Pauci-immune Small Vessel Vasculitis Research Articles

Eosinophilic granulomatosis with polyangiitis: a review article

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare form of ANCA-associated vasculitis (AAV) within the group of small vessel vasculitides. It is defined by vasculitis of small and medium-sized vessels with granulomatous inflammation and blood and tissue eosinophilia. Almost all patients have allergic symptoms with bronchial asthma and rhinosinusitis symptoms. Further clinical manifestations vary depending on the localisation, severity, and type of disease manifestation. Eosinophilic infiltration and inflammation may result in rhinosinusitis, pneumonitis, gastrointestinal involvement, and cardiomyopathy. The latter, in particular, is associated with a poorer prognosis. As a necrotising pauci-immune small-vessel vasculitis, EGPA, similar to the other AAVs, can cause pulmonary infiltrates with alveolar haemorrhage, glomerulonephritis, cutaneous vasculitis with purpura as well as central and peripheral neurologic injuries. The presence of perinuclear ANCA (pANCA) with specificity against myeloperoxidase (MPO) is observed in approximately one-third of patients but is not specific to EGPA. MPO-ANCA-positive patients are more likely to have peripheral neurologic involvement and glomerulonephritis, whereas ANCA-negative patients are more likely to have cardiac and pulmonary involvement. What is frequently challenging in the clinical routine is to differentiate EGPA from the hypereosinophilic syndrome (HES). The therapeutic approach to EGPA depends on whether the severity of the disease is potentially organ or life-threatening. For severe forms of EGPA, acute therapy mainly includes glucocorticoids in combination with cyclophosphamide. Rituximab has come to be mentioned as an alternative treatment option in the guidelines. Various immunosuppressive therapies are available for remission maintenance. In EGPA without severe organ involvement, IL-5 blockade with mepolizumab is an approved treatment.

Intrathecal injection of methotrexate and dexamethasone for vasculitis granuloma of the fourth ventricle: a case report and literature review.

Granulomatosis with polyangiitis (GPA) is a pauci-immune small vessel vasculitis characterised by neutrophil-mediated vasculitis and granuloma. The presence of intracranial parenchymal space-occupying lesions is rarely seen in GPA patients. In this manuscript, we report a case of GPA with granuloma of the fourth ventricle accompanied by obstructive hydrocephalus. Treatment with glucocorticoids (GCs) and multiple immunosuppressants cyclophosphamide (CYC), mycophenolate mofetil (MMF), and rituximab (RTX) showed poor efficacy in this case. After removal of the granuloma by craniotomy, GPA relapsed within 3months. Under the premise of GC and MMF treatment combined with intrathecal injection of dexamethasone (DXM) and methotrexate (MTX), the intracranial granuloma gradually shrank, and the patient's general condition was alleviated, showing that this is an effective treatment method. Key Points • To date, there are few reports of granulomatous vasculitis combined with granuloma of the fourth ventricle, and our case is the second. • In this case, multiple immunosuppressants and rituximab were ineffective treatments, and the intracranial granuloma was effectively controlled by intrathecal injection of dexamethasone (DXM) and methotrexate (MTX). • Based on this report, it can be suggested that intrathecal injection is effective in treating patients with GPA and central nervous system involvement, but large-scale sample studies are needed.

Genetics of ANCA-associated vasculitis: role in pathogenesis, classification and management.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) comprisesgranulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA), that share features of pauci-immune small-vessel vasculitis and the positivity of ANCA targeting proteinase-3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA). AAV syndromes are rare, complex diseases and their aetio-pathogenesis is mainly driven by the interaction between environmental and genetic factors. In patients with GPA and MPA, the genetic associations are stronger with ANCA specificity (PR3- versus MPO-ANCA) than with the clinical diagnosis, which, in keeping with the known clinical and prognostic differences between PR3-ANCA-positive and MPO-ANCA-positive patients, supports an ANCA-based re-classification of these disorders. EGPA is also made up of genetically distinct subsets, which can be stratified on ANCA-status (MPO ANCA-positive versus ANCA-negative); these subsets differ in clinical phenotype and possibly in their response to treatment. Interestingly, MPO-ANCA-positive patients with either MPA or EGPA have overlapping genetic determinants, thus strengthening the concept that this EGPA subset is closely related to the other AAV syndromes. The genetics of AAV provides us with essential information to understand its varied phenotype. This Review discusses the main findings of genetic association studies in AAV, their pathogenic implications and their potential effect on classification, management and prognosis.

