatological specialists experienced in vasculitis as certified by the Committee for guidelines for the management of vasculitis and vascular disorders of the Japanese Dermatological Association. We sent a questionnaire to 12 dermatological facilities identified through the revised Committee for guidelines for the management of vasculitis and vascular disorders of the Japanese Dermatological Association. Retrospective data obtained from 84 patients at the 12 dermatological facilities between 2012 January 2016 December were evaluated. The 84 patients were categorized into two groups, a systemic steroid treatment group (group 1, n = 52) and a no systemic steroid treatment group (group 2, n = 32). C-reactive protein in group 1 patients was significantly higher than that in group 2 patients. Frequency of fever, arthritis, myalgia- and peripheral neuropathy in group 1 was significantly higher than that in group 2. We propose that these symptoms could serve as early markers for the transfer from cutaneous arteritis to systemic polyarteritis nodosa. We further suggest that patients who are subsequently associated with cerebral hemorrhage and infarction, who are originally diagnosed as having cutaneous arteritis, could progress to systemic polyarteritis nodosa. The study demonstrated that it is important for dermatologists to detect these findings early in order to establish an accurate diagnosis and a timely treatment.

A Monogenic Disease with a Variety of Phenotypes: Deficiency of Adenosine Deaminase 2.

OBJECTIVE: Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive autoinflammatory disorder associated with ADA2 mutations. We aimed to investigate the characteristics and ADA2 enzyme activities of patients with DADA2 compared to non-DADA2 patients. METHODS: This is a descriptive study of 24 patients with DADA2 who were admitted to the Adult and Pediatric Rheumatology, Pediatric Haematology, and Pediatric Immunology Departments of Hacettepe University. All ADA2 exons were screened by Sanger sequencing. Serum ADA2 enzyme activity was measured by modified spectrophotometric method. RESULTS: Twenty-four patients with DADA2 were included: 14 with polyarteritis nodosa (PAN)-like phenotype (Group 1); 9 with Diamond-Blackfan anemia (DBA)-like features, and 1 with immunodeficiency (Group 2). Fourteen PAN-like DADA2 patients did not have the typical thrombocytosis seen in classic PAN. Inflammatory attacks were evident only in Group 1 patients. Serum ADA2 activity was low in all patients with DADA2 except one, who was tested after hematopoietic stem cell transplantation. There was no significant difference in ADA2 activities between PAN-like and DBA-like patients. In DADA2 patients with one ADA2 mutation, serum ADA2 activities were as low as those of patients with homozygote DADA2. ADA2 activities were normal in non-DADA2 patients. ADA2 mutations were affecting the dimerization domain in Group 1 patients and the catalytic domain in Group 2 patients. CONCLUSION: We suggest assessing ADA2 activity along with genetic analysis because there are patients with one ADA2 mutation and absent enzyme activity. Our data suggest a possible genotype-phenotype correlation in which dimerization domain mutations are associated with PAN-like phenotype, and catalytic domain mutations are associated with hematological manifestations.

Serum lysosomal-associated membrane protein-2 levels are increased in small and medium-vessel vasculitis, especially in polyarteritis nodosa.

