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Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): Treatment and prognosis

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): Treatment and prognosis
Author:
Talmadge E King, Jr, MD
Section Editors:
Kevin R Flaherty, MD, MS
Richard J Glassock, MD, MACP
Bruce S Bochner, MD
Deputy Editor:
Paul Dieffenbach, MD
Literature review current through: Nov 2022. | This topic last updated: May 10, 2022.

INTRODUCTION — Eosinophilic granulomatosis with polyangiitis (EGPA; Churg-Strauss) is classified as an antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis of the small and medium-sized arteries, although the vasculitis is often not apparent in the initial phases of the disease, and approximately 60 percent do not have detectable ANCA [1].

The most commonly involved organ is the lung, although vasculitis of extrapulmonary organs is largely responsible for the morbidity and mortality associated with EGPA. The goals of therapy are to achieve rapid onset of remission (particularly organ-threatening manifestations), maintain a long remission, and minimize complications of therapy.

The treatment and prognosis of EGPA will be reviewed here. The epidemiology, pathogenesis, clinical features, and diagnosis of this disorder are discussed separately. (See "Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)" and "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)".)

ASSESSING VASCULITIS SEVERITY — The 2021 American College of Rheumatology/Vasculitis Foundation (ACR/VF) guidelines approach initial treatment of EGPA by differentiating patients with severe EGPA that is organ or life-threatening from those with nonsevere disease [1]. Organ or life-threatening features include, but are not limited to, active glomerulonephritis, pulmonary hemorrhage, cerebral vasculitis, progressive peripheral or cranial neuropathy, gastrointestinal bleeding due to vasculitis, pericarditis, or myocarditis.

Two other scoring systems are used to assess vasculitis disease activity in patients with EGPA and other vasculitides: the "five-factor score" (FFS) and the Birmingham Vasculitis Activity Score (BVAS). The FFS, while it does not distinguish severe and nonsevere disease for initial EGPA management, may be helpful for identifying patients in need of more aggressive treatment (table 1) [1,2]. The BVAS is a research tool that is seldom used in clinical practice [3].

Five-factor score (FFS) – The FFS, initially devised in 1996 [4], was revised in 2011 (table 1) [2]:

Age >65

Cardiac insufficiency

Gastrointestinal involvement

Renal insufficiency (stabilized peak plasma creatinine concentration >1.7 mg/dL [150 micromol/L])

Absence of ear, nose, and throat (ENT) manifestations (presence is associated with a better prognosis)

The presence of each factor is given one point. The FFS score ranges from 0 to 2: a score of 0 is given when none of the factors are present, a score of 1 for one factor, and a score of 2 for two or more factors. This scoring system has also been correlated with prognosis. (See 'Prognosis' below.)

Birmingham Vasculitis Activity Score (BVAS) – The BVAS has largely been applied in clinical research to patients with granulomatosis with polyangiitis and microscopic polyangiitis, but is also used in EGPA [5,6]. The score includes both general symptoms (arthralgia, arthritis, and fever) and involvement of eight major organ systems (skin, mucous membranes, ear/nose/throat, cardiovascular, pulmonary, gastrointestinal, renal, nervous system) [3]. At each site, persistent symptoms or manifestations (eg, sensorineural deafness, pulmonary nodule, alveolar hemorrhage) are given one point and new or worse symptoms are given two points. The score ranges from 0 (complete remission) to a maximum of 68. (See "Overview of the management of vasculitis in adults", section on 'Monitoring'.)

REMISSION INDUCTION — The primary therapy for EGPA is systemic glucocorticoids [1]. An additional immunomodulatory agent is typically added, guided by disease severity and specific organ involvement [1,7]. (See 'Assessing vasculitis severity' above.)

Asthma is additionally managed according to current guidelines, as described separately. (See "An overview of asthma management", section on 'Initiating pharmacologic treatment' and "Treatment of severe asthma in adolescents and adults", section on 'Adjusting controller therapy'.)

Systemic glucocorticoids — Systemic glucocorticoid therapy is the mainstay of treatment for EGPA. For adults with evidence of systemic vasculitis, treatment is initiated with prednisone (or equivalent) at a dose of 0.5 to 1 mg/kg (up to 80 mg) per day [1,8]. The higher dose is used for patients with more severe vasculitis (eg, impending respiratory failure, cardiac involvement, glomerulonephritis, neuropathy). With acute multiorgan disease, intravenous (IV) glucocorticoid (eg, methylprednisolone 500 to 1000 mg IV daily for three to five days) is used for initial therapy, followed by oral glucocorticoid therapy as noted [1,9,10].

