evolving concepts - churg strauss syndrome

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Discovery Medicine, Volume 9, number 46, Pages 243-252, March 2010

Abstract: Churg-Strauss syndrome is a rare, small-

sized 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 fur-

ther 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 vasculi-

tis in an affected-tissue biopsy. Although these dis-

ease hallmarks are now well-known, its pathophysi-

ological mechanisms remain to be fully understood.

Several gene polymorphisms and immune dysregu-

lations 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 predom-

inantly involved pathway. Only half the patients ini-

tially have severe life-threatening manifestations,

like cardiac involvement, which require prompt

aggressive treatments based on combined corticos-

teroids and immunosuppressants (mainly

cyclophosphamide). Other less severe disease forms

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 need-

ed in Churg-Strauss syndrome’s therapeutic man-

agement, and better understanding of the complex

disease mechanisms may aid such a quest. [Discov

Med 9(46):243-252, March 2010]

Introduction

Since its first description as allergic granulomatousangiitis in 1951 (Churg and Strauss, 1951), and subse-quently its affiliation with the small-sized vessel sys-temic necrotizing vasculitides and, more specifically,the so-called subgroup of antineutrophil cytoplasmicautoantibody (ANCA)-associated vasculitides in theearly 1990s, knowledge about the pathophysiologicalmechanisms of Churg-Strauss syndrome has greatlyimproved. Its natural clinical history and progressionare better understood, but the syndrome’s potential sub-sets are not yet totally elucidated. Major advances havealso been made in the therapeutic management ofaffected patients, but much remains to be done becausesustained off-treatment remissions are quite rare andpatients often require a long-term low-dose corticos-teroid therapy (Cohen et al., 2007; Ribi et al., 2008).International studies and workshops on vasculitis clas-sification, immunology, genetics, and treatments areongoing or planned. Here, we review the current knownaspects of Churg-Strauss syndrome.

Churg-Strauss Syndrome:

Evolving Concepts

Christian Pagnoux

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.

Email: [email protected].

Discovery Medicine

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Main Epidemiological, Clinical, and Biological

Characteristics of Churg-Strauss Syndrome

Churg-Strauss syndrome is a rare disease, with an annu-al incidence ranging between 0.5 and 6.8 per millioninhabitants and a prevalence of 10.7-14 per millioninhabitants (Pagnoux et al., 2007; Watts et al., 2005),with a mean age at onset around 50 years and no sexpreponderance. No strong evidence of a differentialgeographical distribution pattern has been reported sofar, nor a blatant change in its frequency over the pastdecades. However, some studies reported a slightlyhigher prevalence in northern, as opposed to southern,Europe, and in urban, as compared to rural, regions.

Several exogenous triggering factors for disease onsetor flares have been identified or, more cautiously, sus-pected in some European or North American studies.They include vaccinations, desensitizations, and drugs,such as macrolides, carbamazepine, quinine, and alsoanti-asthma agents, like leukotriene-receptor antago-nists and, more recently, omalizumab, a recombinantmonoclonal anti-immunoglobulin E (IgE) antibody(Bibby et al., 2010; Pagnoux et al., 2007). These lattertwo often provide the opportunity for substantial taper-ing or withdrawal of corticosteroids in asthmaticpatients, thereby unmasking an underlying ‘formefruste’ of Churg-Strauss syndrome, which had so farbeen controlled by corticosteroids, but a direct trigger-ing role of these agents cannot be excluded (Bibby etal., 2010). Whether or not “common” asthma representsa risk factor for Churg-Strauss syndrome per se has notbeen clearly determined, because both conditions sharesome underlying mechanisms. The earliest studiesreported a higher annual incidence of Churg-Strausssyndrome in asthmatic patients treated with non-leukotriene-modifying asthma drugs (64.4 per millionasthmatics) or a leukotriene-receptor antagonist (about60 per million asthmatics). A more recent study report-ed a somewhat lower Churg-Strauss syndrome inci-dence of 34.6 per million asthmatics per year (Harroldet al., 2005), which remains higher than in the generalpopulation; but other reported incidences varied from 0to 67 according to disease definition. Whereas asthmaoften clusters in families, familial cases of Churg-Strauss syndrome are exceptional, diminishing the geneand environmental factor impact on the latter. However,results of several genetic studies suggested some pre-disposing hereditary factors, like the HLA-DRB1*04and HLA-DRB1*07 alleles and the HLA-DRB4 gene,which are more frequent in Churg-Strauss syndromepatients than healthy controls, the interleukin IL10.2

haplotype, which is associated with enhanced IL-10expression, and possibly the CD226 Gly307Ser poly-morphism (Wieczorek et al., 2010).