OBJECTIVES: Lysosomal-associated membrane protein-2 (LAMP-2) is a highly glycosylated type I glycoprotein ex- pressed on the membranes of neutrophils, endothelial cells and other cells, which are closely linked to subsets of systematic vasculitis. The aim of this study was to investigate whether serum LAMP-2 can be used as a biomarker in small and medium vessel vasculitis (SMVV). METHODS: Serum samples from 39 patients with SMVV (including ANCA-associated vasculitis (AAV) and polyarteritis nodosa (PAN)) confirmed by angiography and/or biopsy and 78 healthy controls (HC) were collected. Serum LAMP-2 levels were determined by enzyme-linked immunosorbent assay. RESULTS: Serum LAMP-2 levels in SMVV patients were increased compared with HC (p<0.001). Serum LAMP-2 levels were significantly different between patients with active stage and those with inactive stage (p=0.024). Patients with renal involvement had higher LAMP-2 levels than patients with non-renal involvement at presentation (p=0.022). Furthermore, serum LAMP-2 levels were correlated with Birmingham Vasculitis Activity Score (BVAS), C-reactive protein (CRP), hypersensitive CRP (Hs-CRP), serum creatinine (Scr) and 24-hour proteinuria (all p<0.05). Among SMVV subsets, serum LAMP-2 levels were signi cantly higher in PAN compared with AAV (p=0.003). In PAN patients, serum LAMP-2 levels were correlated with BVAS and Hs-CRP (all p<0.05). CONCLUSIONS: Serum LAMP-2 levels can reflect the disease activity and renal involvement of SMVV. Furthermore, serum LAMP-2 levels were significantly higher in PAN compared with AAV, and associated with disease activity. LAMP-2 might be a potential biomarker for SMVV, especially in PAN.

[A complex clinical case of polyarteritis nodosa through the prism of kidneys].

Polyarteritis nodosa is a chronic systemic vasculitis, characterized by the autoimmune, necrotising lesion of the walls of the small- and medium-bore visceral and peripheral arteries, resulting in vessel aneurysms and the secondary degeneration of organs and systems. All types of vessels (arteries, veins, capillaries) can be affected or, alternatively, the process can be limited predominantly to the vessels of one system, the clinical symptoms depending on the bore and location of the affected vessels. Varying degrees of the lesion, varying combinations and sequencing, the compensation abilities of the vessel disorders can blur the clinical picture, even though early pathomorphological changes are quite pronounced. The article presents the clinical case of a later stage of polyarteritis nodosa, which demonstrates the polymorphism of clinical symptoms and the necessity of applying modern diagnostic methods and a timely treatment with a view to reducing the frequency of fatal outcomes.

Association of five-factor score with the mortality in Japanese patients with polyarteritis nodosa.

AIM: To determine mortality and its predictive factors in Japanese patients with polyarteritis nodosa (PAN). METHODS: This retrospective single-center study determined the mortality of 18 patients with PAN who were admitted to Juntendo University Hospital from 1994 to 2016. The variables at baseline, including patient demographics, clinical characteristics, and treatment, were analyzed for their association with mortality. RESULTS: The median age of onset was 57.0 years. The 1-year survival rate was 100% (16/16) and the 5-year survival rate was 80.0% (8/10). The relationship between mortality, as defined by the survival rate and each variable was evaluated by Cox univariate analysis. A higher 2009 five-factor score (FFS) was associated with increased mortality, with a hazard ratio of 2.34 (p = .04). Analysis of the secondary outcome of relapse-free survival time revealed an association with rapid progressive renal failure, Birmingham Vasculitis Activity Score (BVAS), the 1996 FFS, and the 2009 FFS, with hazard ratios of 7.28 (p = .048), 1.26 (p = .02), 2.32 (p = .03), and 1.82 (p = .04), respectively. CONCLUSION: We investigated mortality, relapse-free survival, and their predictive factors in Japanese patients with PAN. The BVAS and the 1996 FFS at diagnosis may be prognostic factors for relapse-free survival, and the 2009 FFS at diagnosis may be a prognostic factor for both mortality and relapse-free survival.

Presence of anti-phosphatidylserine-prothrombin complex antibodies and anti-moesin antibodies in patients with polyarteritis nodosa.

