Antineutrophil Cytoplasmic Antibody Associated Vasculitis

Classification

The ACR classification criteria for GPA, derived primarily from adult data, performed poorly in classifying childhood GPA. Consequently, a pediatric-specific adaptation of ACR criteria, the EULAR/Pediatric Rheumatology International Trials Organization (PRINTO)/Pediatric Rheumatology European Society (PReS) criteria, were developed using pediatric data (see Chapter 32 ). The EULAR/PRINTO/PReS criteria, which incorporates laryngotracheal stenosis and the presence of ANCA as individual criteria, are compared with the ACR criteria in Table 36.1 . The EULAR/PRINTO/PReS criteria for GPA had improved sensitivity compared with the ACR criteria (93% vs. 83%) in the validation cohort that included a wide spectrum of vasculitides. The sensitivities of both criteria were much reduced (77% and 62%, respectively) when applied to a cohort of 155 pediatric patients that included only those with AAV and unclassified vasculitis. This discrepancy likely reflects the absence of criteria for MPA in both classification systems, and the inability of GPA criteria to discriminate MPA patients among a cohort that did not include patients with large-vessel vasculitis. In one report, many pediatric patients classified as having GPA according to ACR criteria could be described as having MPA according to the International Chapel Hill Consensus Conference (CHCC) disease definitions.

Epidemiology

Population studies in adults estimate an overall annual incidence range between 0.5 and 20 cases per 1 million persons and a prevalence of 20 to 160 cases per 1 million persons. ^, A recent study from the United States using an administrative claims database reported an incidence rate of 12.8 cases per 1 million person-years. Regional differences of GPA have been described with higher incidences in both Norway and areas of the United Kingdom compared with Spain and Japan. ^, A study in New Zealand similarly describes a higher incidence in higher latitudes. A cyclical pattern of occurrence of GPA has also been noted. ^,

Less is known about the incidence of GPA in children and adolescents. Reported incidence rates of GPA from the US administrative database study and a Swedish regional study were, respectively, 1.8 and 1.4 cases per 1 million children. A Canadian study reported an average incidence rate of 0.9 per million children per year from 1994 to 2003, increasing to 6.4 cases per million per year from 2004 to 2008 in Southern Alberta. A recent French study also reported an increasing annual incidence of combined AAV from 0.10 per million children in 1986 to 1990 to 0.45 per million children in 2006 to 2010.

In the general population, the peak incidence of GPA is in the sixth decade, ^, and men outnumber women 1.6:1 to1:1. ^, In the pediatric population, the disease occurs in the second decade of life, with a female preponderance.

Pathogenesis

The cause of GPA is unknown, although it is likely a multifactorial disease. ^, As with many other polygenic systemic autoimmune diseases, GPA is probably the result of interactions between genetic factors predisposing to loss of self-tolerance and triggering environmental exposures. Recent data from genome-wide association studies (GWAS) provide strong support for the genetic role in the etiology of AAV. ^{, ,} The strongest associations are with major histocompatibility complex (MHC) class II genes, and specifically in GPA, with the HLA-DP region. ^, Non-MHC genes identified as associated with AAV include PTPN22 (encoding protein tyrosine phosphatase nonreceptor type 22), SERPINA1 (encoding α1-antitrypsin), PRTN3 (encoding PR3), and SEMA6A (encoding semaphorin 6a).

Environmental factors that have been implicated as triggers for the development of GPA include infections ( Staphylococcus aureus ^, and other respiratory tract infections), drugs (including propylthiouracil, hydralazine, and minocycline), ^, and silica dust. ^,

Triggering factors along with genetic predisposition and immune dysregulation ^, may establish a cascade that includes release of proinflammatory cytokines, release and translocation of ANCA antigens to the cell surface, and priming of neutrophils. Primed neutrophils activated by ANCA are key effector cells of endothelial injury, including through release of neutrophil extracellular traps and mediation of complement activation. The alternative complement pathway is also involved in an inflammatory amplification loop. Although autoantibodies probably play a key role in GPA pathogenesis, the characteristic presence of granulomas suggests a more complex process with involvement of cellular immunity and cell-mediated hypersensitivity. Elucidation of the intricate immune pathways and processes is ongoing.

