Churg-Strauss Syndrome: Evolving Concepts

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1 Discovery Medicine 243 Churg-Strauss Syndrome: Evolving Concepts Christian Pagnoux Abstract: Churg-Strauss syndrome is a rare, smallsized vessel systemic necrotizing vasculitis that was first described in the early 1950s. Its most typical presentation consists of the appearance, in a patient with late-onset asthma, of vasculitic manifestations, like fever, cutaneous purpura and mononeuritis multiplex. In such a setting, the combination of blood eosinophilia and inflammatory syndrome is highly suggestive of the diagnosis, which can be further supported by the detection of antineutrophil cytoplasmic autoantibodies (ANCN), especially P- ANCA with anti-myeloperoxidase specificity, in almost 40% of the patients, and the presence of eosinophilic granulomas and/or necrotizing vasculitis in an affected-tissue biopsy. Although these disease hallmarks are now well-known, its pathophysiological mechanisms remain to be fully understood. Several gene polymorphisms and immune dysregulations are surely implicated, ranging from direct eosinophil toxicity to T- or even B-cell dysfunctions and, altogether, suggesting the existence of different disease stages and subsets according to the predominantly involved pathway. Only half the patients initially have severe life-threatening manifestations, like cardiac involvement, which require prompt aggressive treatments based on combined corticosteroids and immunosuppressants (mainly cyclophosphamide). Other less severe disease forms Christian Pagnoux, M.D., M.P.H., is at the Department of Internal Medicine, French Vasculitis Study Group, National Referral Center for Necrotizing Vasculitides and Systemic Scleroderma, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, Paris, France. christian.pagnoux@cch.aphp.fr. can usually be controlled with corticosteroids alone. Even though this current standardized therapy quite effectively and safely obtains remission, more than three-quarters of all the patients will remain corticosteroid-dependent, mostly because of residual asthma and/or eosinophilia. Hence, progress is needed in Churg-Strauss syndrome s therapeutic management, and better understanding of the complex disease mechanisms may aid such a quest. [Discov Med 9(46): , March 2010] Introduction Since its first description as allergic granulomatous angiitis in 1951 (Churg and Strauss, 1951), and subsequently its affiliation with the small-sized vessel systemic necrotizing vasculitides and, more specifically, the so-called subgroup of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides in the early 1990s, knowledge about the pathophysiological mechanisms of Churg-Strauss syndrome has greatly improved. Its natural clinical history and progression are better understood, but the syndrome s potential subsets are not yet totally elucidated. Major advances have also been made in the therapeutic management of affected patients, but much remains to be done because sustained off-treatment remissions are quite rare and patients often require a long-term low-dose corticosteroid therapy (Cohen et al., 2007; Ribi et al., 2008). International studies and workshops on vasculitis classification, immunology, genetics, and treatments are ongoing or planned. Here, we review the current known aspects of Churg-Strauss syndrome. Discovery Medicine Discovery Medicine, Volume 9, number 46, Pages , March 2010

2 244 Main Epidemiological, Clinical, and Biological Characteristics of Churg-Strauss Syndrome Churg-Strauss syndrome is a rare disease, with an annual incidence ranging between 0.5 and 6.8 per million inhabitants and a prevalence of per million inhabitants (Pagnoux et al., 2007; Watts et al., 2005), with a mean age at onset around 50 years and no sex preponderance. No strong evidence of a differential geographical distribution pattern has been reported so far, nor a blatant change in its frequency over the past decades. However, some studies reported a slightly higher prevalence in northern, as opposed to southern, Europe, and in urban, as compared to rural, regions. Several exogenous triggering factors for disease onset or flares have been identified or, more cautiously, suspected in some European or North American studies. They include vaccinations, desensitizations, and drugs, such as macrolides, carbamazepine, quinine, and also anti-asthma agents, like leukotriene-receptor antagonists and, more recently, omalizumab, a recombinant monoclonal anti-immunoglobulin E (IgE) antibody (Bibby et al., 2010; Pagnoux et al., 2007). These latter two often provide the opportunity for substantial tapering or withdrawal of corticosteroids in asthmatic patients, thereby unmasking an underlying forme fruste of Churg-Strauss syndrome, which had so far been controlled by corticosteroids, but a direct triggering role of these agents cannot be excluded (Bibby et al., 2010). Whether or not common asthma represents a risk factor