We measured both serum anti-phosphatidylserine-prothrombin complex (anti-PSPT) antibodies and anti-moesin antibodies, as well as various cytokines (interleukin [IL]-2, IL-4, IL-5, IL-10, IL-13, IL-17, granulocyte macrophage colony-stimulating factor, γ-interferon, tumor necrosis factor-α) levels in polyarteritis nodosa (PAN) patients with cutaneous manifestations. All patients showed the presence of a histological necrotizing vasculitis in the skin specimen. They were treated with i.v. cyclophosphamide pulse therapy (IV-CY) and prednisolone therapy or steroid pulse therapy. The immunological assessments were performed on sera collected prior to and after treatment with IV-CY or steroid pulse therapy. We found a significant positive correlation between serum anti-moesin antibodies and both clinical Birmingham Vasculitis Activity Scores and Vasculitis Damage Index. Anti-PSPT antibody and IL-2 levels after treatment in PAN patients were significantly lower than before treatment. In contrast, anti-moesin antibody levels were higher following IV-CY or steroid pulse therapy compared with the pretreatment levels. In the treatment-resistant PAN patients (n = 8), anti-PSPT antibody levels after treatment were significantly lower than before treatment. In contrast, anti-moesin antibody levels after treatment in the patients were significantly higher compared with the pretreatment levels. Immunohistochemical staining revealed moesin overexpression in mainly fibrinoid necrosis of the affected arteries in the PAN patients. We suggest that measurement of serum anti-PSPT antibody levels could serve as a marker for PAN and aid in earlier diagnosis of PAN. We also propose that elevated serum anti-moesin antibodies could play some role of the exacerbation in patients with PAN.

Acute myocardial infarction as a manifestation of systemic vasculitis.

Acute myocardial infarction (AMI) is one of the major causes of mortality and morbidity worldwide. In Central Europe, causes of AMI other than atherosclerosis are unusual. Coronary artery vasculitis is one potential non-atherosclerotic process causing AMI. Herein, the authors depict a very rare case of AMI as a clinical manifestation of polyarteritis nodosa (PAN), a necrotizing systemic vasculitis. A 49-year-old male patient presented to our clinic with abdominal pain and markedly elevated concentrations of C­reactive protein, creatinine and high-sensitivity cardiac troponin T. Electrocardiography showed new repolarization abnormalities in aVF and III. Besides PAN-typical angiographic findings, including bilateral renal artery microaneuryms as well as different arterial occlusions, coronary angiography displayed a complete thrombotic occlusion of the right coronary artery without any other coronary pathology. The present case report demonstrates AMI as very rare but deleterious complication in patients suffering from PAN, and highlights that this life-threatening event can occur even at a very early stage of PAN-related coronary affection.

Pancreatic mass as an initial manifestation of polyarteritis nodosa: a case report and review of the literature.

Classic polyarteritis nodosa (PAN) that targets medium-sized muscular arteries and microscopic polyangiitis (MPA), characterized by inflammation of small-caliber vessels and the presence of circulating myeloperoxidase anti-neutrophil cytoplasmic antibodies (MPO-ANCA), are distinct clinicopathological entities of systemic vasculitis. A 66-year-old woman presented with fever, cholestasis and positive MPO-ANCA. Radiological examination showed a pancreatic mass compressing the bile duct. Therefore, we performed pancreatoduodenectomy. Histopathological examination revealed that necrotizing vasculitis predominantly affecting the medium-sized vessels, spared arterioles or capillaries in the pancreas, a finding consistent with PAN. Unexpectedly, renal biopsy revealed small-caliber vasculitis and glomerulonephritis, supporting MPA. The initial manifestation of a pancreatic mass associated with vasculitis has only been reported in 7 articles. Its diagnosis is challenging because no reliable clinico-radiological findings have been observed. Clinicians should be aware of such cases and early diagnosis followed by immunosuppression is mandatory. Our findings may reflect a polyangiitis overlap syndrome coexisting between pancreatic PAN and renal MPA.

VEGF levels in diagnosis of vasculitic neuropathy.

