ANCA-Positive Small-Vessel Vasculitis Following SARS-CoV-2 Vaccination—A Systematic Review

As vaccinations against the SARS-CoV-2 virus have become a crucial tool in controlling the spread of the disease, reports of rare health complications have emerged, including new-onset antineutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitis (AAV). We systematically reviewed new-onset AAV following COVID-19 vaccination case reports and case series published in three databases before January 2024 following PRISMA guidelines to understand the characteristics of possible causal relationships or coincidences. In total, 404 articles were screened respectively by title, abstracts, and full-texts. Thirty-four papers fulfilled the inclusion criteria and have been analyzed, covering 44 patients with new-onset AAV after COVID-19 vaccination with no prior history of COVID-19 infection. Data regarding patients’ metrics, comorbidities, vaccination characteristics, symptoms, diagnostics, treatment, and outcomes were investigated and summarized. The cohort consisted predominantly of females. AAV diagnosis was confirmed via biopsy, with renal dysfunction as a prevailing manifestation. In most cases, the first symptoms of AAV developed after the second dose; moreover, Pfizer-BioNTech was the most frequently administered vaccine among the analyzed cohort. Primary treatment involved glucocorticoid therapy, with a mostly favourable response. This systematic review aims to raise awareness among clinicians in the field regarding this rare but possible complication, to promote the prompt recognition and diagnosis of de novo ANCA-positive small-vessel vasculitis in timely association with SARS-CoV-2 vaccination.


Introduction
Immunization stands as an instrument for global health and development achievements, annually preserving millions of lives worldwide.Vaccines reduce the risks of getting a disease by operating in harmony with the body's innate defences.Following vaccination, the immune system is prompted to react, thereby establishing a shield of protection [1].
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in more than 670 million infections and almost 7 million deaths globally [2].With the ongoing COVID-19 pandemic and the emergence of new variants of SARS-CoV-2, there is a critical demand for vaccines.These vaccines are essential for safeguarding individuals at elevated risk of complications and potentially controlling disease outbreaks through the establishment of herd immunity [3].In early 2021, the first vaccines were introduced to stop the pandemic.Also, approximately 68.2% of the world's population has been fully vaccinated against this disease.
Vaccination has long been recognized as an integral part of primary care medicine, serving to prevent a wide array of common and potentially life-threatening diseases.However, they can cause common side effects, including injection site pain, redness, and swelling and systemic symptoms such as fever, malaise, headache, and lymphadenopathy.However, it is important to acknowledge the potential for more serious adverse events associated with certain vaccinations [5].Recently, there have been an increasing number of reports of autoimmune diseases either flaring up or occurring de novo.These include autoimmune glomerulonephritis, autoimmune rheumatic diseases, and autoimmune hepatitis [2].Furthermore, there is a growing acknowledgement of the occurrence of new-onset antineutrophil cytoplasmic antibody (ANCA)-associated small-vessel vasculitis in connection with SARS-CoV-2 vaccinations [6].
ANCA-associated vasculitis (AAV) is a group of small-vessel vasculitis characterized by the severe inflammation of small blood vessels.This disorder manifests through a breakdown in the body's tolerance to neutrophil primary granule proteins, such as leukocyte proteinase 3 (PR3) or myeloperoxidase (MPO) [7].AAV is clinically classified into three main types, granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA), each presenting distinct clinical features [8,9].
Although ANCA antibodies are primarily present in AAV, they can also be useful in diagnosing other diseases.It is important to note that ANCA antibodies are associated with a heterogeneous group of rare autoimmune diseases that cause vasculitis with varying symptoms [10].
In our study, we focused solely on ANCA-positive small-vessel vasculitis, as the criteria for qualifying individual disease entities are precisely defined according to ACR-EULAR (American College of Rheumatology-European League Against Rheumatism) guidelines.The ACR-EULAR has recently introduced a new classification system.It take into account ANCA testing and modern imaging techniques, resulting in improved specificity and sensitivity.Therefore, in each case we were able to ascertain that the developed disease was associated with ANCA antibodies, confirmed by laboratory tests and biopsy [9,11].We summarized the characteristics and clinical presentation of ANCApositive small-vessel vasculitis cases reported in the literature since the beginning of the COVID-19 pandemic.