for Churg-Strauss syndrome per se has not been clearly determined, because both conditions share some underlying mechanisms. The earliest studies reported a higher annual incidence of Churg-Strauss syndrome in asthmatic patients treated with nonleukotriene-modifying asthma drugs (64.4 per million asthmatics) or a leukotriene-receptor antagonist (about 60 per million asthmatics). A more recent study reported a somewhat lower Churg-Strauss syndrome incidence of 34.6 per million asthmatics per year (Harrold et al., 2005), which remains higher than in the general population; but other reported incidences varied from 0 to 67 according to disease definition. Whereas asthma often clusters in families, familial cases of Churg- Strauss syndrome are exceptional, diminishing the gene and environmental factor impact on the latter. However, results of several genetic studies suggested some predisposing hereditary factors, like the HLA-DRB1*04 and HLA-DRB1*07 alleles and the HLA-DRB4 gene, which are more frequent in Churg-Strauss syndrome patients than healthy controls, the interleukin IL10.2 haplotype, which is associated with enhanced IL-10 expression, and possibly the CD226 Gly307Ser polymorphism (Wieczorek et al., 2010). The most typical clinical presentation of Churg-Strauss syndrome is the appearance of vasculitic manifestations in a patient with known allergic rhinitis, nasal and sinus polyposis, and late-onset asthma (almost constant, and usually preexisting for 5-10 years). General symptoms (i.e., fever or weight loss), mononeuritis multiplex, and/or necrotic cutaneous purpura are the most frequent manifestations at disease onset, in combination with elevated blood eosinophilia and inflammatory syndrome. The detection of ANCA, especially P-ANCA (with perinuclear labeling pattern in indirect immunofluorescence) with anti-myeloperoxidase (antimpo) specificity (in enzyme-linked immunosorbent assay), strongly supports the diagnosis, but they are present in only 35-40% of the patients (Sablé-Fourtassou et al., 2005; Sinico and Bottero, 2009). While Lanham et al. (1984) commendably described in the 1980s that Churg-Strauss disease most typically emerges through 3 successive phases (prodromic phase, with asthma and allergic manifestations; then, eosinophil infiltration into tissues, especially lung and/or myocardium; and eventually, systemic and vasculitic phase), not all patients experience this clear-cut stepwise progression and many have overlapping manifestations from these different phases. In addition to almost constant asthma and airflow obstruction, lung manifestations include patchy and transient alveolar (eosinophilic) infiltrates and/or pleurisy, and, rarely, lung non-excavated nodules or alveolar hemorrhage. Allergic rhinitis, sinusitis, and/or nasal polyposis can be observed in 60-80% of the patients. Notably, Churg-Strauss syndrome patients must be evaluated for heart involvement, because it carries a poor prognosis, has therapeutic implications, and can be paucisymptomatic. In the earliest studies, heart involvement was reportedly occurring in up to 50-60% of the patients (Lanham et al., 1984) and represented the major cause of mortality, accounting for 48% of patient deaths (Guillevin et al., 1999). In more recent reports, outcomes were better. For instance, Neumann et al. (2009) reported that there were only two deaths from severe endomyocarditis among the 22 patients with cardiac involvement, with recovery of nearly normal cardiac function in almost all of the survivors. However, the reported cardiac manifestations and their frequencies are strongly dependent on which cardiac

3 245 investigations were done. Cardiac magnetic resonance imaging might reveal clinically silent and echographically undisclosed myocardial involvement, whose clinical significance is uncertain today (Bhagirath et al., 2009; Neumann et al., 2009). Cardiac screening with magnetic resonance imaging can better delineate inflammatory pericardial involvement and reveal microvasculitis of the epi- and myocardial vessels, endo- and/or myocardial inflammation, and/or less reversible fibrosis. These are supposedly attributable to eosinophil infiltration and/or ischemic lesions due to coronary artery vasculitis, which, nonetheless, is rare in Churg-Strauss syndrome (Bhagirath et al., 2009). Intraventricular thrombi are other, but rare, possible cardiovascular abnormalities, usually also visible on echocardiography. Positron-emission tomography has also been used to evaluate cardiac involvement, with some interesting results. Peripheral neuropathy occurs very frequently in Churg- Strauss syndrome, due to epineurial necrotizing vasculitis with resulting axonal ischemia, and affects 50-80% of the patients (Wolf et al., 2009). Peripheral neuropathy mainly consists of mononeuritis multiplex (60-75% of the patients with peripheral nerve involvement), but asymmetric or symmetric sensory or sensorimotor polyneuropathies or, more rarely, Guillain-Barré-like