Journal of Autoimmunity xxx (2014) 1e5
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Diagnosis and classification of eosinophilic granulomatosis with polyangiitis (formerly named ChurgeStrauss syndrome) Luc Mouthon*, Bertrand Dunogue, Loïc Guillevin Department of Internal Medicine, National Referral Center for Rare Autoimmune and Systemic Diseases, INSERM U1016, Hôpital Cochin, Assistance PubliqueeHôpitaux de Paris, Université Paris Descartes, 27, rue du faubourg Saint-Jacques, 75679 Paris Cedex 14, France
a r t i c l e i n f o
a b s t r a c t
Article history: Received 7 October 2013 Accepted 13 October 2013
Recently, a group of experts in the field suggested to rename ChurgeStrauss syndrome as eosinophilic granulomatosis with polyangiitis (EGPA). This condition, first described in 1951, is a rare small- and medium-sizedevessel vasculitis characterized by an almost constant association with asthma and eosinophilia, and, by the presence of anti-myeloperoxidase (MPO) antineutrophil cytoplasm antibodies (ANCA) in 30e38% of the patients. Vasculitis typically develops in a previously asthmatic and eosinophilic middle-aged patient. Asthma is severe, associated with eosinophilia and extrapulmonary symptoms. Most frequently EGPA involves the peripheral nerves and skin. Other organs, however, may be affected and must be screened for vasculitis, especially those associated with a poorer prognosis, such as the heart, kidney and gastrointestinal tract, as assessed by the recently revised Five-Factor Score (FFS). Recent insights, particularly concerning clinical differences associated with ANCA status, showed that EGPA patients might constitute a heterogeneous group. Thus, EGPA patients with anti-MPO ANCA suffered more, albeit not exclusively, from vasculitis symptoms, such as glomerulonephritis, mononeuritis multiplex and alveolar hemorrhage, whereas ANCA-negative patients more frequently develop heart involvement. This observation led to the hypothesis that EGPA might be divided into different clinical and pathophysiological subtypes, which could be managed better with more specifically adapted therapies. For now, EGPA treatment still relies mainly on corticosteroids and, when necessary for patients with poorer prognoses, combined immunosuppressant drugs, especially cyclophosphamide. Overall survival of EGPA patients is good, despite not uncommon relapses. Ó 2014 Elsevier Ltd. All rights reserved.
Keywords: Eosinophilic granulomatosis with polyangiitis ChurgeStrauss syndrome Diagnosis criteria ANCA Classification
1. Introduction Eosinophilic granulomatosis with polyangiitis (EGPA), formerly named ChurgeStrauss syndrome (CSS), is a rare systemic smalland medium-sized-vessel vasculitis, which distinguishes itself from other small-vessel vasculitides by the presence of severe asthma, and blood and tissue eosinophilia. EGPA was first described in 1951 by Jacob Churg and Lotte Strauss [1] and was initially called allergic angiitis and granulomatosis. Thus, histological findings in these very first patients included necrotizing vasculitis, eosinophilic infiltrates in tissues and granulomas. Since it is rare to identify the three lesions in the same patient, the diagnosis of EGPA mainly relies on clinical parameters. Since then, specific criteria, which are now reliable tools for classifying EGPA among vasculitides [2,3] (Table 1), have been established.
* Corresponding author. Tel.: þ33 (0) 1 58 41 20 31; fax: þ33 (0) 1 58 41 20 80. E-mail address: [email protected] (L. Mouthon).
EGPA is most commonly revealed by the onset of vasculitis manifestations e mononeuritis multiplex, purpura and general symptoms e and eosinophilia, in a previously asthmatic patient. However, some patients may develop asthma or eosinophilia simultaneously with vasculitis and sometimes although rarely, in the weeks following its onset [4]. In two recent series, a minority (less than 10%) of patients do not have asthma [5,6]. Another feature of EGPA is its association, among 30e40% of the patients, with antineutrophil cytoplasm antibodies (ANCA) [5e8]. The clinical presentation of these ANCA-positive patients differs significantly from that of ANCA-negative patients, with more frequent mononeuritis multiplex and glomerular nephritis in the former, and more cardiomyopathy in the latter [5,7,8]. This observation led to the hypothesis that EGPA might be divided into different clinical and pathophysiological subtypes, which could be managed better with more specifically adapted therapies. For now, EGPA treatment still relies mainly on corticosteroids and, when necessary for patients with poorer prognoses [9], combined immunosuppressant drugs, especially cyclophosphamide.
0896-8411/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jaut.2014.01.018
Please cite this article in press as: Mouthon L, et al., Diagnosis and classification of eosinophilic granulomatosis with polyangiitis (formerly named ChurgeStrauss syndrome), Journal of Autoimmunity (2014), http://dx.doi.org/10.1016/j.jaut.2014.01.018
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L. Mouthon et al. / Journal of Autoimmunity xxx (2014) 1e5
3. Clinical features Table 1 Churg Strauss syndrome: American College of Rheumatology classification criteria [2]. Asthma Eosinophilia History of allergy Pulmonary infiltrates, non fixed Paranasal sinus abnormalities Extravascular eosinophils 4 out of 6 criteria should be present
Overall survival of EGPA patients is good, despite not uncommon relapses.
