Peripheral Neuropathies
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Nov. 16, 2024
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Systemic small-vessel vasculitis …
- Updated 06.18.2024
- Released 05.08.1995
- Expires For CME 06.18.2027
Systemic small-vessel vasculitis
Introduction
Overview
The nomenclature for vasculitis has been updated to account for size of the inflamed vessel, immunopathogenesis, and clinical features. Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis includes microscopic polyangiitis, granulomatosis with polyangiitis, and eosinophilic granulomatosis with polyangiitis. All affect small vessels and involve autoantibody formation against the antigens proteinase 3 and myeloperoxidase. There are no defined diagnostic criteria. The authors discuss management of ANCA-associated vasculitis, including the diagnosis based on clinical manifestations with challenges determining disease activity and damage. The increasing role of antibody markers and prognostic features are discussed. The most recent data on targeted immunotherapies are reviewed with regards to induction of remission, maintenance treatment, and side effects.
Key points
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• ANCA-associated vasculitis is the current nomenclature for small-vessel vasculitides, including microscopic polyangiitis (MPA, vasculitis without granulomatosis), granulomatosis with polyangiitis (GPA, vasculitis and granulomatosis but no asthma), and eosinophilic granulomatosis with polyangiitis (EGPA, vasculitis, granulomatosis, asthma, eosinophilia). | |
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• They are associated with antineutrophil cytoplasmic antibodies (ANCA) with specificity against proteinase 3 (predominant in GPA) or myeloperoxidase (predominant in MPA and EGPA). Depending on the subtype, there are different phenotypes and treatment responses. | |
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• The conditions are characterized by formation of granulomas and inflammation of small arteries, arterioles, venules, and capillaries. Inflamed vessels may rupture or become occluded, giving rise to a broad array of clinical symptoms and signs related to a systemic inflammatory response, end-organ microvascular injury, or the mass effect of granulomas (44). | |
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• The most commonly affected tissues are the upper and lower respiratory tract, kidneys, skin, and peripheral nerves. | |
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• Treatment with immunosuppressant therapy is required to induce remission of disease activity, after which patients are transitioned to more gentle maintenance immunosuppression. Two randomized controlled trials (RAVE and RITUXVAS) have shown that rituximab is non-inferior to cyclophosphamide for remission induction in severe granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). The RAVE trial also showed superiority of rituximab for patients presenting with a severe disease relapse. | |
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• A randomized trial (MAINRITSAN) showed that rituximab infusions every 6 months were superior to azathioprine as maintenance therapy for PR3 3 ANCA vasculitis. |
Historical note and terminology
Historically, vasculitic diseases have been characterized and categorized by their clinical manifestations and often were named after their first discoverer. In 1931, Heinz Klinger described a patient with destructive sinusitis, uremia, granulomatosis of the spleen, glomerular lesions, and arteritis, whom he believed had a variant of polyarteritis nodosa. It was Friedrich Wegener who first recognized this pathologic process as a distinct disease entity in 1936, terming it “rhinogenous granulomatosis.” The name "Wegener granulomatosis" was introduced in 1947, and in 1994, the Chapel Hill Consensus Conference produced the first nomenclature system for Wegener and other idiopathic vasculitides. In 1951, J Churg and L Strauss first described 13 cases with severe disseminated necrotizing granulomatous vasculitis in addition to extravascular granulomas in patients with asthma, fever, and eosinophilia, which then became known as Churg-Strauss syndrome (10).
The trend in vasculitis research is to move towards using accurate, descriptive disease names in place of eponyms, accounting for immunopathogenesis and combining disease entities based on their etiology and treatment response. The discovery of specific ANCA antibodies was a significant advance, not only for characterization of different types of vasculitis, but also for their role in disease pathogenesis and utility as a biomarker (107).
In 2010, the American College of Rheumatology, American Society of Nephrology, and European League Against Rheumatism joined forces to endorse a name change from “Wegener granulomatosis” to “granulomatosis with polyangiitis” (GPA) (50). Churg-Strauss syndrome has now been recognized by the 2012 revised nomenclature for vasculitides as “eosinophilic granulomatosis with polyangiitis” (EGPA) and based on the association with ANCA antibodies, combines the group of ANCA-associated vasculitis together with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).
In 2012 at the Chapel Hill Consensus Conference, noninfectious (aseptic) vasculitides were further classified based on the immunopathology and predominantly affected vessel size (47; 47):
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1. Large vessel vasculitis | ||
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a. Takayasu arteritis | ||
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2. Medium vessel vasculitis | ||
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a. Polyarteritis nodosa | ||
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3. Small vessel vasculitides | ||
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a. With no immune deposits: ANCA-associated vasculitis (discussed here) | ||
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i. Anti-glomerular-basement-membrane disease | ||
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4. Single organ vasculitis (such as primary central nervous system vasculitis) | ||
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5. Vasculitis associated with systemic disease | ||
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a. Lupus vasculitis | ||
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6. Vasculitis associated with probable etiology includes | ||
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a. Hepatitis B– and C–associated vasculitis | ||
This classification provides definitions of vasculitis once the diagnosis is made but does not provide diagnostic criteria, which are still in need of development. The finding that combined treatment with cyclophosphamide and prednisone leads to remission in approximately 90% of patients in a disease state once considered fatal was a milestone in treatment and has served as the basis for ever-evolving protocols targeting various stages of the diseases, with greater efficacy and less toxicity.
The current standard management of severe ANCA-associated vasculitis still consists of remission induction therapy with glucocorticoids combined with rituximab or, less often now, cyclophosphamide. Several studies have shown that reduced-dose regimens of glucocorticoids are noninferior to the previously used high-dose regimens for, therefore, less cumulative exposure to glucocorticoids. Avacopan use may even lead to new steroid-free therapeutic approaches, at least for some selected patients (81).
Clinical manifestations
Presentation and course
In this article, we focus on antineutrophil cytoplasmic antibody-associated vasculitis, predominantly affecting small vessels. Vasculitis means inflammation of blood vessel walls. All intraparenchymal vessels are small vessels; therefore, ANCA-associated vasculitis affects organs (47). When first manifesting, ANCA-associated vasculitis can affect only one or multiple organs. The presentation varies widely, from a limited disease to a life-threatening generalized systemic vasculitis. It is important to differentiate between acute disease activity, organ damage due to the disease, and complications from treatment, as all impact management.
The disease can persist for many years in a limited form, and spontaneous remissions are possible. Frequently affected tissues include the upper and lower respiratory tract, kidneys, skin, and peripheral nerves. Acute exacerbations may be accompanied by nonspecific inflammatory symptoms, such as arthralgia, fever, and myalgia. Symptoms depend on which vessels are involved: involvement of dermal venules results in purpura; inflammation of the capillaries results in pulmonary hemorrhage or glomerulonephritis; affected vessels in the epineurium result in peripheral neuropathy; and small vessels in the eye and orbit result in ocular inflammation (48). Some ANCA vasculitides (GPA and EGPA) have extravascular granulomatous inflammation, which seems separate from vasculitic inflammation, mostly affecting the respiratory tract (48).
Systemic ANCA-associated vasculitides (AAV) are further categorized depending on the clinical presentation and pathology (48):
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1. MPA: vasculitis but no evidence of granulomatosis, asthma, or eosinophilia |
Further classification can be made based on ANCA type. The two best-described subtypes are myeloperoxidase and proteinase 3. Because patients with different subtypes differ in outcomes and HLA association, it is useful to account for the specific subtype in the name, such as MPO-ANCA MPA or PR3-ANCA GPA (48). In 2022, the American College of Rheumatology (ACR) and the European Alliance of Associations for Rheumatology (EULAR) jointly proposed new classification criteria for ANCA-associated vasculitis (the 2022 ACR/EULAR criteria) (77).
Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). There is substantial overlap in many of the clinical features of the ANCA-associated vasculitides, mostly between GPA and MPA. Differentiation based on clinical features is difficult but can be confirmed by pathology (eg, absent granulomatous inflammation suggests microscopic polyangiitis) and supported by ANCA types: MPA typically directed against myeloperoxidase and in GPA against proteinase 3. Treatment recommendations for active disease do not differ between the two diseases.
The upper airways are affected in 85% to 90% of patients with GPA, with sinusitis, serous otitis media, sensorineural hearing loss, and subglottic stenosis (102). Lung disease occurs in more than 80% and may involve both the airways and parenchyma. Airways are typically affected by stenoses and ulcerations, whereas parenchymal disease manifests with nodules, cavitary lesions, consolidations, and alveolar hemorrhage. Renal disease is recognized by the presence of microscopic hematuria, proteinuria, and rising serum creatinine, with pauci-immune necrotizing glomerulonephritis seen on biopsy. A review of 735 patients enrolled in several treatment studies and followed for extent of organ damage at 6 months revealed that more patients with MPA (with MPO ANCA) had proteinuria (MPA:GPA: 50.7% vs. 31.6%) and GFR<50 mL/min (46.5% vs. 22.8%), while otolaryngologic damage was more frequent in patients with GPA (along with PR3 ANCA), such as hearing loss (MPA:GPA: 4.2% vs. 22.5%) and nasal crusting or blockage (3.7% vs. 29.1%). These differences largely remained stable at long-term follow up at 7 years, with progression to end-stage renal disease more common in MPA (20% vs. 9%) (80).
