ANCA-associated vasculitis in children

INTRODUCTION

Childhood-onset anti-neutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAVs) are a group of systemic autoimmune disorders characterized by inflammatory cells infiltration, necrosis of small-medium blood vessels and autoantibodies to the neutrophil proteins leukocyte proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA). Primary AAVs in children are rare with a higher female preponderance, a peak age at onset in the second decade and median age at diagnosis 12–14 years [1]. They are classified into [2] granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA) and renal-limited AAVs (Fig. 1). GPA, the estimated incidence of which in Europe is less than 1 per 2 million population/year, is more common than MPA and EGPA but recently literature demonstrated that MPA was more frequent than GPA in children [3].

CAUSES

AAVs may be primary or secondary. Several factors may have a role:

• Genetic: a correlation with the antigenic specificity of ANCA rather than the clinical phenotype has been suggested, with PR3-ANCA correlating with HLA-DP and genes encoding alpha-antitrypsin and proteinase 3, whereas anti-MPO-ANCA is mainly associated with HLA-DQ.

• Dysregulation of adaptive and innate immunity: involving B- and T-CD8+ memory cells, leading to a pathogenic production of ANCA and neutrophils activation. A role of complement alternative pathways has been proposed, especially of anaphylatoxin C5a and C5a receptor.

• Environmental triggers: silica, farming or organic solvents, associated with an increased risk of EGPA.

• Infections: Staphylococcus aureus, HIV or COVID-19 can be triggers.

• Drugs: penicillamine, propylthiouracil, dapsone and cocaine adulterated with levamisole. The presence of both anti-MPO and anti-PR3 antibodies in the same patient suggests drug-induced vasculitis.

PRESENTATION

Patients present general symptoms such as weight loss, poor feeding and fever preceding systemic manifestations. Localized forms affecting single organs may lead to delayed diagnoses. There is an overlap in clinical features of GPA and MPA since both may present a high incidence of gastrointestinal manifestations (chronic nausea, diarrhea, abdominal pain), muco-cutaneous manifestations (oral and genital ulcers, palpable purpura, petechial rash, livedo, subcutaneous nodules) and musculoskeletal manifestations (arthralgia, myalgia, arthritis). MPA can be distinguished from GPA clinically by the lack of granulomatous manifestations and serologically by its more frequent association with MPO-ANCA. Both EGPA and GPA are characterized by granulomatous inflammation and necrotizing vasculitis involving small- and medium-sized vessels, but EGPA is distinguished from GPA by eosinophilia and asthma.

Granulomatosis with polyangiitis

GPA involves upper and lower respiratory tract and kidneys with pauci-immune crescentic glomerulonephritis. It may present a chronic course as localized granulomatosis or lead to acute manifestations of small vessel vasculitis (pulmonary haemorrhages and/or rapidly progressive renal involvement). Diagnosis can be made with three of the following criteria [4]: typical histopathological findings, upper airways involvement, laryngo-tracheo-bronchial stenosis, pulmonary/renal involvement and ANCA positivity. Children present a higher incidence of initial GPA-associated ischaemic abdominal pain and risk of developing subglottic stenosis and saddle nose deformity than adults [5]. GPA can involve eyes (episcleritis, orbital pseudotumour, uveitis, conjunctivitis), nervous system (headache, peripheral neuropathy) and cardiovascular system (venous thrombosis, valvular lesions). Typically presents PR3-ANCA positivity.

Microscopic polyangiitis

Renal disease is the most frequent manifestation with segmental pauci-immune necrotizing and crescentic glomerulonephritis presenting with hypertension, oedema, proteinuria and haematuria. It typically spares upper respiratory tract and involves lower respiratory tract leading to haemoptysis, chronic anaemia, pulmonary haemorrhage with lung hemosiderosis. Compared with GPA, pulmonary manifestations are milder and less frequent, whereas renal involvement tends to be more severe [6]. It can affect the eyes (episcleritis and conjunctivitis), nervous system (peripheral neuropathy) and cardiovascular system. MPO-ANCA positivity is typically detected.

