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Update on eosinophilic granulomatosis with polyangiitis
Allergology International xxx (xxxx) xxx
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Invited Review Article
Update on eosinophilic granulomatosis with polyangiitis Shunsuke Furuta*, Taro Iwamoto, Hiroshi Nakajima Department of Allergy and Clinical Immunology, Chiba University Hospital, Chiba, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 21 May 2019 Available online xxx
Eosinophilic granulomatosis with polyangiitis (EGPA) (formerly Churg-Strauss syndrome) is a rare form of anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis characterized by eosinophil-rich granulomatous inflammation and small to medium-size vessel vasculitis associated with bronchial asthma and eosinophilia. Its rarity and unique features such as eosinophilic inflammation have delayed progress of research regarding EGPA for several years, compared to other forms of ANCA-associated vasculitis. However, recently, attention to EGPA as a research subject has been gradually increasing. To resolve problems in existing criteria for EGPA, new classification criteria for EGPA generated by a large international cohort will be launched and is being expected to accelerate future studies. Pathogenesis and roles of ANCA in EGPA are still largely unknown; however, it has been reported that glomerulonephritis is more frequent in ANCA-positive patients than in ANCA-negative patients, while heart failure is more frequent in ANCA-negative patients than in ANCA-positive patients. In addition, a recent genome-wide association study has suggested the presence of two genetically distinct subgroups of EGPA, which correspond to ANCA-positive and -negative subgroups. Although responses to glucocorticoids in EGPA are generally good, patients with EGPA often experience a relapse. Currently, there is no standard therapy for EGPA based on accumulation of clinical trial results. Recently, clinical benefits of mepolizumab for EGPA were proved by a randomized controlled trial and mepolizumab was approved for EGPA. In addition, various new drugs are under evaluation. To find optimal use of these drugs and to resolve unmet needs, such as relapse prevention, will be needed in future. Copyright © 2019, Japanese Society of Allergology. Production and hosting by Elsevier B.V. This is an open access
Keywords: Anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis Eosinophil Eosinophilic granulomatosis with polyangiitis Mepolizumab Rituximab
article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction Eosinophilic granulomatosis with polyangiitis (EGPA) (formerly Churg-Strauss syndrome) was first described by Churg and Strauss in 1951.1 They found asthmatic patients who developed necrotizing vasculitis, eosinophilic inflammation and extravascular granulomas. The disease is now recognised as one form of antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) characterized by eosinophil-rich granulomatous inflammation and small to medium-size vessel vasculitis associated with asthma and eosinophilia. EGPA is the rarest among AAV and it has been reported that annual incidence and prevalence of EGPA were 0.9e2.4 per million2e5 and 10.7e17.8 per million,6e9 respectively, depending on geographic regions and applied criteria. Its rarity and unique features such as eosinophilic inflammation have delayed progress of research regarding EGPA for several years, compared to
* Corresponding author. Department of Allergy and Clinical Immunology, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba 260-8670, Japan. E-mail address: [email protected] (S. Furuta). Peer review under responsibility of Japanese Society of Allergology.
other forms of AAV, microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). Pathogenesis and roles of ANCA in EGPA are still largely unknown, and there is no standard therapy for EGPA based on accumulation of clinical trial results. However, attention to EGPA as a research subject has been recently increasing. In this review, we highlight recent topics in EGPA.
Disease definition and classification criteria Several criteria for EGPA were developed with different purposes and different methods. The nomenclature of the primary systemic vasculitis syndromes including EGPA was defined by the Chapel Hill consensus conference (CHCC) (Table 1).10 The American College of Rheumatology (ACR) had proposed classification criteria for seven vasculitis syndromes including Churg-Strauss syndrome in 1990 (Table 2).11 The criteria developed by Lanham et al. in 1984 have also been widely used (Table 3).12 The original CHCC definitions were published in 1994. The consensus was made by expert opinion in order to standardise the nomenclature. Its key concept was classifying various vasculitides according to the predominant size of diseased blood vessels based
https://doi.org/10.1016/j.alit.2019.06.004 1323-8930/Copyright © 2019, Japanese Society of Allergology. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).
Please cite this article as: Furuta S et al., Update on eosinophilic granulomatosis with polyangiitis, Allergology International, https://doi.org/ 10.1016/j.alit.2019.06.004
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Table 1 Definition of ANCA-associated vasculitis by the 2012 Chapel Hill Consensus Conference. CHCC2012 Names
CHCC2012 Definitions
ANCA Associated Vasculitis
Necrotizing vasculitis, with few or no immune deposits, predominantly affecting small vessels (i.e., capillaries, venules, arterioles and small arteries), associated with MPO-ANCA or PR3ANCA. Not all patients have ANCA. Add a prefix indicating ANCA reactivity, e.g. PR3-ANCA, MPO-ANCA, ANCAnegative. Necrotizing vasculitis, with few or no immune deposits, predominantly affecting small vessels (i.e., capillaries, venules, or arterioles). Necrotizing arteritis involving small and medium arteries may be present. Necrotizing glomerulonephritis is very common. Pulmonary capillaritis often occurs. Granulomatous inflammation is absent. Necrotizing granulomatous inflammation usually involving the upper and lower respiratory tract, and necrotizing vasculitis affecting predominantly small to medium vessels (e.g., capillaries, venules, arterioles, arteries and veins). Necrotizing glomerulonephritis is common. Eosinophil-rich and necrotizing granulomatous inflammation often involving the respiratory tract, and necrotizing vasculitis predominantly affecting small to medium vessels, and associated with asthma and eosinophilia. ANCA is more frequent when glomerulonephritis is present.
Microscopic Polyangiitis
Granulomatosis with Polyangiitis
Eosinophilic Granulomatosis with Polyangiitis
Table 2 The 1990 classification criteria for Churg-Strauss syndrome by the American College of Rheumatology. Criteria Asthma Eosinophilia >10% Neuropathy, mono or poly Pulmonary infiltrates, non-fixed Paranasal sinus abnormality Extravascular eosinophils For classification purpose, a patient shall be said to have the disease if at least 4 of these 6 criteria are positive.
Table 3 The diagnostic criteria by Lanham et al. Criteria Asthma Peak peripheral blood eosinophil count >1.5 106/cc Systemic vasculitis involving two or more extrapulmonary organs All three criteria should be fulfilled for diagnosis of the disease.
on histology and clinical manifestations. In 2012, the CHCC definition was revised to reflect recent advances, to add new categories such as single organ vasculitis and variable vessel vasculitis, and to rename vasculitides to descriptive titles. Churg-Strauss syndrome was formally renamed to EGPA. In the 2012 CHCC system, small vessel vasculitis was sub-divided into AAV and immune complex small vessel vasculitis. AAV which includes MPA, GPA and EGPA was defined as a group of pauci-immune necrotizing vasculitides associated with ANCA. EGPA was defined as a subgroup of AAV
characterised by eosinophil-rich and necrotizing granulomatous inflammation, necrotizing vasculitis predominantly affecting small to medium vessels, and association with asthma and eosinophilia. The 1990 ACR classification criteria have been the most popular classification criteria for the disease, however it has been developed before widespread ANCA testing. Methodologically, 20 cases diagnosed as EGPA (Churg-Strauss syndrome) by each submitting physician were used as the gold standard, and were compared to a non-selective control group of small, medium and large vessel vasculitides. In addition, validation of the ACR criteria has never been performed. In 1984, Lanham and his associates reviewed 16 patients with Churg-Strauss syndrome in their institution and 138 literature cases. They proposed the diagnostic criteria, which consisted of three clinical findings. Lanham criteria were developed before establishing the concept of AAV and did not require histological findings. Discrimination of hypereosinophilic syndrome is unclear in Lanham criteria. Thus, it might not be enough for study purpose; however, it has been still widely used in daily clinical practise because of its simplicity capturing the essence of the disease. Presence of bronchial asthma is needed for diagnosing the disease in Lanham criteria, while asthma is not mandatory in the ACR criteria. Application of the ACR criteria alone results in frequent overlaps between each vasculitis. The CHCC system was limited due to its requirement for histology, resulting in many unclassified cases. To reduce diagnostic overlaps and unclassified cases, Watts et al. developed a stepwise algorithm for diagnosing AAV and polyarteritis nodosa in 2007.13 The step of diagnosing EGPA (ChurgStrauss syndrome) exists the most upstream in this diagnostic algorithm, and presence/absence of EGPA (Churg-Strauss syndrome) is judged by using the ACR and Lanham criteria. The problems in these systems and the need for newer classification and diagnosis criteria of vasculitides were reviewed by a European League Against Rheumatism (EULAR)/ACR working group in 2010. This led to the launch of a large, international, prospective, observational study, Diagnosis and Classification of Vasculitis Study (DCVAS), to develop both revised classification criteria and a validated set of diagnostic criteria.14 Recently, the draft of new classification criteria for EGPA using the DCVAS dataset including 226 EGPA patients has been proposed at the 19th International Vasculitis and ANCA Workshop,15 and is waiting for final endorsement by EULAR and ACR. In the DCVAS, the gold standard cases were selected by consensus of expert panel and classification items were identified with a data-driven manner by comparing each AAV subtype to other small vessel vasculitides. The new classification criteria for EGPA have also been tested in the dataset for validation. The new criteria are expected to have better sensitivity and specificity than the previous ones.