BACKGROUND: Vascular endothelial growth factor (VEGF) is secreted from endothelial cells and pericytes in response to hypoxia. It induces angiogenesis and microvascular hyperpermeability. We observe serum VEGF concentrations in some patients with vasculitic neuropathy. METHODS: Plasma VEGF was measured using GenWay's human VEGF ELISA Kit, which is based on standard sandwich enzyme-linked immune-sorbent assay technology. Human VEGF specific-specific monoclonal antibodies are precoated onto 96-well plates. The human specific detection polyclonal antibodies are biotinylated. The test samples and biotinylated detection antibodies were added to the wells subsequently and then followed by washing with PBS or TBS buffer. Avidin-Biotin-Peroxidase Complex was added and unbound conjugates were washed away with PBS or TBS buffer. HRP substrate TMB was used to visualize HRP enzymatic reaction. The VEGF levels were measured in 5 patients with vasculitic neuropathy and 8 healthy controls. RESULTS: Plasma VEGF was higher in subjects with vasculitic neuropathy as compared to controls. In the control group, we obtained VEGF levels from 9.8 pg/mL up to 15 pg/mL with an average of 11.6 pg/mL for males and 8.9 pg/mL up to 14.5 pg/mL with average of 11.2 pg/mL for females. In female patients with vasculitic neuropathy the plasma VEGF levels were between 79.9 pg/mL and 111.2 pg/mL, with an average of 92.375 pg/mL. We had one case with vasculitic neuropathy in men, in which the plasma VEGF level was 102.9 pg/mL. CONCLUSIONS: The results from our study indicate that plasma VEGF levels are significantly associated with vasculitic neuropathy and may be used to predict this disease.

D-dimer levels as a marker of cutaneous disease activity: case reports of cutaneous polyarteritis nodosa and atypical recurrent urticaria.

IMPORTANCE: Biochemical markers of disease allow clinicians to monitor disease severity, progression, and response to treatment. C-reactive protein and erythrocyte sedimentation rate are commonly used biochemical markers of inflammatory disease. We present 2 cases that indicate that D-dimer levels may be useful as a potential biochemical marker of disease activity in certain cutaneous inflammatory conditions. OBSERVATIONS: We report 2 cases in which clinical disease activity correlates with D-dimer levels. The first case is a woman in her 50s with a diagnosis of cutaneous polyarteritis nodosa. The second case is a man in his 20s with recurrent urticaria. In both patients, plasma D-dimer levels increased with clinical evidence of disease activity and decreased with treatment and resolution of the disease flare. Interestingly, serum C-reactive protein levels did not correlate with disease activity and were found to be normal during clinically active disease. CONCLUSIONS AND RELEVANCE: We show the potential value of D-dimer measurements as a marker of vasculocentric and/or vasculopathic inflammation and suggest that vascular endothelial damage may be ongoing in certain cutaneous inflammatory conditions.

Clinical and laboratory profile of childhood polyarteritis nodosa in a Bangladeshi tertiary hospital.

INTRODUCTION: Polyarteritis nodosa in children is a rare necrotizing vasculitis affecting mainly small and medium-size arteries. OBJECTIVE: To describe the different clinical patterns and laboratory profiles of polyarteritis nodosa patients in a tertiary care hospital. METHODOLOGY: This was a retrospective cohort study carried out in the Department of Paediatrics, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh during the period January 2007 to December 2012. A total of 13 patients fulfilling the European League Against Rheumatism/Paediatric Rheumatology International Trial Organization/Paediatric Rheumatology European Society (EULAR/PRINTO/PRES) classification criteria were enrolled in this study. Data was collected via a predesigned questionnaire. RESULTS: Age range was 3-12 years, male : female ratio was 9 : 4. The duration of symptoms was 2-16 weeks. All the children had fever, anorexia and generalized weakness. Subcutaneous nodules were present in 77% of cases followed by arthritis and rash (69%), muscle pain (54%) and abdominal pain (38%). Impaired peripheral pulses were present in 54%, ulceration and gangrene was present in 31% and auto-amputation was present in 15% of cases. All the patients had high erythrocyte sedimentation rates followed by neutrophilic leukocytosis and thrombocytosis (85% and 62%). Skin biopsy was positive in 77% of cases and angiographic abnormalities were present in 23% of cases. CONCLUSION: Most clinical and laboratory profiles of polyarteritis nodosa in our center, such as age, sex, fever, rash, arthritis and abdominal pain, were mostly similar to other reports; however some late cases were found in this series with complications such as gangrene and auto-amputation.