The most typical clinical presentation of Churg-Strausssyndrome is the appearance of vasculitic manifestationsin a patient with known allergic rhinitis, nasal and sinuspolyposis, and late-onset asthma (almost constant, andusually preexisting for 5-10 years). General symptoms(i.e., fever or weight loss), mononeuritis multiplex,and/or necrotic cutaneous purpura are the most frequentmanifestations at disease onset, in combination withelevated blood eosinophilia and inflammatory syn-drome. The detection of ANCA, especially P-ANCA(with perinuclear labeling pattern in indirect immuno-fluorescence) with anti-myeloperoxidase (antiMPO)specificity (in enzyme-linked immunosorbent assay),strongly supports the diagnosis, but they are present inonly 35-40% of the patients (Sablé-Fourtassou et al.,2005; Sinico and Bottero, 2009). While Lanham et al.(1984) commendably described in the 1980s thatChurg-Strauss disease most typically emerges through3 successive phases (prodromic phase, with asthma andallergic manifestations; then, eosinophil infiltration intotissues, especially lung and/or myocardium; and even-tually, systemic and vasculitic phase), not all patientsexperience this clear-cut stepwise progression andmany have overlapping manifestations from these dif-ferent phases.

In addition to almost constant asthma and airflowobstruction, lung manifestations include patchy andtransient alveolar (eosinophilic) infiltrates and/orpleurisy, and, rarely, lung non-excavated nodules oralveolar hemorrhage. Allergic rhinitis, sinusitis, and/ornasal polyposis can be observed in 60-80% of thepatients. Notably, Churg-Strauss syndrome patientsmust be evaluated for heart involvement, because it car-ries a poor prognosis, has therapeutic implications, andcan be paucisymptomatic. In the earliest studies, heartinvolvement was reportedly occurring in up to 50-60%of the patients (Lanham et al., 1984) and representedthe major cause of mortality, accounting for 48% ofpatient deaths (Guillevin et al., 1999). In more recentreports, outcomes were better. For instance, Neumannet al. (2009) reported that there were “only” two deathsfrom severe endomyocarditis among the 22 patientswith cardiac involvement, with recovery of nearly nor-mal cardiac function in almost all of the survivors.

However, the reported cardiac manifestations and theirfrequencies are strongly dependent on which cardiac

Discovery Medicine, Volume 9, number 46, March 2010

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investigations were done. Cardiac magnetic resonanceimaging might reveal clinically silent and echographi-cally undisclosed myocardial involvement, whose clin-ical significance is uncertain today (Bhagirath et al.,2009; Neumann et al., 2009). Cardiac screening withmagnetic resonance imaging can better delineateinflammatory pericardial involvement and revealmicrovasculitis of the epi- and myocardial vessels,endo- and/or myocardial inflammation, and/or lessreversible fibrosis. These are supposedly attributable toeosinophil infiltration and/or ischemic lesions due tocoronary artery vasculitis, which, nonetheless, is rare inChurg-Strauss syndrome (Bhagirath et al., 2009).Intraventricular thrombi are other, but rare, possiblecardiovascular abnormalities, usually also visible onechocardiography. Positron-emission tomography hasalso been used to evaluate cardiac involvement, withsome interesting results.