In addition to the respiratory tract, which is almost constantly involved in EGPA as asthma, any organ system can be affected, either through eosinophil infiltration, granuloma or, most frequently, vasculitis. Once the vasculitic process begins, systemic symptoms appear, often accompanied by organ-associated vasculitic symptoms, like mononeuritis multiplex and necrotic vascular purpura. However, not all EGPA patients have such characteristic disease onset, as clinical manifestations may vary widely. Moreover, once EGPA is suspected, vasculitis involvements of the gut, kidney and/or heart must be sought, because of their proven significant association with poorer prognoses [9]. Herein we will not describe all clinical manifestations of EGPA, which are encountered with various frequencies in the different studies [4,19,29e33], as summarized in Table 2.
2. Epidemiology 2.1. Incidence and prevalence EGPA is a rare disease and one of the less common vasculitides. Its prevalence, in the general population, ranges from 10.7 [10] to 13 [11] cases/million inhabitants, with an annual incidence of 0.5e6.8 new cases/million inhabitants [12e14], depending on their geographical location and the classification criteria applied. Among the asthmatic population, the EGPA incidence is higher, ranging from 34.6 [15] to 64.4 [12] cases/million patient-years. Notably, the incidence of EGPA among asthmatics does not vary, whatever the previous treatments taken, especially concerning their use of leukotriene-receptor antagonists. EGPA may occur at all ages, with a mean age at diagnosis of 48 years [4], without clear sex predominance. 2.2. Triggering factors EGPA seems to develop following an inflammatory response directed at target antigens. Thus, a number of observations have been reported of patients described as having developed EGPA after being exposed to certain triggering agents. Various environmental agents have been involved, including infectious agents [4], drugs, desensitization or vaccination which could trigger the occurrence of EGPA [7]. Thus, macrolides [16], carbamazepine [17] and quinine [18], and, finally, allergic hyposensitizations and vaccinations [19] have been reported to trigger EGPA. Other triggers have been considered, particularly the use of anti-asthmatic drugs, like the leukotriene-receptor antagonists, montelukast, zafirlukast [20e 23], and, more recently, the recombinant anti-IgE monoclonal antibody, omalizumab [24e26]. However, the number of studies supporting these observations is limited, and it might be that incriminated drugs are only indirectly implicated, due to their efficacy that allows to taper the glucocorticoid dose, revealing latent EGPA. It seems that these drugs, as well as other factors might in fact represent only one of a multistep process [27] leading to the occurrence of the disease, and should not lead to preclude to use them if it is absolutely needed. Thus, if some patients developed disease flares after vaccination, this should not preclude us not to vaccine fragile patients, particularly when they are exposed to infections. We have recently conducted a prospective study in patients with systemic inflammatory diseases including EGPA patients and observed that vaccination was well tolerated [28]. The authors of a recent caseecrossover study [27] concluded that the montelukasteEGPA link could be drug-related, essentially as a consequence of steroid-tapering, or be purely coincidental, with the drug having been prescribed to treat already present EGPA that had not yet been diagnosed.
4. Complementary investigations Blood hypereosinophilia, high IgE titers and anti-MPO P-ANCAe positivity are the three main laboratory anomalies found in EGPA. Inflammation is present in 80% of these patients; it is intense and often accompanied by anemia (83%) [4]. Eosinophilia fluctuates during EGPA but is a constant symptom. An eosinophil count exceeding 1500/mm3 or 10% of the total white blood cell count has been retained as one of the diagnostic criteria for EGPA [29]. Its mean value ranges from 4400 to 8190 [4,7,8], but eosinophils may disappear rapidly after corticosteroids are started. IgE is elevated at diagnosis in 75% of patients but is non-specific, and is usually not seen in patients taking corticosteroids for their asthma. ANCA, predominantly P-ANCA of anti-MPO specificity, are present in close to 40% of EGPA patients but some can be antiproteinase 3 (PR3). ANCA titers do not correlate with diseaseevolution characteristics. Rheumatoid factor-positivity was reported for 22 of the 41 (53.6%) published cases [29]. Antinuclear antibodies are usually absent. Eosinophil-containing bronchoalveolar lavage fluid is also possible [34]. Renal involvement should be sought by measuring the serum creatinine level and urinalysis, to search for proteinuria and hematuria. Finally, biopsies with histological evidence of granulomas (18%), tissue eosinophilia (52%) and/or necrotizing small-vessel vasculitis (55%) also contribute to diagnosing EGPA [7]. Among imaging techniques, chest X-ray is the first examination to be done. In our experience, it revealed abnormalities in 37.5% of the patients [4] who had bilateral and migratory infiltrates or mixed interstitial patchy alveolar opacities, which can be further evaluated by chest CT scans. Angiography, when performed, may show typical stenoses consistent with vasculitis in up to one-third of the patients [4], extremely rarely associated with microaneurysms. Imagery is also important to detect cardiac abnormalities, which must systematically be sought because of their poor prognosis. It should initially consist of an electrocardiogram, chest X-ray, and echocardiogram. Coronary arteriography may be decisive in detecting underlying ischemic cardiopathy, distinct from EGPA cardiomyopathy. Recently, CMRI was shown to perform better at detecting myocardial involvement in EGPA patients [35,36]. After gadolinium injection, T1-weighted cardiac sequences may reveal centromyocardial, subepicardial and/or subendocardial myocardial delayed enhancement.