syndromes can also be observed. Central nervous system, cranial nerve (mostly IX, V) involvement, and/or ischemic optic neuritis are less frequent (Pagnoux et al., 2006). Skin lesions are observed in 40-75% of the patients, most typically including palpable purpura (Figure 1), often necrotic, predominantly on the legs and feet, cutaneous nodules (one-third of the patients with skin manifestations) or papules, and sometimes migratory urticarial rashes. Histology of skin biopsies is informative in approximately half of the patients, with non-specific leukocytoclastic (peri-)vasculitis and sometimes necrotizing vasculitis, eosinophil infiltration and/or, more rarely, granulomatous vasculitis, or extravascular eosinophilic granulomas, Figure 1. Necrotic purpura of the legs. especially in nodules (Pagnoux et al., 2006). Gastrointestinal tract is involved in 10-40% of the patients, ranging from mild abdominal pain to lifethreatening bowel ischemia and perforations. Kidneys are less frequently affected, in 5-30% of the patients and mostly consisting of necrotizing glomerulonephritis. Venous thrombotic events have been reported to occur at a non-negligible frequency during active phases of the disease, like in other small-sized vessel vasculitides (i.e., Wegener s granulomatosis and microscopic polyangiitis). Thus, the diagnosis of Churg-Strauss syndrome relies on the combination of suggestive clinical findings, blood hypereosinophilia (usually >1,500/mm 3 and with bystander high IgE titres), and, when possible, biopsy of an affected tissue. Muscle and/or nerve biopsies (Figure 2) yielded the greatest sensitivity in patients with myalgias and/or peripheral neuropathy, but can, by themselves, lead to definitive sensory sequelae, although usually limited in size. The detection of ANCA, generally antimpo ANCA, strongly supports the diagnosis, but, as stated above, only 40% of the patients are ANCA-positive. Differential diagnoses are listed in Table 1. Parasitic infections and hypereosinophilic syndromes are among the main diagnoses to evoke and actively look for. Therefore, lymphocyte immunophenotyping, T-cell

4 246 clonal studies, and molecular analyses to detect Fip1- like 1 (FIP1L1)-platelet-derived growth factor receptor-α (PDGFRA) gene fusion should probably be done for every patient suspected of having Churg- Strauss syndrome. The tests are highly recommended for those patients who are ANCA-negative with or without histologically proven vasculitis, in order to detect myeloid neoplasms associated with eosinophilia and abnormalities of PDGFRA, platelet-derived growth factor receptor-β (PDGFRB), or fibroblast growth factor receptor 1 (FGFR1) (Tefferi et al., 2010). However, one cannot totally exclude a potential overlap between some of these entities, which include lymphocytic or idiopathic hypereosinophilic syndromes, some Churg- Strauss syndrome cases, as well as fortuitous associations, especially with parasitic infections. An Evolving Disease, with Diverse Clinical and Immunological Patterns Other than the 3 successive phases described by Lanham et al. (1984), Churg-Strauss syndrome has been divided into several other subsets. These subgroup divisions can be based on disease activity and/or sever- Figure 2. Histology of a muscle and nerve biopsy showing vasculitis, with fibrinoid necrosis of the vessel wall (star) and massive surrounding eosinophilic infiltration (arrowheads).

5 247 Table 1. Main Differential Diagnoses of Churg-Strauss Syndrome Other systemic vasculitides Microscopic polyangiitis Wegener s granulomatosis Polyarteritis nodosa Giant-cell arteritis Henoch-Schönlein purpura Others: cutaneous leukocytoclastic vasculitis, cryoglobulinemic vasculitis Hypersensitivity reactions Hypersensitivity vasculitis (mainly drug-related) DRESS (drug rash with eosinophilia and systemic symptoms) Eosinophilic/hypersensitivity pneumonitis (drugs, pneumallergens ) Idiopathic chronic eosinophilic pneumonia (Carrington s disease) Infections Helminthiases/nematodoses (toxocarosis/larva migrans, anguillulosis, ankylostomiasis, trichinosis, ascaridiasis, oxyurosis, trichocephalosis ) Other parasitic infections with blood and/or tissue eosinophilia (liver distomatosis, bilharziosis, filarioses, onchocercosis, taeniases, hydatidosis, alveolar echinococcosis, myases, anisakiasis, gnathostomiasis, rarely toxoplasmosis) Allergic bronchopulmonary aspergillosis Human immunodeficiency virus infection (and/or hepatitis C virus infection) (Primary) hypereosinophilic syndrome (blood eosinophilia >1,500/mm 3 for >6 months) Lymphoid hypereosinophilic syndrome Myeloid hypereosinophilic syndrome (FIP1L1 PDGFRA gene fusion) Other malignant hemopathies and solid cancers Lymphomas (mainly T and Hodgkin s lymphomas) Myeloproliferative neoplasms Myelodysplastic syndromes Acute or chronic leukemias Solid cancers mainly gastrointestinal tract, breast or lung cancers (blood eosinophilia and, more rarely, authentic paraneoplastic