The musculoskeletal system is involved in approximately 60% of patients. Arthralgias and myalgia are often seen (88). Orbital masses (pseudotumors, more common in GPA) can cause proptosis, diplopia, or vision loss. Other ocular manifestations include scleritis, keratitis, conjunctivitis, episcleritis, and uveitis. Nasolacrimal duct obstruction is most typical of GPA (88).
GPA or MPA can be limited to one organ before evidence of systemic vasculitis. However, it is recommended to include them in the ANCA-associated vasculitis category if the patients are ANCA-positive and have typical clinical manifestations and granulomatous disease on pathology (then GPA), eg, of the respiratory tract.
Neurologic manifestations. Both the peripheral and central nervous systems may be affected in GPA (42). Between 10% and 45% of patients will develop peripheral nerve disease, most commonly either a sensorimotor polyneuropathy or mononeuritis multiplex due to vasculitis and ischemia of the vasa nervorum. In a study of 128 consecutive patients, 56 developed a polyneuropathy, 31 had a distal symmetric polyneuropathy, and 25 had a mononeuritis multiplex (18). The majority of patients develop neuropathy within the first 2 years of disease, with males and the elderly being more frequently affected. Although 35% of neuropathies will resolve within the first 6 months, 15% continue to be symptomatic over 5 years (97).
The central nervous system is affected in about 10% of patients, typically with cerebral vasculitis and pachymeningitis. Other potential manifestations include cranial neuropathies (cranial nerve I, II, VI, and VII usually), cerebrovascular accidents, intracerebral hemorrhage, cerebritis, Horner syndrome, myelopathy, and cerebral vein thrombosis (70; 89). Diabetes insipidus has been reported as a result of granulomatous involvement of the posterior pituitary.
In a large French cohort group, peripheral neuropathy was observed at 6 months (MPA:GPA 7.9% versus 15%). After 7 years, more patients with MPA had developed neuropathy as well: 14.1% versus 22.2% (80).
Eosinophilic granulomatosis with polyangiitis (EGPA). EGPA is a disease characterized by nongranulomatous eosinophilic inflammation, necrotizing granulomatous inflammation often involving the respiratory tract, and necrotizing vasculitis; it is associated with asthma and blood eosinophilia. Typically, the disease develops in three stages, starting out in the second or third decade with prodromes of asthma (present in 96% to 100% of patients), sinusitis, nasal polyps, rhinitis, otitis media, or sensorineural hearing loss (29; 31). The disease progresses to the eosinophilic phase with blood eosinophilia and lung involvement, manifesting as pulmonary infiltrates, heart and gastrointestinal involvement (mostly involving small bowel), otherwise unexplained abdominal pain, bleeding, and, on occasion, intestinal perforation. The disease then can progress to a third, vasculitic, phase (31).
Three studies showed that ANCA-positive patients differed from ANCA-negative patients in their clinical manifestations. Compared to ANCA- negative patients, ANCA-positive patients more frequently had a vasculitic pattern with peripheral neuropathy, renal involvement, or purpura (likely ANCA-mediated) but less frequently had cardiomyopathy (82; 90; 12). ANCA antibodies are positive in approximately 40% of these patients (82; 90; 105; 12; 29; 31); they are mostly characterized by a perinuclear pattern (pANCA) at their immunofluorescence assay and are mostly directed against the neutrophil myeloperoxidase. Common laboratory findings in patients with EGPA beyond ANCA are marked hypereosinophilia (at least > 1500 eosinophils/µL or > 10% of the total white blood cells) as well as an increase in nonspecific inflammatory markers (ESR, CRP), which are elevated in a majority of cases (29). In 116 patients with EGPA, 26.7% showed signs of renal dysfunction, and 13.8% had rapidly progressive renal insufficiency (90). ANCA was more common in patients with nephropathy than without (75.0% vs. 25.7%), and all patients with necrotizing crescentic glomerulonephritis were ANCA-positive. Skin involvement encompasses purpura (most common), pseudo-urticarial rash, hives, subcutaneous nodules, livedo reticularis, and gangrenous necrotic lesions (12).
A retrospective study of 383 patients with EGPA in the French Vasculitis Study Group cohort revealed that at diagnosis 91.1% of the patients had asthma, and the remainder of patients developed it within 6 months after diagnosis. The most common EGPA manifestations at diagnosis included weight loss (49.3%), mononeuritis multiplex (46.0%), peripheral neuropathy (51.4%), nonerosive sinusitis or polyposis (41.8%), skin lesions (39.7%), and lung infiltrates (38.6%). Furthermore, patients presented with cardiovascular involvement (27.4%), such as pericarditis (15.1%), Raynaud phenomenon, or deep venous thrombosis, and 16.4% presented with cardiomyopathy, gastrointestinal tract involvement (23.2%), and kidney involvement (21.7%). Less common manifestations were alveolar hemorrhage (4.2%), cranial neuropathies (3.1%), or CNS manifestations (5.2%), including ischemic stroke (2.1%) or hemorrhagic stroke (0.5%). Of the patients tested, 31% tested were ANCA positive, most (66%) with a perinuclear pattern but some with cytoplasmic or mixed pattern; 62% had myeloperoxidase specificity, 3.7% had proteinase 3 specificity on ELISA, and few had a mixed pattern. Interestingly, none of the patients who were initially ANCA-negative subsequently tested positive (12).
Neurologic manifestations. The central nervous system can be involved, with ischemic stroke or hemorrhagic stroke (68) or both (01), and this can be the initial clinical presentation. One case has been published with ischemic stroke post tPA administration with hemorrhagic transformation. Concern was raised about safety of tPA in this population given the presumed increased risk of bleeding (23). Wolf and colleagues followed newly diagnosed patients with EGPA and monitored neurologic involvement at diagnosis and follow up prospectively: 12 of 14 patients had neurologic involvement as acute or subacute mononeuropathy multiplex (most common), axonal polyneuropathy, cranial neuropathy (II and VII), ischemic infarcts in basal ganglia, and myositis. Commonly affected nerves were the sural nerve (n = 11), common peroneal nerve (n = 8), tibial nerve (n = 8), and median nerve (n = 8). Nerve biopsy results were not reported, except one combined muscle and nerve biopsy that showed interstitial myositis. The onset of both types of neuropathies (mononeuritis multiplex and axonal polyneuropathy) was rather rapid--within a few days or weeks. New symptoms were rare with appropriate treatment. There was no correlation with inflammatory markers. CSF was normal in most cases (6/8). It was observed that six of eight patients with a multiplex mononeuropathy and two of three patients with an axonal polyneuropathy initially suffered from severe neuropathic pain that improved with immunosuppressive therapy (112).
Prognosis and complications
Here we will discuss general prognostic concepts whereas more treatment-specific outcomes will be discussed in the management outcomes section of this article. The prognosis for patients with granulomatosis with polyangiitis (GPA) has improved with the use of immunosuppressive therapy, but the overall survival and risk of relapse vary depending on the severity and extent of organ involvement. One retrospective study going back 4 decades found that overall, 5-year survival rates in patients with a diagnosis from 1996 or later were superior to those of cohorts with a diagnosis previous to 1996 (43). ANCA specificity is predictive of relapse, and a patient’s ANCA-associated vasculitis (AAV) type can affect their life expectancy. Patients with autoantibodies against PR3 are more than twice as likely to relapse as those who have autoantibodies against the MPO protein. Approximately 75% to 90% of patients with GPA have PR3-ANCA, and 55% of patients with microscopic polyangiitis (MPA) carry autoantibodies against MPO. The age at diagnosis also affects life expectancy. Patients who are older at the time of diagnosis experience a lower life expectancy than those diagnosed at younger ages. A 2018 study conducted in 85 patients with renal biopsy-proven ANCA-associated vasculitis found that a diagnosis age of 58 years or older was associated with shorter patient survival time (84). Overall, untreated patients have a 90% mortality rate within 2 years. The long-term survival in patients with GPA and MPA has improved with the use of cyclophosphamide and rituximab. Patients with GPA and MPA still have a higher mortality rate compared with the general population. A meta-analysis of observational studies of patients with GPA and MPA reported a 2.7-fold increased risk of death in patients compared with the general population (95% CI: 2.26–3.24) (99).
The major causes of death in patients with GPA and MPA are complications from immunosuppressive therapy (primarily infection) and complications from the underlying disease, including renal, pulmonary, and cardiovascular disease.
Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). Prior to recognition by Fauci and colleagues that cyclophosphamide and prednisone could induce remission in a majority of patients, prognosis in GPA was dismal, with a mean patient survival of 5 months (24). With better therapies, however, survival has dramatically improved, with over 90% of patients achieving remission. ANCA-associated vasculitides are now considered chronic diseases with relapses. Cumulative survival for patients with ANCA-associated vasculitis (observed in a large cohort with 52% GPA and 48% MPA) is estimated to be 88% at 1 year, 85% at 2 years, and 78% at 5 years (26). Flossman found no difference in survival in patients with either GPA or MPA or patients with different ANCA specificities. It was observed that 44% of the deaths occurred within the first year after enrollment and were due to infection (48%) or active vasculitis (19%). For patients who died after 1 year of enrollment, the causes were mostly cardiovascular disease (26%), malignancy (22%), or infection (20%). Patients with GPA have a significantly increased risk of myocardial infarction, especially early after the diagnosis of GPA (02). Infection also plays a major role in mortality both in induction and maintenance phase. There is a higher mortality compared to the general population (mortality risk ratio [MRR]: 3.8 [95% CI: 2.6–5.6], MRR: 4.0 for men [95% CI: 2.5–6.3], MRR 3.4 for women [95% CI: 1.6–7.2]). Advanced renal impairment and higher disease activity were predictors of mortality, as measured by the Birmingham Vasculitis Activity Score (BVAS), which categorizes organ involvement and disease activity in each organ system (66; 26). Advanced renal failure and higher age were independent risk factors for treatment-related toxicity, including infections (26). Further risk factors for infections are level of aggressiveness of induction therapy, the cumulative exposure to steroids, and dialysis dependence (54).
ANCA-associated vasculitis with pulmonary involvement and with presence of large cavities predisposes to fungal infections. Antibiotic coverage with trimethoprim-sulfamethoxazole is recommended in the early induction phase for all types of immunosuppression. More individualized preventive strategies are recommended, depending on laboratory markers such as serum creatinine or the lymphocyte counts including CD4+ T cell count (54).
In addition to specific organ-related damage, patients with GPA are significantly more likely to suffer from depression (22% vs. 7%) and fibromyalgia symptoms as compared to the general population. Fatigue is also extremely common, significantly limiting activities in nearly half of these patients. Sleep disorders are reported in up to 29%. Interestingly, these symptoms often persist during periods of remission and do not correlate well with disease duration, activity level, or damage (35). Patient perspectives on disease impact reveal that fatigue and low energy account for the greatest burden of disease for patients with GPA, eclipsing even certain severe manifestations, such as the requirement for dialysis (37).
Eosinophilic granulomatosis with polyangiitis (EGPA). Samson and colleagues prospectively evaluated 118 patients with EGPA with a mean follow-up of 81.3 months who were enrolled in two prospective, randomized, clinical trials. Overall survival 1-, 3-, 5-, and 7-year rates were 98%, 94%, 92%, and 90%, respectively, regardless of baseline severity of disease, number of relapses, ANCA-positivity, or eosinophil counts. Long-term remission was achieved in 29% of patients. Age 65 years or older was the only factor significantly associated with higher mortality. Patients with cardiomyopathy had a lower survival rate (66; 12; 85). Long-term organ damage was common, usually chronic asthma and peripheral neuropathy. The risk of relapse was higher for patients with MPO ANCA and lower for those with greater than 3000 eosinophils/mm3 (12; 85). Compared to ANCA-negative patients, ANCA-positive patients more frequently had clinical vasculitic manifestations, such as peripheral neuropathy or renal involvement, but less frequently had cardiomyopathy. Their mortality rate was lower, despite the slightly higher risk of relapses (12).
Sinico and colleagues examined retrospectively 116 patients and found a similar mortality rate (90). Five-year mortality rates were 11.7% in patients with nephropathy. Five of the 10 patients who died had renal involvement, and the authors considered that nephropathy might be associated with a poor prognosis.
A retrospective literature analysis in 2008 revealed a survival in EGPA of 93% to 94% at 1 year and 60% to 97% at 5 years (66). The absence of any of the five manifestations, incorporated in the Five Factor Score (FFS), (proteinuria, renal failure, gastrointestinal involvement, cardiomyopathy, and absence of otolaryngologic symptoms) was associated with a good prognosis, while the presence of two or more of the factors increased mortality in EGPA.
Clinical vignette
A 30-year-old woman presented with insidious-onset sinus congestion and facial pain not responsive to multiple courses of antibiotics. Over the following 2 months, she developed progressive fatigue and weight loss, along with dyspnea and two discrete episodes of hemoptysis. She was hospitalized but continued to worsen, developing bilateral hearing loss, migratory arthralgias, and sudden, new-onset numbness and weakness in the right hand.
Physical examination was notable for saddle-nose deformity, nasal crusting, right tympanic membrane perforation, and sensory loss and motor weakness in the distribution of the right ulnar nerve. Chest x-ray, followed by chest CT revealed multiple cavitary lung nodules. Bronchoscopy with bronchoalveolar lavage was negative for bacterial, mycobacterial, or fungal organisms. CBC revealed stable counts; creatinine was preserved, and urinalysis was negative for protein or blood. ESR was markedly elevated at 100 mm/hr. C-ANCA and p-ANCA were negative; however, CT-guided lung biopsy of a nodule revealed granulomatous inflammation and necrotizing vasculitis.
She was diagnosed with severe, generalized GPA and was treated with oral prednisone 60 mg once daily and rituximab (four weekly infusions). Trimethoprim/sulfamethoxazole three times weekly was added, along with daily calcium 1000 mg and vitamin D 1000 IU. The hemoptysis resolved, and she was discharged home. As an outpatient, prednisone was tapered, and 3 months later, azathioprine was added at 150 mg once daily. The systemic features, joint pain, sinus symptoms, weakness, and dyspnea resolved. Follow-up chest CT 3 months later showed significant improvement.
Biological basis
Etiology and pathogenesis
The exact etiology of ANCA-associated vasculitis is unknown. It is believed to result from a combination of genetic predisposition, epigenetic factors, and environmental exposure, which lead to the production of pathogenic antineutrophil cytoplasmic autoantibodies (ANCAs) that target neutrophil granule proteins with disordered regulation of neutrophil extracellular traps, resulting in necrotizing vascular inflammation (69).
The presence of ANCA and their specificity vary based on ANCA-associated vasculitis syndrome (103). ANCAs are found in approximately 70% to 80% of patients with GPA and 80% to 90% of patients with MPA. The PR3-ANCA are prevalent in GPA, and MPO-ANCA are more prevalent in MPA; however, there are a small group of patients with GPA who can be MPO-ANCA positive. ANCAs are considered to be central in the development of vascular inflammation. Proteinase 3 and myeloperoxidase are intracellular granules found within neutrophils. For autoantibody-antigen interactions to occur, neutrophils must first be “primed” by circulating inflammatory cytokines such as TNF-alpha, IL-1, and IL-18 to express these antigens on their plasma membranes. Once accessible, ANCA binds to proteinase 3 or myeloperoxidase on the cell surface via the Fab portion of the autoantibody, while the Fc portion activates receptors on the same neutrophil, nearby neutrophils, or endothelial cells, resulting in adherence of neutrophils to the endothelium and transmigration through the vessel wall. Neutrophils bound by ANCA degranulate and undergo a respiratory burst, releasing lytic enzymes and reactive oxygen species that cause vascular necrosis and inflammation. There is concomitant activation of the alternative complement pathway and recruitment of additional leukocytes to perpetuate the damage (53). Complement activation is an important part of the pathogenesis as there seems to be an amplification loop between neutrophil and complement activation, which has therapeutic implications (87).
The pathogenesis of extravascular granulomatous inflammation remains less well understood. Vasculitic manifestations are more prominent in ANCA-positive patients with EGPA, whereas eosinophilic manifestations are more common in ANCA-negative patients. Both result from neutrophil migration into the tissues of the upper and lower respiratory tract in response to a stimulus, possibly infection. ANCAs present in the tissues bind to neutrophils and stimulate activation and degranulation via a similar process as described earlier. Acutely activated neutrophils cause tissue necrosis and fibrin deposition. This inflammatory episode serves to recruit monocytes to the area, which then convert to macrophages and form multinucleated giant cells (48). In addition to humoral mechanisms of autoimmunity, there is also evidence for T-cell dysregulation in ANCA-associated vasculitis. Normally, regulatory CD4 T cells help downregulate lymphocyte activation and, therefore, inhibit B-cell production of autoantibodies. In ANCA-associated vasculitis, regulatory T cells are less effective and fewer in number as compared to controls, and this correlates with a higher risk of relapse (48). B-cell regulation is also impaired. Patients with active ANCA-associated disease have a reduced percentage of circulating CD5+ B cells, whereas patients in remission have a normal percentage. With rituximab therapy, the degree of normalization of circulating CD5+ B cells may correlate with more persistent remission, but this requires further investigation (48).
Genome-wide association studies have identified several genes involved in ANCA-associated vasculitis susceptibility (69). The strongest associations are with major histocompatibility complex class II (MHC II) genes. European genome-wide association studies show increased PR3-ANCA association with HLA-DP and MPO-ANCA with HLA-DQ. A genome-wide association study of North American patients also identified an association between GPA and HLA-DP. In the Japanese population, HLA-DR alleles were strongly associated with MPO-ANCAs. Therefore, antigen recognition is important in ANCA-associated disease. That the initial antigen recognized by antigen-presenting cells is different in PR3-ANCA-associated disease as opposed to MPO-ANCA-associated disease argues that they are genetically distinctive diseases (48).
In some studies, PR3-ANCA is associated with a higher rate of relapses compared to MPO-ANCA, suggesting a genetic basis (108; 61). PR3-ANCA-associated vasculitis (PR3-AAV) may differ from MPO-ANCA-associated vasculitis (MPO-AAV) with regard to treatment response, relapse rate, and outcome. Further trials should separate study patients with PR3-AAV and MPO-AAV and will provide clarification whether “PR3-AAV” and “MPO-AAV” are more accurate terms for disease entities than “GPA” and “MPA” (52).