Materials and Methods
The research methods adhered to the PRISMA guidelines [12].

Search Strategy
A thorough systematic search was conducted, utilizing the Mendeley search engine, alongside screening of PubMed, Emboss, and Scopus databases.The scope of the research encompassed papers published from 1 January 2020 to 1 January 2024.Three researchers (K.L., A.W, and M.B.) independently conducted searches using a predefined set of keywords: (ANCA OR "antineutrophil cytoplasmic antibody" OR "ANCA-associated" OR Wegener OR granulomatosis OR "eosinophilic granulomatosis" OR "Churg-Strauss" OR microscopic OR "MPO-ANCA" OR "PR3-ANCA" OR MPO OR PR3) AND (vasculitis OR "granulomatosis polyangiitis" OR syndrome OR "de novo vasculitis" OR vasculitides) AND (COVID-19 OR "SARS-CoV-2" OR COVID) AND (Moderna OR Pfizer OR AstraZeneca OR Sputnik OR Janssen OR Sinopharm OR Novavax OR "CoronaVac" OR Covaxin OR Sanofi) AND (vaccination OR vaccine).Initially, 621 papers were identified, which underwent automatic exclusion of non-English articles and removal of duplicates, resulting in 404 papers for further analysis.Subsequently, the title, abstracts, and full texts of the remaining papers were meticulously reviewed by the three authors (K.L., A.W, M.B), with consensus reached on inclusion for evaluation.The comprehensive literature review yielded 34 papers, documenting 44 cases meeting the criteria for de novo ANCA-positive small-vessel vasculitis in temporal association with SARS-CoV-2 vaccination, as illustrated in Figure 1.
Vaccines 2024, 1, 0 small-vessel vasculitis in temporal association with SARS-CoV-2 vaccination, as illu in Figure 1.Data regarding patients' metrics, comorbidities, vaccination characteristics, sym diagnostics, treatment, and outcomes are summarized and depicted in Table 1.Data regarding patients' metrics, comorbidities, vaccination characteristics, symptoms, diagnostics, treatment, and outcomes are summarized and depicted in Tables 1-5.

Criteria for Inclusion and Exclusion
The inclusion criteria encompassed all case reports published in English, involving patients aged 18 years or older, exhibiting de novo ANCA-vasculitis subsequent to COVID-19 vaccination, and confirmed through laboratory testing for AAV.Conversely, exclusion criteria comprised cases of AAV following SARS-CoV-2 infection, AAV relapses, manifestations of the disease lacking ANCA positivity, undocumented or untested ANCA status, and confirmed history of COVID-19 infection.

Results
After conducting a thorough examination of the full text, 34 studies encompassing 44 patients were incorporated into the analysis.Percentages were derived from the number of patients who reported specific parameters.Acquired data are graphically presented in Figures 2 and 3.

Criteria for Inclusion and Exclusion
The inclusion criteria encompassed all case reports published in English, involving patients aged 18 years or older, exhibiting de novo ANCA-vasculitis subsequent to COVID-19 vaccination, and confirmed through laboratory testing for AAV.Conversely, exclusion criteria comprised cases of AAV following SARS-CoV-2 infection, AAV relapses, manifestations of the disease lacking ANCA positivity, undocumented or untested ANCA status, and confirmed history of COVID-19 infection.

Results
After conducting a thorough examination of the full text, 34 studies encompassing 44 patients were incorporated into the analysis.Percentages were derived from the number of patients who reported specific parameters.Acquired data are graphically presented in Figures 2 and 3
Digestive tract symptoms were also observed in 3 cases (6.8%), manifested by vomiting.

Outcome
The outcome has been reported in all cases (n = 44).Recovery has been achieved in 30 cases (68.2%), while partial recovery was observed in 10 cases (22.7%).Additionally, 6 patients (13.6%) were dialysis-independent at the time of follow-up.Fatalities have been reported in 2 out of 44 cases (4.5%).