vasculitis) Miscellaneous Eosinophilic fasciitis (Shulman syndrome) L-Tryptophan-related eosinophilia-myalgia syndrome (or, more rarely now, toxic oil syndrome) Other systemic disease, with or without associated vasculitis (rheumatoid arthritis, dermatomyositis ) Crohn s disease, ulcerative colitis (inflammatory bowel diseases) Sarcoidosis (Löfgren s syndrome) Systemic mastocytosis Eosinophilic esophagitis and/or gastritis Cholesterol emboli syndrome Gleich syndrome (episodic angioedema with eosinophilia, and frequently increased polyclonal serum IgM and IgE levels) Kimura disease (painless subcutaneous swellings and nodules, with neck and head lymphadenopathies, salivary gland hypertrophy, elevated serum IgE level, and possible nephritic syndrome, mainly due to mesangial proliferative glomerulonephritis affecting almost exclusively Asian subjects)

6 248 ity, prognostic scores, and biological parameters, for example, the presence or absence of ANCA and genetic polymorphisms (Pagnoux and Guillevin, 2010). Once the pathophysiological mechanisms and the respective roles of eosinophils, ANCA, and other immune system players are completely elucidated, other subsets might be identified in the future. Patients can be stratified as having poor-prognosis Churg-Strauss syndrome when they have one or more of the following five-factor score (FFS) parameters: proteinuria >1 g/day, peak serum creatinine level >140 µmol/l (1.58 mg/dl), specific cardiomyopathy, gastrointestinal tract involvement, and central nervous system involvement (Guillevin et al., 1996). When the FFS was devised in 1996, patients 5-year overall survival was 88%, 74%, and 54% when 0, 1, or 2 of these parameters were present at diagnosis, respectively. At diagnosis, the majority of the patients (55% of a cohort studied by the group that devised the score) had none of these factors, clearly emphasizing that not all patients suffer from such severe and life-threatening manifestations (Guillevin et al., 1999). ANCA origin and its role and mechanisms of action in Churg-Strauss syndrome remain unknown and largely unexplored. To date, no animal model of Churg-Strauss syndrome has been established to further help elucidate these points. Recently, a mouse model of experimental eosinophilic skin vasculitis, induced by IgE-mediated cutaneous reverse passive Arthus reaction, was developed, but it lacks systemic vasculitis and extravascular granulomas and, more importantly, it does not produce ANCA (Ishii et al., 2009). Available models, based on immunization with MPO, passive antimpo ANCA, or cell transfers, only develop features of microscopic polyangiitis. However, it was advanced that ANCA might play a role in Churg-Strauss syndrome, because their presence often precedes the onset of the vasculitic manifestations in those positive patients. Keogh and Specks (2003) reported in their study on 91 patients (including 74 with available ANCA-testing results) that ANCA-positivity was only associated with central nervous system involvement. The results of three other investigations (Baldini et al., 2009; Sablé-Fourtassou et al., 2005; Sinico et al., 2005), which had included a total of 243 patients, showed that ANCA-positive patients suffered more frequently from renal and/or peripheral nervous system involvement(s), alveolar hemorrhage, purpura, and more often biopsy-proven vasculitis. Conversely, ANCA-negative patients were more prone to have cardiac manifestations, lung involvement (other than alveolar hemorrhage), and/or systemic vasculitis features. ANCA-positivity has also been postulated as an indicator for more severe disease, as reflected by the higher FFS and Birmingham vasculitis activity score (BVAS) at diagnosis of ANCA-positive patients. ANCA-positivity s prognostic value is unsure and controversial. At 5 years, survival and relapse rates were similar for both ANCA-positive and -negative patients in one study (91.8% and 46.3% for ANCA-positive patients versus 97.1% and 35.4% for ANCA-negative patients, respectively) (Sinico et al., 2005). However, in the most recent of these three studies on 38 patients (Baldini et al., 2009), antimpo ANCA reappearance or titer increase was associated with a significantly higher risk of relapse. No patient subgroups have yet been so clearly delineated based on other biological parameters. Each disease phase may exhibit a specific cytokine pattern. T-helper type-2 (Th2) cytokines (mainly interleukins IL-4, IL-5, IL-13, and IL-10) favor eosinophil differentiation, activation, proliferation, and their subsequent adhesion to endothelium and tissue infiltration. T-helper type-1 (Th1) cytokines [tumor necrosis factor (TNF)-α, interferon-γ and IL-2] would rather favor macrophage activation, initially non-eosinophilic granuloma formation, and vascular damage. Th2 immunological pathway is supposed to be predominant during early phases of the disease (asthma). At vasculitis onset, a switch toward Th1 pattern predominance would occur, at least