Pathogenesis Pathogenesis of EGPA remains largely unknown. However, like many other autoimmune diseases, both genetic and environmental factors appear to contribute to the development of EGPA. Recently, Lyons et al. performed a first genome-wide association study (GWAS) with 684 EGPA patients16 and found that the risk genes were separated by the ANCA status. As with MPA and other autoimmune diseases, HLA-DQ was detected as a risk allele in MPOANCA-positive EGPA. Variants at GATA3, TSLP, LPP, and BACH2, which may contribute to eosinophilic inflammation, were detected in total EGPA. On the other hand, variants at IRF1/IL5 and GPA33 were associated with MPO-ANCA-negative EGPA. GPA33 gene encodes a cell surface glycoprotein that potentially has a role in maintaining barrier function in the intestinal epithelium17 and also
Please cite this article as: Furuta S et al., Update on eosinophilic granulomatosis with polyangiitis, Allergology International, https://doi.org/ 10.1016/j.alit.2019.06.004
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in bronchial tissue.18 This fact may give a clue why ANCA status strongly correlates with specific organ manifestations. In AAV other than EGPA, associations with environmental factors, such as air pollutants, infections and drugs have been investigated.19 Apoptosis of neutrophils induced by the instillation of silica may act as a trigger in the development of ANCA. Peptides from Staphylococcus aureus have strong homology with peptides from complementary PR3, which could underlie the development of PR3-ANCA. Drugs such as cocaine, levamisole and propylthiouracil are well-known as triggers of AAV. Recent studies have revealed that propylthiouracil induces abnormal conformation of neutrophil extracellular traps (NETs), resulting in the resistance to the degradation by DNaseI and subsequent development of MPOANCA production and vasculitiis.20 However, involvement of environmental factors in EGPA remains largely unclear. A possible pathogenic role of cysteinyl-leukotriene receptor antagonists for asthma treatment has been suggested, but now it is considered that they are not a trigger of EGPA.21 Eosinophilic inflammation is one of cardinal features in EGPA. From this point of view, IL-5, a principal eosinophil-activating cytokine, seems to be involved in the pathogenesis of EGPA. IL-5 is produced by Th2 cells and induces the differentiation and maturation of human eosinophils.22 In addition, IL-5 inhibits the apoptosis of human eosinophils.23,24 Group 2 innate lymphoid cells (ILC2s) also produce IL-5 even in the absence of acquired immunity.25,26 Activated eosinophils exert proinflammatory effects by releasing cytotoxic granule proteins and lipid mediators, thereby
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inducing tissue damage and inflammation.27 Cytotoxic granule proteins released from eosinophils include major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), and eosinophil-derived neurotoxin (EDN). Presence of ANCA is another aspect of EGPA. As to MPA and GPA, a direct pathogenic role of ANCA in the formation of small vessel vasculitis has been established based on experimental data and associations of ANCA with disease activity.19 ANCA activates neutrophils, and then activated neutrophils attack vessel wall via degranulation and the formation of NETs. Meanwhile, a role of ANCA in EGPA is still unclear, especially about association between ANCA and eosinophilic inflammation. Some conditions in EGPA, such as glomerulonephritis and alveolar haemorrhage, are observed more frequently in ANCA-positive EGPA patients28e31 and like MPA and GPA, often show small vessel vasculitis without local eosinophilic inflammation. It is assumed that ANCA in EGPA also had a pathogenic role in at least such conditions. Possible mechanisms underlying eosinophilic inflammation and ANCA-mediated vasculitis in EGPA were summarised in Fig. 1. Histopathology The hallmark of histological findings in EGPA is necrotizing small vessel vasculitis accompanied by eosinophil infiltrates and perivascular and extravascular granulomas. Vasculitis presents fibrinoid necrosis in the wall of the vessels and rupture of internal elastic lamina. Granulomas in EGPA patients consist of eosinophilic
Fig. 1. Overview of the genetic predisposition, eosinophilic inflammation, and ANCA-mediated inflammation putatively involved in the development of EGPA. Environmental factors together with genetic predisposition provoke eosinophilic and ANCA-mediated inflammation. Eosinophilic inflammation; IL-5 is produced mainly by Th2 cells and ILC2s. IL-5 binds to the IL-5 receptor on eosinophils to induce eosinophilopoiesis in the bone marrow and also induce activation and prolonged survival of eosinophils in the tissues. ANCAmediated inflammation; Proinflammatory cytokines and complement alternative pathway prime neutrophils. ANCA binds to the primed neutrophils via Fcg receptors or MPO protein expressed on the cell surface, leading to the production of reactive oxygen species (ROS), the release of proteolytic enzymes and the formation of neutrophil extracellular traps (NETs). ANCA, antineutrophil cytoplasmic antibody; APC, antigen-presenting cell; BAFF, B cell activating factor belonging to the TNF family; GM progenitor, granulocytemacrophage progenitor; ILC2, group 2 innate lymphoid cell; MPO, myeloperoxidase; NETs formation, neutrophil extracellular traps formation.
Please cite this article as: Furuta S et al., Update on eosinophilic granulomatosis with polyangiitis, Allergology International, https://doi.org/ 10.1016/j.alit.2019.06.004
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necrotic matrix surrounded by palisading giant cells, which is called palisading granuloma.1,11,32 However, these histological findings are not always found in the same site. Typical pathohistological presentations of EGPA are different among the affected organs. In purpura of the skin, a wide range of conditions between eosinophilic vasculitis and leukocytoclastic vasculitis without eosinophilic infiltration is observed.33 It is difficult to distinguish from other small vessel vasculitides histologically in the case lacking eosinophil infiltration. Necrotising vasculitis and eosinophilic granulomas are seen in pneumonitis and lung nodules. Cardiac involvement shows mixture of eosinophilic infiltration in myocardium and endocardium causing myocarditis and endocarditis, and small vessel vasculitis.34 Gastrointestinal involvement shows erosion with eosinophilic infiltration and sometimes vasculitis and eosinophilic granuloma. On the other hand, eosinophilic infiltration is rarely observed in peripheral nerve and kidney involvements. Peripheral neuropathy features necrotizing vasculitis in a small artery in the epineural space. Renal histology is characterized by pauciimmune necrotizing crescentic glomerulonephritis.34,35 Eosinophilic infiltration is sometimes observed in the interstitium of the kidney. Interestingly, peripheral neuropathy and glomerulonephritis are the organ involvements associated with ANCA-positive EGPA patients.28e31
Demographics and clinical manifestations There are several studies with large cohorts of EGPA patients from different geographic areas (Table 4).28e30,36,37 Although patient characteristics in these cohorts were mostly common, some manifestations varied among the cohorts. Those differences might be caused by the applied criterion, referral bias and underlying genetic differences. According to those studies, median age at onset of EGPA is 49e59 years old. There is no extreme gender bias in EGPA patients, and female rate is 48e64%. Almost all patients (>90%) have a history of bronchial asthma, and the duration from onset of asthma to diagnosis of EGPA is median 5e9 years. Eosinophil counts in most studies were highly elevated in accordance with the ACR or Lanham criterion (median around 8000/mL), while German group reported milder elevation of eosinophils (median 1100/mL). Serum C-reactive protein level is median 2.5e6.6 mg/dl. Serum creatinine level is not markedly elevated (median 0.68e1.01 mg/dl), which is different from other forms of AAV, MPA
and GPA. ANCA is positive in 30e47% of EGPA patients, and usually the subtype of ANCA is MPO-ANCA.28e31,36,37 Regarding organ involvements, peripheral nerve and paranasal sinuses are the most frequent organ in most of the previous studies (51e98% and 48e96%, respectively).28e30,36,37 Peripheral nerve involvement typically presents multiple mononeuropathies, while distal symmetrical polyneuropathy (24%), asymmetric polyneuropathy (3%) and lumber radiculopathy (3%) are sometimes observed.38 Subsequently, lung involvement is also frequently seen (around 40e60%). Migrating patchy infiltrates with peripheral dominance, which are very similar to eosinophilic pneumonitis, are a typical manifestation of lung in EGPA patients. Pulmonary nodules, granulomatous mass lesions or alveolar haemorrhage are relatively rare.31,39 Heart and gastrointestinal involvements are less frequent in EGPA, but are more associated with a mortality risk than nerve, sinus and lung involvements. Kidney involvement was observed in around 20e25% of the patients in most of the studies, and far less common than in MPA and GPA. Kidney biopsy usually presents a pauci-immune focal segmental necrotising glomerulonephritis with crescentic formation, which is indistinguishable from other forms of AAV.40 Eosinophil infiltration or eosinophilic granuloma is usually absent in kidney biopsy specimens. Frequencies of organ involvements differ between ANCApositive and -negative EGPA patients.28e31 Glomerulonephritis, alveolar haemorrhage and peripheral nerve neuropathy are more frequent in ANCA-positive patients than in ANCA-negative patients, whereas heart involvement is more frequent in ANCA-negative patients than in ANCA-positive patients. Clinical manifestations in ANCA-positive EGPA patients are closer to other forms of AAV, MPA and GPA. Interestingly, a recent GWAS revealed that EGPA comprised two genetically and clinically distinct subsets.28 ANCApositive EGPA is sharing an MHC association with MPA, while ANCA-negative EGPA is genetically more similar to asthma (Table 5).