A case of cutaneous polyarteritis nodosa with elevated serum interleukin-6 levels complicated by leg arterial stenosis and destructive arthropathy of the left ankle.

We report a case of a 60-year-old female with cutaneous polyarteritis nodosa (CPN) of the left ankle, accompanied by elevated serum interleukin (IL)-6 levels. Computed tomographic angiography revealed severe narrowing of medium-sized arteries in her left leg. Destructive arthropathy in the left ankle was identified by X-ray and magnetic resonance imaging. This is the first Japanese case of severe CPN complicated by destructive arthropathy. Quantification of serum IL-6 might be useful in diagnosis and evaluation of CPN.

Treatment for cutaneous arteritis patients with mononeuritis multiplex and elevated C-reactive protein.

Cutaneous arteritis (cutaneous polyarteritis nodosa, CA) is a necrotizing vasculitis of arteries within the skin. CA is a new classification under single-organ vasculitis, as adopted by the 2012 Chapel Hill consensus conference (CHCC 2012). Some patients originally diagnosed as having CA could develop additional disease manifestations that warrant reclassifying as systemic polyarteritis nodosa (PAN) according to the CHCC 2012. We retrospectively investigated 101 patients with CA seen at our department between 2003 and 2012. There was a significantly higher frequency of inflammatory plaques and leg edema in CA patients with elevated C-reactive protein (CRP) compared to CA patients with normal CRP. Similarly, there were significant differences in the incidence of arthralgia and mononeuritis multiplex between the two patient groups. We found significantly positive correlations between CRP and creatinine titers in serum in all 101 CA patients. Prednisolone was administrated in a significantly greater percentage of patients with elevated CRP compared to patients with normal CRP. Repeated i.v. cyclophosphamide pulse therapy (IV-CY) with prednisolone therapy at an early stage resulted in complete resolution without adverse effects or severe complications. We regard inflammatory plaques and leg edema with elevated serum CRP as an indication of a more severe condition, and treated them effectively with prednisolone. Assuming mononeuritis multiplex and/or arthritis exist with elevated CRP, we propose that earlier treatment by IV-CY with prednisolone should be indicated for CA patients who demonstrate these more severe manifestations to prevent progression to PAN.

Anti-carbonic anhydrase III autoantibodies in vasculitis syndrome.

AIM: To identify autoantibodies useful in the diagnosis of primary vasculitides. METHODS: The presence of antibodies against proteins in the lysate of mouse blood vessels was examined by two-dimensional electrophoresis followed by Western blotting for the pooled serum sample from patients with various forms of vasculitis: polyarteritis nodosa (PAN), microscopic polyangiitis (MPA), Wegener's granulomatosis (WG) and Takayasu's arteritis (TA). Autoantigenicity in patients with vasculitides was examined by Western blotting and enzyme-linked immunosorbent assay (ELISA). Clinicopathological correlations between the positivity of the autoantibodies and clinical status of patients with the vasculitis were examined. RESULTS: The autoantigen detected in the lysate of pooled sera from patients with vasculitides was identified by mass spectrometry as carbonic anhydrase III (CAIII). ELISA showed significantly higher prevalence of anti-CAIII antibodies in MPA patients (MPA, 11/23 [47.8%]; healthy controls, 2/32 [6.3%]; P < 0.001). Further, anti-CAIII antibody-positive MPA patients had higher vasculitis activity scores compared to anti-CAIII antibody-negative patients, and a weak and not significant negative correlation was observed between anti-CAIII antibody levels and myeloperoxidase - anti-nuclear cytoplasmic antibody (MPO-ANCA) levels. No significant differences were found in anti-CAIII autoantibody levels between MPA and the other primary vasculitides. CONCLUSION: We found significantly high prevalence of anti-CAIII antibody levels in sera from MPA patients. Although the number of samples available in this study is small and anti-CAIII autoantibodies display weak specificity for MPA, anti-CAIII antibodies may be useful for diagnosing MPA in patients who have no ANCA, as well as for assessing disease activity.