Clinical Characteristics
In this study, we present a comprehensive analysis of de novo ANCA-positive smallvessel vasculitis onset following COVID-19 vaccination.In our cohort, females accounted for the majority of reported cases (61.4%), contrasting with the global prevalence.However, the mean age of 57 years was consistent with global trends [47].Among the analyzed patients diagnosed with EGPA, a majority (60.0%) had a history of asthma.Prior studies have strongly associated asthma with EGPA, as a crucial prodromal syndrome often manifesting many years before the active vasculitis phase.In patients with persistent asthma that is difficult to control, consideration should be given to the possibility of EGPA diagnosis [48][49][50].According to ACR/EULAR criteria from 2022, clinical and laboratory criteria for EGPA assign obstructive airway disease and nasal polyps, respectively, +3 points each, and blood eosinophil count ⩾ 1 × 10 9 /L for +5 points, which strongly correlates with symptoms of asthma.

Vaccines
The administration of vaccinations and the number of doses among the analyzed patients aligns with previous global data, as per the distribution reported by the European Union [51].More than half of the patients developed their first symptoms after the first dose, and over one-third experienced symptoms after the second dose.This suggests that new-onsets of AAV may occur more frequently after the initial vaccination protocol rather than booster doses.The relationship between vaccines and autoimmune reactions is well-documented in the literature, with several theories proposed.Molecular mimicry, defined as the structural similarity between certain human proteins and antigens present in the vaccine, can lead to cross-reactions.In this scenario, the immune system may recognize human proteins as pathogens in the vaccines [2].It has been established that the SARS-CoV-2 spike glycoprotein exhibits mimicry with certain human proteins such as alveolar lung surfactant proteins [52].Adjuvants, included in vaccines to enhance and prolong the immune response, may also contribute significantly to triggering vaccinerelated autoimmunity by activating cells of the innate immune system [2].This emphasizes the importance of considering autoimmune disease after vaccination in the differential diagnosis.Despite that, vaccination remains a crucial tool during the pandemic and should not be withheld or restricted.
The cause of autoimmune diseases remains unclear, but genetic, immunological, hormonal, and environmental factors are believed to be significant triggers.Typically, autoimmunity does not lead to clinical symptoms unless another event, such as exposure to an environmental factor, prompts overt expression [53].While there are certain theories regarding vaccine-related autoimmunity mechanisms, further studies are necessary.Nonetheless, in predisposed cases, COVID-19 vaccines may indeed trigger the onset of de novo AAV [54,55].

Clinical Presentation
Based on clinical presentation, antineutrophil cytoplasmic antibody-associated vasculitis encompasses three primary diseases: granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, and microscopic polyangiitis.The clinical spectrum of AAV is extensive, resulting in diverse presentations, ranging from a skin rash to severe, life-threatening multisystem disease [56].However, it most frequently affects the upper airways, lungs, kidneys, nervous system, and eyes [57].
The initial manifestations of AAV in most patients occurred within 1 to 3 weeks after vaccination.In our cases, weakness, fever, and headache, accompanied by inflammatory reactions, were the most frequent presentations.AAV may begin and present with constitutional symptoms suggestive of chronic inflammatory disease (fatigue, weight loss, fever, night sweats, myalgia, or polyarthralgia) [58].It can complicate the initial clinical approach to the patient and early identification of the disease, leading to delay in diagnosis and treatment [59].
In our cases, a notable occurrence of dyspnea, pulmonary hemorrhage, and haemoptysis was observed, particularly among patients diagnosed with GPA and EGPA.Additionally, all patients diagnosed with GPA exhibited symptoms of sinusitis, consistent with the characteristic granulomatous lesions of the upper and lower respiratory tract often seen in GPA patients [60].Lower respiratory tract involvement is a prevailing clinical characteristic, occurring in 45% to 67% of individuals diagnosed with ANCA-associated vasculitis, as indicated by studies [57,59].The incidence of pulmonary involvement is higher in patients with granulomatosis with polyangiitis (GPA) and eosinophilic granulomatosis with polyangiitis (EGPA) (85-90%) than in patients with microscopic polyangiitis (MPA) (25-60%) [61].
Renal involvement is another leading clinical feature of ANCA-associated vasculitis, occurring in approximately 50% to 65% of patients [62].We noted a significant prevalence of renal symptoms, elevated creatinine levels and extremity edema, particularly among patients diagnosed with GPA and MPA.Kidney involvement was confirmed through organ biopsy, revealing Pauci-immune crescentic glomerulonephritis in the majority of cases.According to the 2022 ACR/EULAR Classification Criteria for AAV, Pauci-immune glomerulonephritis serves as a histological criterion for both MPA and GPA, with a scoring range of +3 for MPA and +2 for GPA [11].
Approximately 30% of patients with ANCA-associated vasculitis may clinically exhibit symptoms such as muscle weakness, difficulty walking, numbness, and peripheral neuropathy [57,63].Among our patients, symptoms related to the nervous and musculoskeletal systems were also noted.Predominantly, patients exhibited extremities paresthesia, hearing loss, myalgia, and arthralgia.
Dermatologic features may manifest in fewer than 20% of patients with ANCAassociated vasculitis [64].Purpuric macules and erythematous patch lesions were the most characteristic presentations observed in the cases.However, cutaneous manifestations observed in AAV may exhibit varying clinical presentations among patients with GPA, MPA, and EGPA [65].