Eosinophilic granulomatosis with polyangiitis

Patients present asthma, sinusitis, lungs infiltrates, eosinophilia and nasal polyps. Literature reports associated cardiomyopathy, skin lesions such as purpura and urticarial skin rash, gastrointestinal involvement and neuropathy. Kidney biopsy is characterized by prominent eosinophil-rich inflammation in granulomas surrounding necrotizing vasculitis of interlobular-sized and larger vessels. MPO-ANCA are detected.

Renal limited vasculitis

Characterized by renal histopathology pattern of pauci-immune, necrotizing crescentic or ANCA-associated glomerulonephritis (AAGN) without vasculitis in other organs, associated with MPO-ANCA. In children AAGN is the second cause of rapidly progressive glomerulonephritis, after immune-mediated diseases [6].

DIAGNOSIS OF AAVs

Biopsy of an affected organ remains the gold standard. First-line investigations include:

• Laboratory analysis: inflammatory markers, complete blood count, kidney, liver, thyroid and pancreatic function tests.

• Immunological screening: diagnosis is strongly suggested by ANCA positivity. PR3-ANCA account for the majority of ANCA with cytoplasmic immunofluorescence patterns (C-ANCA) and are usually associated with GPA, while MPA, EGPA and renal-limited vasculitis are usually associated with MPO-ANCA that commonly match with perinuclear immunofluorescence pattern (P-ANCA).

• Infectious disease screening: particularly bacterial endocarditis must be ruled out.

• Imaging: chest-ray, computed tomography or magnetic resonance to assess organ involvement.

MANAGEMENT

The initial goal is remission followed by prevention of relapses. Induction therapy for patients with normal kidney function includes steroids and mycophenolate mofetil (MMF) as suggested by Kidney Disease: Improving Global Outcomes (KDIGO) guidelines [7]. Patients with more severe crescentic glomerulonephritis and/or reduced estimated glomerular filtration rate (eGFR) are treated with intravenous methylprednisolone in association with either rituximab or cyclophosphamide and plasma exchanges in the most severe cases [8]. Maintenance protocols can last 2–4 years, and include steroids in tapering doses associated with rituximab or MMF, considered more effective than azathioprine (AZA) in case of renal involvement. Oral cyclophosphamide or methotrexate are alternatives. Main objectives are improving long-term outcomes and decreasing irreversible organ damage. Kidney transplantation is recommended for children with kidney failure during clinical remission.

PROGNOSIS

AVVs in children are associated with higher relapse rate, more severe damage and longer maintenance therapies than adults. However, a multicentre study including 105 children demonstrated that mortality was low and 61% achieved inactive disease at 12 months on induction therapy with cyclophosphamide and/or RTX or MTX, followed by maintenance therapy with RTX, MMF, AZA or MTX. However, one-third had kidney damage with persistent proteinuria, eGFR <50% or kidney failure, and 24% had a minor relapse after reaching inactive disease [8]. In fact, in paediatric AAVs, kidney involvement is often severe and may lead to rapidly progressive glomerulonephritis or nephrotic proteinuria, and kidney failure may occur early during follow-up [9]. Indeed, another multicentre study reported a renal survival of 70% at 1 year and 60% at 10 years of follow-up [3]. Severe kidney involvement at diagnosis is the most important prognostic indicator of long-term renal outcome. Patients with eGFR <50 mL/min/1.73 m² have a 50% risk for death or kidney failure at 5 years and renal histological patterns of sclerotic or mixed lesions are associated with worse outcome than crescentic or focal findings [9]. Morbidity is accrued by relapses, which negatively impact the quality of life due to disease-related damage and therapy side effects [10].

ACKNOWLEDGEMENTS

The authors would like to thank Professor Jean-Paul Duong Van-Huyen, Professor of Pathology at Necker Enfants Malades Hospital, APHP, Paris Cité University (France) for his valuable contribution to the histopathological image.

DATA AVAILABILITY STATEMENT

There are no new data associated with this article. No new data were generated or analysed in support of this work.

CONFLICT OF INTEREST STATEMENT

None declared.

REFERENCES