Effective Management of a Rare Case of Pediatric ANCA-Associated Vasculitis With Rituximab and Mycophenolate Mofetil

Introduction

Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) refers to a group of conditions characterized by inflammation of small blood vessels, such as capillaries, venules, and arterioles [1]. These conditions often span multiple systems and usually present with necrotizing arteritis, often accompanied by minimal immune deposits [1]. AAV is a spectrum that encompasses several diseases, including microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA; formerly Wegener’s granulomatosis), eosinophilic GPA (formerly Churg-Strauss syndrome), and renal-limited ANCA vasculitis [2]. These conditions are associated with the presence of circulating autoantibodies (ANCA) that target myeloperoxidase (MPO) or proteinase 3 [1]. While AAV is more commonly seen in the adult population, studies have reported a rising incidence in children, with an increase from 0.1 to 0.4 cases per million [2], while other reports estimated an annual incidence of 0.5 to 1.1 cases per million [3]. Due to the rarity of AAV in pediatric patients, treatment strategies are often adapted from adult studies, which may not be appropriate for younger individuals [4]. Therefore, this indicates the need for more reporting in the pediatric population in order to develop various treatment approaches. Herein, we describe a rare case of pediatric AAV in a 6-year-old girl successfully treated with corticosteroids, rituximab, and mycophenolate mofetil, resulting in sustained remission at 5-year follow-up.

Case Report

A 6-year-old girl with a history of eczema herpeticum, on acyclovir therapy, presented with a 2-week history of progressively worsening bilateral lower extremity pain and weakness. She refused to bear weight and experienced intermittent fevers, with a maximum recorded temperature of 39.2°C. These symptoms developed following a recent rhino-enterovirus infection. Two days after her admission, she developed microscopic hematuria. Initial laboratory workup revealed normal creatinine and complement levels (C3 and C4). Antistreptolysin O, anti–double-stranded DNA, and anti-Smith antibodies were negative, making poststreptococcal glomerulonephritis and systemic lupus erythematosus less likely. Urinalysis showed hematuria, with more than 50 red blood cells (RBCs) per high-power field (reference range, 0–2/hpf), proteinuria, and an elevated protein/creatinine (P/C) ratio of 0.58 (reference range, 0–0.1). There was no evidence of urinary tract infection. Imaging studies ruled out nephrolithiasis. Inflammatory markers were markedly elevated, with an erythrocyte sedimentation rate (ESR) of 79 mmol/h (reference range, 0–20 mmol/h) and a C-reactive protein (CRP) level of 90 mg/L (reference range, 0–3.2 mg/L). Given these findings, a renal biopsy was performed to evaluate for acute interstitial nephritis or IgA nephropathy (Figures 1–5). Unexpectedly, the biopsy revealed pauci-immune crescent glomerulonephritis, with 11 of 23 glomeruli showing evidence of crescent formation (Figure 1). Serologic testing was positive for perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) and MPO antibodies, confirming a diagnosis of AAV.

The patient was initiated on high-dose intravenous methylprednisolone at a dose of 10 mg/kg for 3 days, followed by 2 mg/kg of oral prednisone and enalapril. Despite this therapy, 2 weeks later, she developed gross hematuria and worsening proteinuria, with a P/C ratio of 1.1 (reference range, 0–0.1). Due to the inadequate response to steroid monotherapy, she was treated with weekly rituximab for a total of 4 weeks.

Approximately 5 weeks after starting the induction therapy, the patient’s condition improved. Proteinuria decreased, the P/C ratio declined to 0.88, and the hematuria improved to 3–9 RBCs/hpf (reference range, 0–2/hpf). She was transitioned to maintenance therapy with mycophenolate mofetil and rituximab every 4 to 6 months, adjusted according to her CD20 antibody level. After 24 months, she was transitioned to yearly rituximab treatment. At 5-year follow-up, the patient remained in remission. Urinalysis demonstrated no proteinuria or hematuria, with a mildly elevated P/C ratio of 0.2 (reference range, 0–0.1). At the time of this report, the patient was continuing daily enalapril and yearly rituximab infusions.

Discussion

This case highlights the importance of recognizing that AAV, while rare in children, can present with rapidly progressive renal involvement and requires timely diagnosis and individualized treatment. There are several learning objectives from studying this case report. First, pediatric AAV can mimic postinfectious or autoimmune conditions, which makes early recognition and renal biopsy critical for accurate diagnosis. Second, corticosteroid therapy may not be sufficient. Lastly, rituximab combined with mycophenolate mofetil can provide a safe and effective long-term treatment in children by achieving remission with fewer complications than with cyclophosphamide.