Little is known about patients with ANCA-associated vasculitis who test positive for ANCAs (MPA or GPA). It is unclear whether ANCAs cannot be detected with the current available techniques or whether they have different pathomechanisms (47). These patients are oftentimes excluded from treatment trials. A new autoantigen specificity for lysosomal-associated membrane protein 2 (LAMP-2) remains controversial as the results were not reproduced in two later studies (48). ANCAs also occur in patients with inflammatory bowel disease, but they typically do not have a specificity for proteinase 3 or myeloperoxidase (48).
In EGPA, the presence or absence of ANCA is associated with two different clinical phenotypes, supporting the role of ANCA in disease pathomechanism. Presence of ANCA is associated with renal involvement, peripheral neuropathy, and biopsy-proven vasculitis, whereas ANCA absence is associated with heart disease (82; 105). ANCAs were found in 75.0% of patients with nephropathy and in only 25.7% of patients without nephropathy. All patients with necrotizing crescentic glomerulonephritis were ANCA-positive (90). The ANCA status in EGPA also has an association with prognosis: the risk of relapse is significantly higher for MPO-ANCA-positive patients at diagnosis (12; 85), but the mortality is lower (12), which may be related to the fact that cardiomyopathy is a major risk factor for death and more common in ANCA-negative patients.
The development of GPA may require exposure to an environmental trigger, resulting in disruption of autoimmune homeostasis; however, this has not been proven. ANCA-associated vasculitis onset and relapses often follow an infectious episode or exposure to medications or vaccines. Thus, environmental triggers, including occupational exposures (silica, organic solvents, farming-related agents) have been associated with a higher risk of MPA and EGPA (103). A systematic review and meta-analysis of silica with ANCA-associated vasculitis did confirm an association and the development of ANCA-associated vasculitis (69).
Infection with Staphylococcus aureus is frequently implicated based on the high prevalence of nasal carriage of S aureus in patients with ANCA-associated vasculitis and evidence for prevention of relapse with high-dose trimethoprim-sulfamethoxazole therapy (94). With respect to pathogenesis, S aureus secretes superantigens that may stimulate T- and B-cell proliferation and release of inflammatory cytokines to “prime” neutrophils for ANCA binding (06). A retrospective study of patients with ANCA-associated vasculitis in Sweden between 2000 and 2016 found a prior respiratory tract infection was associated with the development of an MPO-AAV (21). In addition to infection, silica-containing compounds and medications, including hydralazine and propylthiouracil, and levamisole-adulterated cocaine induce a similar small-vessel vasculitis. Smoking is associated with MPO-ANCA AAV onset and relapses, whereas the association in patients with GPA is controversial (08).
In EGPA, leukotriene receptor antagonists are related to disease onset, but the role in triggering EGPA is still uncertain. They may have unmasked previous existing disease by their steroid-sparing effect and enabling steroid tapers without flare-up of disease (105; 29).
Histopathology. Pathologically, GPA and EGPA are characterized by both a necrotizing small- to medium-vessel vasculitis affecting the capillaries, arterioles, venules, arteries, and veins (04) and granulomatous inflammation. The typical histopathological lesion in GPA consists of areas of necrosis of variable size with a surrounding granulomatous reaction, including giant cells. Vasculitis, often with luminal occlusion, occurs adjacent to necrotic foci. Deposits of immune complexes and complement are absent. Granulomas in GPA contain CD4+CD28- T cells (catalysts of inflammation), monocyte-derived tissue macrophages, giant cells, and large numbers of neutrophils surrounding a necrotic center (67).
In contrast, patients with MPA also have the characteristic necrotizing vasculitis, but granulomatous inflammation is generally absent (69). Both MPA and GPA are associated with a pauci-immune necrotizing crescentic glomerulonephritis.
EGPA was originally identified on autopsy as a pathological triad consisting of eosinophilic infiltration, necrotizing vasculitis, and extravascular granuloma formation (10). Because glucocorticoids are used commonly and early, pathology-based identification of granulomas has become infrequent. Typically, they would show a core of necrotic eosinophilic material surrounded by palisading lymphocytes and epithelioid and multinucleated giant cells (31). Renal biopsy can reveal necrotizing crescentic glomerulonephritis but also eosinophilic interstitial nephritis, mesangial glomerulonephritis, and focal sclerosis (90).
Epidemiology
Epidemiological studies in ANCA-associated vasculitis are challenging. These are relatively rare diseases with variation in geographical distribution and ethnicity of patients and overlapping features. However, the global incidence of ANCA-associated vasculitis has been increasing over the past 4 decades, which has been attributed to increased awareness and availability of ANCA testing (21).
ANCA-associated vasculitis predominantly affects Caucasians, and both men and women are equally affected (13). Incidence varies by region and subtype, with the highest incidence in North America (33 per million person-years) (21). Of the AAV, GPA has the highest incidence, whereas EGPA has the lowest incidence. MPA has a reported annual incidence of 5.9 per million in the United Kingdom (110). Although there was no major difference in ANCA-associated vasculitis incidence between Japan and the United Kingdom, MPA and MPO-ANCA was more common in Japan compared to GPA (83% of patients with ANCA-associated vasculitis met criteria for microscopic polyangiitis) (27), whereas PR3-ANCAs and GPA are more common in Western countries (69).
It may affect any age group; however, the majority of new cases are diagnosed between 65 to 74 years of age (110). Although considered rare in childhood, a study from Southern Alberta, Canada, indicated an average annual incidence in pediatric patients of 2.75 cases per million (32), which is not considerably different from that seen in adults. The prevalence of GPA varies from 30 per million population in a hospital-based United States study (13), to 60 per million in a population-based German study (78) and 148 per million in a British population-based study (110). The prevalence of MPA in a United Kingdom-based study was 63.1 per million (110). The incidence of GPA shows no seasonal variation but has periodicity, with peaks occurring every 7.6 years, supporting a possible infectious trigger for this disease (110).
Although nonwhite populations are less commonly affected by GPA, the HLA-DRB1*15 allele is associated in African Americans with higher risk of ANCA-associated vasculitis with positive PR3-ANCA, typically corresponding to the GPA phenotype (05).
EGPA can manifest at any age, but mean age at onset has been described between 40 and 60 years (90; 29; 31). The estimated annual incidence is 0.11 to 2.66 per 1 million people, with an overall prevalence of 10.7 to 14 per 1 million adults. There is no gender predominance or ethnic predisposition in EGPA (75).
Prevention
ANCA-associated vasculitis is an autoimmune disease. There are no known preventable measures to date. In EGPA, triggering factors such as treatment with leukotriene antagonists remain highly controversial as they may help unmask the disease, but may not play a role in disease etiology.
Differential diagnosis
When assessing features of small-vessel vasculitis, it is important to consider both primary and secondary etiologies. In the primary vasculitides, there is considerable overlap among the ANCA-associated vasculitides, but distinctions remain. MPA may be differentiated from GPA by the absence of upper respiratory tract manifestations and granulomatous inflammation, and ANCAs are usually directed against myeloperoxidase. EGPA is distinguished by characteristic allergic rhinitis, nasal polyposis, asthma, and peripheral eosinophilia. In contrast to GPA, only 40% of these patients will have a positive ANCA, usually directed against myeloperoxidase.
In the absence of clinical or histologic evidence of vasculitis or absence of ANCA, it may be difficult to differentiate between EGPA and other systemic eosinophilic disorders, such as chronic eosinophilic pneumonia, allergic bronchopulmonary aspergillosis, or hypereosinophilic syndrome. However, response to treatment is usually better and faster in EGPA than in primary systemic eosinophilic disorders; therefore, treatment response can help to re-evaluate the initial diagnosis (12).
Panarteritis nodosa is one of the main elements of differential diagnosis. It is a necrotizing arteritis of the medium and small arteries and needs to be distinguished from the ANCA-associated vasculitis. Although it can appear similar clinically and pathologically, it is not associated with ANCA, granulomatous inflammation, or glomerulonephritis. A typical finding in panarteritis nodosa are medium artery aneurysms, which are not present in ANCA-associated vasculitis (47).
Secondary causes of small-vessel vasculitis should also be considered, including those related to rheumatic diseases, such as systemic lupus erythematosus, rheumatoid arthritis, Sjögren syndrome, cryoglobulinemia, and sarcoidosis. Infection-associated vasculitides include infectious endocarditis, syphilis, mycobacteria, leprosy, hepatitis B, hepatitis C, and HIV, and in some cases, fungal infections. Numerous medications induce small-vessel vasculitis; notable among these are propylthiouracil and hydralazine. In addition, the adulterant levamisole, found in up to 70% of all cocaine seized in North America, is now a well-recognized cause of thrombotic microangiopathy with necrotic cutaneous lesions and retiform purpura that may mimic GPA. In these patients, neutropenia (uncommon in GPA) and positive p-ANCA, with specificity against human neutrophil elastase, are frequently reported (30). Malignancy-associated vasculitides should be ruled out when appropriate.
With respect to saddle nose or midline destructive lesions, the differential diagnosis includes relapsing polychondritis; congenital syphilis; cocaine-induced destruction; or midline lethal granuloma, now identified as NK/T-cell lymphoma.