Differential diagnosis A differential diagnosis for EGPA includes other small vessel vasculitides and eosinophilic disorders. Although symptoms of organ involvements are similar with other vasculitides, EGPA is usually distinguishable by the presence of eosinophilia and asthma. As to eosinophilic disorders, parasitic infections, drug allergy and haematological malignancies such as Hodgkin lymphoma should
Table 4 Clinical manifestations among the previous studies.
Patient number Study period Country Age at onset Female rate Eosinophil count C-reactive protein Serum Creatinine ANCA-positive Organ involvements Nerve Skin Eye ENT Lung Heart Intestine Kidney
Sinico et al.
Durel et al.
Moosig et al.
Comarmond et al.
Saku et al.
Tsurikisawa et al.
n ¼ 93 1989e2004 Italy 51.6 y 58% 4400/ml ND ND 37%
n ¼ 101 1990e2011 France, UK, Italy 49.2 y 57% ND ND ND 43%
n ¼ 150 1990e2009 Germany 49.1 y 49% 1100/ml 2.50 mg/dl 0.90 mg/dl 30%
n ¼ 383 1957e2009 France 50.3 y 48% 7569/ml 6.69 mg/dl 1.01 mg/dl 31%
n ¼ 188 1996e2015 Japan 59.7 y 64% 8775/ml 2.90 mg/dl 0.68 mg/dl 47%
n ¼ 121 1999e2015 Japan 53.3 y 65% 8528/ml ND ND 35%
64% 52% ND 77% 50% 16% 21% 26%
66% 46% 20% 96% 54% 20% 25% 26%
76% 49% 12% 93% 61% 46% 28% 18%
51% 39% 6% 48% 38% 16% 23% 21%
88% 41% 5% 50% 34% 11% 12% 18%
98% 46% ND 91% 67% 73% 78% 35%
ENT, Ear, Nose and Throat.
Please cite this article as: Furuta S et al., Update on eosinophilic granulomatosis with polyangiitis, Allergology International, https://doi.org/ 10.1016/j.alit.2019.06.004
S. Furuta et al. / Allergology International xxx (xxxx) xxx Table 5 Genetically and clinically subgroups in EGPA. Group 1 Genetic association
HLA-DQA1, HLA-DRB1 (shared with ANCA-associated vasculitis) MPO-ANCA positive Glomerulonephritis Frequent Neuropathy Frequent Heart failure Less frequent Rituximab response Better Mepolizumab response Lack of data
Group 2 GPA33, IL-5 (shared with asthma) negative Less frequent Less frequent Frequent Worse Good
be excluded firstly. Eosinophilic pneumonia and allergic bronchopulmonary mycosis should be considered next if clinical manifestations are restricted to lung. Both diseases often occur in asthma patients and present migrating pulmonary infiltrates. If the patients have extrapulmonary organ involvements with eosinophilia, idiopathic hypereosinophilic syndrome (HES) and IgG4-related disease can be important differential diagnoses. HES usually occurs in a patient who lacks a history of allergic disease, and bone marrow examination and a test for FIP1L1-PDGFRa fusion gene are required in diagnostic procedure. IgG4-related disease is a local/ systemic disorder characterised by IgG4-secreting plasma cells and fibrosis, which is sometimes accompanied by eosinophilia and asthma. Histopathologic examination is essential for diagnosis of IgG4-related disease, and the measurement of serum IgG4 levels is helpful. HES and IgG4-related disease can fulfil the 1990 ACR criteria or Lanham criteria. Distinguishing those diseases from EGPA is sometimes difficult in the case of ANCA-negative and/or lacking histopathologic examination. Treatments So far, EGPA has been excluded from most of randomised controlled trials for AAV because of its rarity and unique features, such as involvement of eosinophils in the pathogenesis. Reliable evidence of treatment for EGPA is limited, and there are no strong recommendations for treatment of EGPA at the moment.41 Glucocorticoids is usually used as a remission induction therapy for EGPA. Glucocorticoids can diminish human eosinophils via direct and indirect mechanisms42 and are effective in reducing eosinophilic inflammation in EGPA. In combination with glucocorticoids, immunosuppressants are often used for treatment of EGPA. French Vasculitis Study Group developed five factor score (FFS), which predicted a mortality risk in patients with small to medium-size vessel vasculitis, by using a large mixed cohort of MPA, EGPA and polyarteritis nodosa in 1996,43 and then they have revisited FFS in 2011 (Table 6).44 Following trials by the same group suggested that cyclophosphamide use in remission induction phase improved mortality in severe EGPA patients with higher FFS.45,46 Although glucocorticoid therapy with or without immunosuppressants leads to successful remission in the majority of EGPA patients,45,47 it has been well-known that EGPA patients experience frequent relapses during glucocorticoid tapering.28e30,36,37 Long-term maintenance Table 6 The revised five factor score by French Vasculitis Study Group. Factor Age >65 years Presence of symptomatic cardiac insufficiency Presence of severe gastrointestinal involvement (bowel perforation, bleeding, and pancreatitis) Presence of renal insufficiency (creatinine >150 mmol/L). Absence of ear, nose, and throat symptoms
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therapy with immunosuppressants is often used for preventing the relapse of EGPA. However, the efficacy of immunosuppressant maintenance therapy is still controversial. Large retrospective studies suggested the efficacy of azathioprine as maintenance therapy,28,29 while a randomised controlled trial (CHUSPAN2) for non-severe vasculitides including EGPA (n ¼ 51), MPA (n ¼ 25) and polyarteritis nodosa (n ¼ 19) showed that azathioprine was not superior to placebo in preventing relapse.48 The mixed subjects in the CHUSAPAN2 trial reduced the certainty of conclusion for each vasculitis. In addition, azathioprine was administered for only 12 months in the trial. The efficacy of long-term azathioprine maintenance therapy for EGPA is still unclear. Interleukin-5 is well-known as a key mediator in eosinophil activation.22e24 Thus, the efficacy of mepolizumab, a humanized monoclonal antibody against interleukin-5, was evaluated in patients with EGPA. Results of the double-blind, randomised placebocontrolled trial (MIRRA) were reported in 2017.49 In the MIRRA trial, relapsing or refractory EGPA patients receiving 7.5 mg/day or more of prednisolone were randomly assigned to receive mepolizumab (n ¼ 68) or placebo (n ¼ 68) in addition to standard care. Proportions of ANCA-positive patients were 10% and 9% in mepolizumab group and placebo group, respectively, which were biased to ANCA-negative compared to general population of EGPA patients. The glucocorticoid dose was rapidly reduced according to a standardised schedule. Dose of prednisolone with 4 mg/day or less was included in