Peripheral neuropathy occurs very frequently in Churg-Strauss syndrome, due to epineurial necrotizing vas-culitis with resulting axonal ischemia, and affects 50-80% of the patients (Wolf et al., 2009). Peripheral neu-ropathy mainly consists of mononeuritis multiplex (60-75% of the patients with peripheral nerve involvement),but asymmetric or symmetric sensory or sensorimotorpolyneuropathies or, more rarely, Guillain-Barré-likesyndromes can also be observed. Central nervous sys-tem, cranial nerve (mostly IX,V) involvement, and/orischemic optic neuritis are lessfrequent (Pagnoux et al.,2006). Skin lesions areobserved in 40-75% of thepatients, most typically includ-ing palpable purpura (Figure1), often necrotic, predomi-nantly on the legs and feet,cutaneous nodules (one-thirdof the patients with skin mani-festations) or papules, andsometimes migratory urticarialrashes. Histology of skin biop-sies is informative in approxi-mately half of the patients,with non-specific leukocyto-clastic (peri-)vasculitis andsometimes necrotizing vasculi-tis, eosinophil infiltrationand/or, more rarely, granulo-matous vasculitis, or extravas-cular eosinophilic granulomas,

especially in nodules (Pagnoux et al., 2006).Gastrointestinal tract is involved in 10-40% of thepatients, ranging from mild abdominal pain to life-threatening bowel ischemia and perforations. Kidneysare less frequently affected, in 5-30% of the patientsand mostly consisting of necrotizing glomerulonephri-tis. Venous thrombotic events have been reported tooccur at a non-negligible frequency during active phas-es of the disease, like in other small-sized vessel vas-culitides (i.e., Wegener’s granulomatosis and micro-scopic polyangiitis).

Thus, the diagnosis of Churg-Strauss syndrome relieson the combination of suggestive clinical findings,blood hypereosinophilia (usually >1,500/mm3 and withbystander high IgE titres), and, when possible, biopsyof an affected tissue. Muscle and/or nerve biopsies(Figure 2) yielded the greatest sensitivity in patientswith myalgias and/or peripheral neuropathy, but can, bythemselves, lead to definitive sensory sequelae,although usually limited in size. The detection ofANCA, generally antiMPO ANCA, strongly supportsthe diagnosis, but, as stated above, only 40% of thepatients are ANCA-positive.

Differential diagnoses are listed in Table 1. Parasiticinfections and hypereosinophilic syndromes are amongthe main diagnoses to evoke and actively look for.Therefore, lymphocyte immunophenotyping, T-cell

Figure 1. Necrotic purpura of the legs.


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clonal studies, and molecular analyses to detect Fip1-like 1 (FIP1L1)-platelet-derived growth factorreceptor-α (PDGFRA) gene fusion should probably bedone for every patient suspected of having Churg-Strauss syndrome. The tests are highly recommendedfor those patients who are ANCA-negative with orwithout histologically proven vasculitis, in order todetect myeloid neoplasms associated with eosinophiliaand abnormalities of PDGFRA, platelet-derived growthfactor receptor-β (PDGFRB), or fibroblast growth fac-tor receptor 1 (FGFR1) (Tefferi et al., 2010). However,one cannot totally exclude a potential overlap between

some of these entities, which include lymphocytic oridiopathic hypereosinophilic syndromes, some Churg-Strauss syndrome cases, as well as fortuitous associa-tions, especially with parasitic infections.

An Evolving Disease, with Diverse Clinical and

Immunological Patterns

Other than the 3 “successive” phases described byLanham et al. (1984), Churg-Strauss syndrome hasbeen divided into several other subsets. These subgroupdivisions 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).


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Table 1. Main Differential Diagnoses of Churg-Strauss Syndrome

Other systemic vasculitides

Microscopic polyangiitis

Wegener’s granulomatosis

Polyarteritis nodosa

Giant-cell arteritisHenoch-Schönlein purpuraOthers: 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, fila-

rioses, onchocercosis, taeniases, hydatidosis, alveolar echinococcosis, myases, anisakiasis, gnathostomiasis, rarely toxoplasmosis)

Allergic bronchopulmonary aspergillosisHuman immunodeficiency virus infection (and/or hepatitis C virus infection)

(Primary) hypereosinophilic syndrome (blood eosinophilia >1,500/mm3 for >6 months)Lymphoid hypereosinophilic syndromeMyeloid hypereosinophilic syndrome (FIP1L1–PDGFRA gene fusion)