In its most severe form, GPA may present with alveolar hemorrhage and rapidly progressive glomerulonephritis. In this case, additional causes of pulmonary-renal syndrome should be considered, such as microscopic polyangiitis, anti-GBM disease, systemic lupus, and catastrophic antiphospholipid antibody syndrome.
Diagnostic workup
The workup for ANCA-associated vasculitis includes laboratory testing, imaging, and, if possible, a biopsy of affected tissue as directed by the clinical symptoms and signs.
Laboratory workup. Nonspecific laboratory abnormalities seen in GPA or MPA include leukocytosis, normocytic anemia, and thrombocytosis. A drop in hemoglobin can raise the suspicion of alveolar hemorrhage. EGPA is characterized by marked peripheral eosinophilia (usually > 1500 cells/μl or > 10% of total leucocyte count) (31). Renal function may be impaired, and inflammatory markers such as ESR or CRP may be significantly elevated. All patients with suspected ANCA-associated vasculitis should have a urinalysis performed for detection of hematuria and proteinuria, and, if present, microscopy to evaluate for dysmorphic RBCs and RBC casts. If proteinuria is discovered, a urine protein/creatinine ratio is essential to quantify proteinuria. Select testing to rule out other diseases should be performed, including antinuclear antibody, complements, anti-GBM antibodies, cryoglobulins, viral serology, and blood cultures.
For EGPA, serologic testing for toxocariasis, aspergillus, and human immunodeficiency virus is indicated. A peripheral blood smear (looking for dysplastic eosinophils or blasts) is useful (33). Paraneoplastic eosinophilia may be considered in atypical cases. For further details of work up in atypical cases, we recommend review of the EGPA Consensus Task Force recommendations (33).
Antineutrophil cytoplasmic antibody testing. ANCA testing is important in supporting the diagnosis of ANCA-associated vasculitis and to help differentiate the types of ANCA-associated vasculitis. It is still recommended that ANCA first be measured by immunofluorescence to detect a cytoplasmic (c) or perinuclear (p) pattern, followed with antigen-specific testing by ELISA in order to maximize sensitivity and specificity. With low antibody titers, immunofluorescence can be negative, whereas antigen-specific testing is positive (15). In GPA, c-ANCA pattern is detected in 80% to 95% of patients, with specificity against proteinase 3, whereas p-ANCA pattern with specificity against myeloperoxidase may be found in 5% to 20% (40). MPA mostly has ANCA directed against myeloperoxidase (76%) but also EGPA against myeloperoxidase (40%). In a meta-analysis of ANCA sensitivity and specificity, PR3 was 80% sensitive and 93% specific, whereas MPO was 58% sensitive and 96% specific (08). No circulating ANCA can be identified in approximately 10% of patients. Thus, the absence of ANCA antibodies does not rule out ANCA-associated vasculitis, particularly if disease is limited, and it is useful to recheck during the course of the disease. An atypical ANCA (where ANCA is positive by immunofluorescence, but negative for specificity against proteinase 3 or myeloperoxidase) or negative ANCA should raise suspicion for the presence of another autoimmune disease, such as ulcerative colitis, primary sclerosing cholangitis, autoimmune hepatitis, connective tissue diseases, or rheumatoid arthritis. Besides AAV, ANCA can also be seen in patients with other autoimmune diseases and vasculitides, which can lead to a false diagnosis of AAV.
Imaging procedures. Imaging of the chest should be performed in patients with suspected ANCA-associated vasculitis. Up to 34% of patients may have asymptomatic disease in GPA (39). If pulmonary involvement is suspected, chest CT should be urgent. Chest CT may reveal nodules, cavitary lesions, infiltrates, and ground glass opacities suggestive of hemorrhage. CT of the sinuses and MRI of the brain may also be useful to evaluate the sinuses, orbits, and brain. In patients with suspected ear, nose, and throat involvement, a nasal and laryngeal visualization by an ear, nose, and throat specialist should be conducted for the evaluation of otorhinolaryngology manifestations.
Histological confirmation. Definitive diagnosis of ANCA-associated vasculitis requires histologic confirmation. Demonstration of necrosis and pauci-immune vasculitis is characteristic. Granulomatous inflammation is diagnostic for GPA (but not present in microscopic polyangiitis) and is seen in EGPA along with eosinophilia. Biopsy should be taken from an involved organ site as “blind” biopsies rarely produce useful findings. Definitive pathology from tissue can vary by biopsy site, with kidney biopsies having the highest diagnostic yield. Skin biopsy of a fresh vasculitic lesion is the least invasive approach; however, it often reveals only nonspecific leukocytoclastic vasculitis. Yield of ear-nose-throat biopsies vary, with the highest success rate in patients with macroscopic abnormalities in the nasal cavity (78). Renal biopsy should be performed if there is evidence of kidney involvement to establish the diagnosis and to assess for disease activity and chronicity. This is confirmed by a pauci-immune segmental necrotizing glomerulonephritis. Transbronchial biopsies are rarely diagnostic due to inadequate tissue sampling; however, open lung biopsy or video-assisted thorascopic biopsy of affected lung tissue has a high yield. Cultures and special stains should be performed on tissue samples to exclude infection.
Biopsy remains the gold standard and is strongly recommended. In clinical practice, a diagnosis may be established with a clinical presentation and ANCA testing consistent with ANCA-associated vasculitis and if mimics have been excluded (08).
Other tests. Bronchoalveolar lavage may be useful in ruling out infectious causes of lung infiltrates or nodules. It is instrumental in diagnosing alveolar hemorrhage when serial aliquots instilled into the pulmonary tree are increasingly hemorrhagic. EMG is performed when peripheral nerve involvement is suspected.
Assessing activity and damage. Regular assessments will determine disease activity in patients with ANCA-associated vasculitis (78). Instruments combining scores from each of the potentially involved organ systems have proven useful in monitoring disease course and therapy; of these, the Birmingham Vasculitis Activity Score is most commonly used. This tool measures signs of vasculitic activity that have existed for a maximum of 4 weeks (95; 98). Each symptom is then graded according to severity and organ system affected. Damage is measured by the Vasculitis Damage Index, which measures the accumulation of irreversible injury caused either by the disease or its therapy over time (22; 98).
In EGPA, differentiating disease activity from worsening of underlying asthma and sinusitis is challenging but important for treatment decisions. An attempt has been made to find biomarkers indicating disease activity. In studies of patients with EGPA with active disease and prior to treatment, eotaxin-3, TARC/CCL17, and IgG4 were identified as potential biomarkers of disease activity (76; 14; 106). However, in a prospective, longitudinal EGPA cohort study, these serum biomarkers (as well as ESR, CRP, and eosinophil count) did not discriminate between periods of remission and active disease within individual patients (20). Given that this disease is rare, numbers are small and further studies are needed.
Management
Treatment of ANCA-associated vasculitis is organized into two phases: induction and maintenance therapy. Induction therapy is usually for 3 to 6 months, with a goal of achieving disease remission. Patients are then switched to maintenance therapy for prevention of relapse. Medications are selected according to severity of disease. Non-severe disease is neither organ- nor life-threatening (eg, sinusitis, rhinosinusitis, asthma, mild systemic symptoms, uncomplicated cutaneous disease, mild inflammatory arthritis), whereas severe disease refers to organ involvement that will result in serious morbidity and mortality if not treated aggressively (eg, alveolar hemorrhage, glomerulonephritis, central nervous system vasculitis, mononeuritis multiplex, cardiac involvement, mesenteric ischemia, limb/digit ischemia). Treatment protocol for GPA and MPA are very similar to each other but are different to that of EGPA.
Typical induction and maintenance protocols for GPA and MPA are summarized and reviewed in Table 1 (28; 55; 59; 52; 60).