the definition of remission in the MIRRA trial. In this trial, mepolizumab led to significantly more accrued weeks of remission than placebo (28% vs. 3% of the participants had 24 weeks of accrued remission, p < 0.001) and a higher percentage of participants in remission at both week 36 and week 48 (32% vs. 3%, p < 0.001). The efficacy of mepolizumab with minimal adverse effects was clearly shown, and mepolizumab was approved for EGPA. However, it was also shown that mepolizumab alone or with 4 mg/day or less of prednisolone could not achieve sustained remission in the majority of relapsing/refractory EGPA patients. Recently, the post hoc analysis of the MIRRA trial showed the proportion of remission with 7.5 mg/day or less of prednisolone, which was closer to a target dose in real world than the original analysis of the trial, was higher in the mepolizumab group than the placebo group (87% vs. 53%, p < 0.001).50 Mepolizumab is now a good therapeutic option for EGPA, especially for sparing glucocorticoids in ANCA-negative EGPA patients, although its optimal use has not been fully studied yet. Another anti-interleukin-5 monoclonal antibody, reslizumab, and an anti-interleukin-5 receptor monoclonal antibody, benralizumab, are now being investigated for EGPA (NCT02947945 and NCT03010436, respectively). Presence of pathogenic autoantibodies, ANCA, produced by B cells is one of the main features of AAV. B cell depletion therapy by rituximab, an anti-CD20 monoclonal antibody, has already been established as a part of the standard treatment for both MPA and GPA.41 In addition to other forms of AAV, retrospective studies suggested that rituximab was also effective for EGPA patients.51,52 Mohammad et al. reported 41 EGPA patients treated with rituximab (15 had refractory, 21 had relapsing, and 5 had new onset disease). By 12 months, 88% of the patients improved and glucocorticoid doses decreased in all patients. In their cohort, 80% of ANCA-positive patients achieved remission, while only 38% of ANCA-negative patients achieved remission (p ¼ 0.013). They suggested rituximab was more effective for patients with ANCApositive EGPA than for those with ANCA-negative EGPA. Currently, two randomised placebo-controlled trials (the REOVAS [NCT02807103] and MAINRITSEG trials [NCT03164473]) by French group are evaluating the efficacy of rituximab for EGPA as remission induction therapy compared to cyclophosphamide and as remission maintenance therapy compared to azathioprine, respectively.
Please cite this article as: Furuta S et al., Update on eosinophilic granulomatosis with polyangiitis, Allergology International, https://doi.org/ 10.1016/j.alit.2019.06.004
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Regarding other drugs, IFN-a is known to counteract Th2 responses, and small studies suggested its efficacy in both remission induction and maintenance in EGPA.53 However, its unfavourable safety profile has restricted its use. Anti-IgE monoclonal antibody, omalizumab, has sometimes been used for EGPA. It is effective for asthma in EGPA patients; however, its effect on EGPA is still unclear.54,55 Efficacy of high-dose intravenous immunoglobulin therapy (IVIG) in remission induction for severe EGPA was reported,56 and IVIG was approved for refractory EGPA in Japan in 2010. Japanese group also suggested IVIG might be effective for chronic residual peripheral neuropathy, though the sample size of the trial was limited (n ¼ 23).57 The mechanism of recovery from neurologic damage has not been clarified. Certainly, treatment options for EGPA are increasing, though a standard therapy has not been established yet. Optimal use of those treatments, such as concomitant use of glucocorticoids and the best combination of the treatments, should be investigated in future trials. A recent GWAS16 suggested treatment strategies might be different between ANCA-positive and -negative EGPA patients.
Outcomes Response to glucocorticoids in EGPA is generally good, and glucocorticoid-based induction therapy achieved remission in most cases.45,47 Consequently, patients with EGPA have a favourable prognosis in terms of survival.28,30,36,37,58 The cumulative survival rates at 5 and 10 years from the disease onset are 88e97% and 78e89%, respectively. Although deaths are infrequent in EGPA, the previous studies identified higher age at disease onset and heart failure as risk factors for mortality.30,36,37 On the other hand, EGPA patients frequently relapse during glucocorticoid tapering,28e30,36,37,58 and it has been reported that the number of relapses was associated with cumulative organ damages of AAV patients.59 Cumulative relapse free survival rate at 5 years from the disease onset is 54e64%.28,30,58 Lower eosinophil count at the disease onset was identified as a risk factor for relapse in the plural studies,28,30,58 though the underlying mechanism was unknown. Asthma exacerbation during glucocorticoid tapering has sometimes been considered as a sign for high risk of relapse. Recently, Saku et al. investigated this issue and reported that asthma exacerbation and relapse of vasculitis in EGPA were independent of each other.28 Except persistent airway obstruction due to bronchial asthma, neurologic damage is the most frequent sequelae observed in around 40% of EGPA patients.29,58 Neurologic damage alone dose not affect patient survival; however, it significantly deteriorates patient's physical function and quality of life. IVIG might be effective for chronic residual peripheral neuropathy in EGPA patients.57 The outcomes reported by the previous retrospective studies were based on the data from the cohort treated by the conventional glucocorticoids and immunosuppressants. Newer therapies such as mepolizumab and rituximab will potentially change the outcomes of EGPA.
Conclusion The new classification criteria for EGPA will be launched and will accelerate future studies. The recent GWAS suggested the two distinct subgroups, and clinical manifestations are partly different between the subgroups. Mepolizumab is now approved for EGPA, and various new drugs are under evaluation. To find optimal use of these drugs and to resolve the unmet needs, such as relapse prevention, will be needed.
Conflict of interest HN reports receiving grant support from GlaxoSmithKline, Chugai Pharmaceutical (Roche group) and Teijin Pharma. The rest of the authors have no conflict of interest.