Most patients with EGPA, who do not have poor prognostic factors, achieve a remission with glucocorticoid therapy alone, although relapses are common [11]. In a study of 72 patients without poor prognosis factors (ie, no cardiac, renal, or central nervous system involvement) followed for five years or longer, 93 percent achieved a remission with glucocorticoid therapy alone [11]. However, patients with involvement of the heart, kidney, gastrointestinal tract, or central nervous system usually require additional immunosuppressive therapy as described below. (See 'Glucocorticoid dosing and taper' below and 'Cyclophosphamide' below.)

Severe EGPA — For patients with severe EGPA and organ or life-threatening disease manifestations as defined by the American College of Rheumatology/Vasculitis Foundation (ACR/VF) guidelines (see 'Assessing vasculitis severity' above), we recommend including cyclophosphamide or rituximab in the remission induction regimen rather than glucocorticoids alone or glucocorticoids plus mepolizumab, in agreement with the ACR/VF guidelines [1].

Choice of agent

Preference for cyclophosphamideCyclophosphamide may be preferred in patients with active cardiac involvement because cardiomyopathy is an independent predictor of mortality in EGPA and experience with cyclophosphamide is more robust in these patients [1]. In addition, cyclophosphamide may be preferred over rituximab in patients who are antineutrophil cytoplasmic antibody (ANCA)-negative and have severe neurologic or gastrointestinal manifestations.

Preference for rituximabRituximab may be preferred in patients with a positive ANCA, active glomerulonephritis, prior cyclophosphamide therapy, and those at risk for gonadal toxicity [1].

Cyclophosphamide — Cyclophosphamide is a remission induction agent that is added to systemic glucocorticoids for patients with severe, multi-organ EGPA [1,4,12-21]. The decision to add cyclophosphamide is based on the severity of disease in terms of number of organ systems involved and degree of impairment. A five-factor score (FFS) of 2 or greater (table 1), which correlates with severe disease, is associated with greater mortality among patients who are treated with glucocorticoids alone, compared with those who also receive cyclophosphamide [16,18]. We favor cyclophosphamide in such patients due to the prompt onset of action and improved outcomes with cyclophosphamide. (See 'Assessing vasculitis severity' above.)

Dosing and administrationCyclophosphamide can be administered orally (eg, 1.5 to 2 mg/kg every day for three to six months) or intravenously (eg, 15 mg/kg every two weeks for three doses and then every three weeks for at least three doses) with dose reductions for kidney function and age ≥70 years, as described for granulomatosis with polyangiitis (GPA) [1,17]. Insufficient data are available for EGPA to make a clear recommendation between oral and intravenous therapy. Extrapolating from GPA, outcomes with daily and monthly regimens are similar; a slightly greater risk of bladder toxicity with the daily regimen and a slightly greater risk of relapse with the monthly regimen have been noted. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Cyclophosphamide-based regimen'.)

Dosing and monitoring considerations for daily and monthly administration of cyclophosphamide are described separately. Mercaptoethane sulfonate (Mesna) is sometimes used to reduce bladder toxicity during infusions of cyclophosphamide, although practices vary among vasculitis centers [1,9,20]. (See "General principles of the use of cyclophosphamide in rheumatic diseases".)

The duration of cyclophosphamide therapy remains controversial. When used to treat GPA, typically a six-month regimen is used. In a preliminary study of patients with EGPA, those receiving six pulses of cyclophosphamide had a greater number of mild relapses than those receiving 12 pulses (94 versus 41 percent) [19]. However, we favor six pulses of cyclophosphamide as further data are needed to clarify whether the benefits of 12 pulses of cyclophosphamide outweigh the additional risks. (See "General toxicity of cyclophosphamide in rheumatic diseases" and "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Cyclophosphamide-based regimen'.)

Efficacy – The efficacy of cyclophosphamide in EGPA is supported by the following studies:

In a meta-analysis of 277 patients with EGPA, microscopic polyangiitis, and polyarteritis and an FFS of 2 (table 1), survival was significantly prolonged among patients treated with cyclophosphamide and glucocorticoids rather than glucocorticoids alone [18].