Other malignant hemopathies and solid cancers

Lymphomas (mainly T and Hodgkin’s lymphomas)Myeloproliferative neoplasms Myelodysplastic syndromesAcute or chronic leukemiasSolid 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 mastocytosisEosinophilic esophagitis and/or gastritisCholesterol emboli syndromeGleich 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, mainlydue to mesangial proliferative glomerulonephritis – affecting almost exclusively Asian sub-jects)


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ity, prognostic scores, and biological parameters, forexample, the presence or absence of ANCA and geneticpolymorphisms (Pagnoux and Guillevin, 2010). Oncethe pathophysiological mechanisms and the respectiveroles of eosinophils, ANCA, and other immune systemplayers are completely elucidated, other subsets mightbe identified in the future.

Patients can be stratified as having “poor-prognosis”Churg-Strauss syndrome when they have one or more ofthe following five-factor score (FFS) parameters: pro-teinuria >1 g/day, peak serum creatinine level >140µmol/l (1.58 mg/dl), specific cardiomyopathy, gastroin-testinal tract involvement, and central nervous systeminvolvement (Guillevin et al., 1996). When the FFS wasdevised in 1996, patients’ 5-year overall survival was88%, 74%, and 54% when 0, 1, or ≥2 of these parame-ters were present at diagnosis, respectively. At diagno-sis, the majority of the patients (55% of a cohort studiedby the group that devised the score) had none of thesefactors, clearly emphasizing that not all patients sufferfrom such severe and life-threatening manifestations(Guillevin et al., 1999).

ANCA origin and its role and mechanisms of action inChurg-Strauss syndrome remain unknown and largelyunexplored. To date, no animal model of Churg-Strausssyndrome has been established to further help elucidatethese points. Recently, a mouse model of experimentaleosinophilic skin vasculitis, induced by IgE-mediatedcutaneous reverse passive Arthus reaction, was devel-oped, but it lacks systemic vasculitis and extravasculargranulomas and, more importantly, it does not produceANCA (Ishii et al., 2009). Available models, based onimmunization with MPO, passive antiMPO ANCA, orcell transfers, only develop features of microscopicpolyangiitis.

However, it was advanced that ANCA might play a rolein Churg-Strauss syndrome, because their presenceoften precedes the onset of the vasculitic manifestationsin those positive patients. Keogh and Specks (2003)reported in their study on 91 patients (including 74 withavailable ANCA-testing results) that ANCA-positivitywas only associated with central nervous systeminvolvement. 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 243patients, showed that ANCA-positive patients sufferedmore frequently from renal and/or peripheral nervoussystem involvement(s), alveolar hemorrhage, purpura,and more often biopsy-proven vasculitis. Conversely,ANCA-negative patients were more prone to have car-

diac manifestations, lung involvement (other than alve-olar hemorrhage), and/or systemic vasculitis features.ANCA-positivity has also been postulated as an indica-tor for more severe disease, as reflected by the higherFFS and Birmingham vasculitis activity score (BVAS)at diagnosis of ANCA-positive patients. ANCA-positiv-ity’s prognostic value is unsure and controversial. At 5years, survival and relapse rates were similar for bothANCA-positive and -negative patients in one study(91.8% and 46.3% for ANCA-positive patients versus97.1% and 35.4% for ANCA-negative patients, respec-tively) (Sinico et al., 2005). However, in the most recentof these three studies on 38 patients (Baldini et al.,2009), antiMPO ANCA reappearance or titer increasewas associated with a significantly higher risk ofrelapse.