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44. Guillevin L, Pagnoux C, Seror R, Mahr A, Mouthon L, Le Toumelin P, French Vasculitis Study Group (FVSG). The Five-Factor Score revisited: assessment of prognoses of systemic necrotizing vasculitides based on the French Vasculitis Study Group (FVSG) cohort. Medicine (Baltimore) 2011;90:19e27. ne JP, Lauque D, et al. Treatment of 45. Ribi C, Cohen P, Pagnoux C, Mahr A, Are Churg-Strauss syndrome without poor-prognosis factors: a multicenter, prospective, randomized, open-label study of seventy-two patients. Arthritis Rheum 2008;58:586e94. ne JP, Mouthon L, Le Guern V, et al. Churg46. Cohen P, Pagnoux C, Mahr A, Are Strauss syndrome with poor-prognosis factors: a prospective multicenter trial comparing glucocorticoids and six or twelve cyclophosphamide pulses in fortyeight patients. Arthritis Rheum 2007;57:686e93. 47. Pagnoux C, Guilpain P, Guillevin L. Churg-Strauss syndrome. Curr Opin Rheumatol 2007;19:25e32. chal X, Pagnoux C, Baron G, Que meneur T, Ne el A, Agard C, et al. Adding 48. Pue azathioprine to remission-induction glucocorticoids for eosinophilic granulomatosis with polyangiitis, microscopic polyangiitis or polyarteritis nodosa without poor prognosis factors a randomized-controlled trial. Arthritis Rheumatol 2017;69:2175e86. 49. Wechsler ME, Akuthota P, Jayne D, Khoury P, Klion A, Langford CA, et al. Mepolizumab or placebo for eosinophilic granulomatosis with polyangiitis. N Engl J Med 2017;376:1921e32. 50. Steinfeld J, Bradford ES, Brown J, Mallett S, Yancey SW, Akuthota P, et al. Evaluation of clinical benefit from treatment with mepolizumab for patients with eosinophilic granulomatosis with polyangiitis. J Allergy Clin Immunol 2018. https://doi.org/10.1016/j.jaci.2018.11.041. 51. Mohammad AJ, Hot A, Arndt F, Moosig F, Guerry MJ, Amudala N, et al. Rituximab for the treatment of eosinophilic granulomatosis with polyangiitis (Churg-Strauss). Ann Rheum Dis 2016;75:396e401. 52. Thiel J, Troilo A, Salzer U, Schleyer T, Halmschlag K, Rizzi M, et al. Rituximab as induction therapy in eosinophilic granulomatosis with polyangiitis refractory to conventional immunosuppressive treatment: a 36-month follow-up analysis. J Allergy Clin Immunol Pract 2017;5:1556e63. €rster M, Happe J, Forberg T, Moeser A, Neumann T, et al. Inter53. Seeliger B, Fo feron-a for induction and maintenance of remission in eosinophilic granulomatosis with polyangiitis: a single-center retrospective observational cohort study. J Rheumatol 2017;44:806e14. 54. Jachiet M, Samson M, Cottin V, Kahn JE, Le Guenno G, Bonniaud P, et al. Anti-IgE monoclonal antibody (Omalizumab) in refractory and relapsing eosinophilic granulomatosis with polyangiitis (Churg-Strauss): data on seventeen patients. Arthritis Rheumatol 2016;68:2274e82. 55. Celebi Sozener Z, Gorgulu B, Mungan D, Sin BA, Misirligil Z, Aydin O, et al. Omalizumab in the treatment of eosinophilic granulomatosis with polyangiitis (EGPA): single-center experience in 18 cases. World Allergy Organ J 2018;11:39. 56. Tsurikisawa N, Taniguchi M, Saito H, Himeno H, Ishibashi A, Suzuki S, et al. Treatment of Churg-Strauss syndrome with high-dose intravenous immunoglobulin. Ann Allergy Asthma Immunol 2004;92:80e7. 57. Koike H, Akiyama K, Saito T, Sobue G, Research Group for IVIg for EGPA/CSS in Japan. Intravenous immunoglobulin for chronic residual peripheral neuropathy in eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome): a multicenter, double-blind trial. J Neurol 2015;262:752e9. chal X, Devilliers H, Ribi C, Cohen P, Stern M, et al. Long-term out58. Samson M, Pue comes of 118 patients with eosinophilic granulomatosis with polyangiitis (ChurgStrauss syndrome) enrolled in two prospective trials. J Autoimmun 2013;43:60e9. €glund P, et al. Gluco59. Robson J, Doll H, Suppiah R, Flossmann O, Harper L, Ho corticoid treatment and damage in the anti-neutrophil cytoplasm antibodyassociated vasculitides: long-term data from the European Vasculitis Study Group trials. Rheumatology (Oxford) 2015;54:471e81.
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Invited Review Article
Update on eosinophilic granulomatosis with polyangiitis Shunsuke Furuta*, Taro Iwamoto, Hiroshi Nakajima Department of Allergy and Clinical Immunology, Chiba University Hospital, Chiba, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 21 May 2019 Available online xxx
Eosinophilic granulomatosis with polyangiitis (EGPA) (formerly Churg-Strauss syndrome) is a rare form of anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis characterized by eosinophil-rich granulomatous inflammation and small to medium-size vessel vasculitis associated with bronchial asthma and eosinophilia. Its rarity and unique features such as eosinophilic inflammation have delayed progress of research regarding EGPA for several years, compared to other forms of ANCA-associated vasculitis. However, recently, attention to EGPA as a research subject has been gradually increasing. To resolve problems in existing criteria for EGPA, new classification criteria for EGPA generated by a large international cohort will be launched and is being expected to accelerate future studies. Pathogenesis and roles of ANCA in EGPA are still largely unknown; however, it has been reported that glomerulonephritis is more frequent in ANCA-positive patients than in ANCA-negative patients, while heart failure is more frequent in ANCA-negative patients than in ANCA-positive patients. In addition, a recent genome-wide association study has suggested the presence of two genetically distinct subgroups of EGPA, which correspond to ANCA-positive and -negative subgroups. Although responses to glucocorticoids in EGPA are generally good, patients with EGPA often experience a relapse. Currently, there is no standard therapy for EGPA based on accumulation of clinical trial results. Recently, clinical benefits of mepolizumab for EGPA were proved by a randomized controlled trial and mepolizumab was approved for EGPA. In addition, various new drugs are under evaluation. To find optimal use of these drugs and to resolve unmet needs, such as relapse prevention, will be needed in future. Copyright © 2019, Japanese Society of Allergology. Production and hosting by Elsevier B.V. This is an open access
Keywords: Anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis Eosinophil Eosinophilic granulomatosis with polyangiitis Mepolizumab Rituximab
article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction Eosinophilic granulomatosis with polyangiitis (EGPA) (formerly Churg-Strauss syndrome) was first described by Churg and Strauss in 1951.1 They found asthmatic patients who developed necrotizing vasculitis, eosinophilic inflammation and extravascular granulomas. The disease is now recognised as one form of antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) characterized by eosinophil-rich granulomatous inflammation and small to medium-size vessel vasculitis associated with asthma and eosinophilia. EGPA is the rarest among AAV and it has been reported that annual incidence and prevalence of EGPA were 0.9e2.4 per million2e5 and 10.7e17.8 per million,6e9 respectively, depending on geographic regions and applied criteria. Its rarity and unique features such as eosinophilic inflammation have delayed progress of research regarding EGPA for several years, compared to
* Corresponding author. Department of Allergy and Clinical Immunology, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba 260-8670, Japan. E-mail address: [email protected] (S. Furuta). Peer review under responsibility of Japanese Society of Allergology.
other forms of AAV, microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). Pathogenesis and roles of ANCA in EGPA are still largely unknown, and there is no standard therapy for EGPA based on accumulation of clinical trial results. However, attention to EGPA as a research subject has been recently increasing. In this review, we highlight recent topics in EGPA.
Disease definition and classification criteria Several criteria for EGPA were developed with different purposes and different methods. The nomenclature of the primary systemic vasculitis syndromes including EGPA was defined by the Chapel Hill consensus conference (CHCC) (Table 1).10 The American College of Rheumatology (ACR) had proposed classification criteria for seven vasculitis syndromes including Churg-Strauss syndrome in 1990 (Table 2).11 The criteria developed by Lanham et al. in 1984 have also been widely used (Table 3).12 The original CHCC definitions were published in 1994. The consensus was made by expert opinion in order to standardise the nomenclature. Its key concept was classifying various vasculitides according to the predominant size of diseased blood vessels based
https://doi.org/10.1016/j.alit.2019.06.004 1323-8930/Copyright © 2019, Japanese Society of Allergology. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).
Please cite this article as: Furuta S et al., Update on eosinophilic granulomatosis with polyangiitis, Allergology International, https://doi.org/ 10.1016/j.alit.2019.06.004
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Table 1 Definition of ANCA-associated vasculitis by the 2012 Chapel Hill Consensus Conference. CHCC2012 Names
CHCC2012 Definitions
ANCA Associated Vasculitis
Necrotizing vasculitis, with few or no immune deposits, predominantly affecting small vessels (i.e., capillaries, venules, arterioles and small arteries), associated with MPO-ANCA or PR3ANCA. Not all patients have ANCA. Add a prefix indicating ANCA reactivity, e.g. PR3-ANCA, MPO-ANCA, ANCAnegative. Necrotizing vasculitis, with few or no immune deposits, predominantly affecting small vessels (i.e., capillaries, venules, or arterioles). Necrotizing arteritis involving small and medium arteries may be present. Necrotizing glomerulonephritis is very common. Pulmonary capillaritis often occurs. Granulomatous inflammation is absent. Necrotizing granulomatous inflammation usually involving the upper and lower respiratory tract, and necrotizing vasculitis affecting predominantly small to medium vessels (e.g., capillaries, venules, arterioles, arteries and veins). Necrotizing glomerulonephritis is common. Eosinophil-rich and necrotizing granulomatous inflammation often involving the respiratory tract, and necrotizing vasculitis predominantly affecting small to medium vessels, and associated with asthma and eosinophilia. ANCA is more frequent when glomerulonephritis is present.
Microscopic Polyangiitis
Granulomatosis with Polyangiitis
Eosinophilic Granulomatosis with Polyangiitis
Table 2 The 1990 classification criteria for Churg-Strauss syndrome by the American College of Rheumatology. Criteria Asthma Eosinophilia >10% Neuropathy, mono or poly Pulmonary infiltrates, non-fixed Paranasal sinus abnormality Extravascular eosinophils For classification purpose, a patient shall be said to have the disease if at least 4 of these 6 criteria are positive.