FC064: Histopathological and Clinical Outcomes of Anca Negative Versus Anca Positive Pauci-Immune Glomerulonephritis

Abstract BACKGROUND It has been suggested that pauci-immune small vessel vasculitis exhibits a different spectrum of disease in the absence of detectable circulating anti-neutrophil cytoplasmic autoantibodies (ANCA). This study aims to investigate the differences in clinical presentation, renal histopathological and clinical outcomes amongst vasculitis patients with or without detectable circulating ANCA. METHOD A cohort study of biopsy proven pauci-immune glomerulonephritis was constructed from a single centre between 2006 and 2016 and followed up until June 2021. Patients were stratified by ANCA status at the time of diagnosis and primary outcomes compared the histopathological classification, clinical presentation and outcomes including mortality and end stage renal disease (ESRD) of those with ANCA negative and positive disease. Secondary outcomes looked at multivariate survival and logistic models comparing remission and relapse rates between the two groups. RESULTS From 146 patients, 21.9% (n = 32) had ANCA negative disease with a male predominance of 66% (n = 21) and a younger mean age at diagnosis compared to those with positive ANCA serology; 51.44 ± 19.57 years versus 65.6 ± 12.10 years, respectively (P ≤ 0.001). ANCA negative serology was associated with more renal limited disease (n = 20, 62.3% versus n = 44, 38.6% ANCA positive) and the presence of extra-renal disease with ENT and constitutional symptoms occurred more frequently in ANCA positive patients (27% versus 0%; P = 0.0013). There was a comparable spread across the Berden classification, with no significant difference seen between the positive and negative groups (Table 1). The predominant class across both cohorts was focal classification. At the time of diagnosis, ANCA-negative patients had lower eGFR than those with positive ANCA serology (14.0 versus 18.0 mL/min/1.73 m2; P = 0.09 922). At the end of follow-up, 53.1% (n = 17) of ANCA-negative patients had progressed to end stage renal disease (ESRD) which was higher than those with ANCA positivity (n = 13, 11.7%). When adjusting for age, sex and induction therapy, the hazard ratio (HR) for ESRD was five times higher in ANCA-negative patients compared to ANCA positive [HR 5.20 (2.02–13.39); P ≤ 0.001]. Mortality rates were higher in the ANCA-negative cohort (Figure 1). Following HR calculations and multivariate analysis, age was associated with a higher risk of death. In addition, despite the ANCA-negative cohort being younger, when adjusting for age, sex and induction therapy, the HR of death was three times higher in the ANCA-negative cohort [HR 3.0 (1.36–6.63); P = 0.007]. CONCLUSION Our single-centre experience suggests that ANCA negative disease tends to occur in younger patients, with a higher rate of renal limited disease. Seronegative disease is less likely to relapse but is associated with a high mortality rate. The reasons for these differences between ANCA-positive and ANCA-negative cohorts are complex and multifaceted. Some reports hypothesize that the cause for severe disease at presentation in the absence of circulating ANCA is due to a delay in diagnosis and treatment by clinicians [1,2]. This study provides the impetus for further trials looking at ANCA-negative and ANCA-positive disease.

Serological testing in small vessel vasculitis.

Serological analysis has a central role in the diagnostic work-up of patients with suspected small vessel vasculitis, both for establishing a specific diagnosis and for the monitoring of response to therapy. Autoantibodies can be detected in all forms of primary small vessel vasculitis as well as in the most common forms of secondary vasculitis. For primary vasculitis the most important serological test is for ANCA. ANCA can be found in 75-95% of patients with pauci-immune small vessel vasculitis leading to this subgroup of vasculitides being named ANCA associated vasculitis. ANCA levels often follow this disease course, but the value of serial ANCA testing is controversial. Other important autoantibodies in primary small vessel vasculitis are anti-glomerular basement membrane antibodies, anti-C1q, anti-galactose deficient IgA and cryoglobulins. A wide variety of systemic inflammatory diseases and infections can be complicated by small vessel vasculitis and detected by serological testing. Important examples are SLE, rheumatoid arthritis, Hepatitis C and HIV.