No patient subgroups have yet been so clearly delineat-ed based on other biological parameters. Each diseasephase may exhibit a specific cytokine pattern. T-helpertype-2 (Th2) cytokines (mainly interleukins IL-4, IL-5,IL-13, and IL-10) favor eosinophil differentiation, acti-vation, proliferation, and their subsequent adhesion toendothelium and tissue infiltration. T-helper type-1(Th1) cytokines [tumor necrosis factor (TNF)-α,interferon-γ and IL-2] would rather favor macrophageactivation, initially non-eosinophilic granuloma forma-tion, and vascular damage. Th2 immunological pathwayis supposed to be predominant during early phases ofthe disease (asthma). At vasculitis onset, a switchtoward Th1 pattern predominance would occur, at leasttransiently. Though elegant and straightforward tounderstand, the theory of stepwise changes of thisTh1/Th2 balance that would account for the differentclinical and histological findings of Churg-Strauss syn-drome has already and is likely to be further consideredtoo simplistic and outdated.

Other associated or intermediate cells, like hematopoi-etic CD34+ progenitor cells, capable of producing IL-5,or newly-identified Th17 cells, and/or more importantimmune dysfunctions are certainly implicated.Defective eosinophil apoptosis, albeit still debated, andendothelial or regulatory T-cell functional abnormalitiesmight also have a pathophysiological role. At diseaseonset or relapse, patients reportedly have fewerCD4+CD25+ regulatory T-cells producing IL-10, as wellas CD4+CD25- T-cells producing IL-2, than those inremission or subjects with asthma. The role ofeosinophil granule contents (major basic protein,eosinophilic cationic protein, and eosinophil-derivedneurotoxins) also has to be considered, and so as IgE


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and circulating IgE-containing immune complexes,oxygen radicals, and lysosomal proteolytic enzymesreleased by activated neutrophils (Kallenberg, 2005).IL-5 and eotaxin-3 (CCL26), an eosinotacticchemokine, have been shown as other potential markersof disease activity.

Finally, a role for B-cells in the pathophysiology ofChurg-Strauss syndrome is far more hypothetical andmainly relies on indirect evidence, like the presence ofANCA in some patients and a few reports on effectivetreatment with rituximab, a monoclonal anti-CD20 anti-body (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 theFFS can initially be treated with corticosteroids alone.As demonstrated in a prospective study on 72 suchpatients (Ribi et al., 2008), 93% of them achievedremission on corticosteroids alone but 35% relapsed(essentially during the first year of treatment), after amean follow-up of 56 months. More importantly, 79%of them persistently required low-dose corticosteroidtherapy, chiefly because of residual asthma, and, ulti-mately, 26% of all study patients needed the adjunctionof an immunosuppressant (mainly cyclophosphamideor azathioprine) at some time to control their disease.Conversely, it is mandatory that patients with one poor-prognosis factor or more receive induction therapy witha combination of corticosteroids and an immunosup-pressant, mainly cyclophosphamide (Cohen et al.,2007). A prospective, non-blinded, randomized, thera-peutic trial from the French Vasculitis Study Group(FVSG) demonstrated, based on 48 such patients, thatsuch regimen combining pulsed intravenous cyclophos-phamide therapy (600 mg/m2 every 2 weeks for 1month, then every 4 weeks thereafter), achieved com-plete remission in 87.5% of them. Notably, in that trial,no maintenance therapy was prescribed after stoppingcyclophosphamide (after 6 or 12 pulses) and relapseswere 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 hadto take low-dose corticosteroids (mean dose: 8.6mg/day, range: 0-15), and sometimes the immunosup-pressant (18%). Overall survival was 97% at 5 years inthe former of these studies, and 92% at 8 years in thelatter that included more severely ill patients.

The results of those studies underscore three points.

First, the overall global outcomes of the patients werequite good and have greatly improved over the past fewdecades. Second, patients with poor-prognosis factorshould be treated like those with Wegener’s granulo-matosis and receive a staged, remission-induction-maintenance therapy. The former should combine corti-costeroids and cyclophosphamide, with the latter beingswitched to a less toxic immunosuppressant, like aza-thioprine or, possibly, methotrexate, once remission hasbeen obtained. The optimal duration of maintenancetherapy remains unknown, but the entire induction-maintenance regimen should last at least 18-24 months.Third, despite the application of the above-mentionedstrategies, residual asthma manifestations, mild andfluctuating eosinophilia, and/or lingering vasculiticmanifestations often necessitate prolonged continuationof low-dose corticosteroids.

