ANCA-Associated Vasculitis: Advancement in Pathogenesis, Clinical Features and Management

Anti-Neutrophil Cytoplasmic Autoantibody (ANCA)-Associated Vasculitides (AAVs) are rare disorders characterized by inflammation of the small blood vessels resulting in ischemia or haemorrhage. The main phenotypes of AAVs are Granulomatosis with Polyangiitis (GPA), Microscopic Polyangiitis (MPA), and Eosinophilic Granulomatosis with Polyangiitis (EGPA). Although the pathogenesis of these disorders is still incompletely understood, distinct roles for T cells subsets and ANCA autoantibodies were underscored. AAVs present in the head, neck, lung, kidney, skin, heart, eyes, and intestine. The treatment of AAVs aims to induce and maintain remission and rapidly control of the disease activity. Rituximab, the first major alternative to cyclophosphamide plus glucocorticoids therapy, has enhanced the management of AAVs. However, continuous evaluation is constantly needed to manage the uncommon clinical features which may accompany the disease. This review summarizes the major findings of recent studies related to the three kinds of AAVs focusing on new novelties of their pathogenesis, clinical manifestations, and management.


Introduction
Vasculitides refer to a group of pathological conditions resulting from inflammation of blood vessels, with consequent adverse effects such as ischemia and hemorrhage. According to vessels size, they are usually classified into three groups; small, medium, and large vessel vasculitides. Granulomatous Polyangiitis (GPA), Microscopic Polyangiitis (MPA), and Eosinophilic Granulomatosis with Polyangiitis (EGPA) are the main AAVs types which usually affect small-vessels and characterized by the presence of ANCA autoantibodies in patient's serum [1,2]. Although they are idiopathic, their pathogenesis and management still a hot topic [3,4]. Divers factors were involved in AAVs pathogenesis including, T cells and complement system activation, and genetic and environmental factors [5]. The details of AAVs pathogenesis are incompletely unexplained. However, evidence related to patients with AAVs suggests a role for macrophage or monocyte in increasing the intensity of tissue injury. In addition, serum of AAVs patients characterized by increased levels of colony stimulating factor 1 (CSF1) [6]. Johansson ÅC et al. found that AAVs pathogenesis was amplified through phagocytes behaviors impairment [7]. ANCApositive glomerulonephritis is may seem to be accompanied with increased C-Reactive Protein (CRP), an acute-phase protein of inflammation related to interleukin 6 (IL-6). Moreover, of primary contributors in AAVs pathogenesis are the leukocytes via damage caused by their migration and invasion. AAVs genetic background knowledge is increased by additional genome-wide association study (GWAS) results and other genomic approaches [8].
In diagnosis, the common laboratory tools in AAVs diagnosis are indirect Immunofluorescence test (IFT) for ANCA screening and then confirm positive results by enzyme-linked immunosorbent assay (ELISA) to differentiate proteinase 3 (PR3)-ANCA or c-ANCA from myeloperoxidase (MPO)-ANCA or p-ANCA ( Figure 1). In treatment, therapeutic strategies have been established for AAVs associated with increasing evidence related to their pathogenesis.
These strategies aim to prevent disease relapse, reduce drugs toxicity, and limit disease consequences [9]. Two phases are considered in AAVs treatment, the first is an induction of remission, and the second is for rapid control of disease activity [10].
Currently, the monoclonal antibodies, rituximab, and mepolizumab have been reported as novel drugs in AAVs treatment [11,12]. Our previous data confirmed that TNF-α blockers in rheumatic diseases e. g. rheumatoid arthritis compromised the disease activity [13] whereas, TNF-α blocker, etanercept characterized by increasing solid malignancies development [14].
The majority of patients with AAVs develop new cascades of events led to new severe symptoms. Thus, Grayson and his co-workers suggested that continuous evaluation of patients with established vasculitis remains critical [15]. AAVs research directed towards investigating the disease duration optimization and maintenance therapy frequency as well as targeted treatment development which could unravel successful treatment or cure for AAVs. In this review, we focused on the outputs of current studies related to the main three kinds of AAVs, and prospects of alternative treatments or cure.

Granulomatosis with Polyangiitis (GPA)
GPA is a rheumatic systemic small vessels inflammation that affects multiple organs and usually accompany with c-ANCA or rarely p-ANCA autoantibodies. The most predominantly affected population category is age bracket of 40 -55 years. The disease is frequently presented in a sino-nasal cavity, kidney, and the lung ( Figure 1

GPA Clinical Features and Management: a new Progress
GPA clinical manifestations were summarized in Table 1.
The most common sites involved in GPA are ear, nose, and throat (ENT); lungs; and kidneys (ELK) (Figure 1

Eosinophilic Granulomatosis with Polyangiitis (EGPA)
It is an autoimmune reaction of unknown cause that produces

EGPA Clinical Features and Management: A New Progress
It has been hypothesized that the ENT involvement in EGPA patients is an essential aspect. Therefore, nose and ear are the commonest sites where the clinical manifestations of EGPA are presented ( Figure 1).

Microscopic Polyangiitis (MPA)
MPA is a member of small vessel vasculitis that often has a fatal outcome, and its histology shows little or no immune deposits. In

MPA Clinical Features and Management: A New Progress
Clinical manifestations of MPA are so variable including the pulmonary and renal involvement, and skin manifestations ( Figure   1). Also, severe co-trimoxazole-induced hypoglycaemia, crescentic  [78,79].
On the other hand, The Azathioprine hypersensitivity is presented as cardiogenic shock and weet's syndrome in a patient with MPA [80]. In addition, MPA may be associated with fibrosing interstitial lung disease (ILD), primary biliary cirrhosis, Sjogren's syndrome, and Hashimoto's thyroiditis [81,82]. In Japanese patients, kidney survival was affected in relapsed MPA associated with infectious complication [83]. Indeed, phenotypes difference in patients with MPA from Europe and Japan has been explained [84].
Despite there are no standard treatment protocols for treatment of MPA patients, the effective communication between rheumatology, pulmonary, and nephrology physicians could improve disease management. Renal survival in MPA Chinese patients was promoted by glucocorticoids and mycophenolate mofetil (MMF) therapy [85]. However, MPA Japanese patients with renal involvement couldn't get satisfactory results after treatment by cyclophosphamide and corticosteroid [86]. Other monoclonal antibodies, rituximab and Tocilizumab (TCZ) monotherapy could be a novel choice in some MPA patients [11,87]. Management protocols based on rituximab and MMF in children with MPA were achieved satisfactory outputs [88]. Meanwhile, MPA with cholecystitis elderly patient had been successfully treated using mizoribine [89]. As well, therapy directed at T cells might be an alternative treatment option for a rare MPA case with GIT involvement [90]. Unfortunately, disseminated mycetoma caused by Nocardia pseudobrasiliensis in MPA patient on long-term corticosteroid therapy was observed as a unique case in Korea [91]. Currently, gabexate by its antiinflammatory functions could be helpful in MPA management [92].

Concluding Remarks
The exact cause of AAVs is still not fully understood and we are yet to have complete remission. Patients with AAVs develop new severe symptoms. Therefore, continuous monitoring and evaluation remains critical to avert, control, or prevent unforeseen complications that could emanate from the disease.

Author Contributions
All authors made significant contribution to the development of this manuscript.

Competing Interest
The authors declare that they have no competing interest. None of the authors has any financial or other interest influencing the output of this review.