Patients with an FFS of 1, particularly in the presence of cardiac or central nervous system involvement, tend to have a higher mortality than those with an FFS of 0 [4,17,19] (table 1). In a series of patients with an FFS of 1, a lower mortality was noted among those who were treated with cyclophosphamide compared with a separate group in which only some of the patients received cyclophosphamide (7 versus 26 percent mortality, respectively) [4].

Rituximab — Rituximab is an anti-CD20 monoclonal antibody directed against B cells that is licensed for the treatment of GPA and microscopic polyangiitis (MPA) in the United States and Europe. Several case reports and case series have described improvement in refractory or relapsing EGPA [22-35].

Dosing and administration [1]:

Adults: 375 mg/m2 IV weekly for four doses or 1000 mg IV on days 1 and 15

Children: 375 mg/m2 IV weekly for four doses or 575 mg/m2 for patients with body surface area ≤1.5m2 or 750 mg/m2 for patients with body surface area >1.5m2 with a typical maximum of 1 g per infusion, administered on days 1 and 15

Efficacy – Response to rituximab was assessed in a retrospective study of 41 patients seen at four highly specialized vasculitis centers [33]. After the first infusion with rituximab, improvements in disease activity (remission and partial response) were achieved in 83 percent of patients at six months, and at 12 months the improvement rate was nearly 90 percent. Although the prednisolone dose could be reduced in most patients, only 6 percent of patients were off all treatment with prednisolone by the end of the observation period. Rituximab appeared to cause immediate and severe bronchospasm in two patients with ANCA-negative EGPA [36]. A subsequent study in patients with relapsing EGPA showed that rituximab reduced disease activity and prednisolone requirement, but relapses occurred despite maintenance rituximab [37]. In a single-center retrospective cohort study of 17 patients with EGPA (13 positive for myeloperoxidase antibodies [MPO]) who presented with severe uncontrolled or glucocorticoid-dependent asthma and received rituximab for remission induction, rituximab appeared to be safe and had glucocorticoid-sparing efficacy for asthma control [38]. A small, retrospective study showed improved cardiac function with lower circulating eosinophil numbers after rituximab therapy in ANCA-negative and ANCA-positive EGPA patients with myocardial or endocardial involvement [39]. (See "Overview of biologic agents and kinase inhibitors in the rheumatic diseases", section on 'B-cell depletion and inhibition'.)

A systematic review of observational studies including 368 adults with EGPA showed that the majority of the evaluable EGPA patients treated with rituximab achieved remission (80 percent partial and complete remission rate). However, heterogeneity among these studies limit interpretation of results, and methodologic differences prevent comparison of rituximab with other biologic agents [40].

Nonsevere EGPA — Nonsevere EGPA is defined as absence of life or organ-threatening manifestations [1]. Patients with nonsevere EGPA often have rhinosinusitis, asthma, eosinophilic pneumonia or transient eosinophilic pulmonary infiltrates, and mild systemic disease (eg, uncomplicated cutaneous) manifestations.

Mepolizumab — For adults with nonsevere EGPA, we suggest adding mepolizumab to systemic glucocorticoids rather than cyclophosphamide, rituximab, or methotrexate in agreement with the ACR/VF guidelines [1]. Other anti-IL-5 agents may also be effective, but supportive evidence is less robust.

The use of anti-IL-5 or anti-IL-5 receptor therapy in severe asthma and other conditions such as hypereosinophilic syndrome is described separately. (See "Treatment of severe asthma in adolescents and adults", section on 'Anti-IL-5 therapy' and "Hypereosinophilic syndromes: Treatment", section on 'Mepolizumab'.)

Dosing and administration – The dose of mepolizumab for the treatment of EGPA, advised by the ACR/VF guidelines and approved by the FDA, is 300 mg every four weeks; this dose is higher than the dose of 100 mg every four weeks approved by the FDA for severe asthma [41]. Whether the 300 mg dose is superior to a 100 mg dose for EGPA has not been determined. A multicenter, retrospective analysis of 203 EGPA patients treated with mepolizumab (168 received 100 mg/four weeks; 35 received 300 mg/four weeks) showed comparable efficacy for the control of the systemic and respiratory disease manifestations and a similar low rate of adverse events [42]. Other data suggest that mepolizumab 100 mg every four weeks may be effective in treating severe asthma in many EGPA patients with vasculitis in remission, but a higher dose may be needed for optimal outcomes in some patients [43,44]. The two doses should be compared in the setting of a controlled trial.