Clinical Manifestations

The triad of upper and lower respiratory tract inflammation and renal disease is characteristic of childhood GPA. ^{, ,} The largest cohort describes 183 patients collected within A Registry for Children with Vasculitis (ARChiVe) and includes patients accumulated since the earlier report of 65 patients. The median age at diagnosis was 14 years (range 2 to 18) and the median interval from symptom onset to diagnosis was 2.1 months (range 0 to 73). At disease onset, the most common features were constitutional symptoms followed by renal (83%); pulmonary (74%); and ear, nose, and throat (ENT) (70%) manifestations. Less frequently involved were the musculoskeletal system (65%), skin (47%), eyes (43%), gastrointestinal tract (36%), and nervous system (20%). A list of clinical features according to organ system and their frequencies is shown in Table 36.2 . These findings were similar to those of the next largest pediatric GPA cohort described by Bohm et al., except the ARChiVe cohort had higher frequencies of renal (83% vs. 68%) and gastrointestinal involvement (36% vs. 16%) and lower frequency of ENT involvement (70% vs. 91%). Clinical features in the largest cohort of pediatric patients with MPA are listed for comparison. In contrast to the adult experience ^, and two smaller pediatric series, ^, so-called limited or localized GPA, defined by the absence of kidney disease, occurred in a minority of children at the time of diagnosis. ^, The spectrum of pulmonary manifestations in the ARChiVe cohort included chronic cough (54%), hemoptysis or alveolar hemorrhage (42%), and respiratory failure (12%). Although upper and lower respiratory tract features were similarly frequent at disease presentation in studies with follow-up, upper respiratory tract features accumulated and were reported in 91% and 96% of patients. ^, One study reported that subglottic stenosis was five times as common in pediatric-onset GPA compared with adults, and this feature was subsequently included in the EULAR/PReS classification criteria. In the ARChiVe cohort, subglottic stenosis occurring in 10% was no more frequent than otitis/mastoiditis or hearing loss, less frequent than nasal and sinus involvement, and no more frequent than in adult studies. ^{, ,} Its inclusion as a pediatric classification criterion reflected its specificity in children rather than an increased frequency. In a cohort of 28 patients from the Cleveland Clinic, a quaternary referral center for vasculitis, airway stenosis with careful screening at diagnosis occurred in 36% of children, increasing to 50% at follow-up; among the 14 patients with airway stenosis, the tracheobronchial tree was involved in five. Damage to the nasal cartilage, characteristic of long-standing disease, may result in a saddle-nose deformity, similar to that seen in relapsing polychondritis ( Fig. 36.2 ).