Please cite this article in press as: Mouthon L, et al., Diagnosis and classification of eosinophilic granulomatosis with polyangiitis (formerly named ChurgeStrauss syndrome), Journal of Autoimmunity (2014), http://dx.doi.org/10.1016/j.jaut.2014.01.018
L. Mouthon et al. / Journal of Autoimmunity xxx (2014) 1e5
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Table 2 Main clinical manifestations of ChurgeStrauss syndrome. Manifestations
Chumbley Lanham Guillevin Gaskin Haas Abu-Shakra Guillevin Comarmon Moosig et al. 1977 [30] et al. 1984 [29] et al., 1987 [19] et al.a 1991 [31] et al. 1991 [32] et al., 1994 [33] et al. 1999 [4] et al. 2013 [5] et al. 2013 [6]
Number of patients Male/female sex ratio Mean age (years) Asthma General symptoms Lung infiltrates Pleurisy Ear, nose and throat Mononeuritis multiplex Gastrointestinal Cardiac Arthralgias Myalgias Skin Purpura Nodules Kidney involvement
30
16
43
21
16
12
96
383
150
21/9
12/4
24/19
14/7
12/4
6/6
45/51
199/184
76/74
47 100 e 27 e 70
38 100 e 72 29 70
43.2 100 72 77 e 21
46.5 100 e 43 e e
42.5 100 100 62 25 10
48 100 100 58 e 83
48.2 100 70 38 e 47
50.3 91.1 87.6 38.6 8.9 48
49.1 92.7 78 58 7.3 93.3
63
66
67
70
75
92
78
46
56
17 16 20 e 66 e 27 20
59 47 51 68 e 48 30 49
37 49 28 e e 28 21 16
58 15 43 e 50 e e 80
56 56 31 43 68 25 25 31
8 42 42 33 67 e e 8
33 30 41 54 51 31 19 16
23.2 16.4 29.8 38.9 39.7 22.5 9.7 21.7
28.7 46.7 51.3 32.7 49.3 34.7 17.3 18.7
Results are expressed as percentages unless stated otherwise. a Nephrology department patients.
5. Nomenclature Recently, a group of experts in the field suggested to rename ChurgeStrauss syndrome as eosinophilic granulomatosis with polyangiitis (EGPA) [37]. Both appellations may be indifferently used at the moment; however, in order to qualify diseases around descriptions more than eponymes [38], the EGPA denomination should progressively replace that of ChurgeStrauss.
However, those criteria are not diagnostic, as their goal is to classify patients as having a probable diagnosis of EGPA, but only once vasculitis has already been diagnosed. New diagnostic criteria currently being discussed include, for example, anti-MPO ANCA, and clinical and biological redefinitions of EGPA.
6. Diagnostic criteria
EGPA etiology remains unknown. Its pathogenesis, has long been thought to develop through three successive phases: asthma, blood and tissue eosinophilia, and, finally, vasculitis based on clinical observations [29]. A closer look at possible pathophysiological EGPA subtypes found a clear clinical difference between patients with and without ANCA. Findings based on two cohorts, described by Sinico [8] and our group [7], showed ANCA frequency in EGPA to be just under 40%: 37.6% and 38%, respectively. These results were confirmed by our recent report on a cohort of 383 patients with EGPA [5], with ANCA frequency of 31%. Most often, EGPA patients’ ANCA have a perinuclear fluorescence-labeling pattern (P-ANCA), with anti-myeloperoxidase (MPO) specificity, as assessed by an enzyme-linked immunosorbent assay (ELISA). In these studies, EGPA patients with anti-MPO ANCA suffered more, albeit not exclusively, from vasculitis symptoms, such as glomerulonephritis, mononeuritis multiplex and alveolar hemorrhage, than ANCA-negative patients [5,7,8].
Today, EGPA diagnosis remains essentially clinical. Diagnosis confirmation is important, but cannot be obtained in all cases. ANCA, when present, represent a major argument for the diagnosis of EGPA. However, as previously mentioned, these antibodies may be absent. Eosinophilia and anti-MPO ANCA further corroborate the diagnosis. Finally, although not mandatory, histological proof of EGPA can confirm the diagnosis, with skin, nerve and muscle biopsies sites having the highest respective sensitivities of 67.4%, 65.7%, and 47.9% [4]. For example [4], biopsies confirmed EGPA for 91.6% of our patients. A clinical redefinition of EGPA, established in 1984 by Lanham et al. [29] (Table 3), has allowed clinicians diagnose EGPA with good specificity and sensitivity without relying on histological findings. The three diagnostic criteria are asthma, blood eosinophilia exceeding 1500/mm3, and evidence of vasculitis involving two or more organs. However, that definition has been criticized: first, asthma may follow and not precede the vasculitic phase; second, eosinophilia may sometimes fluctuate and disappear, either spontaneously or after initiation of corticosteroids; and, finally, vasculitis, despite certain characteristic clinical manifestations, may be hard to confirm without a biopsy. Other criteria have been proposed, especially for classification purposes, notably the ACR and Chapel Hill criteria (Table 1). Table 3 Lanham diagnostic criteria for Churg Strauss syndrome. Asthma Blood eosinophilia exceeding 1500/mm3 Evidence of vasculitis involving two or more organs.