transiently. Though elegant and straightforward to understand, the theory of stepwise changes of this Th1/Th2 balance that would account for the different clinical and histological findings of Churg-Strauss syndrome has already and is likely to be further considered too simplistic and outdated. Other associated or intermediate cells, like hematopoietic CD34 + progenitor cells, capable of producing IL-5, or newly-identified Th17 cells, and/or more important immune dysfunctions are certainly implicated. Defective eosinophil apoptosis, albeit still debated, and endothelial or regulatory T-cell functional abnormalities might also have a pathophysiological role. At disease onset or relapse, patients reportedly have fewer CD4 + CD25 + regulatory T-cells producing IL-10, as well as CD4 + CD25 - T-cells producing IL-2, than those in remission or subjects with asthma. The role of eosinophil granule contents (major basic protein, eosinophilic cationic protein, and eosinophil-derived neurotoxins) also has to be considered, and so as IgE

7 249 and circulating IgE-containing immune complexes, oxygen radicals, and lysosomal proteolytic enzymes released by activated neutrophils (Kallenberg, 2005). IL-5 and eotaxin-3 (CCL26), an eosinotactic chemokine, have been shown as other potential markers of disease activity. Finally, a role for B-cells in the pathophysiology of Churg-Strauss syndrome is far more hypothetical and mainly relies on indirect evidence, like the presence of ANCA in some patients and a few reports on effective treatment with rituximab, a monoclonal anti-cd20 antibody (Koukoulaki et al., 2006; Pepper et al., 2008). Patient Outcomes Under Currently Recommended Treatment Are Quite Good, but New Therapeutics Are Needed Patients without poor-prognosis factors according to the FFS can initially be treated with corticosteroids alone. As demonstrated in a prospective study on 72 such patients (Ribi et al., 2008), 93% of them achieved remission on corticosteroids alone but 35% relapsed (essentially during the first year of treatment), after a mean follow-up of 56 months. More importantly, 79% of them persistently required low-dose corticosteroid therapy, chiefly because of residual asthma, and, ultimately, 26% of all study patients needed the adjunction of an immunosuppressant (mainly cyclophosphamide or azathioprine) at some time to control their disease. Conversely, it is mandatory that patients with one poorprognosis factor or more receive induction therapy with a combination of corticosteroids and an immunosuppressant, mainly cyclophosphamide (Cohen et al., 2007). A prospective, non-blinded, randomized, therapeutic trial from the French Vasculitis Study Group (FVSG) demonstrated, based on 48 such patients, that such regimen combining pulsed intravenous cyclophosphamide therapy (600 mg/m 2 every 2 weeks for 1 month, then every 4 weeks thereafter), achieved complete remission in 87.5% of them. Notably, in that trial, no maintenance therapy was prescribed after stopping cyclophosphamide (after 6 or 12 pulses) and relapses were therefore frequent (73.8%), especially in the 6- pulse group (85.7%). Another important finding was, that after a mean follow-up of 8 years, 81.2% still had to take low-dose corticosteroids (mean dose: 8.6 mg/day, range: 0-15), and sometimes the immunosuppressant (18%). Overall survival was 97% at 5 years in the former of these studies, and 92% at 8 years in the latter that included more severely ill patients. The results of those studies underscore three points. First, the overall global outcomes of the patients were quite good and have greatly improved over the past few decades. Second, patients with poor-prognosis factor should be treated like those with Wegener s granulomatosis and receive a staged, remission-inductionmaintenance therapy. The former should combine corticosteroids and cyclophosphamide, with the latter being switched to a less toxic immunosuppressant, like azathioprine or, possibly, methotrexate, once remission has been obtained. The optimal duration of maintenance therapy remains unknown, but the entire inductionmaintenance regimen should last at least months. Third, despite the application of the above-mentioned strategies, residual asthma manifestations, mild and fluctuating eosinophilia, and/or lingering vasculitic manifestations often necessitate prolonged continuation of low-dose corticosteroids. Taken together, these results indeed plead for new treatments or strategies. For patients with no poor-prognosis factor, the adjunction of an immunosuppressant to corticosteroids as first-line therapy might be more effective than corticosteroids alone. Cyclophosphamide was proven effective towards this goal on a small group of 25 patients, but carried an unacceptable toxicity (Gayraud et al., 1997). Metzler et al. (2004) tested intravenous methotrexate (0.3 mg/kg/week) in this indication, starting after a relatively long median of 5 months post-corticosteroid initiation. Six and two out