Efficacy – The efficacy of mepolizumab in patients with EGPA has been assessed in a randomized trial [45] and in case reports [46-48]:

In a multicenter trial, 136 patients with relapsing or refractory EGPA were randomly assigned to receive mepolizumab 300 mg or placebo, subcutaneously every four weeks for 52 weeks [45]. Mepolizumab led to significantly more accrued weeks of remission (Birmingham Vasculitis Activity Score [BVAS] 0 and prednisone ≤4 mg/day), than placebo (odds ratio [OR] 5.91, 95% CI 2.68-13.03) and a higher percentage of participants in remission at weeks 36 and 48 (OR 16.74, 95% CI 3.61-77.56). Overall, 44 percent of mepolizumab-treated subjects were able to taper prednisolone or prednisone to 4 mg/day or less, compared with 7 percent of subjects taking placebo. However, 47 percent of participants in the mepolizumab group did not achieve remission.

In 10 patients with refractory or relapsing EGPA (defined by a BVAS of >3), mepolizumab was administered in nine infusions, 750 mg once every four weeks, followed by maintenance therapy with methotrexate and glucocorticoids (tapered dosage to <7.5 mg/day) [46]. Eight patients achieved a BVAS of 0 and a glucocorticoid dose less than 7.5 mg/day. One additional patient achieved a BVAS of 0, but was not able to decrease the glucocorticoid dose below 7.5 mg/day. Another patient achieved a remission, but was subsequently excluded from the study due to nonadherence. After switching to methotrexate, two major and five minor relapses occurred over a median follow-up of 10 months. (See 'Assessing vasculitis severity' above.)

Mepolizumab was administered monthly for four doses to seven patients with EGPA [47]. The patients who were all on systemic glucocorticoid therapy had a decrease in peripheral eosinophil counts and were able to decrease their prednisone dose by 60 percent. By 20 weeks after discontinuation of mepolizumab, peripheral eosinophils had increased to premepolizumab levels, and asthma exacerbations had necessitated an increase in systemic glucocorticoids almost to the premepolizumab level.

In a case report, EGPA, manifest by asthma, mononeuritis multiplex, and pulmonary opacities with 60 percent eosinophils on bronchoalveolar lavage, was refractory to high-dose prednisone and cyclophosphamide, but responded to intravenous administration of mepolizumab (750 mg/month) [48].

Methotrexate, azathioprine, mycophenolate as alternative agents — Alternative induction regimens for patients with nonsevere EGPA (eg, FFS of 1, but mild nonorgan-threatening disease) include initial treatment with glucocorticoids plus azathioprine, methotrexate, or mycophenolate [1,49,50]. These agents are preferred over cyclophosphamide or rituximab in patients with nonsevere EGPA because of lower toxicity [1], but have not been compared directly with mepolizumab.

The use of an alternative induction regimen was evaluated in a study of 100 patients with early systemic ANCA-positive vasculitides (including EGPA) that compared glucocorticoids plus methotrexate with glucocorticoids plus cyclophosphamide [49]. The remission success rate was similar at six months (90 and 94 percent, respectively). However, the methotrexate regimen was less successful for patients with more extensive disease or pulmonary involvement. (See 'Methotrexate' below.)

MethotrexateMethotrexate is typically initiated at a dose of 15 mg/week orally or subcutaneously, with increases in dose every two to eight weeks of 5 mg/week up to 25 mg/week, as described for granulomatosis with polyangiitis. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Dosing of methotrexate'.)

AzathioprineAzathioprine is typically initiated at a dose of 50 mg/day if thiopurine methyltransferase (TPMT) testing has not been performed prior to initiation of therapy. If this dose is tolerated well at one week, the daily dose can be increased over several weeks to 2 mg/kg per day. If TPMT testing is performed prior to the initiation of therapy and is normal, azathioprine can be initiated at 2 mg/kg per day; the maximum dose should generally not exceed 200 mg/day. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Dosing of azathioprine' and "Pharmacology and side effects of azathioprine when used in rheumatic diseases".)

Mycophenolate – The ACR/VF guidelines include mycophenolate as an alternative induction agent, but data in EGPA are limited [1]. Dosing of mycophenolate mofetil in EGPA would follow recommendations for GPA with a dose of 750 to 1500 mg orally twice daily (total 1.5 to 3 g daily). Details of dosing are provided separately. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Dosing of mycophenolate' and "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases".)