7. Clinical classification
8. Differential diagnosis The differential diagnosis of EGPA depends on each patient’s predominant clinical manifestations. Before vasculitis onset, concomitant eosinophilia, asthma and lung infiltrates may resemble certain parasitic infections, like helminthiases, or allergic bronchopulmonary aspergillosis. At this stage, it may be difficult to differentiate chronic eosinophilic pneumonia from EGPA [39]. However, when systemic vasculitis manifestations appear, asthma and a somewhat lower sensitivity to corticosteroids tend to favor a diagnosis of EGPA. Hypereosinophilic syndrome (HES) is another differential diagnosis difficult to distinguish, because some HES patients may
Please cite this article in press as: Mouthon L, et al., Diagnosis and classification of eosinophilic granulomatosis with polyangiitis (formerly named ChurgeStrauss syndrome), Journal of Autoimmunity (2014), http://dx.doi.org/10.1016/j.jaut.2014.01.018
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L. Mouthon et al. / Journal of Autoimmunity xxx (2014) 1e5
have neuropathy, albeit rarely mononeuritis multiplex, and cardiopathy and pulmonary manifestations [40]. The main differences tilting the pendulum in favor of EGPA are: ANCA, vasculitis manifestations or biopsy-confirmed vasculitis and, finally, a somewhat lower eosinophil count. However, for most patients suspected of having EGPA, especially those without ANCA or biopsy-proven vasculitis, lymphocyte immunophenotyping, clonal T-cell studies and molecular analyses to detect Fip1-like 1 (FIP1L1)eplateletderived growth factor receptor-alpha (PDGFA) gene fusion, in search of lymphoid or myeloid forms of HES, should probably be performed. Once vasculitis becomes predominant in the clinical picture, the main differential diagnoses of EGPA are other systemic vasculitides, especially GPA and polyarteritis nodosa. Whereas EGPA and polyarteritis nodosa share numerous clinical characteristics, like mononeuritis multiplex, articular and muscular lesions, and gastrointestinal symptoms, EGPA is usually easily distinguishable by asthma, atopic history, eosinophilia and lung infiltrates [1]. Finally, GPA, another ANCA-associated vasculitis that shares common characteristics with EGPA is usually ruled out by the presence of asthma, eosinophilia, non-destructive sinus involvement, mononeuritis multiplex and, when present, the anti-MPOespecific ANCA (versus anti-PR3 in GPA) [41]. 9. Prognosis and outcome EGPA prognosis is generally good, even though historically, before the advent of corticosteroid therapy, it was almost always fatal. EGPA prognosis has been revolutionized by the use of corticosteroids and immunosuppressant(s) [42]. Whereas in 1950, the 5year survival of patients with polyarteritis nodosa (not yet separated from EGPA) was 10%, today, the overall 5-year survival of EGPA may reach 97% [43]. However, not all EGPA patients share the same prognosis, as it depends on the initial degree of disease extension and organ(s) involvement. The original, prognostic Five-Factor Score (FFS) [44] was obtained by univariate and multivariate analyses of 342 vasculitis patients, including 82 with EGPA. The five factors (each accorded 1 point) conferring a higher risk of mortality rate were: 1) proteinuria > 1 g/24 h; 2) serum creatinine level > 140 (150 in the revised version of FFS) mmol/l; 3) myocardial involvement; 4) severe gastrointestinal involvement; and 5) central nervous system involvement. The FFS helps identify which patients who, because of their higher risks of relapse and mortality, require more aggressive immunosuppressive treatment. Based on a new study of 1108 consecutive patients suffering from systemic necrotizing vasculitides, including GPA, we recently revised the FFS [9]. The following five criteria, each again accorded 1 point, are now significantly and independently associated with higher 5-year mortality: 1) age over 65 years; 2) cardiac symptoms; 3) gastrointestinal involvement; 4) renal insufficiency characterized by serum creatinine > 150 mmol/l; and 5) the absence of ear, nose and throat manifestations. According to this new definition, revised FFS of 0, 1 or 2 are associated with respective 5-year mortality rates of 9%, 21% or 40%. 10. Conclusion Recently, ChurgeStrauss syndrome has been renamed EGPA. Much progress has been made over the past 30 years in understanding, redefining and treating EGPA. What is becoming ever more apparent is the broad heterogeneity of EGPA patients’ phenotypes. New patient subsets have been identified, with the most obvious being those with and without ANCA, as their clinical presentations differ. Management of EGPA patients is now more effective and, thus, its good prognosis is even better, compared to other vasculitides.
