Eosinophilic Granulomatosis Polyangiitis (EGPA)

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1 Disease Entity

Eosinophilic granulomatosis with polyangiitis (EGPA), formerly Churg-Strauss syndrome, is a small to medium-sized vessel necrotizing vasculitis associated with asthma and eosinophilia. 1 First described in 1951 by Churg and Strauss in asthmatic patients with necrotizing vasculitis, eosinophilic infiltration, and granulomas in the extravascular space, EGPA is a part of vasculitis diseases belonging to antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV), along with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA), formerly Wegener granulomatosis.1,2 However, given its clinical and therapeutic differences from other AAVs, EGPA is separately classified with guidelines provided by the American College of Rheumatology (ACR).3

1.1 Epidemiology

EGPA is not as common as the other AAVs with estimated annual incidence and prevalence at 4 and 18 cases per million, respectively.4 However, the annual incidence increases to about 67 cases per million among asthmatic patients.5 The average age of diagnosis ranges between 38 – 54 years and there is no notable ethnic, familial, or gender predisposition.6,7

1.2 Pathogenesis

The precise pathogenesis of EGPA remains ill-defined but is likely similar to other inflammatory autoimmune diseases including AAV. There may be a connection to environmental factors (e.g., allergen, infection, vaccination, and medication exposure) as well as a genetic predisposition.1,7,8 Leukotriene receptor antagonist medications used to treat asthma have been suggested to increase the incidence of EGPA.8 However, it has also been suggested that this may be a mere association based on leukotriene receptor antagonist use in conjunction with tapering of glucocorticoid that caused resurfacing of EGPA.9 In terms of genetic predisposition, the genome-wide association study (GWAS) on EGPA conducted by Lyons et al. in 2018 revealed different genetic associations between MPO-ANCA positive and MPO-ANCA negative EGPA that served to explain differing clinical symptoms and organ manifestation of the disease associated to EGPA ANCA status.10 1.3

Pathophysiology

Eosinophilia is one of the hallmark features of EGPA and undoubtedly, shares similar process to allergy and parasitic responses.11 EGPA is characterized by increased T cell differentiation to Th2 type, increased inflammatory cytokines (e.g., IL-4, IL-13, and IL-5), and recruitment, activation, and inhibition of apoptosis of eosinophils.1,9 Once activated, eosinophils release cytotoxic granules, including eosinophil basic proteins, eosinophil-derived neurotoxin, and eosinophil cationic protein, that result in tissue damage and inflammation.1,8 This process is further exacerbated by the production of IL-25 by the eosinophils which serves a critical role in EGPA mediated tissue destruction.12 2. Diagnosis 2.1 History The clinical manifestations of EGPA include vasculitic and eosinophilic manifestations determined in part by the serum ANCA status. Peripheral neuropathy, glomerulonephritis, and purpura are more associated with ANCA positivity, while lung infiltration, gastrointestinal, and cardiac involvements are associated with ANCA negative EGPA.1,8 Lanham et al., in 1984, who first recognized the disease progression, placed the clinical manifestations into three different chronological phases (prodromal phase, eosinophilic phase, vasculitic phase).13 The main symptom during the prodromal phase is asthma, which can precede EGPA by a median of five to nine years. This phase also consists of allergic symptoms such as rhinosinusitis and polyposis.1,7 The prodromal phase is then followed by the eosinophilic phase which is characterized by increased eosinophil count in the tissue and blood leading to organ manifestations. Lastly, the vasculitic phase follows with further organ destruction and vasculitis of the small vessels.7 2.2 Physical Examination Given various organ involvements, the patient presentation may be nonspecific. Adult onset of asthma is one of the most correlated findings of EGPA with a prevalence of over 90% across studies.1,8 Neuropathy is also a common manifestation with prevalence reaching 70% of patients.8 2.3 Ocular Signs and Symptoms The ACR guideline for EGPA diagnosis currently does not include ocular manifestation as of one the required criteria due to its uncommon involvement.14 However, based on a compilation of longitudinal studies involving EGPA patients, ocular findings were present in 6% to 20% of the patients.1 Ocular finding is largely manifested as either orbital inflammation or ischemic vasculitis. Orbital inflammation leads to diseases that include dacryoadenitis, myositis, episcleritis, perineuritis, conjunctival granuloma, and episcleritis that tend to be more chronic and negative ANCA. In contrast, ischemic vasculitis may produce transient (e.g., amaurosis fugax) or permanent visual loss (e.g., central retinal artery occlusion (CRAO)) or ischemic optic neuropathy (ION) that are more acute and associated with positive ANCA.15,16 However, Akella et al. reviewed 46 ophthalmic EGPA cases and concluded that the correlation between ANCA positivity and ischemic vasculitis may not be consistent.17 Nikandish et al. also reported CRAO in an ANCA negative EGPA patient, further reinforcing that types of ocular manifestations may not always correlate with the ANCA status.18 Regardless, Akella et al. reported that CRAO was one of the most common ocular manifestations of EGPA followed by ischemic optic neuropathy. The study also revealed that the ocular manifestations are presented on average six years after the diagnosis of asthma, thereby recommending a baseline ophthalmic examination five years after the onset of the suspected EGPA symptoms.17 2.4 Systemic Signs and Symptoms EGPA is a multiorgan disease with a wide range of clinical manifestations. In general, constitutional symptoms such as fever, weight loss, and malaise are present with asthma, nasal polyps, rhinitis, otitis media, facial nerve palsy, and other upper respiratory symptoms being most prevalent in up to 96% of patients according to one study.1 Neuropathy is also common in patients with reports of multiplex mononeuritis, including foot and wrist drops. This is followed by lower respiratory diseases like eosinophilic pneumonitis, peripheral nodular opacities, alveolar hemorrhages, and bronchiectasis. Heart manifestations also commonly include endocarditis and pericarditis, as well as arrhythmia and valvular defects, while pauci-immune focal segmental glomerulonephritis and rapidly progressive glomerulonephritis are some of the common renal findings. Lastly, patients can present with livedo reticularis, palpable purpura or nodules on the scalp and extremities, and GI symptoms such as abdominal pain and bleeding.1,8,15,16 2.5 Diagnostic Procedures According to the 2022 ACR guideline criteria for EGPA, clinical, laboratory, and biopsy criteria are required. These criteria are based on a scoring system, where a score greater than 6 is required to diagnose EGPA.14 Table 2: American College of Rheumatology / European Alliance of Associations for Rheumatology 2022 classification guideline for EGPA.14 Clinical Criteria Score Obstructive airway disease +3 Nasal polyps +3 Mononeuritis multiplex +1 Laboratory and Biopsy Criteria Blood eosinophil count > 1x109 / liter +5 Extravascular eosinophilic-predominant inflammation on biopsy +2 Positive test for cytoplasmic antineutrophil cytoplasmic antibodies (cANCA) or antiproteinase 3 (anti-PR3) antibodies –3 Hematuria –1 A score of > 6 is required for EGPA classification