Central Nervous System Involvement in ANCA-Associated Vasculitis: What Neurologists Need to Know.

Objective: To provide a comprehensive review of the central nervous system (CNS) involvement in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), including the pathogenesis, clinical manifestations, ancillary investigations, differential diagnosis, and treatment. Particular emphasis is placed on the clinical spectrum and diagnostic testing of AAV.Recent Findings: AAV is a pauci-immune small-vessel vasculitis characterized by neutrophil-mediated vasculitis and granulomatousis. Hypertrophic pachymeninges is the most frequent CNS presentation. Cerebrovascular events, hypophysitis, posterior reversible encephalopathy syndrome (PRES) or isolated mass lesions may occur as well. Spinal cord is rarely involved. In addition, ear, nose and throat (ENT), kidney and lung involvement often accompany or precede the CNS manifestations. Positive ANCA testing is highly suggestive of the diagnosis, with each ANCA serotype representing different groups of AAV patients. Pathological evidence is the gold standard but not necessary. Once diagnosed, prompt initiation of induction therapy, including steroid and other immunosuppressants, can greatly mitigate the disease progression.Conclusions and Relevance: Early recognition of AAV as the underlying cause for various CNS disorders is important for neurologists. Ancillary investigations especially the ANCA testing can provide useful information for diagnosis. Future studies are needed to better delineate the clinical spectrum of CNS involvement in AAV and the utility of ANCA serotype to classify those patients.Evidence Review: We searched Pubmed for relevant case reports, case series, original research and reviews in English published between Sep 1st, 2001 and Sep 1st, 2018. The following search terms were used alone or in various combinations: “ANCA,” “proteinase 3/PR3-ANCA,” “myeloperoxidase/MPO-ANCA,” “ANCA-associated vasculitis,” “Wegener's granulomatosis,” “microscopic polyangiitis,” “Central nervous system,” “brain” and “spinal cord”. All articles identified were full-text papers.

Cathelicidin antimicrobial peptide as a serologic marker and potential pathogenic factor in antineutrophil cytoplasmic antibody-associated vasculitis

Antineutrophil cytoplasmic antibodies are associated with pauci-immune small-vessel vasculitis and crescentic glomerulonephritis. Cathelicidin LL37 is the human member of a family of antimicrobial peptides that are released from activated neutrophils and monocytes at sites of acute inflammation. Zhang and colleagues evaluated serum levels of cathelicidin LL37 and interferon-alpha in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and glomerulonephritis. Increased levels of cathelicidin LL37 and interferon-alpha were associated with AAV patients, particularly those with glomerular crescent formation. Cathelicidin LL37 may also be involved in the pathogenesis of AAV and thus could be a target for novel therapy. Cathelicidin LL37 is a promising new biomarker for active AAV, including aggressive crescentic glomerulonephritis, and may prove to be both a prognostic marker and a guide for treatment.

Mediastinal-Renal Syndrome: A Rare Manifestation of Granulomatosis with Polyangiitis

Granulomatosis with polyangiitis (GPA) is a distinct systemic disorder of obscure etiology characterized by necrotizing granulomatous inflammation and pauci-immune small-vessel vasculitis. Anti-neutrophil cytoplasmic antibodies (ANCA) appear to play an important role in the pathogenesis of GPA. Herein, we report a rare case of GPA presenting with ANCA-associated pauci-immune necrotizing and crescentic glomerulonephritis accompanied by a mediastinal mass and mediastinal lymphadenopathy in the absence of pulmonary parenchymal involvement. Furthermore, we describe the effects of plasmapheresis and concomitant immunosuppression on renal and mediastinal disease.