Polyarteritis nodosa clinically mimicking nonocclusive mesenteric ischemia.

Here, we present the case of a 74-year-old Japanese man with segmental intestinal necrosis, which developed after treatment with pulsed methylprednisolone for mononeuritis multiplex. The patient was weakly positive for myeloperoxidase (MPO)-anti-neutrophil cytoplasmic antibody (ANCA). Computed tomography and surgical findings were compatible with nonocclusive mesenteric ischemia (NOMI). He underwent small intestinal resection by emergency surgery and an intestinal fistula was made. Pathologically, necrotizing vasculitis with fibrinoid necrosis was present in medium to small-sized arteries, which was equivalent to Arkin's classification II-IV. Most of the arteries had fibrous intimal thickening, which was considered to obstruct the arteries and thus cause segmental intestinal necrosis. A diagnosis of polyarteritis nodosa (PAN) was made, and intravenous cyclophosphamide pulse therapy was added to the therapeutic regimen. This patient was successfully treated with these multidisciplinary therapies and his stoma was finally closed. This is a very rare and indicative case of PAN weakly positive for MPO-ANCA and clinically mimicking NOMI, which occurred even after treatment with pulsed methylprednisolone.

Lysosomal-associated membrane protein-2 plays an important role in the pathogenesis of primary cutaneous vasculitis.

OBJECTIVES: Recent research suggests that lysosomal-associated membrane protein-2 (LAMP-2) could be one of the target antigens in the pathogenesis of vasculitides. We established a transgenic rat model, env-pX rats, with various vasculitides including cutaneous vasculitis. Human primary cutaneous vasculitis includes cutaneous polyarteritis nodosa (CPN) and Henoch-Schönlein purpura (HSP). We measured serum anti-LAMP-2 antibody levels in morbid env-pX rats and injected anti-LAMP-2 antibody into premorbid env-pX rats. We further measured serum anti-LAMP-2 antibody levels in patients with CPN and HSP. METHODS: Cutaneous vasculitis was observed in ∼30% of 6-month-old morbid env-pX rats. In contrast, these findings were rare in premorbid env-pX rats under 3 months old. We also examined 85 patients with CPN and 36 adult patients with HSP. Serum anti-LAMP-2 antibody levels were determined using ELISA. Premorbid env-pX rats under 3 months old were given an i.v. injection of anti-LAMP-2 antibody at day 0 and day 7. At day 14, these rats underwent histopathological and direct immunofluorescence examination. Cell surface LAMP-2 expression of rat neutrophils was examined by flow cytometry. RESULTS: Serum anti-LAMP-2 antibody levels were significantly higher in morbid env-pX rats than in wild-type normal rats. In addition, the levels in the cutaneous vasculitis group of morbid env-pX rats were significantly higher than the no cutaneous vasculitis group. Intravenous anti-LAMP-2 antibody injection into premorbid env-pX rats under 3 months old induced infiltration of neutrophils into cutaneous small vessels. Anti-LAMP-2 antibody-binding neutrophils were detected there. LAMP-2 expression on the cell surface of neutrophils in premorbid env-pX rats under PMA stimulation was higher compared with controls. Serum anti-LAMP-2 antibody levels in CPN and HSP were significantly higher than those of healthy controls. CONCLUSION: These data support a positive relationship between anti-LAMP-2 antibody and cutaneous vasculitis.