High prevalence of autoantibodies to hLAMP-2 in anti-neutrophil cytoplasmic antibody-associated vasculitis

The involvement of autoantibodies to human lysosome-associated membrane protein-2 (hLAMP-2) in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is controversial because of the absence of confirmatory data subsequent to the initial reports of their high prevalence in this disease. We characterized three assays for anti-hLAMP-2 antibodies: ELISA and Western blotting assays using unglycosylated recombinant hLAMP-2 expressed in Escherichia coli, and an indirect immunofluorescence assay using stably transfected ldlD cells that expressed glycosylated full-length hLAMP-2 on the plasma membrane. The assays detected autoantibodies to hLAMP-2 in human sera reproducibly and with comparable sensitivity and the assays gave the same results in 80.5% of the test panel of 40 selected positive and negative sera. In untreated patients at presentation, the frequencies of autoantibodies to LAMP-2 were 89%, 91%, and 80%, respectively, among three groups of patients with ANCA-associated vasculitis from Vienna, Austria (n=19); Groningen, the Netherlands (n=50) and Cambridge, United Kingdom (n=53). Prevalence of LAMP-2 autoantibodies was similar in both those with myeloperoxidase-ANCA and proteinase 3-ANCA. Furthermore, we detected LAMP-2 autoantibodies in two ANCA-negative patients. LAMP-2 autoantibodies rapidly became undetectable after the initiation of immunosuppressive treatment and frequently became detectable again during clinical relapse. We conclude that when robust assays are used, circulating autoantibodies to hLAMP-2 can be detected in most European patients with ANCA-associated vasculitis. Large-scale prospective studies are now needed to determine whether they are pathogenic or merely an epiphenomenon.     

Novel therapies for anti-neutrophil cytoplasmic antibody-associated vasculitis

High-dose corticosteroids in combination with cytotoxic drugs are universally accepted as the initial approach in vasculitides that are associated with anti-neutrophil cytoplasmic antibodies. Cyclophosphamide is the most effective cytotoxic drug and is used in more severe cases. Because cyclophosphamide has more severe short- and long-term side-effects than methotrexate, methotrexate is used in less severe cases. New prospects for the treatment of vasculitis include novel immunosuppressive agents (e.g. mycophenolate, 15-deoxyspergualin, and leflunomide), sequential chemotherapy (e.g. cyclophosphamide followed by azathioprine or cyclophosphamide followed by methotrexate), intravenous immunoglobulin, tumour necrosis factor-alpha directed therapy, anti-lymphocyte directed therapy (e.g. antithymocyte globulin or anti CD52/anti CD4 antibodies), anti-adhesion molecule directed therapy (e.g. anti-CD18 or intercellular adhesion molecule-1 antisense) or immunoablation using high-dose cytotoxic medication with or without stem cell rescue.     

Clinicopathological features of neuropathy in anti-neutrophil cytoplasmic antibody-associated vasculitis

Microscopic polyangiitis (MPA), Churg–Strauss syndrome (CSS), and Wegener’s granulomatosis are anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides that may affect both the central and peripheral nervous systems. In these diseases, the frequency of concomitant peripheral neuropathy is particularly high in MPA and CSS. As opposed to kidney and lung involvement, which may be life threatening, peripheral neuropathy due to vasculitis alone does not significantly affect survival, although it can disturb day-to-day functioning and quality of life of patients. In this article, we describe clinical and pathological features of neuropathy in ANCA-associated vasculitides, focusing on MPA and CSS. A mononeuritis multiplex pattern instead of a symmetric polyneuropathy pattern characterizes the neuropathic features of MPA and CSS. Pathological findings of vasculitic neuropathy are characterized by axonal degeneration of nerve fibers caused by vasculitis-induced ischemia in both MPA and CSS. Hence, CSS- and MPA-associated neuropathies share common neuropathic features, but the extent of systemic organ involvement is significantly higher in MPA cases, resulting in poorer survival rates.     

Prognostic value of proteinuria monitoring in anti-neutrophil cytoplasmic antibody-associated vasculitis

Clinical and Experimental Nephrology - To determine the prognostic significance of proteinuria monitoring in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). We...     