Wegener's granulomatosis: a review of clinical features and an update in diagnosis and treatment

Wegener's granulomatosis (WG) is an idiopathic, systemic inflammatory disease characterized by necrotizing granulomatous inflammation and pauci-immune small-vessel vasculitis of upper and lower respiratory tract and kidneys. The condition affects both genders equally, although some inconsistent gender differences have been observed. The aetiology of WG remains unknown although a number of exogenous factors have been suggested to be of aetiological relevance. Most clinical characteristics of this disease are non-specific, making clinical diagnosis challenging. Histopathological examination of lesional and peritoneal tissue is not pathognomonic, but is an essential investigation to confirm the presence of disease and exclude other disorders. At present, despite the increasingly wide range of potential therapies, cyclophosphamide plus corticosteroids remain the most recognized and effective means of inducing and sustaining remission of WG.

Diagnostics and Therapy of Antineutrophil Cytoplasmic Antibody (ANCA) Associated Vasculitides

Granulumatosis with polyangiitis (wegener's)/GPA microscopic polyangiitis (MPA) and Churg Strauss syndrome (CSS) are primary systemic vasculitides which predominantly affect small vessels, showing a high association with a positive C/PR3-ANCA in GPA and P/MPO-ANCA in MPA, so called ANCA-associated vasculitides (AAV). The diagnostic work-up relies on an interdisciplinary approach including imaging techniques and laboratory tests in order to assess disease stage and extent. The golden standard remains the histological proof of a necrotizing, pauci-immune small vessel vasculitis, in GPA additionally non-caseating granuloma is found mainly in the respiratory tract. Treatment is adapted to disease stage and extent and relies on a combination of a cytotoxic plus a tapering regimen of glucocorticosteroids. Induction of remission in "early systemic" disease without organ- and life-threatening organ manifestations and a near normal kidney function can be achieved with methotrexate. In the generalized phase with significant renal dysfunction cyclophosphamide is the mainstay of therapy, in rapidly progressive glomerulonephritis with an imminent dialysis indication plasmapheresis is performed additionally. When remission is achieved, usually after 3-6 months of induction treatment, cyclophosphamide is switched to azathioprine as maintenance of remission drug. Alternative therapies are methotrexate provided the kidney function is normal or Leflunomide in the long-term follow-up the relapse rate in ANCA-associated vasculitis is approximately 50% in 5 years, irrespective of the drug used for maintenance treatment. The relapse rate is significantly higher in GPA than in MPA and CSS.

Pathogenesis of antineutrophil cytoplasmic autoantibody vasculitis

Antineutrophil cytoplasmic autoantibodies (ANCAs) are associated with vasculitis. Current therapy involves administration of toxic therapy that is not optimally effective. This review will summarize evidence for the pathogenicity of ANCAs, which will suggest possible strategies for improving treatment. Pauci-immune small vessel vasculitis is associated with antibodies against myeloperoxidase (MPO-ANCA) and proteinase 3 (PR3-ANCA). One research group has reported a high frequency of autoantibodies against lysosomal-associated membrane protein 2 (LAMP-2) in patients with MPO-ANCA or PR3-ANCA. Epigenetic dysregulation appears to be the basis for increased MPO and PR3 neutrophil gene expression in ANCA disease. Release of neutrophil extracellular traps may be involved in initiating the ANCA autoimmune response and causing vessel injury. Generation of C5a by alternative pathway activation is involved in pathogenesis in mouse models. Intervention strategies in mice that target antigens, antibodies and inflammatory signaling pathways may translate into novel therapies. Animal models of LAMP-ANCA and PR3-ANCA disease have been proposed. Molecular mimicry and responses to complementary peptides may be initiating events for ANCAs. T cells, including regulatory T cells, have been implicated in the origin and modulation of the ANCAs, as well as in the induction of tissue injury. Our basic understanding of the origins and pathogenesis of ANCA disease is advancing. This deeper understanding already has spawned novel therapies that are being investigated in clinical trials. This brief review shows that there are more questions than answers, and new questions are emerging faster than existing questions are being answered.