Table 3 The diagnostic criteria by Lanham et al. Criteria Asthma Peak peripheral blood eosinophil count >1.5 106/cc Systemic vasculitis involving two or more extrapulmonary organs All three criteria should be fulfilled for diagnosis of the disease.
on histology and clinical manifestations. In 2012, the CHCC definition was revised to reflect recent advances, to add new categories such as single organ vasculitis and variable vessel vasculitis, and to rename vasculitides to descriptive titles. Churg-Strauss syndrome was formally renamed to EGPA. In the 2012 CHCC system, small vessel vasculitis was sub-divided into AAV and immune complex small vessel vasculitis. AAV which includes MPA, GPA and EGPA was defined as a group of pauci-immune necrotizing vasculitides associated with ANCA. EGPA was defined as a subgroup of AAV
characterised by eosinophil-rich and necrotizing granulomatous inflammation, necrotizing vasculitis predominantly affecting small to medium vessels, and association with asthma and eosinophilia. The 1990 ACR classification criteria have been the most popular classification criteria for the disease, however it has been developed before widespread ANCA testing. Methodologically, 20 cases diagnosed as EGPA (Churg-Strauss syndrome) by each submitting physician were used as the gold standard, and were compared to a non-selective control group of small, medium and large vessel vasculitides. In addition, validation of the ACR criteria has never been performed. In 1984, Lanham and his associates reviewed 16 patients with Churg-Strauss syndrome in their institution and 138 literature cases. They proposed the diagnostic criteria, which consisted of three clinical findings. Lanham criteria were developed before establishing the concept of AAV and did not require histological findings. Discrimination of hypereosinophilic syndrome is unclear in Lanham criteria. Thus, it might not be enough for study purpose; however, it has been still widely used in daily clinical practise because of its simplicity capturing the essence of the disease. Presence of bronchial asthma is needed for diagnosing the disease in Lanham criteria, while asthma is not mandatory in the ACR criteria. Application of the ACR criteria alone results in frequent overlaps between each vasculitis. The CHCC system was limited due to its requirement for histology, resulting in many unclassified cases. To reduce diagnostic overlaps and unclassified cases, Watts et al. developed a stepwise algorithm for diagnosing AAV and polyarteritis nodosa in 2007.13 The step of diagnosing EGPA (ChurgStrauss syndrome) exists the most upstream in this diagnostic algorithm, and presence/absence of EGPA (Churg-Strauss syndrome) is judged by using the ACR and Lanham criteria. The problems in these systems and the need for newer classification and diagnosis criteria of vasculitides were reviewed by a European League Against Rheumatism (EULAR)/ACR working group in 2010. This led to the launch of a large, international, prospective, observational study, Diagnosis and Classification of Vasculitis Study (DCVAS), to develop both revised classification criteria and a validated set of diagnostic criteria.14 Recently, the draft of new classification criteria for EGPA using the DCVAS dataset including 226 EGPA patients has been proposed at the 19th International Vasculitis and ANCA Workshop,15 and is waiting for final endorsement by EULAR and ACR. In the DCVAS, the gold standard cases were selected by consensus of expert panel and classification items were identified with a data-driven manner by comparing each AAV subtype to other small vessel vasculitides. The new classification criteria for EGPA have also been tested in the dataset for validation. The new criteria are expected to have better sensitivity and specificity than the previous ones.
Pathogenesis Pathogenesis of EGPA remains largely unknown. However, like many other autoimmune diseases, both genetic and environmental factors appear to contribute to the development of EGPA. Recently, Lyons et al. performed a first genome-wide association study (GWAS) with 684 EGPA patients16 and found that the risk genes were separated by the ANCA status. As with MPA and other autoimmune diseases, HLA-DQ was detected as a risk allele in MPOANCA-positive EGPA. Variants at GATA3, TSLP, LPP, and BACH2, which may contribute to eosinophilic inflammation, were detected in total EGPA. On the other hand, variants at IRF1/IL5 and GPA33 were associated with MPO-ANCA-negative EGPA. GPA33 gene encodes a cell surface glycoprotein that potentially has a role in maintaining barrier function in the intestinal epithelium17 and also
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in bronchial tissue.18 This fact may give a clue why ANCA status strongly correlates with specific organ manifestations. In AAV other than EGPA, associations with environmental factors, such as air pollutants, infections and drugs have been investigated.19 Apoptosis of neutrophils induced by the instillation of silica may act as a trigger in the development of ANCA. Peptides from Staphylococcus aureus have strong homology with peptides from complementary PR3, which could underlie the development of PR3-ANCA. Drugs such as cocaine, levamisole and propylthiouracil are well-known as triggers of AAV. Recent studies have revealed that propylthiouracil induces abnormal conformation of neutrophil extracellular traps (NETs), resulting in the resistance to the degradation by DNaseI and subsequent development of MPOANCA production and vasculitiis.20 However, involvement of environmental factors in EGPA remains largely unclear. A possible pathogenic role of cysteinyl-leukotriene receptor antagonists for asthma treatment has been suggested, but now it is considered that they are not a trigger of EGPA.21 Eosinophilic inflammation is one of cardinal features in EGPA. From this point of view, IL-5, a principal eosinophil-activating cytokine, seems to be involved in the pathogenesis of EGPA. IL-5 is produced by Th2 cells and induces the differentiation and maturation of human eosinophils.22 In addition, IL-5 inhibits the apoptosis of human eosinophils.23,24 Group 2 innate lymphoid cells (ILC2s) also produce IL-5 even in the absence of acquired immunity.25,26 Activated eosinophils exert proinflammatory effects by releasing cytotoxic granule proteins and lipid mediators, thereby
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inducing tissue damage and inflammation.27 Cytotoxic granule proteins released from eosinophils include major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), and eosinophil-derived neurotoxin (EDN). Presence of ANCA is another aspect of EGPA. As to MPA and GPA, a direct pathogenic role of ANCA in the formation of small vessel vasculitis has been established based on experimental data and associations of ANCA with disease activity.19 ANCA activates neutrophils, and then activated neutrophils attack vessel wall via degranulation and the formation of NETs. Meanwhile, a role of ANCA in EGPA is still unclear, especially about association between ANCA and eosinophilic inflammation. Some conditions in EGPA, such as glomerulonephritis and alveolar haemorrhage, are observed more frequently in ANCA-positive EGPA patients28e31 and like MPA and GPA, often show small vessel vasculitis without local eosinophilic inflammation. It is assumed that ANCA in EGPA also had a pathogenic role in at least such conditions. Possible mechanisms underlying eosinophilic inflammation and ANCA-mediated vasculitis in EGPA were summarised in Fig. 1. Histopathology The hallmark of histological findings in EGPA is necrotizing small vessel vasculitis accompanied by eosinophil infiltrates and perivascular and extravascular granulomas. Vasculitis presents fibrinoid necrosis in the wall of the vessels and rupture of internal elastic lamina. Granulomas in EGPA patients consist of eosinophilic
Fig. 1. Overview of the genetic predisposition, eosinophilic inflammation, and ANCA-mediated inflammation putatively involved in the development of EGPA. Environmental factors together with genetic predisposition provoke eosinophilic and ANCA-mediated inflammation. Eosinophilic inflammation; IL-5 is produced mainly by Th2 cells and ILC2s. IL-5 binds to the IL-5 receptor on eosinophils to induce eosinophilopoiesis in the bone marrow and also induce activation and prolonged survival of eosinophils in the tissues. ANCAmediated inflammation; Proinflammatory cytokines and complement alternative pathway prime neutrophils. ANCA binds to the primed neutrophils via Fcg receptors or MPO protein expressed on the cell surface, leading to the production of reactive oxygen species (ROS), the release of proteolytic enzymes and the formation of neutrophil extracellular traps (NETs). ANCA, antineutrophil cytoplasmic antibody; APC, antigen-presenting cell; BAFF, B cell activating factor belonging to the TNF family; GM progenitor, granulocytemacrophage progenitor; ILC2, group 2 innate lymphoid cell; MPO, myeloperoxidase; NETs formation, neutrophil extracellular traps formation.