The clinical features of anti-neutrophil cytoplasmic antibody-associated systemic vasculitis in Chinese children

Anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis is reported mainly in adults. Studies in children are limited. The current study retrospectively analyzed the clinical characteristics and pathology of ANCA-associated systemic vasculitis in children in our hospital during the past 7 years. Twenty-four pediatric patients were diagnosed as having ANCA-associated systemic vasculitis, including 19 patients with microscopic polyangiitis (MPA), one with Wegener’s granulomatosis (WG), three with propylthiouracil (PTU)-induced ANCA-positive vasculitis and one with anti-glomerular basement membrane (GBM) disease. Of patients with primary ANCA-associated systemic vasculitis (MPA and WG), with an average age of 10.8±2.8 (6–14) years, 18 patients (90%) were female and two (10%) were male. Nineteen patients (95%) were p-ANCA/MPO-ANCA positive and one (5%) was c-ANCA/PR3-ANCA positive. The interval between onset and diagnosis was 8.5±24.3 (0.2–108) months. The majority of the patients (85%) had multi-organ involvement. All patients had clinical evidence of renal involvement and presented with hematuria and proteinuria. Of 20 patients, 16 (80%) also had acute renal failure, and five patients were dialysis dependent. Nine patients underwent renal biopsy and were diagnosed with necrotizing and crescentic glomerulonephritis. However, six biopsies showed immune complex deposition. All patients received immunosuppressive therapy including prednisone and cyclophosphamide, and ten patients also received intravenous administration of methylprednisone pulse therapy according to their clinical situation and renal pathology. Sixteen patients achieved clinical remission, and four patients presented as treatment failure. Patients were followed up for 12.3±5.1 months (median 12 months; range 1 to 91 months). Ten patients maintained their clinical remission, and ten progressed to renal failure requiring dialysis. Our study showed that the clinical features and pathology of primary ANCA-associated systemic vasculitis in children were similar to those of adults, but there were a predominance of female patients and late diagnoses. We suggest that early recognition and prompt aggressive treatment might improve outcome.     

Prospective study of TNFalpha blockade with infliximab in anti-neutrophil cytoplasmic antibody-associated systemic vasculitis

Tumor necrosis factor alpha (TNFalpha) plays an important role in the pathogenesis of anti-neutrophil cytoplasmic antibody-associated systemic vasculitis. TNFalpha blockade is a potential therapy for these disorders. METHODS: An open-label, multi-center, prospective clinical trial in two subgroups was performed. Study I examined acute disease, either first presentation or relapse (Birmingham Vasculitis Activity Score [BVAS] > or = 10; n = 16); study II examined persistent disease (BVAS > or = 4; n = 16). Patients received infliximab (5 mg/kg) at 0, 2, 6, and 10 wk. Concomitant therapy in study I included prednisolone and cyclophosphamide. Study II patients continued their existing treatment regimens, with prednisolone tapered according to clinical status. RESULTS: Mean age was 52.4 yr, 53% of the patients were female, and follow-up was 16.8 mo. Twenty-eight patients (88%) achieved remission (14 per study group). BVAS decreased from 12.3 (confidence interval [CI] = 10.5 to 14.0) at entry to 0.3 (CI = 0.2 to 0.9) at wk 14 (P < 0.001). C-reactive protein (mg/L) decreased from 29.4 (CI = 16.8 to 42.0) at entry to 7.0 (CI = 3.3 to 10.9) by wk 14 (P = 0.001). Mean prednisolone dose (mg/d) in study II decreased from 23.8 (CI = 15.0 to 32.5) at entry to 8.8 (CI = 5.9 to 11.7) at wk 14 (P = 0.002). There were two deaths and seven serious infections. Relapse occurred in five patients (three in study II) after a mean of 27 wk. CONCLUSION: TNFalpha blockade with infliximab was effective at inducing remission in 88% of patients with antibody-associated systemic vasculitis and permitted reduction in steroid doses. Severe infections were seen in 21% of patients, and despite continued infliximab, 20% of initial responders experienced disease flares. Infliximab is a promising new therapy for vasculitis both as a component of initial therapy and in the management of refractory disease. These results need confirmation in larger randomized trials.     