Serological Diagnostics
ANCAs, a class of autoantibodies primarily of the IgG type, target antigens located in the cytoplasmic granules of polymorphonuclear neutrophil granulocytes (PMNs).They are notably linked with a category of disorders termed ANCA-associated vasculitis, characterized by systemic vasculitis.There are two major types of ANCAs distinguished by their cellular localization patterns: one type associated with perinuclear staining (p-ANCA), and the other type associated with diffuse cytoplasmic staining (c-ANCA) [66].
c-ANCAs, which specifically react with PR3, are a primary laboratory marker for GPA and are present in 80-90% of patients, with their titer correlating with disease activity.They are also found in MPA, EGPA, and Pauci-immune crescendic glomerulonephritis (25-36%).On the other side, p-ANCAs, that are specifically reacting with MPO, are found in all AAVs, but also in drug-induced immune reactions.Non-specifically reacting with MPO also may occur in the course of non-specific inflammatory bowel diseases (in 60-70% of patients with ulcerative colitis and 10% of individuals with Crohn's disease), autoimmune liver diseases (in 90% of patients with primary sclerosing cholangitis and 70% of patients with autoimmune hepatitis), and HIV infections (18%), as well as in patients with connective tissue diseases (in 20-25% of patients with systemic lupus erythematosus, 20% of patients with mixed connective tissue disease) [10,67,68].
Therefore, conducting a comprehensive evaluation is crucial for confirming the diagnosis of AAV, excluding other potential causes, and evaluating the severity of the disease and its impact on organs.Typically, diagnosis involves a combination of clinical evaluation, serological assays, radiological findings, and histopathological analyses [69].