Taken together, these results indeed plead for new treat-ments or strategies. For patients with no poor-prognosisfactor, the adjunction of an immunosuppressant to cor-ticosteroids as first-line therapy might be more effectivethan corticosteroids alone. Cyclophosphamide wasproven effective towards this goal on a small group of25 patients, but carried an unacceptable toxicity(Gayraud et al., 1997). Metzler et al. (2004) tested intra-venous methotrexate (0.3 mg/kg/week) in this indica-tion, starting after a relatively long median of 5 monthspost-corticosteroid initiation. Six and two out of 11patients with non-life-threatening Churg-Strauss syn-drome entered complete or partial remission, respec-tively. However, in the second part of that study, 11 ofthe 23 patients, who received methotrexate to maintainremission, eventually relapsed, after a median of 9months post-methotrexate onset. However, this strategyof combining corticosteroids and methotrexate allowedsignificant corticosteroid-sparing, up to 53% of thedose during maintenance, and was well-tolerated. TheFVSG is now conducting a prospective, double-blind,randomized trial to evaluate first-line azathioprine (for12 months) combined with corticosteroids for these“good-prognosis” patients (CHUSPAN 2;ClinicalTrials.gov number, NCT00647166).

In parallel, the search for new therapies is in progress.ANCA-positivity led to the use of rituximab in a fewpatients, with some reported efficacy, at least at shortterm and on eosinophil counts (Koukoulaki et al., 2006;Pepper et al., 2008). Notably, rituximab was also effec-tive in a few patients who were ANCA-negative.Conversely, it was reported ineffective and was incrim-inated as having provoked immediate and severe bron-


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chospasms in two other ANCA-negative patients(Bouldouyre et al., 2009). The Mayo Clinic group iscurrently enrolling patients with renal involvement inan open-label study to further determine the efficacyand safety of rituximab in Churg-Strauss syndrome(ClinicalTrials.gov, NCT00424749).

Because interferon-α can reverse Th2-mediatedimmune responses and inhibit eosinophil degranulation,it has been evaluated in some patients with refractorydisease. In a recent, prospective, open-label trial(Metzler et al., 2008), all seven refractory patients whoreceived interferon-α at relatively high doses (3 MUthrice weekly) achieved remissions, after a mean of 3months. Remission persisted during the 6 months oftreatment. However, residual asthma persisted in two ofthem, peripheral neuropathy did not clearly regress intwo others, and interferon-α had to be increased to 15-21 MU/week for another two. More importantly,responses obtained with interferon-α appeared to begenerally transient and patients often relapsed afterstopping it. Furthermore, interferon-α has an appallingtoxicity profile, which limits its wider use in Churg-Strauss syndrome patients, especially those with heartinvolvement.

Omalizumab, a murine monoclonal antibody directedagainst human IgE, has been reported to be beneficial insome patients, but, like for leukotriene-receptor antago-nists previously, it has also been suspected on severaloccasions of triggering Churg-Strauss syndrome(Giavina-Bianchi et al., 2009; Wechsler et al., 2009).Therefore, use of omalizumab should remain excep-tional and is very unlikely to be part of future recom-mendations for managing Churg-Strauss syndromepatients.

Tyrosine-kinase inhibitors, like imatinib, or anti-IL-5antibodies yielded some promising therapeutic resultsfor primary hypereosinophilic syndrome, but their placein Churg-Strauss syndrome therapy remains to be deter-mined (Kahn et al., 2010; Kalsch et al., 2008). Twoopen-label studies on mepolizumab are ongoing, one inGermany (MEPOCHUSS; ClinicalTrials.gov,NCT00716651) and the other in the United States(MATOCSS; ClinicalTrials.gov, NCT00527566). Nonehas yet been initiated on tyrosine-kinase inhibitors totreat Churg-Strauss syndrome. Notably, one patientdeveloped ANCA-positive and biopsy-proven Churg-Strauss syndrome during treatment for asthma withmasitinib mesylate, a new tyrosine kinase inhibitor cur-rently under investigation (Granel et al., 2009).However, in that case, Churg-Strauss syndrome may

have been unmasked as the consequence of the rapidcorticosteroid withdrawal, which was allowed becauseof this new drug’s efficacy on asthma manifestations.