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Please cite this article in press as: Mouthon L, et al., Diagnosis and classification of eosinophilic granulomatosis with polyangiitis (formerly named ChurgeStrauss syndrome), Journal of Autoimmunity (2014), http://dx.doi.org/10.1016/j.jaut.2014.01.018
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Diagnosis and classification of eosinophilic granulomatosis with polyangiitis (formerly named ChurgeStrauss syndrome) Luc Mouthon*, Bertrand Dunogue, Loïc Guillevin Department of Internal Medicine, National Referral Center for Rare Autoimmune and Systemic Diseases, INSERM U1016, Hôpital Cochin, Assistance PubliqueeHôpitaux de Paris, Université Paris Descartes, 27, rue du faubourg Saint-Jacques, 75679 Paris Cedex 14, France
a r t i c l e i n f o
a b s t r a c t
Article history: Received 7 October 2013 Accepted 13 October 2013
Recently, a group of experts in the field suggested to rename ChurgeStrauss syndrome as eosinophilic granulomatosis with polyangiitis (EGPA). This condition, first described in 1951, is a rare small- and medium-sizedevessel vasculitis characterized by an almost constant association with asthma and eosinophilia, and, by the presence of anti-myeloperoxidase (MPO) antineutrophil cytoplasm antibodies (ANCA) in 30e38% of the patients. Vasculitis typically develops in a previously asthmatic and eosinophilic middle-aged patient. Asthma is severe, associated with eosinophilia and extrapulmonary symptoms. Most frequently EGPA involves the peripheral nerves and skin. Other organs, however, may be affected and must be screened for vasculitis, especially those associated with a poorer prognosis, such as the heart, kidney and gastrointestinal tract, as assessed by the recently revised Five-Factor Score (FFS). Recent insights, particularly concerning clinical differences associated with ANCA status, showed that EGPA patients might constitute a heterogeneous group. Thus, EGPA patients with anti-MPO ANCA suffered more, albeit not exclusively, from vasculitis symptoms, such as glomerulonephritis, mononeuritis multiplex and alveolar hemorrhage, whereas ANCA-negative patients more frequently develop heart involvement. This observation led to the hypothesis that EGPA might be divided into different clinical and pathophysiological subtypes, which could be managed better with more specifically adapted therapies. For now, EGPA treatment still relies mainly on corticosteroids and, when necessary for patients with poorer prognoses, combined immunosuppressant drugs, especially cyclophosphamide. Overall survival of EGPA patients is good, despite not uncommon relapses. Ó 2014 Elsevier Ltd. All rights reserved.
Keywords: Eosinophilic granulomatosis with polyangiitis ChurgeStrauss syndrome Diagnosis criteria ANCA Classification
1. Introduction Eosinophilic granulomatosis with polyangiitis (EGPA), formerly named ChurgeStrauss syndrome (CSS), is a rare systemic smalland medium-sized-vessel vasculitis, which distinguishes itself from other small-vessel vasculitides by the presence of severe asthma, and blood and tissue eosinophilia. EGPA was first described in 1951 by Jacob Churg and Lotte Strauss [1] and was initially called allergic angiitis and granulomatosis. Thus, histological findings in these very first patients included necrotizing vasculitis, eosinophilic infiltrates in tissues and granulomas. Since it is rare to identify the three lesions in the same patient, the diagnosis of EGPA mainly relies on clinical parameters. Since then, specific criteria, which are now reliable tools for classifying EGPA among vasculitides [2,3] (Table 1), have been established.
* Corresponding author. Tel.: þ33 (0) 1 58 41 20 31; fax: þ33 (0) 1 58 41 20 80. E-mail address: [email protected] (L. Mouthon).
EGPA is most commonly revealed by the onset of vasculitis manifestations e mononeuritis multiplex, purpura and general symptoms e and eosinophilia, in a previously asthmatic patient. However, some patients may develop asthma or eosinophilia simultaneously with vasculitis and sometimes although rarely, in the weeks following its onset [4]. In two recent series, a minority (less than 10%) of patients do not have asthma [5,6]. Another feature of EGPA is its association, among 30e40% of the patients, with antineutrophil cytoplasm antibodies (ANCA) [5e8]. The clinical presentation of these ANCA-positive patients differs significantly from that of ANCA-negative patients, with more frequent mononeuritis multiplex and glomerular nephritis in the former, and more cardiomyopathy in the latter [5,7,8]. This observation led to the hypothesis that EGPA might be divided into different clinical and pathophysiological subtypes, which could be managed better with more specifically adapted therapies. For now, EGPA treatment still relies mainly on corticosteroids and, when necessary for patients with poorer prognoses [9], combined immunosuppressant drugs, especially cyclophosphamide.
0896-8411/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jaut.2014.01.018
Please cite this article in press as: Mouthon L, et al., Diagnosis and classification of eosinophilic granulomatosis with polyangiitis (formerly named ChurgeStrauss syndrome), Journal of Autoimmunity (2014), http://dx.doi.org/10.1016/j.jaut.2014.01.018
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L. Mouthon et al. / Journal of Autoimmunity xxx (2014) 1e5
3. Clinical features Table 1 Churg Strauss syndrome: American College of Rheumatology classification criteria [2]. Asthma Eosinophilia History of allergy Pulmonary infiltrates, non fixed Paranasal sinus abnormalities Extravascular eosinophils 4 out of 6 criteria should be present
Overall survival of EGPA patients is good, despite not uncommon relapses.
In addition to the respiratory tract, which is almost constantly involved in EGPA as asthma, any organ system can be affected, either through eosinophil infiltration, granuloma or, most frequently, vasculitis. Once the vasculitic process begins, systemic symptoms appear, often accompanied by organ-associated vasculitic symptoms, like mononeuritis multiplex and necrotic vascular purpura. However, not all EGPA patients have such characteristic disease onset, as clinical manifestations may vary widely. Moreover, once EGPA is suspected, vasculitis involvements of the gut, kidney and/or heart must be sought, because of their proven significant association with poorer prognoses [9]. Herein we will not describe all clinical manifestations of EGPA, which are encountered with various frequencies in the different studies [4,19,29e33], as summarized in Table 2.
2. Epidemiology 2.1. Incidence and prevalence EGPA is a rare disease and one of the less common vasculitides. Its prevalence, in the general population, ranges from 10.7 [10] to 13 [11] cases/million inhabitants, with an annual incidence of 0.5e6.8 new cases/million inhabitants [12e14], depending on their geographical location and the classification criteria applied. Among the asthmatic population, the EGPA incidence is higher, ranging from 34.6 [15] to 64.4 [12] cases/million patient-years. Notably, the incidence of EGPA among asthmatics does not vary, whatever the previous treatments taken, especially concerning their use of leukotriene-receptor antagonists. EGPA may occur at all ages, with a mean age at diagnosis of 48 years [4], without clear sex predominance. 2.2. Triggering factors EGPA seems to develop following an inflammatory response directed at target antigens. Thus, a number of observations have been reported of patients described as having developed EGPA after being exposed to certain triggering agents. Various environmental agents have been involved, including infectious agents [4], drugs, desensitization or vaccination which could trigger the occurrence of EGPA [7]. Thus, macrolides [16], carbamazepine [17] and quinine [18], and, finally, allergic hyposensitizations and vaccinations [19] have been reported to trigger EGPA. Other triggers have been considered, particularly the use of anti-asthmatic drugs, like the leukotriene-receptor antagonists, montelukast, zafirlukast [20e 23], and, more recently, the recombinant anti-IgE monoclonal antibody, omalizumab [24e26]. However, the number of studies supporting these observations is limited, and it might be that incriminated drugs are only indirectly implicated, due to their efficacy that allows to taper the glucocorticoid dose, revealing latent EGPA. It seems that these drugs, as well as other factors might in fact represent only one of a multistep process [27] leading to the occurrence of the disease, and should not lead to preclude to use them if it is absolutely needed. Thus, if some patients developed disease flares after vaccination, this should not preclude us not to vaccine fragile patients, particularly when they are exposed to infections. We have recently conducted a prospective study in patients with systemic inflammatory diseases including EGPA patients and observed that vaccination was well tolerated [28]. The authors of a recent caseecrossover study [27] concluded that the montelukasteEGPA link could be drug-related, essentially as a consequence of steroid-tapering, or be purely coincidental, with the drug having been prescribed to treat already present EGPA that had not yet been diagnosed.
4. Complementary investigations Blood hypereosinophilia, high IgE titers and anti-MPO P-ANCAe positivity are the three main laboratory anomalies found in EGPA. Inflammation is present in 80% of these patients; it is intense and often accompanied by anemia (83%) [4]. Eosinophilia fluctuates during EGPA but is a constant symptom. An eosinophil count exceeding 1500/mm3 or 10% of the total white blood cell count has been retained as one of the diagnostic criteria for EGPA [29]. Its mean value ranges from 4400 to 8190 [4,7,8], but eosinophils may disappear rapidly after corticosteroids are started. IgE is elevated at diagnosis in 75% of patients but is non-specific, and is usually not seen in patients taking corticosteroids for their asthma. ANCA, predominantly P-ANCA of anti-MPO specificity, are present in close to 40% of EGPA patients but some can be antiproteinase 3 (PR3). ANCA titers do not correlate with diseaseevolution characteristics. Rheumatoid factor-positivity was reported for 22 of the 41 (53.6%) published cases [29]. Antinuclear antibodies are usually absent. Eosinophil-containing bronchoalveolar lavage fluid is also possible [34]. Renal involvement should be sought by measuring the serum creatinine level and urinalysis, to search for proteinuria and hematuria. Finally, biopsies with histological evidence of granulomas (18%), tissue eosinophilia (52%) and/or necrotizing small-vessel vasculitis (55%) also contribute to diagnosing EGPA [7]. Among imaging techniques, chest X-ray is the first examination to be done. In our experience, it revealed abnormalities in 37.5% of the patients [4] who had bilateral and migratory infiltrates or mixed interstitial patchy alveolar opacities, which can be further evaluated by chest CT scans. Angiography, when performed, may show typical stenoses consistent with vasculitis in up to one-third of the patients [4], extremely rarely associated with microaneurysms. Imagery is also important to detect cardiac abnormalities, which must systematically be sought because of their poor prognosis. It should initially consist of an electrocardiogram, chest X-ray, and echocardiogram. Coronary arteriography may be decisive in detecting underlying ischemic cardiopathy, distinct from EGPA cardiomyopathy. Recently, CMRI was shown to perform better at detecting myocardial involvement in EGPA patients [35,36]. After gadolinium injection, T1-weighted cardiac sequences may reveal centromyocardial, subepicardial and/or subendocardial myocardial delayed enhancement.