of 11 patients with non-life-threatening Churg-Strauss syndrome entered complete or partial remission, respectively. However, in the second part of that study, 11 of the 23 patients, who received methotrexate to maintain remission, eventually relapsed, after a median of 9 months post-methotrexate onset. However, this strategy of combining corticosteroids and methotrexate allowed significant corticosteroid-sparing, up to 53% of the dose during maintenance, and was well-tolerated. The FVSG is now conducting a prospective, double-blind, randomized trial to evaluate first-line azathioprine (for 12 months) combined with corticosteroids for these good-prognosis patients (CHUSPAN 2; ClinicalTrials.gov number, NCT ). In parallel, the search for new therapies is in progress. ANCA-positivity led to the use of rituximab in a few patients, with some reported efficacy, at least at short term and on eosinophil counts (Koukoulaki et al., 2006; Pepper et al., 2008). Notably, rituximab was also effective in a few patients who were ANCA-negative. Conversely, it was reported ineffective and was incriminated as having provoked immediate and severe bron-

8 250 chospasms in two other ANCA-negative patients (Bouldouyre et al., 2009). The Mayo Clinic group is currently enrolling patients with renal involvement in an open-label study to further determine the efficacy and safety of rituximab in Churg-Strauss syndrome (ClinicalTrials.gov, NCT ). Because interferon-α can reverse Th2-mediated immune responses and inhibit eosinophil degranulation, it has been evaluated in some patients with refractory disease. In a recent, prospective, open-label trial (Metzler et al., 2008), all seven refractory patients who received interferon-α at relatively high doses (3 MU thrice weekly) achieved remissions, after a mean of 3 months. Remission persisted during the 6 months of treatment. However, residual asthma persisted in two of them, peripheral neuropathy did not clearly regress in two others, and interferon-α had to be increased to MU/week for another two. More importantly, responses obtained with interferon-α appeared to be generally transient and patients often relapsed after stopping it. Furthermore, interferon-α has an appalling toxicity profile, which limits its wider use in Churg- Strauss syndrome patients, especially those with heart involvement. Omalizumab, a murine monoclonal antibody directed against human IgE, has been reported to be beneficial in some patients, but, like for leukotriene-receptor antagonists previously, it has also been suspected on several occasions of triggering Churg-Strauss syndrome (Giavina-Bianchi et al., 2009; Wechsler et al., 2009). Therefore, use of omalizumab should remain exceptional and is very unlikely to be part of future recommendations for managing Churg-Strauss syndrome patients. Tyrosine-kinase inhibitors, like imatinib, or anti-il-5 antibodies yielded some promising therapeutic results for primary hypereosinophilic syndrome, but their place in Churg-Strauss syndrome therapy remains to be determined (Kahn et al., 2010; Kalsch et al., 2008). Two open-label studies on mepolizumab are ongoing, one in Germany (MEPOCHUSS; ClinicalTrials.gov, NCT ) and the other in the United States (MATOCSS; ClinicalTrials.gov, NCT ). None has yet been initiated on tyrosine-kinase inhibitors to treat Churg-Strauss syndrome. Notably, one patient developed ANCA-positive and biopsy-proven Churg- Strauss syndrome during treatment for asthma with masitinib mesylate, a new tyrosine kinase inhibitor currently under investigation (Granel et al., 2009). However, in that case, Churg-Strauss syndrome may have been unmasked as the consequence of the rapid corticosteroid withdrawal, which was allowed because of this new drug s efficacy on asthma manifestations. Several other agents or therapies have occasionally been reported to be beneficial in some patients with refractory and/or relapsing Churg-Strauss syndrome. Intravenous immunoglobulins may represent an alternative to immunosuppressants in pregnant patients (Hamilos and Christensen, 1991; Rutberg et al., 2002) and have been useful as adjunctive (Danieli et al., 2004) or rescue therapy in some patients with refractory disease, especially those with neuropathy and/or cardiomyopathy (Taniguchi et al., 2007). While no argument clearly supports its systematic administration at the time of diagnosis, plasma exchange might also have a niche in the treatment of ANCA-positive patients with refractory disease, severe kidney involvement, and/or peripheral neuropathy, as demonstrated, or at least suggested, for other ANCA-associated vasculitides (Wegener s granulomatosis and microscopic polyangiitis) (Guillevin and Pagnoux, 2003). More anecdotally, effective use of mycophenolate mofetil, hydroxyurea, cyclosporin A, or TNF-α blockers, like infliximab or etanercept, even though the underlying pathophysiological reasons for their use are less obvious, has also been reported. Finally, adequate management