Several other agents or therapies have occasionallybeen reported to be beneficial in some patients withrefractory and/or relapsing Churg-Strauss syndrome.Intravenous immunoglobulins may represent an alter-native 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 dis-ease, especially those with neuropathy and/or car-diomyopathy (Taniguchi et al., 2007). While no argu-ment clearly supports its systematic administration atthe time of diagnosis, plasma exchange might also havea niche in the treatment of ANCA-positive patients withrefractory disease, severe kidney involvement, and/orperipheral neuropathy, as demonstrated, or at least sug-gested, for other ANCA-associated vasculitides(Wegener’s granulomatosis and microscopic polyangi-itis) (Guillevin and Pagnoux, 2003). More anecdotally,effective use of mycophenolate mofetil, hydroxyurea,cyclosporin A, or TNF-α blockers, like infliximab oretanercept, even though the underlying pathophysiolog-ical reasons for their use are less obvious, has also beenreported.

Finally, adequate management of Churg-Strauss syn-drome patients also includes prophylactic treatments,like co-trimoxazole to prevent pneumocystosis inpatients receiving cyclophosphamide. Because severalparasitic infections can cause blood eosinophilia andbecause corticosteroids represent the basis of theChurg-Strauss syndrome treatment and can exacerbateunderlying parasitic infections, patients should largelybe given one weight-adjusted dose of ivermectin and/oralbendazole, especially when they had travelled or livedin countries endemic for Strongyloides stercoralisinfection or ankylostomiasis.

Symptomatic treatment of asthma manifestations is, ofcourse, indicated and necessary, but the use ofleukotriene-receptor antagonists or omalizumab shouldprobably be avoided or at least be used prudently. Whenfeasible, sperm cryopreservation should be proposedfor males or gonadal preservation for women receivingcytotoxic drugs. Physiotherapy is essential for patientswith motor neuropathy.

Conclusion

Substantial advances have been made in the under-


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standing of immune mechanisms implicated in Churg-Strauss syndrome and its management, since its firstdescription more than half a century ago. While it defin-itively remains a systemic necrotizing small-sized ves-sel vasculitis, its membership in the ANCA-associatedvasculitis group has become more controversial. Morecomplex and numerous mechanisms are involved inChurg-Strauss syndrome (Hoffman and Langford,2005; Pagnoux and Guillevin, 2010) and only 40% ofthe patients are ANCA-positive. Similarly, one of itsearlier denominations, allergic granulomatous angiitis(Churg and Strauss, 1951), has become dated becausenot all patients have (eosinophilic) granulomas.Moreover, several disease subgroups have been identi-fied, essentially based on clinical or biological findings.Other subgroups may be brought forth in the future,relying on more subtle molecular and genetic character-istics.

Therapeutic strategies also require further improve-ment. Treatment should be adapted as closely as possi-ble to each patient’s characteristics, because some man-ifestations carry a higher risk of mortality and relapse,and/or potential treatment-related toxicity. New treat-ments are needed to lower the rate of frequent, low-dose but long-term, corticosteroid-dependence that rep-resents a major issue and the lingering disappointmentin current therapeutic strategies for Churg-Strauss syn-drome.

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, 2009.

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, 2009.

Bibby S, Healy B, Steele R, Kumareswaran K, Nelson H,

Beasley R. Association between leukotriene receptor antago-

nist therapy and Churg-Strauss syndrome: an analysis of the

FDA AERS database. Thorax 65(2):132-8, 2010.

Bouldouyre MA, Cohen P, Guillevin L. Severe bron-

chospasm associated with rituximab for refractory Churg-

Strauss syndrome. Ann Rheum Dis 68(4):606, 2009.

Churg J, Strauss L. Allergic angiitis and periarteritis nodosa.

Am J Pathol 27:277-301, 1951.

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, 2007.

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):1649-54, 2004.

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, 1997.

Giavina-Bianchi P, Giavina-Bianchi M, Agondi RC, Kalil J.