Risk factors for secondary infection in the treatment with anti-neutrophil cytoplasmic antibody-associated vasculitis

Objective To investigate the clinical characteristics and risk factors of secondary infection in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). Methods One hundred and eighteen patients newly diagnosed with AAV at the institute of nephrology, Tongji hospital affiliated to Huazhong university of science and technology, from 2012 to 2017, were analyzed retrospectively. Induction therapy included single corticosteroids, combination of corticosteroids with cyclophosphamide and combination of corticosteroids with other immunosuppressive agents. End point was defined as moderate to severe infection which was diagnosed by the clinical and radiological manifestation as well as microbiological evidences. The infection-related survival curve was drawn to reflect the time when the infection occurred. The clinical baseline variables in patients with and without infection were compared. Multivariate Logistic regression model was used to determine the independent predictors of infection. Receiver-operating characteristic curve (ROC) was plotted for evaluating the predictive value of lymphocyte on moderate to severe infection. Results During follow-up of median 3 months (1-30 months), 88 infection episodes were found in 63 (53.4%) patients, of which 54 times (61.4%) occurred within 6 months after treatment, 46 times (52.3%) happened within 3 months after treatment. The most common organ of infection was lung (62.5%), and the most common pathogen was bacteria (51.1%). Multivariate Logistic regression model showed that lung involvement (OR=4.44, 95%CI 1.59-12.41), moderate reduction of lymphocyte in follow-up (OR=5.69, 95%CI 2.05-15.85) and severe lymphocyte reduction (OR=36.28, 95%CI 3.45-381.17) were independent risk factors of secondary infection in AAV patients (all P＜0.05). ROC curve showed that the area under the curve of lymphocyte as a predictor of severe infection was 0.767 (95%CI 0.64-0.89, P＜0.05). Based on lymphocyte less than 0.49×109/L which was the cut-off value for predicting severe infection, the sensitivity and the specificity were 83.9% and 71.9%, respectively. Conclusions Lung involvement and moderate-severe lymphopenia during follow-up are independent risk factors of secondary infection in AAV patients. Hence, physician should pay more attention to those patients, and adjust treatment in time to avoid the occurrence of infection.     

Rituximab as rescue therapy in anti-neutrophil cytoplasmic antibody-associated vasculitis: a single-centre experience with 15 patients

Background. B-cell depletion with rituximab, a chimeric anti-CD20antibody, is a novel treatment for refractory and relapsingANCA-associated small-vessel vasculitis. Data are limited andmost reports describe single patients or small numbers of patientsfollowed prospectively. Methods. We report a single-centre experience with 15 patientswho received rituximab for refractory or relapsing ANCA-associatedvasculitis. All patients had been treated with corticosteroidsand cyclophosphamide and a variety of other second-line immunosuppressiveagents. None of the patients had evidence of infection and receivedfour infusions of 375 mg/m² of rituximab. Disease activity wasassessed in accordance with the Birmingham Vasculitis ActivityScore (BVAS). BVAS, C-reactive protein and ANCA titres wererecorded at baseline and during follow-up. Results. B-cell depletion was achieved in all patients. Partialor complete remission was seen in 14 of 15 patients with a significantdecline in BVAS compared to baseline (P < 0.007). One patientwith granulomatous ANCA-associated vasculitis did not respondto rituximab. There were no side effects during rituximab infusion.Transient leucopenia was observed in two patients. One patientwith bronchial stenosis died of pneumonia 5.5 months after theinitiation of rituximab treatment. One initially anti-HBc-positive/HBsAg-negativepatient experienced a reactivation of hepatitis B, developedend-stage renal failure and died after refusal of dialysis. Conclusions. We report the largest case series of rituximabuse for ANCA-associated vasculitis so far. Our data supportthat the drug is capable of inducing partial or complete remissionin refractory or relapsing patients. Leucopenia and infectiouscomplications remain a matter of concern.     

Complement in antineutrophil cytoplasmic antibody-associated vasculitis

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a group of autoimmune disorders. It was previously assumed that the complement system is not involved in the development of ANCA-associated vasculitis due to its “pauci-immune” feature in renal histology. However, increasing evidence indicates that activation of the complement system, especially via the alternative complement pathway, plays a crucial role in the pathogenesis of ANCA-associated vasculitis. In this brief review, we discuss the evidence, including in vivo, in vitro, and clinical studies, for complement system activation in ANCA-associated vasculitis.     