Please cite this article in press as: Mouthon L, et al., Diagnosis and classification of eosinophilic granulomatosis with polyangiitis (formerly named ChurgeStrauss syndrome), Journal of Autoimmunity (2014), http://dx.doi.org/10.1016/j.jaut.2014.01.018
L. Mouthon et al. / Journal of Autoimmunity xxx (2014) 1e5
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Table 2 Main clinical manifestations of ChurgeStrauss syndrome. Manifestations
Chumbley Lanham Guillevin Gaskin Haas Abu-Shakra Guillevin Comarmon Moosig et al. 1977 [30] et al. 1984 [29] et al., 1987 [19] et al.a 1991 [31] et al. 1991 [32] et al., 1994 [33] et al. 1999 [4] et al. 2013 [5] et al. 2013 [6]
Number of patients Male/female sex ratio Mean age (years) Asthma General symptoms Lung infiltrates Pleurisy Ear, nose and throat Mononeuritis multiplex Gastrointestinal Cardiac Arthralgias Myalgias Skin Purpura Nodules Kidney involvement
30
16
43
21
16
12
96
383
150
21/9
12/4
24/19
14/7
12/4
6/6
45/51
199/184
76/74
47 100 e 27 e 70
38 100 e 72 29 70
43.2 100 72 77 e 21
46.5 100 e 43 e e
42.5 100 100 62 25 10
48 100 100 58 e 83
48.2 100 70 38 e 47
50.3 91.1 87.6 38.6 8.9 48
49.1 92.7 78 58 7.3 93.3
63
66
67
70
75
92
78
46
56
17 16 20 e 66 e 27 20
59 47 51 68 e 48 30 49
37 49 28 e e 28 21 16
58 15 43 e 50 e e 80
56 56 31 43 68 25 25 31
8 42 42 33 67 e e 8
33 30 41 54 51 31 19 16
23.2 16.4 29.8 38.9 39.7 22.5 9.7 21.7
28.7 46.7 51.3 32.7 49.3 34.7 17.3 18.7
Results are expressed as percentages unless stated otherwise. a Nephrology department patients.
5. Nomenclature Recently, a group of experts in the field suggested to rename ChurgeStrauss syndrome as eosinophilic granulomatosis with polyangiitis (EGPA) [37]. Both appellations may be indifferently used at the moment; however, in order to qualify diseases around descriptions more than eponymes [38], the EGPA denomination should progressively replace that of ChurgeStrauss.
However, those criteria are not diagnostic, as their goal is to classify patients as having a probable diagnosis of EGPA, but only once vasculitis has already been diagnosed. New diagnostic criteria currently being discussed include, for example, anti-MPO ANCA, and clinical and biological redefinitions of EGPA.
6. Diagnostic criteria
EGPA etiology remains unknown. Its pathogenesis, has long been thought to develop through three successive phases: asthma, blood and tissue eosinophilia, and, finally, vasculitis based on clinical observations [29]. A closer look at possible pathophysiological EGPA subtypes found a clear clinical difference between patients with and without ANCA. Findings based on two cohorts, described by Sinico [8] and our group [7], showed ANCA frequency in EGPA to be just under 40%: 37.6% and 38%, respectively. These results were confirmed by our recent report on a cohort of 383 patients with EGPA [5], with ANCA frequency of 31%. Most often, EGPA patients’ ANCA have a perinuclear fluorescence-labeling pattern (P-ANCA), with anti-myeloperoxidase (MPO) specificity, as assessed by an enzyme-linked immunosorbent assay (ELISA). In these studies, EGPA patients with anti-MPO ANCA suffered more, albeit not exclusively, from vasculitis symptoms, such as glomerulonephritis, mononeuritis multiplex and alveolar hemorrhage, than ANCA-negative patients [5,7,8].
Today, EGPA diagnosis remains essentially clinical. Diagnosis confirmation is important, but cannot be obtained in all cases. ANCA, when present, represent a major argument for the diagnosis of EGPA. However, as previously mentioned, these antibodies may be absent. Eosinophilia and anti-MPO ANCA further corroborate the diagnosis. Finally, although not mandatory, histological proof of EGPA can confirm the diagnosis, with skin, nerve and muscle biopsies sites having the highest respective sensitivities of 67.4%, 65.7%, and 47.9% [4]. For example [4], biopsies confirmed EGPA for 91.6% of our patients. A clinical redefinition of EGPA, established in 1984 by Lanham et al. [29] (Table 3), has allowed clinicians diagnose EGPA with good specificity and sensitivity without relying on histological findings. The three diagnostic criteria are asthma, blood eosinophilia exceeding 1500/mm3, and evidence of vasculitis involving two or more organs. However, that definition has been criticized: first, asthma may follow and not precede the vasculitic phase; second, eosinophilia may sometimes fluctuate and disappear, either spontaneously or after initiation of corticosteroids; and, finally, vasculitis, despite certain characteristic clinical manifestations, may be hard to confirm without a biopsy. Other criteria have been proposed, especially for classification purposes, notably the ACR and Chapel Hill criteria (Table 1). Table 3 Lanham diagnostic criteria for Churg Strauss syndrome. Asthma Blood eosinophilia exceeding 1500/mm3 Evidence of vasculitis involving two or more organs.