Anti-IgE in Churg-Strauss syndrome. Thorax 64(3):272;

author reply 272-3, 2009.

Granel B, Rossi P, Koeppel MC, Hermine O, Charpin D.

Churg and Strauss vasculitis in the course of masitinib treat-

ment: a first report. Allergy, [Epub ahead of print], 2009.

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 prospec-

tive study in 342 patients. Medicine (Baltimore) 75(1):17-28,

1996.

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, 1999.

Guillevin L, Pagnoux C. Indications of plasma exchanges for

systemic vasculitides. Ther Apher Dial 7(2):155-60, 2003.

Hamilos DL, Christensen J. Treatment of Churg-Strauss syn-

drome with high-dose intravenous immunoglobulin. J

Allergy Clin Immunol 88(5):823-4, 1991.

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):1076-80, 2005.

Hoffman GS, Langford CA. Are there different forms of life

in the antineutrophil cytoplasmic antibody universe? Ann

Intern Med 143(9):683-5, 2005.

Ishii T, Fujita T, Matsushita T, Yanaba K, Hasegawa M,

Nakashima H, Ogawa F, Shimizu K, Takehara K, Tedder TF,


et al. Establishment of experimental eosinophilic vasculitis

by IgE-mediated cutaneous reverse passive arthus reaction.

Am J Pathol 174(6):2225-33, 2009.

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, 2010.

Kallenberg CG. Churg-Strauss syndrome: just one disease

entity? Arthritis Rheum 52(9):2589-93, 2005.

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, 2008.

Keogh KA, Specks U. Churg-Strauss syndrome: clinical

presentation, antineutrophil cytoplasmic antibodies, and

leukotriene receptor antagonists. Am J Med 115(4):284-90,

2003.

Koukoulaki M, Smith KG, Jayne DR. Rituximab in Churg-

Strauss syndrome. Ann Rheum Dis 65(4):557-9, 2006.

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, 1984.

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 pul-

monary relapse ratio during maintenance treatment. Clin Exp

Rheumatol 22(6 Suppl 36):S52-61, 2004.

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, 2008.

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, 2009.

Pagnoux C, Kluger N, Francès C, Guillevin L. Cutaneous

granulomatous vasculitis and extravascular granulomas.

Expert Rev Dermatol 1(2):315-26, 2006.

Pagnoux C, Guilpain P, Guillevin L. Churg-Strauss syn-

drome. Curr Opin Rheumatol 19(1):25-32, 2007.

Pagnoux C, Guillevin L. Churg-Strauss syndrome: evidence

for disease subtypes? Curr Opin Rheumatol 22(1):21-8,

2010.

Pepper RJ, Fabre MA, Pavesio C, Gaskin G, Jones RB, Jayne

D, Pusey CD, Salama AD. Rituximab is effective in the treat-

ment of refractory Churg-Strauss syndrome and is associated

with diminished T-cell interleukin-5 production.

Rheumatology (Oxford) 47(7):1104-5, 2008.

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, 2008.

Rutberg SA, Ward DE, Roth BJ. Churg-Strauss syndrome

and pregnancy: successful treatment with intravenous

immunoglobulin. J Clin Rheumatol 8(3):151-6, 2002.

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, 2005.

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 cyto-

plasmic antibodies in Churg-Strauss syndrome. Arthritis

Rheum 52(9):2926-35, 2005.

Sinico RA, Bottero P. Churg-Strauss angiitis. Best Pract Res

Clin Rheumatol 23(3):355-66, 2009.

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, 2007.

Tefferi A, Gotlib J, Pardanani A. Hypereosinophilic syn-

drome and clonal eosinophilia: point-of-care diagnostic algo-

rithm and treatment update. Mayo Clin Proc 85(2):158-64,

2010.

Watts RA, Lane S, Scott DG. What is known about the epi-

demiology of the vasculitides? Best Pract Res Clin

Rheumatol 19(2):191-207, 2005.

Wechsler ME, Wong DA, Miller MK, Lawrence-Miyasaki L.

Churg-Strauss syndrome in patients treated with omalizum-

ab. Chest 136(2):507-18, 2009.

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, 2010.

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.

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