Clinicopathological study of myeloperoxidase anti-neutrophil cytoplasmic antibody-associated glomerulonephritis

AIMS: To investigate the potential prognostic factors for myeloperoxidase anti-neutrophil cytoplasmic antibody- (MPO-ANCA) associated glomerulonephritis. MATERIALS: The clinical and pathological findings were reviewed in 17 patients with this type of glomerulonephritis. METHODS: The relationship between the outcome and various clinical and pathological factors were assessed. The relationship between the blood MPO-ANCA level and cellular crescent formation was also investigated. RESULTS: Patients who died had a significantly lower serum albumin and creatinine clearance than those who survived, but there were no differences of age, blood MPO-ANCA, urinary protein, and serum creatinine levels or cellular crescent formation between the two groups. There was a close relationship between blood MPO-ANCA levels and cellular crescent formation. CONCLUSIONS: Hypoalbuminemia and renal dysfunction may be indicators of a poor prognosis in MPO-ANCA-associated glomerulonephritis. Patients with high blood levels of this antibody and increased cellular crescent formation appear to have active disease, but these factors are not statistically associated with a fatal outcome. Therefore, aggressive treatment may be indicated in patients with active disease initially.     

Expression of macrophage migration inhibitory factor in patients with myeloperoxidase anti-neutrophil cytoplasmic antibody-associated glomerulonephritis

AIM AND METHODS: To investigate the relationship between macrophage migration inhibitory factor and clinical or pathological findings in patients with myeloperoxidase anti-neutrophil cytoplasmic antibody MPO-ANCA-associated glomerulonephritis characterized by idiopathic necrotizing crescentic glomerulonephritis, renal biopsy specimens from 16 patients with MPO-ANCA-associated glomerulonephritis and 15 controls were stained using an enzyme antibody method to detect macrophage migration inhibitory factor and macrophages infiltrating the glomeruli. The relationship of this factor with various clinical parameters and with cellular crescents was determined. RESULTS: Macrophage migration inhibitory factor was detected in 11 out of 16 patients with MPO-ANCA-associated glomerulonephritis, but was not found in any of the controls. In the positive patients, the blood MPO-ANCA level was significantly higher than in the negative patients. Both cellular crescents and the number of macrophages infiltrating the glomeruli were significantly increased in the patients positive for macrophage migration inhibitory factor. CONCLUSION: Thus, macrophage migration inhibitory factor may be closely related to cellular crescent formation and disease activity in patients with MPO-ANCA-associated glomerulonephritis.     

Otolaryngologic manifestations of antineutrophil cytoplasmic antibody-associated vasculitis

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is characterized by systemic necrotizing vasculitis, and patients fall into 2 groups: those with proteinase 3-ANCA and those with myeloperoxidase-ANCA. As infections are a trigger of ANCA-associated vasculitis, this disease tends to localize in areas around the upper airway. In this study, the authors compared ear and nasal symptoms between patients with proteinase 3-ANCA and those with myeloperoxidase-ANCA. We undertook a retrospective case series study of 34 patients diagnosed with ANCA-associated vasculitis. The otologic symptoms were divided into 3 types: chronic otitis media, secretory otitis media, and sensorineural hearing loss. Chronic otitis media was more common in patients with proteinase 3-ANCA (P = .001), whereas secretory otitis media was more frequently found in patients with myeloperoxidase-ANCA (P = .007). Crust formation (P = .001), saddle nose (P = .024), and sinusitis (P = .001) were more common in patients with proteinase 3-ANCA than in those with myeloperoxidase-ANCA. Marked differences were observed in the disease spectrum between the 2 ANCA groups.     

Vasculitis working group: Selected unanswered questions related to giant cell arteritis and anti-neutrophil cytoplasmic antibody-associated vasculitis

Evidence to guide assessment and management of patients with vasculitis is lacking for many important clinical questions. The evidence surrounding several common questions about management of vasculitis was reviewed. Patients with giant cell arteritis (GCA) are at risk for developing extra-cranial large vessel inflammation. Clinicians should be aware of this complication and search for large vessel involvement in patients with GCA who have ischemic symptoms. Research is needed to define optimal strategies to identify patients with such complications. Because of the hazards of chronic corticosteroid use, alternative therapies for patients with GCA have been sought but thus far no clear alternatives have been identified. Anti-neutrophil cytoplasmic antibodies (ANCA) are associated with small-vessel vasculitis, including Wegener's granulomatosis and microscopic polyangiitis, but changes in ANCA titers should not be used as a surrogate biomarker for disease activity. Several immunosuppressive agents can be used for maintenance therapy after induction of remission in patients with ANCA-associated vasculitis, with no firm evidence that one agent is superior to others. Collectively, this review shows that more research is needed to provide a firmer body of evidence to support clinical decision-making for patients with vasculitis.