Adult-onset Henoch–Schonlein purpura with positive c-ANCA (anti-proteinase 3): case report and review of literature

Anti-neutrophil cytoplasmic antibodies (ANCA) have two common patterns detected by indirect immunoXuorescence test (IIF test). The cytoplasmic pattern (c-ANCA) that is strongly associated with antibodies against proteinase-3 (PR3) and the perinuclear pattern (p-ANCA) that is mostly directed against myeloperoxidase (MPO). Anti-proteinase 3 and anti-MPO are characteristic for pauci-immune small vessel vasculitis like Wegener’s granulomatosis, microscopic polyangiitis, Churg–Strauss syndrome and idiopathic crescentic glomerulonephritis [1]. In Wegener’s granulomatosis (WG), the combination of c-ANCA with anti-PR3 antibodies has a sensitivity of 58% and a speciWcity of 99% [2]. On the other hand, the presence of c-ANCA (anti-PR3) in immune-complex-mediated vasculitis such as Henoch–Schonlein purpura (HSP) is very unusual. We report a case of biopsy proven HSP associated with IgG c-ANCA (anti-PR3).

Pathologic Classification of Vasculitis

The diagnostic categorization of systemic noninfectious vasculitis rarely can be made definitively based solely on the light microscopic findings but usually requires integration of the pathologic features with immunohistologic, clinical, and/or laboratory data to reach the most clinically useful diagnosis. Nevertheless, knowledgeable pathologic assessment of the histopathology can be critically important in arriving at the appropriate diagnosis. Noninfectious vasculitides can be broadly categorized as large vessel vasculitis, medium-sized vessel vasculitis, and small vessel vasculitis, although it is important to realize that the type of vessel involved is as important as size, and this is only one of many features that must be assessed to reach a diagnosis. Large vessel vasculitides (giant cell arteritis and Takayasu arteritis) have a predilection for the aorta and its major branches, especially those directed to the extremities and the neck and head. Medium-sized vessel vasculitides (polyarteritis nodosa and Kawasaki disease) affect predominantly medium-sized arteries, especially main visceral arteries such as the renal, hepatic, coronary and mesenteric arteries. Small vessel vasculitides (pauci-immune small vessel vasculitis and immune complex small vessel vasculitis) also can affect arteries, but their predominant targets are arterioles, venules, and capillaries. Pauci-immune small vessel vasculitis is associated with circulating antineutrophil cytoplasmic autoantibodies (ANCA) and includes microscopic polyangiitis, Wegener's granulomatosis, and Churg-Strauss syndrome. Precise diagnosis of immune complex small vessel vasculitis often requires immunohistologic characterization of the composition of the immune complexes or serologic detection of pathogenetically related antibodies.

ANCA Vasculitis

Antineutrophil cytoplasmic autoantibodies (ANCA) are associated with systemic and organ-limited vasculitis that most often is characterized immunopathologically by a paucity of vessel wall immunostaining for immunoglobulins. The systemic expressions of ANCA-associated vasculitis include microscopic polyangiitis, Wegener's granulomatosis, and Churg-Strauss syndrome. Microscopic polyangiitis has systemic pauci-immune small vessel vasculitis without evidence for granulomatous inflammation or asthma. Wegener's granulomatosis has pauci-immune small vessel vasculitis accompanied by necrotizing granulomatous inflammation but no asthma. Churg-Strauss syndrome has pauci-immune small vessel vasculitis accompanied by blood eosinophilia and asthma. Although ANCA-associated vasculitis has a predilection for small vessels, such as glomerular capillaries, pulmonary alveolar capillaries, and dermal venules, arteries also can be involved with pathologic changes that are indistinguishable form those of polyarteritis nodosa. ANCA with specificity for proteinase 3 (PR3-ANCA) are predominant in patients with Wegener's granulomatosis, whereas ANCA with specificity for myeloperoxidase (MPO-ANCA) are predominant in patients with microscopic polyangiitis, Churg-Strauss syndrome or renal-limited disease; however, either type of ANCA can occur in any of the clinicopathologic expressions of ANCA-associated vasculitis. Clinical, in vitro, and experimental animal data indicate that ANCA IgG is directly involved in the pathogenesis of ANCA-associated vasculitis.

Should eponyms be actively detached from diseases?