Table 1. Treatment of Patients with GPA and MPA Based on Stage of Treatment and Disease Severity
|
Options for induction of remission (duration of therapy: 3 to 6 months) | ||
|
(A) Prednisone 1 mg/kg/day for 1 month with gradual taper, or intravenous pulse methylprednisolone 1 g/day for 3 days, followed by oral prednisone 1 mg/kg/day as above | ||
|
• Use for all | ||
|
(B) Intravenous rituximab 375 mg/m2 once weekly for 4 weeks (or 1 g followed by a second dose of 1 g 14 days) | ||
|
• Generalized disease (plus steroids as above) | ||
|
• Preferred over cyclophosphamide due to high toxicity associated with cyclophosphamide | ||
|
(C) Intravenous pulse cyclophosphamide (15 mg/kg every 2 weeks for 2 doses, then every 3 weeks) | ||
|
• Generalized disease (plus steroids as above) | ||
|
(D) Oral cyclophosphamide daily (2 mg/kg/day) | ||
|
• Generalized disease (plus steroids as above) | ||
|
(E) Oral or subcutaneous methotrexate (15 to 25 mg once weekly) | ||
|
• For limited disease or generalized disease that is non-organ-threatening or non-life-threatening | ||
|
• Avoid use in moderate to severe renal impairment | ||
|
Options for induction of remission (duration of therapy: 3 to 6 months) | ||
|
(A) Prednisone 1 mg/kg/day for 1 month with gradual taper, or intravenous pulse methylprednisolone 1 g/day for 3 days, followed by oral prednisone 1 mg/kg/day as above | ||
|
• Use for all | ||
|
(B) Oral cyclophosphamide daily (2 mg/kg/day) | ||
|
• Generalized disease (plus steroids as above) | ||
|
(C) Intravenous pulse cyclophosphamide (15 mg/kg every 2 weeks for 2 doses, then every 3 weeks) | ||
|
• Generalized disease (plus steroids as above) | ||
|
• Consider if risk factors for hemorrhagic cystitis or compliance issues | ||
|
(D) Intravenous rituximab 375 mg/m2 once weekly for 4 weeks (or 1 g followed by a second dose of 1 g 14 days) | ||
|
• Generalized disease (plus steroids as above) | ||
|
• Consider for severe disease, for PR3 ANCA-positive patients, relapsing disease, contraindication to cyclophosphamide (including fertility considerations), or compliance issues | ||
|
(E) Oral or subcutaneous methotrexate (15 to 25 mg once weekly) | ||
|
• For limited disease or generalized disease that is non-organ-threatening or non-life-threatening | ||
|
• Avoid use in moderate to severe renal impairment | ||
|
Options for maintenance therapy (recommended use for at least 2 to 4 years, optimal duration unknown) | ||
|
(A) Rituximab 500 to 100 mg every 6 months | ||
|
• Preferred over azathioprine for severe disease given better efficacy to maintain remission | ||
|
(B) Oral azathioprine (2 mg/kg/day) | ||
|
(C) Oral or subcutaneous methotrexate (15 to 25 mg once weekly) | ||
|
• Avoid use in moderate to severe renal impairment (less than 50 mL/min/1.73 m2) | ||
|
(D) Oral mycophenolate mofetil (2 g/day) | ||
|
• If patients are intolerant of or have contraindications to azathioprine, methotrexate, or rituximab | ||
|
Adjunctive medications | ||
|
(A) Oral trimethoprim-sulfamethoxazole DS 800 to 160 mg, three times per week | ||
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• For Pneumocystis jiroveci prophylaxis | ||
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• Recommended for use with high-dose glucocorticoids or prednisone in combination with a cytotoxic agent | ||
|
(B) Oral calcium 1000 mg daily and vitamin D 1000 IU daily | ||
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• For osteoporosis prevention while using glucocorticoids | ||
|
(C) Caution with simultaneous use of NSAIDs with corticosteroid | ||
Induction therapy
The intensity of the initial therapeutic approach must be adjusted for each patient and for the type and seriousness of the ANCA-associated vasculitis in order to avoid two pitfalls: (1) excessive treatment associated with a significant risk of side effects or (2) insufficient treatment with a risk of failure or early relapse (12).
Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA)
Corticosteroids. For life- or organ-threatening GPA or MPA vasculitis, 1 to 3 g of intravenous (IV) methylprednisolone is typically utilized, followed by 1 mg/kg per day of oral prednisone. The optimal duration and tapering schedule of prednisone remains controversial, but patients are generally tapered off completely or reduced to low dose at 5 mg/day within 5 months.
Some studies have focused on reducing cumulative glucocorticoid dose. The Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis (PEXIVAS) trial is a notable multicenter, randomized controlled trial that successfully demonstrated the non-inferiority of a reduced-dose oral glucocorticoid regimen with regards to all-cause mortality and end-stage renal disease. In this trial, the reduced-dose glucocorticoid group had their prednisone reduced by 50% by week 2, and as a result, this group had 60% overall less glucocorticoid exposure within 6 months. This decreased amount of glucocorticoid exposure translated to lower rates of serious adverse events (19% vs. 37%) and serious infections (7% vs. 20%) when compared with the standard glucocorticoid group (109).
Corticosteroid-sparing agents. Both rituximab and cyclophosphamide, in combination with glucocorticoids, are used for remission induction in severe GPA and MPA.
Cyclophosphamide, an alkylating agent that inhibits nuclear DNA replication, thereby affecting rapidly dividing cell populations, has historically been the main corticosteroid-sparing agent for severe ANCA vasculitis. Standard therapy was originally defined by Fauci and colleagues in 1983: daily oral cyclophosphamide 2 mg/kg plus oral prednisone 1 mg/kg per day with gradual taper (24). However, because prolonged use of cyclophosphamide leads to unacceptable toxicities (including 26% to 46% rates of infection, 12% to 43% risk of hemorrhagic cystitis, and 57% risk of infertility), the original protocol has been modified. Cyclophosphamide is now used for a finite period, usually for 3 to 6 months (45). In a further attempt to minimize cyclophosphamide exposure, intravenous cyclophosphamide therapy (15 mg/kg every 2 weeks for three doses and then every 3 weeks for 3 to 6 months) was compared directly with daily oral dosing (2 mg/kg/day) for induction of remission in ANCA-associated vasculitis by de Groot and colleagues in the CYCLOPS trial (16). Despite receiving about half the cumulative dose of drug as compared to the daily oral group, those treated with intravenous cyclophosphamide were equally likely to achieve remission. However, long-term follow-up of these patients demonstrated that intravenous treatment had a higher risk of relapse over time (39.5% vs. 20.8%) (36).
Two seminal trials have demonstrated that rituximab, an anti-CD20 monoclonal antibody that depletes B cells, is equally effective to cyclophosphamide for inducing remission in patients with generalized disease, including those with major renal involvement, with a similar if not improved adverse event profile (96). RITUXVAS was a 24-month, randomized controlled trial involving 44 patients with newly diagnosed ANCA-associated renal vasculitis. Patients received glucocorticoids plus severe ANCA vasculitis. The Rituximab for ANCA-Associated Vasculitis (RAVE) trial was a randomized, placebo-controlled, multicenter, noninferiority trial that compared induction therapy with rituximab (375 mg/m2 per week for 4 weeks) or oral cyclophosphamide (2 mg/kg per day) in 197 patients with GPA or MPA (96). At 26 weeks, remission rates in rituximab-treated patients were similar to those treated with cyclophosphamide (64% vs. 53%). Furthermore, in a post-hoc analysis of the RAVE study, patients with PR3 ANCA-associated vasculitis responded better to rituximab than to cyclophosphamide/azathioprine (104). An important consideration, however, is that patients with alveolar hemorrhage requiring mechanical ventilation or with serum creatinine levels greater than 4 mg/dL were excluded from enrollment in the RAVE trial. Therefore, there is still some uncertainty about the efficacy of rituximab in this population. The second pivotal trial, called RITUXVAS, was a small randomized controlled trial involving 44 patients with newly diagnosed ANCA-associated renal vasculitis. Patients received either rituximab (375 mg/m2/week×4) with two intravenous cyclophosphamide pulses or intravenous cyclophosphamide (15 mg/kg every 2 weeks for three doses followed by infusions every 3 weeks) for 3 to 6 months followed by azathioprine. At 12 and 24 months, the rate of remission was similar between the two groups (51).
Overall, there has been an increasing preference for rituximab over cyclophosphamide due to concerns about the long-term safety of cyclophosphamide, such as the development of bladder cancer, bone marrow failure, myelodysplastic syndrome, and infertility. The American College of Rheumatology 2021 ANCA vasculitis guideline conditionally favors rituximab over cyclophosphamide for remission induction in severe GPA or MPA (09).
Avacopan, a new oral agent that inhibits C5a-mediated neutrophil activation and migration, may be considered as an adjunct along with cyclophosphamide or rituximab for induction of remission in severe GPA or MPA.
The use of avacopan is supported by evidence from the ADVOCATE trial, which essentially demonstrated disease remission with very limited use of glucocorticoids (46). All 331 patients in the trial received standard induction-remission therapy with cyclophosphamide (followed by azathioprine) or rituximab and were randomly assigned to either avacopan 30 mg twice daily or prednisone on a tapering schedule. At 52 weeks, sustained remission was higher in the avacopan group than in the prednisone group (66% vs. 55%). It should be noted that glucocorticoids were used by some patients in the avacopan group in the first few weeks following initiation of treatment, but their mean total dose at the end of the study was approximately only one-third of that in the prednisone group (1676 vs. 3847 mg). As expected, glucocorticoid-induced toxic effects measured by the Glucocorticoid Toxicity Index at week 26 were lower in the avacopan group
Finally, for non-severe GPA and MPA, methotrexate is a reasonable induction agent. The NORAM (NonRenal ANCA-associated Vasculitis Alternatively Treated with Methotrexate) trial demonstrated that in patients with limited disease and without seriously impaired renal function, methotrexate is equivalent to oral cyclophosphamide for inducing remission but does carry a greater risk of relapse (17).
Eosinophilic granulomatosis with polyangiitis (EGPA)
Unlike the other ANCA-associated vasculitides, there have been very few randomized controlled treatment trials for EGPA; hence, treatment recommendations rely on lower quality evidence and expert opinion.
Corticosteroids. Systemic glucocorticoid therapy is the mainstay of treatment for EGPA. For adults with severe EGPA, IV pulse or high-dose oral glucocorticoids are typically used, and the choice between the two is guided by severity of initial presentation.
Corticosteroid-sparing agents. For severe EGPA wherein there is organ or life-threatening disease, glucocorticoids should be combined with either cyclophosphamide or rituximab to induce remission.