7. Clinical classification
8. Differential diagnosis The differential diagnosis of EGPA depends on each patient’s predominant clinical manifestations. Before vasculitis onset, concomitant eosinophilia, asthma and lung infiltrates may resemble certain parasitic infections, like helminthiases, or allergic bronchopulmonary aspergillosis. At this stage, it may be difficult to differentiate chronic eosinophilic pneumonia from EGPA [39]. However, when systemic vasculitis manifestations appear, asthma and a somewhat lower sensitivity to corticosteroids tend to favor a diagnosis of EGPA. Hypereosinophilic syndrome (HES) is another differential diagnosis difficult to distinguish, because some HES patients may
Please cite this article in press as: Mouthon L, et al., Diagnosis and classification of eosinophilic granulomatosis with polyangiitis (formerly named ChurgeStrauss syndrome), Journal of Autoimmunity (2014), http://dx.doi.org/10.1016/j.jaut.2014.01.018
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L. Mouthon et al. / Journal of Autoimmunity xxx (2014) 1e5
have neuropathy, albeit rarely mononeuritis multiplex, and cardiopathy and pulmonary manifestations [40]. The main differences tilting the pendulum in favor of EGPA are: ANCA, vasculitis manifestations or biopsy-confirmed vasculitis and, finally, a somewhat lower eosinophil count. However, for most patients suspected of having EGPA, especially those without ANCA or biopsy-proven vasculitis, lymphocyte immunophenotyping, clonal T-cell studies and molecular analyses to detect Fip1-like 1 (FIP1L1)eplateletderived growth factor receptor-alpha (PDGFA) gene fusion, in search of lymphoid or myeloid forms of HES, should probably be performed. Once vasculitis becomes predominant in the clinical picture, the main differential diagnoses of EGPA are other systemic vasculitides, especially GPA and polyarteritis nodosa. Whereas EGPA and polyarteritis nodosa share numerous clinical characteristics, like mononeuritis multiplex, articular and muscular lesions, and gastrointestinal symptoms, EGPA is usually easily distinguishable by asthma, atopic history, eosinophilia and lung infiltrates [1]. Finally, GPA, another ANCA-associated vasculitis that shares common characteristics with EGPA is usually ruled out by the presence of asthma, eosinophilia, non-destructive sinus involvement, mononeuritis multiplex and, when present, the anti-MPOespecific ANCA (versus anti-PR3 in GPA) [41]. 9. Prognosis and outcome EGPA prognosis is generally good, even though historically, before the advent of corticosteroid therapy, it was almost always fatal. EGPA prognosis has been revolutionized by the use of corticosteroids and immunosuppressant(s) [42]. Whereas in 1950, the 5year survival of patients with polyarteritis nodosa (not yet separated from EGPA) was 10%, today, the overall 5-year survival of EGPA may reach 97% [43]. However, not all EGPA patients share the same prognosis, as it depends on the initial degree of disease extension and organ(s) involvement. The original, prognostic Five-Factor Score (FFS) [44] was obtained by univariate and multivariate analyses of 342 vasculitis patients, including 82 with EGPA. The five factors (each accorded 1 point) conferring a higher risk of mortality rate were: 1) proteinuria > 1 g/24 h; 2) serum creatinine level > 140 (150 in the revised version of FFS) mmol/l; 3) myocardial involvement; 4) severe gastrointestinal involvement; and 5) central nervous system involvement. The FFS helps identify which patients who, because of their higher risks of relapse and mortality, require more aggressive immunosuppressive treatment. Based on a new study of 1108 consecutive patients suffering from systemic necrotizing vasculitides, including GPA, we recently revised the FFS [9]. The following five criteria, each again accorded 1 point, are now significantly and independently associated with higher 5-year mortality: 1) age over 65 years; 2) cardiac symptoms; 3) gastrointestinal involvement; 4) renal insufficiency characterized by serum creatinine > 150 mmol/l; and 5) the absence of ear, nose and throat manifestations. According to this new definition, revised FFS of 0, 1 or 2 are associated with respective 5-year mortality rates of 9%, 21% or 40%. 10. Conclusion Recently, ChurgeStrauss syndrome has been renamed EGPA. Much progress has been made over the past 30 years in understanding, redefining and treating EGPA. What is becoming ever more apparent is the broad heterogeneity of EGPA patients’ phenotypes. New patient subsets have been identified, with the most obvious being those with and without ANCA, as their clinical presentations differ. Management of EGPA patients is now more effective and, thus, its good prognosis is even better, compared to other vasculitides.
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