ANCA-Associated Vasculitis with Systemic Thrombotic Microangiopathy: A Review of Literature

Introduction

Antineutrophil cytoplasmic antibody (ANCA)– associated vasculitis (AAV) is characterized by inflammation of predominantly small- and medium-sized blood vessels, resulting in endothelial injury and tissue damage. These are autoimmune diseases due to antibodies to leukocyte proteinase 3 (PR3) or myeloperoxidase (MPO). The three subtypes of AAV are granulomatous polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatous polyangiitis (EGPA). They are defined according to their clinical features. Since the genetic differences, treatment response, and outcomes are specific to the type of ANCA (PR3 or MPO), AAV is better classified as PR3-AAV or MPO-AAV.¹ The hallmark of GPA includes upper and lower respiratory tract involvement, pulmonary hemorrhage, granulomatous inflammation, and necrotizing glomerulonephritis. MPA is usually associated with severe renal involvement and some features of GPA without granulomatous inflammation. Additionally, thrombocytosis is a conspicuous feature of AAV.²

On the contrary, systemic thrombotic microangiopathy (TMA) is characterized by microangiopathic hemolytic anemia and thrombocytopenia, with a varying degree of impairment to the kidney, brain, lungs, pancreas, and the heart. Various diseases like systemic lupus erythematosus and cryoglobulinemia are associated with TMA; however, the association of AAV and TMA is a rare occurrence.^3,4

Though multiorgan dysfunction is a regular feature of both AAV and systemic TMA, the etiopathogenesis and histology of both the diseases are discrete. Nonetheless, dysregulation of the alternative pathway of the complement cascade is critical to the pathogenesis of both AAV and hemolytic uremic syndrome (HUS). The simultaneous manifestation of both AAV and HUS is rare and exceptional. Although a retrospective review was recently published that described the clinicopathological characteristics of renal-limited TMA in AAV, literature on systemic TMA in AAV has been limited to only a few case reports.⁵ Thus, we report an imperative retrospective review that describes the baseline characteristics, laboratory findings, treatment, and outcome of patients with AAV and systemic TMA (HUS and thrombotic thrombocytopenic purpura [TTP]).

Materials and Methods

We conducted a search on the PubMed database and additional searches from January 1998 to September 2022 using the following terms: “ANCA”, “Antineutrophil cytoplasmic antibody”, “thrombotic thrombocytopenic purpura”, “TTP”, “thrombotic microangiopathy”, “haemolytic uremic syndrome”, and “HUS”. In addition to this, we selected articles in the English language for review, if their title or abstract suggested AAV with TTP, HUS, or TMA. We excluded reports if they described renal-limited TMA or if the patient developed end-stage kidney disease (ESKD) before manifesting TMA. The title, abstracts, and the full text of the case reports were individually checked by two authors (SS and SN) and considered for inclusion if both agreed.

Statistical analysis

Descriptive statistics were used to detail the baseline characteristics of the patients. We expressed the normally distributed continuous variables as mean ± standard deviation (range), non-normally distributed variables as medians with interquartile ranges (IQR), and categorical data as proportions. All analyses were performed using GraphPad Prism version 9 (San Diego, CA 92108).

Results

Our database search led us to 120 English language publications on PubMed. Details of these studies are shown in Figure 1. Out of 120 publications, we identified 14 cases, including our own case report, and one additional case from web-based search. Thus, we included 15 cases for the current review.^6–20 Table 1 is a summary of their clinical features and outcomes.

At presentation, the median age of the patients was 61 years (IQR 57–71 years), and 66.7% of them were females. Patients most commonly (80%) presented with constitutional symptoms like fever, malaise, and loss of appetite. Additionally, 10 patients (66.7%) experienced respiratory failure during their hospitalization [Table 2]. In eight patients, there was a simultaneous occurrence of TMA and AAV, whereas in others the latency between the two diagnoses ranged from one week to six months, with AAV preceding TMA. Most of the patients (66.7%) were MPO-ANCA-positive. All the patients had laboratory parameters consistent with systemic TMA, including progressively worsening anemia and thrombocytopenia with elevated lactate dehydrogenase, low haptoglobin, and presence of schistocytes. None of the cases had a history of accelerated hypertension preceding development of TMA.

Five out of 11 patients (45.45%) had hypocomplementemia. Among the 10 patients tested for ADAMTS13 levels, 8 (80%) had low ADAMTS13 levels. However, only one patient (10%) had levels below 10% (Patient No. 1), which is the cut-off value for confirming TTP diagnosis [Supplementary Table 1].²¹ The remaining reports mandate a better characterization and, in all probability, a further investigation for complement-mediated HUS. In addition to this, three patients (20%), including our case, underwent genetic testing (Patient No. 3, 14, and 15); two cases had pathogenic mutations that predisposed them to develop HUS, and no pathological mutation was identified in the third case [Supplementary Table 1]. Supplementary Table 1 describes laboratory investigations.

Discussion

This case-based review highlights clinical features and renal outcomes of patients with systemic TMA (HUS or TTP) and AAV. The AAV preceding the TMA suggests the former as a probable trigger for the onset of TMA. Admittedly, the kidney outcome was dismal in patients with a synchronous presentation of AAV and TMA.