2.6 Pathology One of the hallmark features of biopsy is eosinophilic infiltration. Fibrinoid necrosis of the vessel wall, rupture of the internal elastic lamina, and granuloma formation with palisading giant cells in the perivascular and extravascular spaces are commonly seen.1 In a histopathology study consisting of 30 EGPA patients, necrotizing vasculitis with eosinophil infiltration in the small vessels is seen in all cases, while necrotizing granulomas in the extravascular space are identified in 73% of the cases.19 However, histopathology differs based on the organ systems. Skin involvement can present with vasculitis with or without eosinophilic infiltration, making it difficult to distinguish from other AAVs. Lung involvement is typically characterized by necrotizing vasculitis with eosinophilic granulomas in pneumonitis and lung nodules. Cardiac involvement presents with eosinophilic infiltration in both the myocardium and endocardium. Gastrointestinal infiltration also shows mucosal erosion with eosinophilic infiltration and inflammation, while peripheral nerve and kidney involvements are often without eosinophilic infiltration.1 2.7 Laboratory Tests Besides clinical and histopathology manifestations, laboratory tests also support EGPA diagnosis. Elevated inflammatory markers such as C-reactive protein and erythrocyte sedimentation rate with eosinophil count greater than 1,500 / mm3 or greater than 10% under complete blood count differential are indicative. Elevated IgE and positive ANCA status are also useful.7 Urine analysis and complete metabolic panel are also conducted when renal involvement is suspected.5 Zwerina et al. described 37 EGPA patients and 123 healthy controls and showed that serum eotaxin-3 had a sensitivity of 87.5% and specificity of 98.6% to EGPA. They concluded that given its correlation to EGPA disease activity, eotaxin-3 has the potential to be used as a biomarker for EGPA.20 2.8 Imaging Migratory infiltrates on chest radiographs are considered one of the key features of EGPA. High-resolution computed tomography (CT) scans are more sensitive to lung parenchymal changes. Results from a retrospective study of high-resolution CT showed peripheral nodular opacities in 25% of EGPA cases, ground glass opacities in 86% of cases, and bronchiectasis and bronchial wall thickening in 66% of EGPA cases.8 An echocardiogram is done if cardiac involvement is suspected.5 2.9 Differential Diagnosis • Parasitic infections • Drug allergy • Hematological malignancies like Hodgkin lymphoma • Acute Eosinophilic pneumonia • Chronic eosinophilic pneumonia • Allergic bronchopulmonary Aspergillosis • Idiopathic hypereosinophilic syndrome • IgG-4 related illnesses. • Granulomatosis with polyangiitis • Microscopic polyangiitis 3. Management The general approach to EGPA treatment is like other AAV (e.g., GPA and MPA) treatments. Induction immunosuppressive therapy followed by remission and maintenance therapy is a common algorithm for EGPA.3 The severity of EGPA is scored based on a five factor score (FFS), an algorithm developed by the French Vasculitis Study Group.1 FFS separates severe from non-severe disease based on a scoring system that accounts for factors such as age, creatinine, and organ involvement.7 Traditionally, cyclosporine and glucocorticoids are used for severe cases and glucocorticoids alone for non-severe cases.3 While glucocorticoids use is effective, prolonged usage results in adverse effects, and tapering of glucocorticoids is known to cause a relapse of asthma and EGPA symptoms in patients.1,3,7 Newer biologic agents like mepolizumab, an anti-interleukin-5 antibody agent, may play a role in EGPA. Mepolizumab binds serum IL-5 to attenuate the growth, activation, and survival of eosinophils.7 In the MIRRA trial (2017), combined therapy with mepolizumab and a tapering dose of glucocorticoids showed a significant increase in accrued remission duration compared to placebo.1 This resulted in the first FDA-approved drug for EGPA and Mepolizumab is suggested as a good therapy for ANCA negative EGPA by decreasing glucocorticoid uses.1,3 Alternatively, rituximab, an anti-CD20 monoclonal antibody, is also determined to be efficacious for EGPA. The drug works by depleting B-cells by binding to their CD20 surface receptors.1 One study involving 41 EGPA patients treated with rituximab demonstrated improvements in 83% of the patients by 6 months with 80% of the ANCA positive EGPA patients achieving remission; and 38% in ANCA negative EGPA patients.21 Thus, both mepolizumab and rituximab show promise as EGPA treatment therapies. Ultimately, even though biologic agents like mepolizumab and rituximab demonstrate efficacy, it is important to tailor drug usage with glucocorticoid for optimal disease remission and maintenance. It is also important to consider the ANCA status and choose treatment options accordingly.1 3.1 Prognosis Response to glucocorticoids is generally favorable and many patients achieve remission with a good prognosis in EGPA. The five-year cumulative survival is 88 – 97%, and the ten-year survival is 78 – 89%. Higher age of disease onset and cardiac and gastrointestinal involvement increase mortality in patients.1,7 Relapse of disease due to glucocorticoid taper contributes to mortality, as these relapses result in organ damage in about 40% of the patients with relapsed EGPA demonstrated neurologic involvement that also contributed to increased mortality.1 4. Summary Clinicians should be aware that EGPA is a small to medium AAV that can affect the eye or orbit. Visual loss from CRAO or ION may occur in EGPA. The ACR diagnostic criteria for EGPA include maximum eosinophil count ≥ 1x109 / liter (+5), obstructive airway disease (+3), nasal polyps (+3), cytoplasmic antineutrophil cytoplasmic antibody (ANCA) or anti–proteinase 3 ANCA positivity (-3), extravascular eosinophilic predominant inflammation (+2), mononeuritis multiplex/motor neuropathy not due to radiculopathy (+1), and hematuria (-1). After excluding mimics of vasculitis, a patient with a diagnosis of small or medium-vessel vasculitis could be classified as having EGPA if the cumulative score was ≥ 6 points. When these criteria were tested in the validation data set, the sensitivity was 85% (95% confidence interval [95% CI] 77% – 91%) and the specificity was 99% (95% CI 98% – 100%)14. Treatment with immunosuppression followed by maintenance therapy may be required for EGPA.3

