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37. ANCA-Associated Vasculitis: A Comprehensive Review of Clinical Presentation, Management, and Outcomes
Authors:
Osmonova G. Zh.
Mohammed Fatah Uddin Kamran,Sanjana Satish Patil,Sanskruti Praveen Pullurwar,Unnati Keshav Thakare
( International Medical Faculty, Osh State University, Osh, Kyrgyzstan)
Abstract
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) rep- resent a group of rare, complex autoimmune disorders characterized by necrotizing inflammation of small blood vessels, with potential for severe organ-threatening and life-threatening manifestations. The present review offers a detailed analysis of AAV which includes granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA). Research findings demonstrate important progress in medical treatments which includes rituximab be- coming the main induction therapy and avacopan introduction and glucocorticoid reduction initiatives. The medical advancements have not eliminated the major health issues which AAV patients face because their death rates stay above average and their disease frequently returns and their treatments produce dangerous side effects. The article presents existing research about AAV epidemiology and clinical symptoms and diagnostic methods and treatment options and long-term prognosis while discussing new discoveries and existing difficulties in this medical specialty.
INTRODUCTION
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) represent a group of uncommon autoimmune diseases which lead to necrotizing inflammation pri- marily in small blood vessels including capillaries and venules and arterioles and small arteries. These disorders are defined by the presence of circulating autoantibodies that target specific neutrophil proteins, primarily proteinase 3 (PR3) and myeloperoxidase (MPO), which play a central role in their pathogenesis. The AAV spectrum contains three separate clinical syndromes which include granulomatosis with polyangiitis (GPA, formerly Wegener’s granulomatosis) and microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA, previously Churg-Strauss syndrome).
The classification and nomenclature of AAV have evolved over time, with the current framework established by the 2012 Revised International Chapel Hill Consensus Con- ference (CHCC). The system shows how ANCA serology relates to clinical phenotypes yet it recognizes that some patients might not have ANCA positivity. Medical experts have started to see ANCA specificity classification (PR3-AAV versus MPO-AAV) as a better predictor of patient outcomes than traditional clinical syndrome classification be- cause these two types show distinct genetic patterns and disease symptoms and different chances of relapse and survival rates.
The European population experiences 10 to 20 new cases of AAV per million people each year while the disease occurs at rates between 46 and 184 cases per million people. The distribution of AAV subtypes shows major differences between different geographical regions. The disease GPA mainly affects people from northern Europe but MPA exists mostly in southern Europe and Asian countries including China and Japan. The peak onset of AAV typically occurs between ages 45-60, with a slight male predominance that varies by specific disorder.
Historically, AAV carried a dismal prognosis, with mortality rates exceeding 80% within one year without effective treatment. The 1970s brought cyclophosphamide and glucocorticoid therapy which transformed AAV from a fatal disease into a manageable condition that achieves remission in more than 90% of cases. The medical treatment advancement brought about dangerous health issues which led to increased infection rates and cancer development and organ failure caused by treatment-related toxicity.
Scientists have dedicated their work to create better treatment methods which keep therapeutic value while reducing harmful side effects. The treatment of AAV has experi- enced a complete transformation through new therapeutic agents which include rituximab and avacopan and other specialized medications. Treatment approaches now focus on re- ducing cyclophosphamide use by using different drugs and shorter treatment periods and minimizing total glucocorticoid intake.
AAV maintains its position as a significant clinical hurdle despite therapeutic progress in the field. The survival rates of patients drop significantly when compared to the normal population during their first year after diagnosis. The condition results in permanent organ damage which leads to heart disease and infections and cancer development and reduced life quality. The condition continues to show up most often in patients who test positive for PR3-ANCA which forces them to stay on immunosuppressive treatment for extended periods despite the potential health risks.
The review presents a complete evaluation of AAV knowledge by showing its clinical signs and medical detection methods and treatment options and patient recovery results. The paper brings together data from contemporary clinical trials and observational studies and consensus guidelines to provide medical practice recommendations and identify areas for future research.
Methods
LITERATURE SEARCH STRATEGY
The research team used a detailed method to find all relevant studies about ANCA- associated vasculitis. The researchers accessed PubMed and PMC together with various biomedical databases to perform their electronic database search. The search method used a dual approach which combined keywords with medical subject headings (MeSH terms) about ANCA-associated vasculitis for the following terms: ”ANCA-associated vasculitis,” ”granulomatosis with polyangiitis,” ”microscopic polyangiitis,” ”eosinophilic granulomatosis with polyangiitis,” ”AAV treatment,” ”vasculitis outcomes,” and ”vasculi- tis complications.” The search included only human research studies which were published in English during the time frame up to October 2023 without any date restrictions.