AAV is a multisystem disease. Constitutional symptoms, like fever and malaise, are common and precede organ-specific symptoms. To begin with, most patients (80%) in the current review had similar complaints. Upper respiratory tract involvement was frequent in PR3-AAV. Consistent with previous studies, lung involvement was present in 80% of patients: more in PR3-positive (100%) than in MPO-positive (70%) patients.^22,23 Similar to a study by Mohammad et al.²² on 129 AAV patients, the most frequent lung parenchymal finding in this review was nodules in PR3-AAV and interstitial pneumonia in MPO-AAV patients. Cerebrovascular events are rare, and infarctions are more common than hemorrhage.²⁴ Our previously published case report was one of few reports that demonstrated intracranial hemorrhage in AAV.¹⁹

Extra-renal manifestations are seen in 20% of patients with TMA and can involve the central nervous system (CNS) and cardiovascular and gastrointestinal systems. Renal manifestations in TMA are variable; however, most HUS patients are dialysis-dependent at presentation. TTP, in contrast to atypical HUS, uncommonly causes severe acute kidney injury.²¹

Until recently, the pathogenesis of AAV and HUS were considered discrete. However, there are a few explanations that may elucidate the rare co-occurrence of both diseases in the same individual. Firstly, pathogenesis of both the conditions involves the same target cell, that is, the endothelial cell. Secondly, emerging evidence from clinical and animal experiments suggests that the complement system is critical for developing AAV.^25–27 C5a, an anaphylatoxin and chemoattractant, is pivotal for the pathophysiology of tissue injury in AAV, and therapeutic blockade of C5a effectively reduces the dose of corticosteroids in AAV with kidney involvement.²⁸ One-third of the patients with AAV have hypocomplementemia, which is associated with poor kidney outcomes. Therefore, abnormal systemic activation of the alternate complement system is involved in the pathogenesis of both diseases. Third, the production of ANCA antibodies in AAV is associated with the formation of neutrophil extracellular traps (NETs).²⁹ These NETs can act as a second hit in precipitating acute attacks of TMA in patients at risk of TMA.³⁰ However, we all agree that in AAV, the evidence for dysregulation of the complement cascade is lacking and is limited to only tissue injury. However, beyond the complement system, there is yet to be a comprehensive explanation for both clinical conditions. Finally, like HUS, TTP may also coexist with AAV, though rarely. The endothelial damage in AAV causes the release of ultralarge von Willebrand factor (ULvWF) multimers from the endothelium.¹² The imbalance between ULvWF and ADAMTS13 activity occurs when massive endothelial injury releases excessive ULvWF multimers, and this surpasses the cleaving capacity of ADAMTS13 and precipitates thrombosis.³¹ In spite of these potential multifactorial explanations, the exact mechanism of this co-occurrence is unclear and requires further evaluation.

In the cases reviewed here, TMA was either simultaneous or succeeding the presentations of AAV. Also, the presence of crescents in a significant number of glomeruli and lack of microangiopathic changes in the renal biopsy indicate AAV as the dominant pathology in such coexistence. Though vasculitic changes are the hallmark findings in AAV, thrombi and microangiopathic changes rarely occur in the arterioles. Microangiopathic changes in the arterioles (of the kidney) might intimate further evaluation for ADAMTS13 levels and complement regulatory proteins/autoantibodies (to CFH or ADAMTS13) or genetic testing in a patient with AAV.

Current guidelines (2021) from the American College of Rheumatology recommend patients with active, severe disease to be treated with rituximab over cyclophosphamide for remission induction to avoid adverse effects like neutropenia, bladder injury, and risk of infertility, even though both provide similar benefits in control of disease activity.³² Glucocorticoids are used simultaneously, beginning with high doses, typically intravenous methylprednisolone (500–1000 mg for three days) and followed by oral prednisolone. Following the PEXIVAS trial, the role of PLEX for severe AAV in preventing death or ESKD is debatable.³³ On the contrary, PLEX remains the important treatment option for TMA.³⁴ The presence of anti-ADAMTS13 antibodies and anti-CFH antibodies warrant immunosuppression. Current evidence strongly recommends the early use of eculizumab; however, we often encounter difficulty in a prompt and definitive diagnosis of atypical HUS and laboratory differentiation from TTP.³⁵ Currently, these two diseases have different management approaches; diagnosing them appropriately while they coexist is crucial.

In terms of adverse renal outcomes of AAV, 59%–80% of AAV with severe renal involvement at presentation are dialysis-independent at 12 months.³⁶ The mortality rate in the current review is consistent with prior studies of AAV and TMA. However, compared to previous studies of TMA and AAV, the incidence of ESKD was numerically higher (40%).⁵

Our review had certain limitations: small sample size, unavailability of kidney biopsy in all patients, and incomplete or inadequate workup for HUS and TTP, to name a few.

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Figure 1:

Search strategy algorithm³⁷. CKD: chronic kidney disease, MHD=maintenance hemodialysis, TMA=thrombotic microangiopathy.

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Conclusion

Coexistence of AAV and TMA are uncommon, and the prognosis is abysmal. Given the rarity of this coexistence, we recommend a comprehensive workup and examination to provide additional insights into the disease.