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necrotic matrix surrounded by palisading giant cells, which is called palisading granuloma.1,11,32 However, these histological findings are not always found in the same site. Typical pathohistological presentations of EGPA are different among the affected organs. In purpura of the skin, a wide range of conditions between eosinophilic vasculitis and leukocytoclastic vasculitis without eosinophilic infiltration is observed.33 It is difficult to distinguish from other small vessel vasculitides histologically in the case lacking eosinophil infiltration. Necrotising vasculitis and eosinophilic granulomas are seen in pneumonitis and lung nodules. Cardiac involvement shows mixture of eosinophilic infiltration in myocardium and endocardium causing myocarditis and endocarditis, and small vessel vasculitis.34 Gastrointestinal involvement shows erosion with eosinophilic infiltration and sometimes vasculitis and eosinophilic granuloma. On the other hand, eosinophilic infiltration is rarely observed in peripheral nerve and kidney involvements. Peripheral neuropathy features necrotizing vasculitis in a small artery in the epineural space. Renal histology is characterized by pauciimmune necrotizing crescentic glomerulonephritis.34,35 Eosinophilic infiltration is sometimes observed in the interstitium of the kidney. Interestingly, peripheral neuropathy and glomerulonephritis are the organ involvements associated with ANCA-positive EGPA patients.28e31
Demographics and clinical manifestations There are several studies with large cohorts of EGPA patients from different geographic areas (Table 4).28e30,36,37 Although patient characteristics in these cohorts were mostly common, some manifestations varied among the cohorts. Those differences might be caused by the applied criterion, referral bias and underlying genetic differences. According to those studies, median age at onset of EGPA is 49e59 years old. There is no extreme gender bias in EGPA patients, and female rate is 48e64%. Almost all patients (>90%) have a history of bronchial asthma, and the duration from onset of asthma to diagnosis of EGPA is median 5e9 years. Eosinophil counts in most studies were highly elevated in accordance with the ACR or Lanham criterion (median around 8000/mL), while German group reported milder elevation of eosinophils (median 1100/mL). Serum C-reactive protein level is median 2.5e6.6 mg/dl. Serum creatinine level is not markedly elevated (median 0.68e1.01 mg/dl), which is different from other forms of AAV, MPA
and GPA. ANCA is positive in 30e47% of EGPA patients, and usually the subtype of ANCA is MPO-ANCA.28e31,36,37 Regarding organ involvements, peripheral nerve and paranasal sinuses are the most frequent organ in most of the previous studies (51e98% and 48e96%, respectively).28e30,36,37 Peripheral nerve involvement typically presents multiple mononeuropathies, while distal symmetrical polyneuropathy (24%), asymmetric polyneuropathy (3%) and lumber radiculopathy (3%) are sometimes observed.38 Subsequently, lung involvement is also frequently seen (around 40e60%). Migrating patchy infiltrates with peripheral dominance, which are very similar to eosinophilic pneumonitis, are a typical manifestation of lung in EGPA patients. Pulmonary nodules, granulomatous mass lesions or alveolar haemorrhage are relatively rare.31,39 Heart and gastrointestinal involvements are less frequent in EGPA, but are more associated with a mortality risk than nerve, sinus and lung involvements. Kidney involvement was observed in around 20e25% of the patients in most of the studies, and far less common than in MPA and GPA. Kidney biopsy usually presents a pauci-immune focal segmental necrotising glomerulonephritis with crescentic formation, which is indistinguishable from other forms of AAV.40 Eosinophil infiltration or eosinophilic granuloma is usually absent in kidney biopsy specimens. Frequencies of organ involvements differ between ANCApositive and -negative EGPA patients.28e31 Glomerulonephritis, alveolar haemorrhage and peripheral nerve neuropathy are more frequent in ANCA-positive patients than in ANCA-negative patients, whereas heart involvement is more frequent in ANCA-negative patients than in ANCA-positive patients. Clinical manifestations in ANCA-positive EGPA patients are closer to other forms of AAV, MPA and GPA. Interestingly, a recent GWAS revealed that EGPA comprised two genetically and clinically distinct subsets.28 ANCApositive EGPA is sharing an MHC association with MPA, while ANCA-negative EGPA is genetically more similar to asthma (Table 5).
Differential diagnosis A differential diagnosis for EGPA includes other small vessel vasculitides and eosinophilic disorders. Although symptoms of organ involvements are similar with other vasculitides, EGPA is usually distinguishable by the presence of eosinophilia and asthma. As to eosinophilic disorders, parasitic infections, drug allergy and haematological malignancies such as Hodgkin lymphoma should
Table 4 Clinical manifestations among the previous studies.
Patient number Study period Country Age at onset Female rate Eosinophil count C-reactive protein Serum Creatinine ANCA-positive Organ involvements Nerve Skin Eye ENT Lung Heart Intestine Kidney
Sinico et al.
Durel et al.
Moosig et al.
Comarmond et al.
Saku et al.
Tsurikisawa et al.
n ¼ 93 1989e2004 Italy 51.6 y 58% 4400/ml ND ND 37%
n ¼ 101 1990e2011 France, UK, Italy 49.2 y 57% ND ND ND 43%
n ¼ 150 1990e2009 Germany 49.1 y 49% 1100/ml 2.50 mg/dl 0.90 mg/dl 30%
n ¼ 383 1957e2009 France 50.3 y 48% 7569/ml 6.69 mg/dl 1.01 mg/dl 31%
n ¼ 188 1996e2015 Japan 59.7 y 64% 8775/ml 2.90 mg/dl 0.68 mg/dl 47%
n ¼ 121 1999e2015 Japan 53.3 y 65% 8528/ml ND ND 35%
64% 52% ND 77% 50% 16% 21% 26%
66% 46% 20% 96% 54% 20% 25% 26%
76% 49% 12% 93% 61% 46% 28% 18%
51% 39% 6% 48% 38% 16% 23% 21%
88% 41% 5% 50% 34% 11% 12% 18%
98% 46% ND 91% 67% 73% 78% 35%
ENT, Ear, Nose and Throat.