STUDY SELECTION AND ELIGIBILITY CRITERIA
The initial literature search identified 352 potential references. The screening process eliminated duplicate studies before researchers evaluated 85 full-text articles for their appropriateness based on their titles and abstracts. The inclusion criteria required four specific study types which included original research studies such as randomized controlled trials and observational cohort studies and case-control studies and systematic reviews and meta-analyses and clinical practice guidelines and consensus statements and studies that documented epidemiological data and clinical characteristics and diagnostic methods and treatment results and AAV-related complications. The study established four exclusion criteria which prohibited case reports and small case series with less than 10 participants and non-English publications and studies that focused only on pathogenic mechanisms without showing clinical outcomes and editorials and commentaries and letters that lacked original data.
DATA EXTRACTION AND SYNTHESIS
A standardized form was used to extract data from the included studies which recorded study design and population details and follow-up duration and participant demograph- ics and clinical characteristics and diagnostic approaches and treatment methods and outcomes including remission and relapse and mortality rates and complications. The as- sessment of evidence quality occurred through suitable tools which included the Cochrane Risk of Bias Tool for randomized trials and the Newcastle-Ottawa Scale for observational studies. The research team chose narrative synthesis because the studies contained various study designs and different patient groups and measurement approaches. The research findings were organized into thematic sections which correspond to the main topics of
AAV that this review discusses.
RESULTS
Clinical Presentation and Disease Classification
AAV presents with different clinical symptoms which start with general symptoms and progress to specific organ damage. The symptoms appear differently in each patient and they develop slowly which leads to delayed diagnosis because about 33 percent of patients wait more than six months for a proper diagnosis. All AAV subtypes display constitutional symptoms which include fever and fatigue and weight loss. The specific organ symptoms depend on the exact AAV type and ANCA antibody type which results in unique clinical patterns:
Granulomatosis with polyangiitis (GPA) causes damage to the respiratory system from nose to lungs and also affects the kidneys. Upper respiratory tract symptoms include bloody nasal discharge, nasal ulceration, sinusitis, chronic otitis media, and potential destruction of nasal cartilage leading to saddle nose deformity. Pulmonary involvement may present as nodules, cavities, or alveolar hemorrhage, which can be severe and fatal. Renal disease manifests as rapidly progressive glomerulonephritis (RPGN) with hyper- tension, proteinuria, and active urinary sediment. Approximately 90% of patients with multisystem active GPA are ANCA-positive, typically with anti-PR3 specificity.
Microscopic polyangiitis (MPA) is characterized by necrotizing vasculitis without gran-
uloma formation. Renal involvement is nearly ubiquitous and often severe, presenting as RPGN. Pulmonary capillaritis causing alveolar hemorrhage occurs less frequently than in GPA but can be life-threatening. MPA is more common in older patients and typically associates with MPO-ANCA positivity.
Eosinophilic granulomatosis with polyangiitis (EGPA) classically presents with asthma, eosinophilia, and necrotizing vasculitis with eosinophilic infiltrates. The disease progresses through three main stages which include the allergic prodromal phase followed by the eosinophilic phase and finally the vasculitic phase. The main cause of death in patients with cardiac involvement stems from eosinophilic myocarditis. ANCA positivity is ob- served in only 30-50% of EGPA cases, typically with MPO specificity, and is associated with higher risk of glomerulonephritis and vasculitic manifestations.
DIAGNOSTIC APPROACH
The diagnosis of AAV requires integration of clinical features, serological testing, histopatho- logical findings, and radiologic studies. The diagnosis becomes difficult because early symptoms show up in various ways while lacking particular characteristics. The assess- ment needs to determine these specific elements as its main objective.
The diagnosis requires detection of ANCA through serological testing. The interna- tional guidelines suggest starting with indirect immunofluorescence (IIF) testing before performing ELISA assays to detect PR3 and MPO antigens. Two classic IIF patterns are recognized: cytoplasmic (C-ANCA), primarily associated with PR3-ANCA, and per- inuclear (P-ANCA), primarily associated with MPO-ANCA. It is important to note that approximately 10% of GPA patients and higher proportions of EGPA patients may be ANCA-negative, thus a negative test does not definitively exclude AAV.