ANCA are primarily IgG autoantibodies that target the cytoplasm of monocytes and neutrophils [1]. There are 2 forms of ANCA: cytoplasmic (c-ANCA) and perinuclear (p-ANCA) [1]. ANCA is particularly significant in diagnosing GPA and MPA. The c-ANCA form is found in 95% of patients with new-onset GPA, while p-ANCA is present in 80% of patients with new-onset MPA [5]. ANCA-positive glomerulonephritis is a rare disorder in children, and the underlying mechanism of this illness has not been fully elucidated. Current theories suggest that a combination of environmental triggers and genetic predisposition contributes to the development of AAV [6]. Furthermore, dysregulation in both the innate and adaptive immune systems is a contributor. Specifically, B-cell dysfunction, pathogenic ANCA production, neutrophil activation, and an imbalance of cellular mediators between helper and effector T-cell responses have been documented [6].

Neutrophils are crucial in initiating endothelial and tissue damage, resulting in vessel wall inflammation [5]. As observed in our reported patient, AAVs have historically been associated with pauci-immune disease, characterized by minimal to no immune deposits in affected tissues [4,7]. However, recent studies have indicated the involvement of the complement alternative pathway in the pathogenesis and progression of AAV. Specifically, early in ANCA-associated glomerulonephritis, activation of C3 and subsequent generation of chemotactic factors C3a and C5a contribute to the formation of immune complexes [7]. Notably, lower serum C3 levels indicate complement consumption, which measures adverse outcomes in AAV and a poorer prognosis [7]. ANCA-associated glomerulonephritis is characterized by necrotizing and crescentic lesions in affected glomeruli, neutrophil degranulation under electron microscopy, and pauci-immune immunofluorescence staining [7]. A renal biopsy is therefore the gold standard for diagnosis and serves as a key predictor of renal outcomes in patients with suspected or confirmed AAV with renal involvement [8]. Our patient’s biopsy was consistent with pauci-immune crescent glomerulonephritis, with 11 of 23 glomeruli demonstrating crescent formation.

The most common clinical presentation of pediatric AAV includes constitutional symptoms, such as fever, fatigue, anorexia, and weight loss, occurring in more than 50% reported cases [6]; our patient exhibited some of these symptoms. Additionally, laboratory findings in pediatric AAV often reveal elevated levels of acute-phase reactants, such as ESR and CRP [5]. Our patient demonstrated elevated ESR and CRP levels of 79 mmol/h and 90.4 mg/L, respectively. While not observed in our case, anemia is the most commonly reported hematological abnormality in the literature [5].

Recent medical advancements in treating systemic vasculitis have greatly improved patient outcomes. The introduction of glucocorticoids and cyclophosphamide has significantly enhanced prognosis in adults [9]. However, due to a lack of controlled trials in pediatric AAV, treatment protocols are primarily based on adult data, following a sequential approach that includes remission induction and maintenance phases [5]. In adults experiencing remission induction or life-threatening AAV, a combination of glucocorticoids and either cyclophosphamide or rituximab is recommended. Similarly, high-dose glucocorticoids and cyclophosphamide for 3 to 6 months was considered the gold-standard therapy for pediatric patients [10]. Recent guidelines from the European League Against Rheumatism propose rituximab as an alternative to cyclophosphamide, because of its comparable efficacy profile [11]. The use of rituximab, an anti-CD20 monoclonal antibody, has increased in recent years due to having a better adverse effect profile than cyclophosphamide, as it poses less risk to fertility and carries a lower risk of malignancy [9,11]. One study showed that after rituximab induction, following up with mycophenolate mofetil as a maintenance medication resulted in 73% of children with MPA remaining off steroids, while 82% never relapsed [8].

Our case describes a pediatric patient with AAV who was successfully treated with steroids, mycophenolate mofetil, and rituximab. To the best of our knowledge, no other reports have documented this exact treatment regimen and in a school-age patient. Pediatric AAV is rare, with only a few similar cases described in older children, sometimes in the context of SARS-CoV-2 infection. One report describes a 12-year-old girl with new-onset anti-MPO ANCA vasculitis following SARS-CoV-2 infection who was successfully treated with methylprednisolone, cyclophosphamide, and rituximab [12]. Another case reported a 17-year-old boy with new-onset AAV in the setting of symptomatic SARS-CoV-2 infection, who achieved remission after treatment with pulse steroids, a prolonged steroid taper, and rituximab [13].

Conclusions

This case highlights the importance of early recognition and tailored treatment strategies for pediatric AAV. This case highlights that AAV, while rare in children, can be effectively managed with rituximab and mycophenolate mofetil to achieve long-term remission.