Treatment and Outcome
Treatment for antineutrophil cytoplasmic autoantibody-associated vasculitis in most patients involved a combination of immunosuppressive medications to control inflammation and prevent further damage to affected organs.The first-line drugs among these patients were glucocorticoids (GC), mostly combined with rituximab (RTX) or cyclophosphamide (CYC).Such therapeutic management corresponds to the updated guidelines on the management of AAV released in 2022 by EULAR.According to EULAR, the gold standard of inducing remission in new-onset patients with active GPA or MPA comprises glucocorticoids with taper after 4-5 months or avacopan supply combined with RTX (or methotrexate (MTX) or mycophenolate mofetil (MMF)) in not organ-/life-threatening cases and combined with RTX or CYC in organ-/life-threatening cases.In new-onset EGPA with organ-/life-threatening symptoms, it is recommended to treat with a combination of high-dose GCs and CYC.However, RTX may be considered as an alternative instead of CYC [70].The choice of therapy should be based on the patient's individual characteristics and clinical condition, with the assumption that RTX is favored over CYC in children and adolescents, pre-menopausal women and men, frail elderly, glucocorticoid-sparing and PR3-ANCA.Preference for RTX over CYC in patients of reproductive age stems from concerns about the long-term safety of CYC according to fertility and preserving reproductive potential.Cyclophosphamide can lead to premature ovarian failure due to a reduction of ovarian reserve and also might increase the risk of male infertility [71].Additionally, there is evidence that CYC has mutagenic effects and may contribute to cancers, including acute leukaemia, bladder and urinary tract cancers, and other malignant neoplasms [72,73].Our cohort consists of 14 patients of reproductive age , 8 females and 6 males; 11 of them were treated by RTX or/and CYC administration.At the same time, the majority of them took RTX, which is recommended for reproductive patients.Cyclophosphamide, if given, was taken by elderly patients.Additionally, the efficacy of combining RTX with CYC in cases of AVV with serum creatinine >350 µmol/L is under investigation [74].Five patients received combined CYC and RTX therapy, with renal impairment expressed by increased serum creatinine level among four of them.According to treatment recommendations, patients with organ-/life-threatening type with rapidly progressive glomerulonephritis should be evaluated for the use of plasmapheresis [70].Among the presented patients, plasmapheresis was used in 18 cases, all with life-threatening symptoms, such as pulmonary hemorrhage and/or renal impairment.For maintenance of remission of GPA and MPA, treatment with RTX is recommended after induction of remission with RTX or CYC.AZA or MTX could also be considered as an alternative.According to recommendations for the maintenance of remission of EGPA, AZA, MTX, mepolizumab, or RTX with GCs taper are suggested.All of the above correspond with the presented treatment strategies in our review.Recent studies have highlighted the beneficial effects of avacopan, a complement receptor C5a inhibitor, in the treatment of renal lesions in AAV patients.It is characterized by a more effective reduction of albuminuria and a lower percentage of serious adverse effects, including a lower rate of white blood cell decline and the risk of severe infections compared with prednisolone [70,75].As avacopan was included in EULAR recommendations as a suggested first-line drug in the treatment of AAV alongside GCs, given its favorable impact on both remission but also fewer adverse effects, it should have been considered as a drug of choice among clinicians [70].With a combination of immunosuppressive medications, remission rates have notably increased over the years.The prompt initiation of therapy is crucial to prevent severe organ damage.Close monitoring and regular follow-ups are integral to managing the disease and reducing the risk of relapse.
There is insufficient evidence to establish causality, whether the vaccine triggered the reaction, revealed an underlying condition, or if it was coincidental.The patient's symptoms and deterioration began after receiving the vaccine, raising concerns about a possible connection.However, in southern Japan, an increase in new-onset AAV cases was observed following the initiation of the COVID-19 vaccination program [76].Nonetheless, a recent study suggests no significant relationship exists between COVID-19 vaccination and new AAV onsets [77].

Limitations
Our study is subject to limitations, with the most important being that the data for our analysis was often incomplete, with not every parameter described.We attempted to select and analyze only the most frequently reported factors.The majority of papers did not provide information about the race of the patients.As a result, we were unable to compare the frequency of occurrence of various AAVs across different continents.In addition, we observed a lack of precise timing of the initial manifestation of symptoms, and in some cases this required calculating the average time based on a range of weeks.Laboratory parameters varied across different laboratories; therefore, we could not compare the antibody titer of ANCA antibodies.Moreover, in most cases only MPO and PR3 antibodies were included in the diagnostic.Currently, AAV diagnostic uses panels containing other antibodies (bactericidal permeability-increasing protein (BPI), lactoferrin, cathepsin G, lysozyme, and elastase) [78].Their use in further work would translate into greater systematization of results and more accurate conclusions about patients with post-COVID-19 vasculitis.
Due to the rarity of AAV-new-onsets after COVID-19 vaccination and the retrospective nature of the events, it is not possible to estimate the relative risk of these adverse events.

Conclusions
This systematic review provides the most recent summary of reported post-COVID-19 vaccine new-onset of ANCA-positive small-vessel vasculitis.We present a comprehensive résumé, with the potential to serve as a reliable source of knowledge on that topic.
Although vaccination is a pillar of the fight against infectious diseases, it should be emphasized that the body on the path of overreaction to vaccination can lead to the development of autoimmune diseases.For this reason, observation of susceptible individuals with even mild post-vaccination symptoms suggesting AAV is crucial to prevent life-threatening conditions.

Figure 1 .
Figure 1.The PRISMA searching strategy flow chart.

Figure 2 .
Figure 2. Charts present proportions of selected results.Figure 2. Charts present proportions of selected results.

Figure 2 .
Figure 2. Charts present proportions of selected results.Figure 2. Charts present proportions of selected results.

Figure 3 .
Figure 3. Charts presenting the contributions of individual systems in symptoms manifestation (a) and treatment used (b).

Figure 3 .
Figure 3. Charts presenting the contributions of individual systems in symptoms manifestation (a) and treatment used (b).