The gold standard for AAV diagnosis confirmation exists in the form of tissue biopsy examination. Characteristic findings include necrotizing vasculitis with few or no immune complex deposits, hence the term ”pauci-immune”. AAV subtypes show different histo- logical characteristics: GPA presents with necrotizing granulomatous inflammation while MPA exhibits necrotizing vasculitis without granulomas and EGPA displays eosinophil- rich inflammation with necrotizing granulomas.
Laboratory and Radiologic Investigations: In most cases, laboratory tests done in the course of the disease reveal the presence of inflammatory markers, such as ESR and CRP, and there are also indicators of chronic disease anemia, an increase in white blood cells, and abnormal urine composition with blood and protein if the kidneys are involved. Doctors can tell the exact position of the disease by performing organ-specific imaging studies (CT chest, sinus CT, MRI). Pulmonary function tests and echocardiogram might be performed depending on the clinical presentation.
Disease Activity Assessment: The use of standardized methods, such as the Birm-
ingham Vasculitis Activity Score (BVAS), offers us the possibility of obtaining objective measures of disease activity and of deciding on treatment accordingly. The BVAS scores the clinical manifestations in ten organ systems, with a score of one or higher indicating the presence of active disease. The Vasculitis Damage Index (VDI) measures the amount of damage that is irreversible due to the disease or its treatment, which has substantial effect on the long-term prognosis.
TREATMENT STRATEGIES
The present AAV treatment approaches are adjusted according to the severity, activity, and individual clinical symptoms of the disease. Usually, the treatment regimens consist of two stages: the induction of remission and the maintenance of remission.
Table 2: Treatment Approaches for ANCA-Associated Vasculitis
Treatment Phase Agents Indications and Key Considerations
Remission Induction
Cyclophosphamide (IV or oral) + glucocorticoids
Rituximab + glucocorti- coids
Plasma exchange + im- munosuppression
Methotrexate or mycophe- nolate mofetil
Standard of care for se- vere, organ-threatening dis- ease. Pulsed IV regimen re- duces cumulative dose and toxicity compared to oral Non-inferior to cyclophos- phamide;preferred in relapsing disease, young patients.More effective in PR3-ANCA patients; allows cyclophosphamide avoidance
Severe renal disease (crea- tinine ¿500 mol/L) or dif- fuse alveolar hemorrhage. Role in rapidly progressive glomerulonephritis with se- vere renal impairment
Non-severe disease without major organ involvement. Not appropriate for organ- or life-threatening disease
Remission Maintenance
Rituximab Increasingly used for main- tenance, especially after rit- uximab induction. Supe- rior to azathioprine in pre- venting relapses in PR3- ANCA patients
Azathioprine Traditional maintenance agent. Lower cost than rituximab but potentially higher relapse risk
Methotrexate Alternative for mainte- nance in non-renal disease. Contraindicated in signifi- cant renal impairment
Mycophenola8te mofetil Alternative maintenance
option. Higher relapse rate compared to azathioprine
Remission Induction: In cases of severe disease where the organs are at risk, the usual course of action is to use a combination therapy consisting of the glucocorticoids and either cyclophosphamide or rituximab. The pivotal RAVE and RITUXVAS studies showed that rituximab was not inferior to cyclophosphamide for induction and might be even better in recurrent disease. Rituximab is especially the drug of choice for patients with a high risk of infertility, previous exposure to cyclophosphamide, or concerns about cyclophosphamide toxicity. Patients with severe renal failure (creatinine ¿500 mol/L) or diffuse alveolar hemorrhage typically receive plasma exchange treatment in addition to the immunosuppressive therapy as a standard procedure.
New guidelines advocate for the use of either a drug or other techniques to minimize glucocorticoids to reduce their toxicity effects and at the same time keep up the desired efficacy. The development of avacopan, an oral C5a receptor antagonist, is the most significant progress so far, as it has shown in clinical trials that glucocorticoid therapy can be reduced or even withdrawn without loss of efficacy.
Remission Maintenance: After the successful induction (usually after 3-6 months), patients are gradually switched to long-term maintenance therapy which is aimed at the prevention of relapse. It has been demonstrated that rituximab is more effective than azathioprine for the maintenance of PR3-ANCA patients, leading to significantly lower rates of relapse. The older maintenance agents consist of azathioprine, methotrexate (for the people with normal kidney function) and mycophenolate mofetil, however the latter might be connected with the problem of higher relapse rates in some studies. The perfect duration of maintenance therapy is still a question mark, but the up-to-date guidelines propose a minimum of 24 months for the majority of the patients, while a longer period should be considered for those with the highest risk of relapse.