Diagnosis

The diagnosis of GPA is based on a combination of clinical features, the presence of serological markers (specifically ANCA and, most commonly, PR3-ANCA or cANCA), and characteristic histopathological findings (inflammation of predominantly small to medium arteries, capillaries or small veins, or pauci-immune glomerulonephritis). The presence of pulmonary hemorrhage and glomerulonephritis (i.e., pulmonary-renal syndrome) is a classic presentation of GPA, and the diagnosis should be considered in any patient who presents with this type of organ involvement. If GPA is suspected, it is important to take a careful and specific history of upper respiratory tract involvement and consider formal otolaryngological assessment. Because one-third of adult patients initially have asymptomatic renal and pulmonary involvement, it is crucial to examine fresh-spun urinary sediment and look for pulmonary changes both radiographically and with pulmonary function testing. An increase in the diffusion capacity of carbon monoxide (DL _CO ) may be the earliest sign of pulmonary hemorrhage. If the disease is limited to a single organ system , tissue diagnosis is desirable to confirm the diagnosis and exclude other diseases. The differential diagnoses include infections (notably mycobacteria, fungi, or helminths, which may also be associated with granulomatous vasculitis), neoplastic disease, sarcoidosis, immunoglobulin (Ig)G4-related disease, and in young children, chronic granulomatous disease. Pulmonary manifestations in ANCA-positive ulcerative colitis patients have also mimicked GPA. Other diseases that can manifest as pulmonary-renal syndromes, such as antiglomerular basement membrane (anti-GBM) disease, systemic lupus erythematosus, mixed connective tissue disease, or IgA vasculitis, should also be considered. Guided kidney biopsy is a relatively safe procedure with a high yield, and the finding of pauci-immune glomerulonephritis together with characteristic serology provides a relatively secure diagnosis. GPA can be more readily distinguished from MPA by the presence of upper airway disease including saddle-nose deformity, nasal septal perforation, subglottic stenosis, dacryocystitis, proptosis associated with periorbital tumor, characteristic lung nodules (distinguished from hemorrhage), or the presence of granuloma in biopsy specimens. Characteristic histological features may be patchy in the lungs, and the yield from biopsies may be low, especially with fine-needle aspirations, but are better with transbronchial or open lung procedures. ^, Upper respiratory tract involvement in patients with GPA (e.g., trachea, ears, nose, sinuses, and eyes) may offer sites for relatively noninvasive biopsy procedures; however, the yield from such sites is disappointingly low. When the disease is isolated to these sites, a definitive diagnosis may be difficult, and the clinician may need to rely on nonspecific or incomplete histopathological confirmation, serological findings, and the combined expertise of multiple disciplines, including the otorhinolaryngologist, ophthalmologist, pathologist, radiologist, and rheumatologist. The need for tissue diagnosis in such cases may be influenced by disease severity, the need to embark upon aggressive therapies such as cyclophosphamide, and the need to exclude other diseases.

Laboratory Examination

White blood cell counts may be elevated particularly in active generalized disease, and associated with normochromic normocytic anemia, thrombocytosis, and markedly elevated erythrocyte sedimentation rates (ESRs) or C-reactive protein levels. ^, In early or localized disease, these tests may be normal or only slightly abnormal. Standard clinical laboratory measures of inflammation (e.g., for guiding therapy withdrawal) are often not useful in distinguishing inactive disease from low levels of inflammation. Among other more commonly used and available inflammatory measures, S100 calcium-binding protein A12 (S100A12) serum levels and neutrophil counts track inflammation best among children with PR3-ANCA disease, and similarly for adult patients, serum calprotectin (S100A8/A9) may have a role. von Willebrand factor antigen (vWFAg), a nonspecific marker of endothelial injury, has been shown to be elevated in other forms of vasculitis during active disease and may be elevated in AAV. Other potential biomarkers of vascular inflammation and injury include matrix metalloproteinase-3 (MMP-3), tissue inhibitor of MMP-1, pentraxin3 (PTX3), and B-cell attracting chemokine 1 (CXCL13).

Proteinuria, microscopic hematuria, and red blood cell casts in a fresh urine sample indicate active glomerular disease. ^, Gross hematuria is uncommon. Persistent elevation of blood urea nitrogen and serum creatinine levels indicates the presence of significant renal disease. A search for other urinary biomarkers of disease activity or relapse continues.

Antinuclear antibodies are present in up to one-third of children tested. ^, Rheumatoid factor is present in approximately 50% of adult and pediatric patients. ^, Children with GPA may be at risk for thrombosis because of antiphospholipid antibodies and factor V Leiden mutations. Antiphospholipid antibodies were evident at presentation in six (18%) of 34 children tested in one series but were not associated with venous thrombosis. The antibodies were present in two of nine children in another series who had venous thrombosis.

In a cohort of 183 children with GPA, ANCAs of any kind (cANCA, pANCA, PR3-ANCA, or MPO-ANCA) were present in 95% of 181 children who were tested. Either cANCA or PR3-ANCA was present in 67%, and either pANCA or MPO-ANCA was present in 26%. Similar frequencies of ANCA positivity were found in other pediatric series ^, and in adult series. ^, The clinical utility of serial ANCA measurements to predict relapse in adults remains controversial, and at best there may be a role for tracking PR3-ANCA in very limited circumstances depending on disease phenotype and treatment choice.