Evidence for the use of cyclophosphamide is supported by a prospective multicenter trial that evaluated 48 EGPA patients with an FFS of 1 or greater (11). This trial showed that 12 cyclophosphamide pulses versus six cyclophosphamide pulses (administered every 2 weeks for 1 month, then every 4 weeks thereafter, at a dose of 0.6 g/m2 per pulse) resulted in fewer mild relapses (41% vs. 94%). However, the response rate or severe relapse rate were unchanged between the two dosing regimens; hence, the optimal dosing for cyclophosphamide is still unknown
Observational studies have highlighted the role of rituximab for remission induction. A randomized controlled trial examining the use of rituximab in EGPA (REOVAS) included 105 patients with new-onset or relapsing EGPA (100). Seventy-seven patients with an FFS of 1 or greater received high-dose steroids plus either 2×1 g rituximab (days 1 and 15) or nine pulses of cyclophosphamide over 13 weeks. The primary endpoint of on-treatment remission was similar at days 180 and 360 in both groups. However, the superiority of design and the lack of fully published results (only abstract) limit conclusions regarding non-inferiority.
For non-severe EGPA, initiation of the IL-5 blocker, mepolizumab, along with glucocorticoids should be considered. The data for use of mepolizumab came from MIRRA, a double-blind, placebo-controlled, phase III study in which 136 patients with relapsing or refractory EGPA were randomly assigned to receive mepolizumab 300 mg every 4 weeks with standard therapy or standard therapy alone (111). Mepolizumab led to significantly more accrued weeks of remission on 4 or less mg/day of prednisone (OR: 5.91, 95% CI: 2.68–13.03) and higher remission rates at weeks 36 and 48 (OR: 16.74, 95% CI: 3.61–77.56).
Maintenance therapy
Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). For severe GPA or MPA, rituximab is now considered the agent of choice for maintenance therapy. Two trials support this recommendation.
The MAINRITSAN trial compared maintenance rituximab and azathioprine in 115 patients with newly diagnosed ANCA vasculitis who had attained remission after initial therapy using cyclophosphamide plus glucocorticoids. Rituximab was given as two 500 mg doses separated by 14 days at baseline and then at months 6, 12, and 18. Azathioprine was given at a dose of 2 mg/kg daily for 12 months followed by 1.5 mg/kg per day for 6 months and then 1 mg/kg daily until month 22. Major relapse at 28 months was found to be lower for the rituximab versus azathioprine group (5% vs. 29%), whereas the number of serious adverse events remained similar in both groups (34).
The RITAZAREM trial compared maintenance rituximab and azathioprine in 188 patients with relapsing ANCA vasculitis (91). These patients were induced with rituximab and glucocorticoids. Patients achieving remission by 4 months were randomized to receive maintenance rituximab 1000 mg every 4 months through month 20 or azathioprine 2 mg/kg/day, tapered after month 24. At month 48, the rate for continued remission was higher for rituximab than azathioprine (0.50 vs. 0.22), whereas rates of serious adverse events were slightly higher in the azathioprine versus rituximab group (56% vs. 44%).
In patients who cannot tolerate or have a contraindication to rituximab (eg, previous allergic reaction to rituximab) azathioprine and methotrexate are equivalent options. Data from the CYCAZAREM trial suggest that cyclophosphamide can be replaced by azathioprine during the maintenance phase, with no increased relapse rate and improved safety (45). Methotrexate is also effective for maintenance therapy; extended 32-month follow-up shows no increased risk of relapse when compared to extended use of cyclophosphamide (57; 58). In a direct comparison, the Wegener Granulomatosis Entretien Trial (WEGENT) demonstrated no difference in either efficacy or safety between methotrexate and azathioprine for maintenance therapy (79).
Mycophenolate mofetil remains an option in those who fail or cannot tolerate azathioprine or methotrexate or rituximab. Although effective, a comparison study showed it was associated with a higher rate of relapse (55% vs. 38%) when compared to azathioprine (38).
The optimal duration of maintenance treatment remains unknown. Patients with PR3-ANCA (compared with MPO-ANCA) and upper respiratory or lung involvement are more likely to relapse (41; 71). Although they may require longer treatment, it is controversial when and if immunosuppression can be discontinued. The MAINRITSAN 3 trial examined longer term rituximab maintenance therapy. The trial included patients from MAINRITSAN2 who were in remission at month 28. Participants then either received placebo or rituximab (500 mg biannually) for an additional 18 months. At 28 months, more patients receiving rituximab versus placebo were relapse free (96% vs. 74%). The number of serious adverse effects or infections were similar between the two groups, but the rituximab group had a lower level of mean gamma-globulin levels (07).
Eosinophilic granulomatosis with polyangiitis (EGPA). The evidence for remission-maintenance therapies in severe EGPA is limited to observational studies and case series. After induction remission, maintenance treatment with azathioprine, methotrexate, mycophenolate mofetil, and rituximab have been utilized. However, no comparative studies have been done to recommend one over the other (65; 62).
Local therapy
Subglottic stenosis is a potentially life-threatening manifestation that is often refractory to standard therapy. For these lesions, local dilatation combined with injection of glucocorticoids is the treatment of choice (56).
Follow-up
In light of the chronicity of GPA, its tendency to relapse, and the toxicity of treatment, long-term follow-up combined with patient education is advisable. Relapses are often foreshadowed by constitutional symptoms, sinusitis, arthralgias, skin lesions, or hematuria. Increase in c-ANCA titers may portend relapse (03); however, other published studies have found no correlation between ANCA level and disease activity (25). Treatment should not be guided by ANCA level alone. However, caution is advised when ANCA-titers change from negative to positive or rise substantially between visits (19).
Outcome measures
Disease outcome is influenced by disease activity, permanent damage from the disease (scarring), and treatment side effects (infections, malignancy, etc). To be able to measure disease activity, evaluate for treatment indications across studies, and compare outcomes, validated assessment instruments are necessary. The Birmingham Vasculitis Activity Score (BVAS) is the most effective validated tool to document disease activity and to define remission and response to therapy (63; 52; 60). Several versions all appear to be of similar validity (63). It includes a list of typical symptoms related to vasculitis based on history or clinical examination findings affecting several organ systems. The Vasculitis Damage Index (VDI) is used to assess permanent damage as a result of vasculitis, but also includes treatment effects (such as osteoporosis, diabetes, cataracts, atrophy and weakness, malignancy, gonadal failure, marrow failure, chemical cystitis, and avascular necrosis) (22; 80). The VDI is correlated with mortality (60). The French Vasculitis Study Group has introduced five prognostic factors as the Five-Factor Score (FFS) in patients with necrotizing vasculitis, which is often used in EGPA. It includes (1) age over 65, (2) creatinine levels (> 150 μmol/L mg/dl), (3) gastrointestinal involvement, (4) cardiac insufficiency, and (5) absence of otolaryngologic symptoms (63; 31). In the absence of reliable biomarkers, these clinical tools are used to guide treatment and compare study results.
Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). Despite therapy-induced clinical remission and ongoing maintenance therapy, between 25% and 59% of patients with ANCA-associated vasculitis will relapse within 5 years. Risk factors for relapse include PR3 ANCA positivity (sHR 1.62) and cardiovascular disease (sHR 1.59), whereas elevated creatinine at presentation (particularly above 200 μmol/l or 2.26 mg/dl) appears protective (66; 108).
Patients previously treated within the RAVE study (randomized, double-blind, placebo-controlled trial comparing rituximab to cyclophosphamide followed by azathioprine for induction of remission in patients with GPA and MPA) were followed for nonsevere relapses between months 1 and 18. The patients developing relapses were more likely to have PR3-ANCAs, GPA, and previous relapses. An increase in prednisone dose led to remission in 80% of patients. However, only 30% of patients were able to maintain second remissions through a mean of 12.5 months, whereas 31 patients (70%) had a second disease relapse, nearly half of them with severe disease. The mean time to second relapse was 9.4 months. Therefore, increase of corticosteroids for nonsevere relapses in ANCA-associated vasculitis achieved only temporary remission, and recurrent relapses were common (64).
No markers predict relapses reliably. In the RAVE trial, increases in ANCA titer did not predict relapses; neither did B cell counts. However, as long as both B cells and ANCA were undetectable, the risk of relapse was low. In a long-term follow-up study, 38% of patients experienced a relapse (108). Patients who were anti-PR3 positive, had cardiovascular involvement, and did not have renal impairment at the time of diagnosis were at the highest risk of relapse.
In most studies, patients who were ANCA-negative or with alveolar hemorrhage on ventilatory support were excluded; therefore, data for these patient populations are sparse (93; 80; 92).
To evaluate long-term organ damage, data from six European Vasculitis Study group trials were combined (CYCAZAREM, MEPEX, CYCLOPS, IMPROVE, RITUXVAS, and NORAM). The extent of damage was assessed via the Vasculitis Damage Index (VDI). Renal, otolaryngologic, and treatment-related (cardiovascular, disease, diabetes, osteoporosis, and malignancy) damage increases over time, with around one third of patients having five or more items of damage at a mean of 7 years postdiagnosis. The most common disease-related symptoms were proteinuria, impaired glomerular filtration rate, hypertension, nasal crusting, hearing loss, and peripheral neuropathy. The most common treatment-related damage was hypertension, osteoporosis, malignancy, and diabetes (80). Lifelong monitoring and patient education are of paramount importance for positive long-term outcomes.