of Churg-Strauss syndrome patients also includes prophylactic treatments, like co-trimoxazole to prevent pneumocystosis in patients receiving cyclophosphamide. Because several parasitic infections can cause blood eosinophilia and because corticosteroids represent the basis of the Churg-Strauss syndrome treatment and can exacerbate underlying parasitic infections, patients should largely be given one weight-adjusted dose of ivermectin and/or albendazole, especially when they had travelled or lived in countries endemic for Strongyloides stercoralis infection or ankylostomiasis. Symptomatic treatment of asthma manifestations is, of course, indicated and necessary, but the use of leukotriene-receptor antagonists or omalizumab should probably be avoided or at least be used prudently. When feasible, sperm cryopreservation should be proposed for males or gonadal preservation for women receiving cytotoxic drugs. Physiotherapy is essential for patients with motor neuropathy. Conclusion Substantial advances have been made in the under-

9 standing of immune mechanisms implicated in Churg- Strauss syndrome and its management, since its first description more than half a century ago. While it definitively remains a systemic necrotizing small-sized vessel vasculitis, its membership in the ANCA-associated vasculitis group has become more controversial. More complex and numerous mechanisms are involved in Churg-Strauss syndrome (Hoffman and Langford, 2005; Pagnoux and Guillevin, 2010) and only 40% of the patients are ANCA-positive. Similarly, one of its earlier denominations, allergic granulomatous angiitis (Churg and Strauss, 1951), has become dated because not all patients have (eosinophilic) granulomas. Moreover, several disease subgroups have been identified, essentially based on clinical or biological findings. Other subgroups may be brought forth in the future, relying on more subtle molecular and genetic characteristics. Therapeutic strategies also require further improvement. Treatment should be adapted as closely as possible to each patient s characteristics, because some manifestations carry a higher risk of mortality and relapse, and/or potential treatment-related toxicity. New treatments are needed to lower the rate of frequent, lowdose but long-term, corticosteroid-dependence that represents a major issue and the lingering disappointment in current therapeutic strategies for Churg-Strauss syndrome. References Baldini C, Della Rossa A, Grossi S, Catarsi E, Talarico R, d Ascanio A, Mosca M, Neri R, Tavoni A, Bombardieri S. Churg-Strauss syndrome: outcome and long-term follow-up of 38 patients from a single Italian centre (in Italian). Reumatismo 61(2):118-24, Bhagirath KM, Paulson K, Ahmadie R, Bhalla RS, Robinson D, Jassal DS. Clinical utility of cardiac magnetic resonance imaging in Churg-Strauss syndrome: case report and review of the literature. Rheumatol Int 29(4):445-9, Bibby S, Healy B, Steele R, Kumareswaran K, Nelson H, Beasley R. Association between leukotriene receptor antagonist therapy and Churg-Strauss syndrome: an analysis of the FDA AERS database. Thorax 65(2):132-8, Bouldouyre MA, Cohen P, Guillevin L. Severe bronchospasm associated with rituximab for refractory Churg- Strauss syndrome. Ann Rheum Dis 68(4):606, Churg J, Strauss L. Allergic angiitis and periarteritis nodosa. Am J Pathol 27: , Cohen P, Pagnoux C, Mahr A, Arène JP, Mouthon L, Le Guern V, André MH, Gayraud M, Jayne D, Blockmans D, et al. Churg-Strauss syndrome with poor-prognosis factors: A prospective multicenter trial comparing glucocorticoids and six or twelve cyclophosphamide pulses in forty-eight patients. Arthritis Rheum 57(4):686-93, Danieli MG, Cappelli M, Malcangi G, Logullo F, Salvi A, Danieli G. Long term effectiveness of intravenous immunoglobulin in Churg-Strauss syndrome. Ann Rheum Dis 63(12): , Gayraud M, Guillevin L, Cohen P, Lhote F, Cacoub P, Deblois P, Godeau B, Ruel M, Vidal E, Piontud M, et al. Treatment of good-prognosis polyarteritis nodosa and Churg- Strauss syndrome: comparison of steroids and oral or pulse cyclophosphamide in 25 patients. French Cooperative Study Group for Vasculitides. Br J Rheumatol 36(12):1290-7, Giavina-Bianchi P, Giavina-Bianchi M, Agondi RC, Kalil J. Anti-IgE in Churg-Strauss syndrome. Thorax 64(3):272; author reply 272-3, Granel B, Rossi P, Koeppel MC, Hermine O, Charpin D. Churg and Strauss vasculitis in the course of masitinib treatment: a first report. Allergy, [Epub ahead of print], Guillevin L, Lhote F, Gayraud M, Cohen P, Jarrousse B, Lortholary O, Thibult N, Casassus P. Prognostic factors in polyarteritis nodosa and Churg-Strauss syndrome. A prospective study in 342 patients. Medicine (Baltimore) 75(1):17-28, Guillevin L, Cohen P, Gayraud M, Lhote F, Jarrousse B, Casassus P. Churg-Strauss syndrome. Clinical study and long-term follow-up of 96 patients. Medicine (Baltimore) 78(1):26-37, Guillevin L, Pagnoux C. Indications of plasma exchanges for systemic vasculitides. Ther Apher Dial 7(2):155-60, Hamilos DL, Christensen J. Treatment of Churg-Strauss syndrome with high-dose intravenous immunoglobulin. J Allergy Clin Immunol 88(5):823-4, Harrold LR, Andrade SE, Go AS, Buist AS, Eisner M, Vollmer WM, Chan KA, Frazier EA, Weller PF, Wechsler ME, et al. Incidence of Churg-Strauss syndrome in asthma drug users: a population-based perspective. J Rheumatol 32(6): , Hoffman GS, Langford CA. Are there different forms of life in the antineutrophil cytoplasmic antibody universe? Ann Intern Med 143(9):683-5, Ishii T, Fujita T, Matsushita T, Yanaba K, Hasegawa M, Nakashima H, Ogawa F, Shimizu K, Takehara K, Tedder TF,