Pathology

The full histological spectrum of GPA includes necrotizing granulomas of the upper and/or lower respiratory tract, with necrotizing or granulomatous vasculitis involving predominantly small arteries and veins (commonly in the lungs but also in other organs) and focal segmental necrotizing glomerulonephritis. Granulomata characterize the disease and show acute and chronic inflammation with central necrosis and histiocytes, lymphocytes, and giant cells; eosinophils may be present in small numbers, which should not be confused with the large numbers found in specimens from EGPA patients ( Fig. 36.3 ). Renal glomeruli are infiltrated with lymphocytes and histiocytes. The earliest renal change may be glomerular thrombosis, but the most commonly reported renal lesions are extracapillary proliferation (with or without fibrinoid necrosis) and crescent formation found in a focal and segmental pattern, followed by necrotizing glomerulonephritis. Renal granulomata are rare. Immunofluorescence microscopy is characteristic of a pauci-immune pattern with scanty deposition of Ig and complement. Dense subendothelial deposits are visible on electron microscopy.

Imaging

The majority of children with GPA have abnormalities on chest radiographs, with both nodules and fixed infiltrates occurring in one-third to half of patients ( Fig. 36.4 ). Cavitations, pleural effusions, and pneumothoraces may also occur. Although these gross abnormalities are readily detectable on conventional radiography, ^, high-resolution computed tomography (HRCT) is more effective at detecting other characteristic changes such as small nodules; linear opacities; focal low attenuation infiltrates ^, ; centrilobular, perivascular densities ; and the computed tomography (CT) “halo” sign associated with hemorrhage ( Fig. 36.5 ). Sinus radiographs or CT scans may demonstrate thickening of the sinus lining, opacification of the frontal or maxillary sinuses, or bony thickening, cavitation, and destruction ( Fig. 36.6 ). However, magnetic resonance imaging (MRI) is superior in defining highly active mucosal disease. MRI is also helpful in visualizing soft tissue changes that involve the nose, orbits, mastoids, and upper airways (i.e., subglottic stenosis). The ¹⁸ F-fluorodeoxyglucose positron emission tomography (PET)/CT scan may also be useful in GPA, especially for delineating disease distribution and guiding biopsies of active lesions.

Treatment

Although previously fatal in most patients, ^, the aggressive and prolonged use of corticosteroids and cyclophosphamide (CYC) induced remission in more than 90% of adult ^, and pediatric patients. Although they are lifesaving, ^, disease relapses were frequent, and CYC-related toxicity (infections, bone marrow failure, infertility, hemorrhagic cystitis, and bladder cancer) was high. ^{, , ,} Current management of patients with GPA remains challenging because of the chronic relapsing course and the need to balance risks of acute accumulating disease burden against short- and long-term treatment risks, ^, while avoiding undertreatment of aggressive disease or overtreatment of milder disease. In general, current recommendations are that more toxic treatments such as CYC and high-dose corticosteroids should be used for patients defined as having more severe disease ( Table 36.3 ), ^, and the duration of these treatments should be limited to a relatively short period (3 to 6 months) of remission induction followed by a longer remission maintenance period (2 to 4 years) of less intensive immune suppression. , , The following sections, Tables 36.4 and 36.5 , and a recent review summarize the conclusions from several clinical trials in adults. It should be noted that the majority of trials have included both GPA and MPA patients, but not patients with EGPA, under the collective rubric of AAV. There have been no trials in children; however, three ongoing trials have included children.

EULAR, the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA), and the Canadian Vasculitis research network (CanVasc) have published guidelines for the management of AAV in adults. , In the absence of pediatric recommendations, these guidelines have also been extrapolated to children; however, in 2018 the first set of pediatric-specific recommendations were published by the Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) initiative, and these represent an important step forward in the management of pediatric AAV.