Complications and mortality in the rituximab studies. In the MAINRITSAN study, severe infections developed in eight patients in the azathioprine group (14%) and in 11 patients in the rituximab group (19%); cancer developed in two patients in the azathioprine group and one in the rituximab group, and two patients in the azathioprine group died (one from sepsis and one from pancreatic cancer) (34).
In the RITUXVAS trial, mortality rates were high (20% overall), and most deaths occurred within the first 3 months when patients were most vulnerable due to active disease and treatment exposure, including corticosteroids. Older age and more severe renal function likely contributed to the higher mortality rate (51). Infections continue to be a major concern contributing to morbidity and mortality, despite introduction of new therapies such as rituximab. In the early induction phase, where most adverse events occur, treatment with trimethoprim-sulfamethoxazole is recommended, independent of the type of immunosuppression, while on corticosteroids (54).
Treatment and outcome in the elderly. Because age is a negative prognostic factor and infections play a major role, studies have been investigating optimal treatment in the elderly, which may differ from younger populations. In an open-label, randomized, controlled trial including 104 patients older than 65 years of age who were newly diagnosed with ANCA-associated vasculitis, including EGPA, and panarteritis nodosa, a rapid corticosteroid dose tapering and limited cyclophosphamide exposure was investigated against conventional dosing (74). The experimental treatment group received corticosteroids for 9 months and a maximum of six 500 mg fixed-dose intravenous cyclophosphamide pulses every 2 to 3 weeks, followed by maintenance azathioprine or methotrexate. The control treatment included 26 months of corticosteroids with 500 mg/m2 intravenous cyclophosphamide pulses every 2 to 3 weeks until remission, then followed by maintenance.
The induction regimen limiting corticosteroid exposure and with fixed low-dose intravenous cyclophosphamide pulses reduced severe adverse events (83), mostly infections (32 [60%] versus 40 [78%] had > 1 SAE [P = 0.04]), in comparison to conventional therapy; there was no significant effect on remission rate. Three-year relapse rates and mortality were high for both groups. (Mortality was 6.7% during induction and reached 20% at 3 years.) SAEs occurred mainly during the first year and the causes of deaths were more likely due to serious adverse events than vasculitis (74).
Safety of rituximab in the elderly population was the goal of a retrospective review of 31 patients with ANCA-associated vasculitis with mean age older than 60 years (19 GPA, 12 microscopic polyangiitis, and 42% with relapsing disease) (101). Nearly all patients achieved remission (n=30), with a mean time to remission of 57 days. The mean prednisone dose at 6 months was 5.6 +/- 4 mg. Remission maintenance therapy was started within 12 months of rituximab in six patients (PR3 ANCA-positive and relapsing disease, four with rituximab, one with azathioprine, and one with mycophenolate mofetil). One-year survival among the 25 patients with available follow-up data was 100%. There were no episodes of infusion reaction or leukopenia. This suggests that rituximab is effective for remission induction in elderly patients with ANCA-associated vasculitis, though there was a high incidence of infectious complications (16.1%). Further prospective studies are needed to evaluate efficacy and safety (101).
Eosinophilic granulomatosis with polyangiitis (EGPA). Compared to GPA and MPA, EGPA has been considered a vasculitis with lower mortality but with remission rates similar to GPA and higher than that of MPA (66). Based on data obtained from two prospective, randomized, clinical trials, survival rates at 1, 3, 5 and 7 years were: 98%, 94%, 92%, and 90%, respectively (85). As for GPA and MPA, there is no reliable biomarker to measure EGPA activity (including ESR, CRP, eosinophilia) (20; 33).
Per the 2015 task force (33), disease remission is defined as the absence of clinical symptoms and biological abnormalities in patients on small doses of prednisone (no cutoff provided) or immunosuppressant doses. Ear-nose-throat manifestations or asthma flares are monitored separately as they may not necessarily reflect vasculitic activity. A relapse is defined as new, recurrent, or worsening of clinical EGPA manifestations (excluding asthma or ear-nose-throat manifestations), resulting in dose adjustments of the immunosuppressive regimen (33).
Among the patients with EGPA, ANCA-positive patients had a lower mortality (12) but more relapses (85). Age was significantly associated with mortality, and patients with cardiomyopathy seemed to have poorer survival rates (both included in FFS) (12). However, the differences between phenotypes based on presence or absence of ANCA has not been studied prospectively for a large cohort of EGPA patients (85). Relapse rates have been described around 41%, mostly affecting the peripheral nervous system, with 57% of relapses occurred when corticosteroid-tapering reached less than 10 mg/day. With treatment modification, remissions were achieved in more than 90% of the patients, but 38% continued to relapse.
At the last follow up after 7 years, most patients (more than 80%) were still treated with corticosteroids, resulting in treatment-related damage. Furthermore, 45% had peripheral neuropathy with disabling symptoms (85).
Special considerations
Pregnancy
Pagnoux described eight pregnancies in four patients with GPA, two in a patient with MPA, and six in three patients with EGPA (72). All mothers survived and live birth children were healthy. There was one first trimester miscarriage in each disease group. There was one therapeutic abortion at 8 weeks (GPA, receiving cyclophosphamide) and one at 5 weeks (EGPA, who had just completed an eventful pregnancy before). Four pregnancies (three patients with GPA and one with MPA) were uneventful from an obstetrical perspective; two had premature rupture of membranes with preterm births (one GPA and one EGPA). A twin pregnancy of an EGPA patient, with heart involvement and an ejection fraction of 53% at pregnancy onset, was complicated by sudden maternal cardiac failure at 32 weeks, leading to caesarean section. The newborns were healthy, and the mother recovered after 5 days of supportive care. Rescue caesarean was also required at 32 weeks for a patient with GPA with impaired renal function due to thrombotic microangiopathy (72). Medications such as azathioprine and corticosteroids were continued, and cyclophosphamide or methotrexate were discontinued (72). The risk of new vasculitis relapse during pregnancy is estimated as less than 10% to 40% with GPA in remission at conception (up to 100% in patients with active disease), 25% to 50% in EGPA (less if in remission at conception), and less than 50% in MPA (but few data are available) (73).
Pregnancy outcome in patients with systemic vasculitis was compared to a group of women matched for age and ethnicity: nine patients with GPA and three with EGPA (86).
The only significant finding was that the median gestational age was significantly lower in the vasculitis group (data reaching significance also included other types of vasculitis): 36 weeks versus 40 weeks in the control group (p< 0.03). Three patients with GPA and one with EGPA had a relapse during pregnancy, which was mild to moderate in nature; three with GPA and one with EGPA relapsed after pregnancy. These findings suggest a higher risk of preterm birth correlate with the findings of Pagnoux (72) though there was no significant increase of miscarriages compared to the control group in this study, as shown by Pagnoux (86).
Overall, it is recommended that patients be well-controlled and in remission at the time of conception. Patients should be monitored closely during pregnancy by a high-risk obstetrician (72). Most maternal complications during pregnancy seem to be due to vasculitis damage (subglottic or bronchial stenoses) and hypertension in GPA, renal insufficiency in microscopic polyangiitis, and asthma or cardiac damage in EGPA.
Cyclophosphamide and azathioprine are both associated with pregnancy risk factor D. Azathioprine and cyclophosphamide can cause congenital anomalies. Cyclophosphamide may cause sterility in males and females (which may be irreversible), and women of childbearing potential should avoid pregnancy while receiving cyclophosphamide and for up to 1 year after completion of treatment. In young women or men with childbearing plans, rituximab should be considered as induction therapy to preserve ovarian (or testicular) function (19; 92).
Anesthesia
Given the frequency of respiratory involvement, including subglottic stenosis, general anesthesia should not be administered without prior pulmonary function tests, ear-nose-throat consultation, and chest radiograph.
Media
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Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Authors
-
Kavitta B Allem MD
Dr. Allem of Scripps Clinic has no relevant financial relationships to disclose.
See Profile -
Megan Lynch DO
Dr. Lynch of Scripps Clinic/Scripps Green Hospital has no relevant financial relationships to disclose.
See Profile -
Phildrich Teh MD
Dr. Teh of Scripps Green Hospital has no relevant financial relationships to disclose.
See Profile
Editor
-
Anthony T Reder MD
Dr. Reder of the University of Chicago received honorariums from Biogen Idec, Genentech, Genzyme, and TG Therapeutics for service on advisory boards and as a consultant and stock options from NKMax America for advisory work.
See Profile
Former Authors
- Margaret E Burnett MD
- Eva Reinhold-Keller MD
- David H Mattson MD PhD
- Alison Clifford MD
- Rula A Hajj-Ali MD
- Johanna Hamel MD
- Andrew Goodman MD
Patient Profile
- Age range of presentation
-
- 1 month to 65+ years
- Sex preponderance
-
- male=female
- Heredity
-
- Heredity may be a factor
- Population groups selectively affected
-
- Caucasians (predominant)
- Occupation groups selectively affected
-
- none selectively affected
ICD & OMIM codes
- ICD-10
-
- Wegener granulomatosis: M31.3
- ICD-11
-
- Granulomatosis with polyangiitis: 4A44.A1
- OMIM
-
- Wegener granulomatosis: %608710
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