Special Considerations: Treatment strategies must be tailored to the individual patient according to the specific clinical situation. For refractory disease the switching between cyclophosphamide and rituximab may be needed or considering other agents. The treat- ment of the relapsing disease should depend on the severity, with the smallest relapses being perhaps handled with an adjustment of glucocorticoids, whereas the big relapses mostly asking for reinduction therapy. ANCA-negative subjects are usually given the same treatment as ANCA-positive ones, but the proof is less strong.
DISCUSSION
Long-Term Outcomes and Prognostic Factors
Notwithstanding the progress of therapy, AAV still has a considerable excess mortality rate when compared to the general population. A detailed examination of 848 patients from seven trials conducted by the European Vasculitis Society (EUVAS) reported that
mortality rates over the period of 20 years hit 36.3% and at 5, 10, and 15 years were 14.2%, 19.9%, and 28.8% higher than the controls of the matched population respectively. The estimated median survival from diagnosis was 17.8 years, significantly lower than the expectation in age- and sex-matched populations. In the multivariable analysis, age, sex, low estimated glomerular filtration rate (eGFR), and low platelet count were identified as independent factors of mortality.
The pattern of death causes in AAV is bimodal. Infections (26%) and active vasculitis mainly account for early deaths (within the first year), indicating both disease severity and treatment-related immunosuppression. The proportion of deaths due to cardiovascular disease (14%) and malignancies (13%) rises as the period of death gets farther from the onset of the disease. This pattern highlights the need for effective disease control to be accompanied by careful management of the complications caused by the treatment throughout the course of the disease.
Relapse risk is another significant problem in maintaining AAV treatment over the long term. Over a period of 44-62 months, the rates of reported relapses varied between 38% and 54%. There are different factors that cause relapse risk, but ANCA specificity is the one that is the most significant. Patients with PR3-ANCA have always illustrated to have higher relapse rates as compared to those with MPO-ANCA, with hazard ratios varying between 1.62-1.77 in different cohorts. Besides, the pattern of organ involvement also plays a role in the determination of relapse risk; for example, upper respiratory tract involvement in GPA and lung involvement in MPA are associated with higher relapse rates.
Treatment Complications and Comorbidities
The treatment-related complications and their enormous burden contribute greatly to the long-term prognosis and the quality of life of the AAV patients:
Infections: The occurrence of infections is the number one reason for AAV patients dying, especially in the first year after diagnosis. In a study analyzing four European trials it was seen that 59% of the one-year deaths were due to treatment-related adverse events, with infections being the main reason. The other 14% of deaths were caused by active vasculitis. If a patient has a lower initial GFR, is on corticosteroid treatment for a longer time, and has lymphocytopenia, then that person is at risk for developing a severe infection. All these findings stress the need for strict monitoring of infections, giving prophylactic treatment where necessary, and devising strategies for patients to be on lower doses of immunosuppressive drugs in the long run.
Cardiovascular Disease: Those suffering from AAV are at a much higher risk for heart problems than the rest of the population. One of the most detailed studies of the Danish registry established the heights of the rates for ischemic heart disease (HR
1.86), myocardial infarction (HR 1.62), heart failure (HR 2.12), atrial fibrillation (HR 2.08), and ischemic stroke (HR 1.58). In patients with AAV, the 5-year absolute risks of all cardiovascular outcomes were considerably high. It seems that one of the main contributors to the higher cardiovascular risk in those suffering from AAV is the use of glucocorticoid drugs in combination with the chronic inflammation, which makes it very important to focus on aggressive management of cardiovascular risk factors in this population.
Malignancy: In earlier times, the use of cyclophosphamide-based treatment led to a higher incidence of bladder cancer and blood-related cancers among the patients, espe- cially if they had received a total dose above 36g. Nowadays, the oncological risk related to cyclophosphamide is lessened significantly by the application of protocols with low total doses of cyclophosphamide or cyclophosphamide-sparing. The incidence of non- melanoma skin cancers is also higher in patients with AAV, which requires skin checks by a dermatologist on a regular basis.