The use of eponymous titles for diseases is a hallowed tradition that conforms to no pattern, but the practice serves both as a shorthand way of referring to complex and poorly-understood syndromes, and an acknowledgment of those who described them. There are many instances, however, in which the name associated with the disease is not that of the first, or even the most significant person involved in its description, and the only reasons for continuing with the label are pragmatism and convenience. Eponyms might lapse from regular use over time or as a result of advances in medical knowledge. But in some circumstances, there is a more specific reason to discourage their use, as in the case of Reiter's syndrome. 1 Lu DW Katz KA Declining use of the eponym “Reiter's syndrome” in the medical literature, 1998–2003. J Am Acad Dermatol. 2005; 53: 720-723 Summary Full Text Full Text PDF PubMed Scopus (36) Google Scholar Hans Reiter (1881–1969) was certainly not the first person to describe postinfective inflammatory mucositis and arthritis, but the main reason behind the move to dissociate his name from the condition is that he is known to have been a high-ranking physician in the Nazi era. Reiter was an enthusiastic supporter of eugenics, and guilty of causing death by experimental infection with typhus of prisoners in concentration camps. 2 Wallace DJ Weisman MH The physician Hans Reiter as prisoner of war in Nuremberg: a contextual review of his interrogations (1945–1947). Semin Arthritis Rheum. 2003; 32: 208-230 Summary Full Text Full Text PDF PubMed Scopus (27) Google Scholar A similar, but rather less clear cut, example forms the subject of the Eponym article in this week's Lancet: Friedrich Wegener and the granulomatous vasculitis which he studied in the 1930s. 3 Woywodt A Haubitz M Haller H Matteson EL Wegener's granulomatosis. Lancet. 2006; 367: 1362-1366 Summary Full Text Full Text PDF PubMed Scopus (92) Google Scholar Wegener's granulomatosisWegener's granulomatosis is a multisystem disorder characterised by necrotising granulomatous inflammation and pauci-immune small-vessel vasculitis.1,2 The prevalence in Europe is estimated to be five per 100 000; the disease occurs more frequently in northern latitudes but the cause of this skewed distribution is unknown. Most patients have initial upper airway symptoms, such as nasal discharge, sinusitis, or epistaxis. The granulomatous inflammatory process can destroy the septum and cause saddle nose deformity. Full-Text PDF

Outcome of renal transplantation in patients with pauci-immune small vessel vasculitis or anti-GBM disease.

Pauci-immune small vessel vasculitis (SVV) and anti-GBM disease are the most common causes of rapidly progressive glomerulonephritis (RPGN) and they frequently lead to end-stage renal disease. For renal replacement therapy, renal transplantation is the preferred treatment option. However, in patients with glomerular diseases, the outcome of renal transplantation can be adversely affected by recurrence of the original disease. The information in the medical literature on the outcome of renal transplantation in patients with RPGN is limited because most data are derived from case studies and from studies involving a small number of patients. We studied the outcome of renal transplantation in patients with pauciimmune SVV or anti-GBM disease, transplanted in our center between 1968 and 2000. Patient and graft survival were compared with a matched control group from our hospital. We specifically looked for any evidence of recurrent disease. Included in the study were 43 patients (31 male, 12 female) with a mean age (+/- SD) of 48 +/- 15 years at transplantation. Patients were diagnosed as Wegener's granulomatosis (n = 8), microscopic polyangiitis (n = 7), renal limited vasculitis (n = 18) and anti-GBM disease (n = 10). The average follow-up was 62 +/- 57 months. No graft was lost due to recurrence of the underlying disease. One patient with Wegener's granulomatosis had a relapse with only extrarenal manifestations 5 months after transplantation. Patient and graft survival at 5 years after transplantation were 77% and 60%. Survival rates were not significantly different from a matched control group of renal transplant patients with other underlying diseases, 79% and 56%, respectively. Patients with pauci-immune SVV or anti-GBM disease developed significantly more malignancies than the control group (p = 0.02). Recurrence of pauci-immune SVV and anti-GBM disease after transplantation is rare. Renal transplantation can be successfully performed in patients with pauciimmune vasculitis or anti-GBM disease. Physicians should be aware of the greater risk of developing malignancies, especially skin cancer.