Please cite this article as: Furuta S et al., Update on eosinophilic granulomatosis with polyangiitis, Allergology International, https://doi.org/ 10.1016/j.alit.2019.06.004
S. Furuta et al. / Allergology International xxx (xxxx) xxx Table 5 Genetically and clinically subgroups in EGPA. Group 1 Genetic association
HLA-DQA1, HLA-DRB1 (shared with ANCA-associated vasculitis) MPO-ANCA positive Glomerulonephritis Frequent Neuropathy Frequent Heart failure Less frequent Rituximab response Better Mepolizumab response Lack of data
Group 2 GPA33, IL-5 (shared with asthma) negative Less frequent Less frequent Frequent Worse Good
be excluded firstly. Eosinophilic pneumonia and allergic bronchopulmonary mycosis should be considered next if clinical manifestations are restricted to lung. Both diseases often occur in asthma patients and present migrating pulmonary infiltrates. If the patients have extrapulmonary organ involvements with eosinophilia, idiopathic hypereosinophilic syndrome (HES) and IgG4-related disease can be important differential diagnoses. HES usually occurs in a patient who lacks a history of allergic disease, and bone marrow examination and a test for FIP1L1-PDGFRa fusion gene are required in diagnostic procedure. IgG4-related disease is a local/ systemic disorder characterised by IgG4-secreting plasma cells and fibrosis, which is sometimes accompanied by eosinophilia and asthma. Histopathologic examination is essential for diagnosis of IgG4-related disease, and the measurement of serum IgG4 levels is helpful. HES and IgG4-related disease can fulfil the 1990 ACR criteria or Lanham criteria. Distinguishing those diseases from EGPA is sometimes difficult in the case of ANCA-negative and/or lacking histopathologic examination. Treatments So far, EGPA has been excluded from most of randomised controlled trials for AAV because of its rarity and unique features, such as involvement of eosinophils in the pathogenesis. Reliable evidence of treatment for EGPA is limited, and there are no strong recommendations for treatment of EGPA at the moment.41 Glucocorticoids is usually used as a remission induction therapy for EGPA. Glucocorticoids can diminish human eosinophils via direct and indirect mechanisms42 and are effective in reducing eosinophilic inflammation in EGPA. In combination with glucocorticoids, immunosuppressants are often used for treatment of EGPA. French Vasculitis Study Group developed five factor score (FFS), which predicted a mortality risk in patients with small to medium-size vessel vasculitis, by using a large mixed cohort of MPA, EGPA and polyarteritis nodosa in 1996,43 and then they have revisited FFS in 2011 (Table 6).44 Following trials by the same group suggested that cyclophosphamide use in remission induction phase improved mortality in severe EGPA patients with higher FFS.45,46 Although glucocorticoid therapy with or without immunosuppressants leads to successful remission in the majority of EGPA patients,45,47 it has been well-known that EGPA patients experience frequent relapses during glucocorticoid tapering.28e30,36,37 Long-term maintenance Table 6 The revised five factor score by French Vasculitis Study Group. Factor Age >65 years Presence of symptomatic cardiac insufficiency Presence of severe gastrointestinal involvement (bowel perforation, bleeding, and pancreatitis) Presence of renal insufficiency (creatinine >150 mmol/L). Absence of ear, nose, and throat symptoms
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therapy with immunosuppressants is often used for preventing the relapse of EGPA. However, the efficacy of immunosuppressant maintenance therapy is still controversial. Large retrospective studies suggested the efficacy of azathioprine as maintenance therapy,28,29 while a randomised controlled trial (CHUSPAN2) for non-severe vasculitides including EGPA (n ¼ 51), MPA (n ¼ 25) and polyarteritis nodosa (n ¼ 19) showed that azathioprine was not superior to placebo in preventing relapse.48 The mixed subjects in the CHUSAPAN2 trial reduced the certainty of conclusion for each vasculitis. In addition, azathioprine was administered for only 12 months in the trial. The efficacy of long-term azathioprine maintenance therapy for EGPA is still unclear. Interleukin-5 is well-known as a key mediator in eosinophil activation.22e24 Thus, the efficacy of mepolizumab, a humanized monoclonal antibody against interleukin-5, was evaluated in patients with EGPA. Results of the double-blind, randomised placebocontrolled trial (MIRRA) were reported in 2017.49 In the MIRRA trial, relapsing or refractory EGPA patients receiving 7.5 mg/day or more of prednisolone were randomly assigned to receive mepolizumab (n ¼ 68) or placebo (n ¼ 68) in addition to standard care. Proportions of ANCA-positive patients were 10% and 9% in mepolizumab group and placebo group, respectively, which were biased to ANCA-negative compared to general population of EGPA patients. The glucocorticoid dose was rapidly reduced according to a standardised schedule. Dose of prednisolone with 4 mg/day or less was included in the definition of remission in the MIRRA trial. In this trial, mepolizumab led to significantly more accrued weeks of remission than placebo (28% vs. 3% of the participants had 24 weeks of accrued remission, p < 0.001) and a higher percentage of participants in remission at both week 36 and week 48 (32% vs. 3%, p < 0.001). The efficacy of mepolizumab with minimal adverse effects was clearly shown, and mepolizumab was approved for EGPA. However, it was also shown that mepolizumab alone or with 4 mg/day or less of prednisolone could not achieve sustained remission in the majority of relapsing/refractory EGPA patients. Recently, the post hoc analysis of the MIRRA trial showed the proportion of remission with 7.5 mg/day or less of prednisolone, which was closer to a target dose in real world than the original analysis of the trial, was higher in the mepolizumab group than the placebo group (87% vs. 53%, p < 0.001).50 Mepolizumab is now a good therapeutic option for EGPA, especially for sparing glucocorticoids in ANCA-negative EGPA patients, although its optimal use has not been fully studied yet. Another anti-interleukin-5 monoclonal antibody, reslizumab, and an anti-interleukin-5 receptor monoclonal antibody, benralizumab, are now being investigated for EGPA (NCT02947945 and NCT03010436, respectively). Presence of pathogenic autoantibodies, ANCA, produced by B cells is one of the main features of AAV. B cell depletion therapy by rituximab, an anti-CD20 monoclonal antibody, has already been established as a part of the standard treatment for both MPA and GPA.41 In addition to other forms of AAV, retrospective studies suggested that rituximab was also effective for EGPA patients.51,52 Mohammad et al. reported 41 EGPA patients treated with rituximab (15 had refractory, 21 had relapsing, and 5 had new onset disease). By 12 months, 88% of the patients improved and glucocorticoid doses decreased in all patients. In their cohort, 80% of ANCA-positive patients achieved remission, while only 38% of ANCA-negative patients achieved remission (p ¼ 0.013). They suggested rituximab was more effective for patients with ANCApositive EGPA than for those with ANCA-negative EGPA. Currently, two randomised placebo-controlled trials (the REOVAS [NCT02807103] and MAINRITSEG trials [NCT03164473]) by French group are evaluating the efficacy of rituximab for EGPA as remission induction therapy compared to cyclophosphamide and as remission maintenance therapy compared to azathioprine, respectively.
Please cite this article as: Furuta S et al., Update on eosinophilic granulomatosis with polyangiitis, Allergology International, https://doi.org/ 10.1016/j.alit.2019.06.004
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Regarding other drugs, IFN-a is known to counteract Th2 responses, and small studies suggested its efficacy in both remission induction and maintenance in EGPA.53 However, its unfavourable safety profile has restricted its use. Anti-IgE monoclonal antibody, omalizumab, has sometimes been used for EGPA. It is effective for asthma in EGPA patients; however, its effect on EGPA is still unclear.54,55 Efficacy of high-dose intravenous immunoglobulin therapy (IVIG) in remission induction for severe EGPA was reported,56 and IVIG was approved for refractory EGPA in Japan in 2010. Japanese group also suggested IVIG might be effective for chronic residual peripheral neuropathy, though the sample size of the trial was limited (n ¼ 23).57 The mechanism of recovery from neurologic damage has not been clarified. Certainly, treatment options for EGPA are increasing, though a standard therapy has not been established yet. Optimal use of those treatments, such as concomitant use of glucocorticoids and the best combination of the treatments, should be investigated in future trials. A recent GWAS16 suggested treatment strategies might be different between ANCA-positive and -negative EGPA patients.
Outcomes Response to glucocorticoids in EGPA is generally good, and glucocorticoid-based induction therapy achieved remission in most cases.45,47 Consequently, patients with EGPA have a favourable prognosis in terms of survival.28,30,36,37,58 The cumulative survival rates at 5 and 10 years from the disease onset are 88e97% and 78e89%, respectively. Although deaths are infrequent in EGPA, the previous studies identified higher age at disease onset and heart failure as risk factors for mortality.30,36,37 On the other hand, EGPA patients frequently relapse during glucocorticoid tapering,28e30,36,37,58 and it has been reported that the number of relapses was associated with cumulative organ damages of AAV patients.59 Cumulative relapse free survival rate at 5 years from the disease onset is 54e64%.28,30,58 Lower eosinophil count at the disease onset was identified as a risk factor for relapse in the plural studies,28,30,58 though the underlying mechanism was unknown. Asthma exacerbation during glucocorticoid tapering has sometimes been considered as a sign for high risk of relapse. Recently, Saku et al. investigated this issue and reported that asthma exacerbation and relapse of vasculitis in EGPA were independent of each other.28 Except persistent airway obstruction due to bronchial asthma, neurologic damage is the most frequent sequelae observed in around 40% of EGPA patients.29,58 Neurologic damage alone dose not affect patient survival; however, it significantly deteriorates patient's physical function and quality of life. IVIG might be effective for chronic residual peripheral neuropathy in EGPA patients.57 The outcomes reported by the previous retrospective studies were based on the data from the cohort treated by the conventional glucocorticoids and immunosuppressants. Newer therapies such as mepolizumab and rituximab will potentially change the outcomes of EGPA.
Conclusion The new classification criteria for EGPA will be launched and will accelerate future studies. The recent GWAS suggested the two distinct subgroups, and clinical manifestations are partly different between the subgroups. Mepolizumab is now approved for EGPA, and various new drugs are under evaluation. To find optimal use of these drugs and to resolve the unmet needs, such as relapse prevention, will be needed.
Conflict of interest HN reports receiving grant support from GlaxoSmithKline, Chugai Pharmaceutical (Roche group) and Teijin Pharma. The rest of the authors have no conflict of interest.
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Please cite this article as: Furuta S et al., Update on eosinophilic granulomatosis with polyangiitis, Allergology International, https://doi.org/ 10.1016/j.alit.2019.06.004