Organ Damage and Quality of Life: The total of the disease and treatment-related harms is considerable for AAV survivors. Long-term follow-up data from EUVAS trials re- vealed that after a mean of 7.3 years, only 7.9% of patients had no items of damage, while 34.4% had accumulated at least five items. Damage items mostly involved development of hypertension (41.5%), osteoporosis (14.1%), cancer (12.6%), and diabetes (10.4%). Not surprisingly, health-related quality of life measurements demonstrate persistent impair- ments in both physical and mental domains compared to general population norms, with fatigue affecting nearly three-quarters of patients. Such findings point strongly to the multidimensional nature of AAVs impact beyond mere measurement of disease activity and making conclusive that the application of comprehensive care focusing on damage prevention and quality of life optimization is of paramount importance.
Evolving Treatment Paradigms and Future Directions
AAV management has undergone major transformations recently, with some of them being of great importance:
Glucocorticoid Minimization: The strong toxicity linked to the standard high-dose, long-term glucocorticoid regimens has been acknowledged and thus less exposure is being aimed at. The successful introduction of avacopan, which showed non-inferior efficacy with vastly less glucocorticoid exposure in the ADVOCATE trial, is a new path in AAV management. This method can reduce the risk of many severe complications which have long been associated with glucocorticoids, such as infections, diabetes, osteoporosis, and cardiovascular problems.
B-cell Targeted Therapies: The successful development of rituximab as an essential part of both initiation and maintenance treatment is one more salient progress. The studies currently being carried out are looking at the anti-CD20 antibodies of the next generation and other B-cell targeting strategies that may produce better effectiveness or safety profiles. The successful use of B-cell depletion therapy in AAV has confirmed the importance of B-cells and autoantibody production in the disease’s development.
Complement Pathway Inhibition: The success of avacopan, which blocks C5a receptor, has been very strong proof on how pivotal the complement system is in AAV pathogen- esis. Hence, this development has greatly sparked interest in other therapies targeting complement and has affirmed the complement system as a promising area for therapeutics in AAV.
Personalized Medicine Approaches: There is now a strong case for the use of stratified medicine based on ANCA specificity, rather than just clinical syndrome, as the only criteria to guide treatment. The different responses to treatment, and also the different patterns of relapse, of PR3-ANCA vs. MPO-ANCA patients indicate that the most efficient management may be different according to the type of serotype. It is likely that future treatment protocols will take ANCA specificity into account along with other clinical and genetic factors in order to give the most suitable therapy to each individual patient’s profile.
Even with these advancements, there are still major challenges that have to be faced. The duration of maintenance therapy is still not clear, and there is no sufficient evi- dence to direct decisions about the discontinuation of immunosuppression. More accurate biomarkers for predicting relapse risk are needed urgently so that it becomes easier to individualize treatment intensity and duration. Furthermore, the management of refrac- tory disease is an area that still requires a lot of work; currently, several novel therapeutic targets are under investigation.
CONCLUSION
ANCA-associated vasculitis is a collection of complex autoimmune diseases with the po- tential to severely affect multiple organs. The understanding of clinical spectrum, diag- nostic methods, and treatment strategies has greatly improved in these conditions. The progression from uniformly fatal results to manageable chronic disease is a significant therapeutic gain, but at the same time, big challenges still exist.
The current treatment paradigms can effectively induce remission in most patients with the help of glucocorticoids combined with either cyclophosphamide or rituximab, followed by a maintenance therapy of a longer duration to prevent relapse. One of the recent advances is the setting of rituximab as the main agent for induction and maintenance, the introduction of avacopan to assist in the minimization of glucocorticoids, and the growing awareness of the importance of ANCA specificity in making treatment decisions. While these improvements have been made, AAV is still a major problem in the medical
field. Patients die earlier than the general population, especially in the first year after diagnosis. The long-term complications include organ damage, heart disease, infections, cancer, and a reduced quality of life. Frequent relapses occur particularly in PR3-ANCA positive patients that require long-term immunosuppressive therapy with its associated risks.
AAV management in the future is expected to put more emphasis on the following areas, which will be the main focus: Firstly, continuous personalization of treatment based on serological, genetic, and clinical factors to maximize the benefit and at the same time reduce the harmful effects. Secondly, creation of new targeted drugs with better safety profiles to meet the needs of the patients who have already been through long-term disease or are in the relapse process. Thirdly, defining and verifying treatment period and biomarkers that will help in therapy customizing. Lastly, new and better ways of dealing with the issues that come with long-term AAV treatment, and thus, enhancing quality of life for the survivors.
The increasing knowledge about the complicated pathogenesis and new therapeutic targets leads to the hope that achieving durable remission with minimal treatment-related toxicity is becoming a more realistic goal. On the other hand, total and proper care through a multidisciplinary approach is still the key to solving the different problems that patients with such complex diseases face.
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