5. References 1. Furuta S, Iwamoto T, Nakajima H. Update on eosinophilic granulomatosis with polyangiitis. Allergology International. 2019;68(4):430-436. doi:10.1016/j.alit.2019.06.004 2. Reddy AK, Lau MK, Sieck EG, Kolfenbach JR, Palestine AG. Retinal artery occlusion followed by contralateral amaurosis fugax in association with eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). American Journal of Ophthalmology Case Reports. 2020;18. doi:10.1016/j.ajoc.2020.100683 3. Ford JA, Aleatany Y, Gewurz-Singer O. Therapeutic advances in eosinophilic granulomatosis with polyangiitis. Current Opinion in Rheumatology. 2022;34(3):158-164. doi:10.1097/BOR.0000000000000873 4. Mohammad AJ. An update on the epidemiology of ANCA-associated vasculitis. Rheumatology (United Kingdom). 2020;59:iii42-iii50. doi:10.1093/rheumatology/keaa089 5. Keogh KA, Specks U. Churg-Strauss syndrome. Seminars in Respiratory and Critical Care Medicine. 2006;27(2):148-157. doi:10.1055/s-2006-939518 6. Venade G, Figueiredo C, Almeida C, Oliveira N, Matos LC. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). Revista da Associacao Medica Brasileira. 2021;66(7):904-907. doi:10.1590/1806-9282.66.7.904 7. Raffray L, Guillevin L. Treatment of Eosinophilic Granulomatosis with Polyangiitis: A Review. Drugs. 2018;78(8):809-821. doi:10.1007/s40265-018-0920-8 8. Greco A, Rizzo MI, de Virgilio A, et al. Churg-Strauss syndrome. Autoimmunity Reviews. 2015;14(4):341-348. doi:10.1016/j.autrev.2014.12.004 9. Keogh K. Leukotriene receptor antagonists and Churg-Strauss syndrome: cause, trigger or merely an association? Published online 2007. 10. Lyons PA, Peters JE, Alberici F, et al. The European Vasculitis Genetics Consortium ‡ , Benjamin Terrier 13 , Richard A Watts 28,29 , Augusto Vaglio 30. Wojciech Szczeklik. 26:20. doi:10.1101/491837 11. Fagni F, Bello F, Emmi G. Eosinophilic Granulomatosis With Polyangiitis: Dissecting the Pathophysiology. Frontiers in Medicine. 2021;8. doi:10.3389/fmed.2021.627776 12. Terrier B, Bièche I, Maisonobe T, et al. Interleukin-25: A cytokine linking eosinophils and adaptive immunity in Churg-Strauss syndrome. Blood. 2010;116(22):4523-4531. doi:10.1182/blood-2010-02-267542 13. LANHAM JG, ELKON KB, PUSEY CD, HUGHES GR. Systemic Vasculitis with Asthma and Eosinophilia. Medicine. 1984;63(2):65-81. doi:10.1097/00005792-198403000-00001 14. Grayson PC, Ponte C, Suppiah R, et al. 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology Classification Criteria for Eosinophilic Granulomatosis With Polyangiitis. Arthritis and Rheumatology. 2022;74(3):386-392. doi:10.1002/art.41982 15. Takanashi T, Uchida S, Arita M, Okada M, Kashii S. Orbital Inflammatory Pseudotumor and Ischemic Vasculitis in Churg-Strauss Syndrome Report of Two Cases and Review of the Literature.; 2001. 16. Nishiyama H, Tajiri T, Yamabe T, et al. Eosinophilic granulomatosis with polyangiitis presenting with central retinal artery occlusion during treatment with anti-interleukin-5 receptor monoclonal antibody. Internal Medicine. 2021;60(22):3631-3634. doi:10.2169/internalmedicine.7027-21 17. Akella SS, Schlachter DM, Black EH, Barmettler A. Ophthalmic Eosinophilic Granulomatosis With Polyangiitis (Churg–Strauss Syndrome): A Systematic Review of the Literature. Ophthalmic Plastic and Reconstructive Surgery. 2019;35(1):7-16. doi:10.1097/IOP.0000000000001202 18. Nikandish M, Saremi Z. Anca-negative churg-strauss syndrome presenting as bilateral central retinal artery occlusion: A case report. Turkish Journal of Ophthalmology. 2021;51(2):127-130. doi:10.4274/tjo.galenos.2020.95852 19. Tabb ES, Duncan LM, Nazarian RM. Eosinophilic granulomatosis with polyangiitis: Cutaneous clinical and histopathologic differential diagnosis. Journal of Cutaneous Pathology. 2021;48(11):1379-1386. doi:10.1111/cup.14065 20. Zwerina J, Bach C, Martorana D, et al. Eotaxin-3 in Churg-Strauss syndrome: A clinical and immunogenetic study. Rheumatology. 2011;50(10):1823-1827. doi:10.1093/rheumatology/keq445 21. Mohammad AJ, Hot A, Arndt F, et al. Rituximab for the treatment of eosinophilic granulomatosis with polyangiitis (Churg-Strauss). Annals of the Rheumatic Diseases. 2016;75(2):396-401. doi:10.1136/annrheumdis-2014-206095

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