10 252 et al. Establishment of experimental eosinophilic vasculitis by IgE-mediated cutaneous reverse passive arthus reaction. Am J Pathol 174(6): , Kahn JE, Grandpeix-Guyodo C, Marroun I, Catherinot E, Mellot F, Roufosse F, Blétry O. Sustained response to mepolizumab in refractory Churg-Strauss syndrome. J Allergy Clin Immunol 125(1):267-70, Kallenberg CG. Churg-Strauss syndrome: just one disease entity? Arthritis Rheum 52(9): , Kalsch AI, Soboletzki M, Schmitt WH, van der Woude FJ, Hochhaus A, Yard BA, Birck R. Imatinib mesylate, a new kid on the block for the treatment of antineutrophil cytoplasmic autoantibodies-associated vasculitis? Clin Exp Immunol 151(3):391-8, Keogh KA, Specks U. Churg-Strauss syndrome: clinical presentation, antineutrophil cytoplasmic antibodies, and leukotriene receptor antagonists. Am J Med 115(4):284-90, Koukoulaki M, Smith KG, Jayne DR. Rituximab in Churg- Strauss syndrome. Ann Rheum Dis 65(4):557-9, Lanham JG, Elkon KB, Pusey CD, Hughes GR. Systemic vasculitis with asthma and eosinophilia: a clinical approach to the Churg-Strauss syndrome. Medicine (Baltimore) 63(2):65-81, Metzler C, Hellmich B, Gause A, Gross WL, de Groot K. Churg Strauss syndrome - successful induction of remission with methotrexate and unexpected high cardiac and pulmonary relapse ratio during maintenance treatment. Clin Exp Rheumatol 22(6 Suppl 36):S52-61, Metzler C, Schnabel A, Gross WL, Hellmich B. A phase II study of interferon-alpha for the treatment of refractory Churg-Strauss syndrome. Clin Exp Rheumatol 26(3 Suppl 49):S35-40, Neumann T, Manger B, Schmid M, Kroegel C, Hansch A, Kaiser WA, Reinhardt D, Wolf G, Hein G, Mall G, et al. Cardiac involvement in Churg-Strauss syndrome: impact of endomyocarditis. Medicine (Baltimore) 88(4):236-43, Pagnoux C, Kluger N, Francès C, Guillevin L. Cutaneous granulomatous vasculitis and extravascular granulomas. Expert Rev Dermatol 1(2):315-26, Pagnoux C, Guilpain P, Guillevin L. Churg-Strauss syndrome. Curr Opin Rheumatol 19(1):25-32, Pagnoux C, Guillevin L. Churg-Strauss syndrome: evidence for disease subtypes? Curr Opin Rheumatol 22(1):21-8, Pepper RJ, Fabre MA, Pavesio C, Gaskin G, Jones RB, Jayne D, Pusey CD, Salama AD. Rituximab is effective in the treatment of refractory Churg-Strauss syndrome and is associated with diminished T-cell interleukin-5 production. Rheumatology (Oxford) 47(7):1104-5, Ribi C, Cohen P, Pagnoux C, Mahr A, Arene JP, Lauque D, Puechal X, Letellier P, Delaval P, Cordier JF, et al. Treatment of Churg-Strauss syndrome without poor-prognosis factors: a multicenter, prospective, randomized, open-label study of seventy-two patients. Arthritis Rheum 58(2):586-94, Rutberg SA, Ward DE, Roth BJ. Churg-Strauss syndrome and pregnancy: successful treatment with intravenous immunoglobulin. J Clin Rheumatol 8(3):151-6, Sablé-Fourtassou R, Cohen P, Mahr A, Pagnoux C, Mouthon L, Jayne D, Blockmans D, Cordier JF, Delaval P, Puéchal X, et al. Antineutrophil cytoplasmic antibodies and the Churg- Strauss syndrome. Ann Intern Med 143(9):632-8, Sinico RA, Di Toma L, Maggiore U, Bottero P, Radice A, Tosoni C, Grasselli C, Pavone L, Gregorini G, Monti S, et al. Prevalence and clinical significance of antineutrophil cytoplasmic antibodies in Churg-Strauss syndrome. Arthritis Rheum 52(9): , Sinico RA, Bottero P. Churg-Strauss angiitis. Best Pract Res Clin Rheumatol 23(3):355-66, Taniguchi M, Tsurikisawa N, Higashi N, Saito H, Mita H, Mori A, Sakakibara H, Akiyama K. Treatment for Churg- Strauss syndrome: induction of remission and efficacy of intravenous immunoglobulin therapy. Allergol Int 56(2):97-103, Tefferi A, Gotlib J, Pardanani A. Hypereosinophilic syndrome and clonal eosinophilia: point-of-care diagnostic algorithm and treatment update. Mayo Clin Proc 85(2):158-64, Watts RA, Lane S, Scott DG. What is known about the epidemiology of the vasculitides? Best Pract Res Clin Rheumatol 19(2): , Wechsler ME, Wong DA, Miller MK, Lawrence-Miyasaki L. Churg-Strauss syndrome in patients treated with omalizumab. Chest 136(2):507-18, Wieczorek S, Holle JU, Epplen JT. Recent progress in the genetics of Wegener s granulomatosis and Churg-Strauss syndrome. Curr Opin Rheumatol 22(1):8-14, Wolf J, Bergner R, Mutallib S, Buggle F, Grau AJ. Neurologic complications of Churg-Strauss syndrome -- a prospective monocentric study. Eur J Neurol 17(4):582-8, 2009.