REMISSION MAINTENANCE

Glucocorticoid dosing and taper — Once disease manifestations have come under control, the glucocorticoid dose is gradually tapered over variable time periods ranging from 3 to 18 months, as tolerated. A portion of patients will need long-term low-dose oral glucocorticoid therapy (eg, prednisone 10 mg/day or less). In the study of 72 patients described above (see 'Systemic glucocorticoids' above), almost 80 percent of those who achieved a remission required long-term low-dose glucocorticoid therapy, mainly to control respiratory disease [11].

For patients whose initial induction therapy was systemic glucocorticoids alone, but persistent disease manifestations have not allowed tapering below a moderate to high dose (eg, prednisone more than 10 mg daily), an immunosuppressive agent is often added for a glucocorticoid-sparing effect. The data in support of this come from case series and extrapolation from the management of granulomatosis with polyangiitis [20,21]. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Maintenance therapy'.)

In EGPA, late relapses of systemic vasculitis after a successful response to treatment are uncommon [51]. However, premature withdrawal of treatment can result in recurrence.

Prevention of complications due to chronic systemic glucocorticoid therapy is discussed separately. (See "Major side effects of systemic glucocorticoids" and "Prevention and treatment of glucocorticoid-induced osteoporosis".)

Choice of maintenance agent — After remission induction (approximately 6 to 12 months), patients are transitioned to a maintenance regimen. The agents employed for maintenance of remission depend in part on the agents that were used for remission induction and response to induction therapy; our approach aligns with that of the American College of Rheumatology/Vasculitis Foundation (ACR/VF) guidelines [1]. Maintenance immunosuppressive therapy is typically continued for 12 to 18 months. Longer-term or indefinite maintenance therapy may be warranted in patients with multiple relapses.

Severe disease

For patients with severe EGPA who received cyclophosphamide for remission induction, we suggest maintenance therapy with methotrexate, azathioprine, or mycophenolate mofetil rather than rituximab [52,53]. The maintenance agent is initiated two to four weeks after the last dose of cyclophosphamide. No comparator studies have been done that help guide the selection of a specific agent. Rituximab has not been studied for remission maintenance in EGPA. (See 'Azathioprine' below and 'Methotrexate' below and 'Mycophenolate mofetil' below.)

For patients with severe EGPA who achieved remission with rituximab, it is reasonable to continue rituximab [1]. (See 'Rituximab' below.)

Nonsevere disease

For patients with nonsevere EGPA who received mepolizumab for remission induction, we suggest continuing mepolizumab and tapering prednisone (or equivalent) as tolerated. (See 'Mepolizumab and other anti-IL-5 agents' below.)

For patients with nonsevere EGPA who achieved remission with methotrexate, azathioprine, or mycophenolate, we suggest continuation of that agent [1].

Azathioprine — In patients with EGPA, azathioprine (AZA) is typically used after induction of remission with cyclophosphamide or as a glucocorticoid-sparing agent in patients requiring long-term treatment with prednisone at doses greater than 15 mg per day [11,54]. Analysis of the thiopurine methyltransferase (TPMT) gene prior to the administration of AZA may help predict those individuals at risk for severe toxicity. When deficiency of the TPMT enzyme is found, we choose an alternate immunosuppressive agent, such as methotrexate or mycophenolate, although data regarding the use of these agents are limited. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Pharmacogenetics and azathioprine toxicity'.)

Different regimens have been reported for initiation of AZA: starting with the target dose of 2 mg/kg lean body weight versus starting at 25 to 50 mg/day for the first week to test for drug hypersensitivity and then increasing by 0.5 mg/kg per day every four to six weeks up to the target dose. In general, we favor going directly to the target dose in order to avoid a relapse during the time that the patient is on suboptimal doses. The direct approach was used successfully in a trial of patients with granulomatosis with polyangiitis [55]. A lower target dose is indicated in patients with renal insufficiency. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Maintenance therapy' and "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Dose titration and monitoring'.)

Following the pattern established for granulomatosis with polyangiitis, the timing of initiation of maintenance AZA is based on whether the patient was on daily or monthly dosing of cyclophosphamide. For patients on daily dosing, the switch is immediate; for those on monthly dosing, AZA is begun approximately two weeks after the last dose of cyclophosphamide. This is delayed further if the white blood cell count is below 4000 cells/microL, or the absolute neutrophil count is below 1500 cells/microL. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Maintenance therapy'.)

Data in support of a role for azathioprine in the treatment of EGPA are limited. An open label trial evaluated azathioprine in 10 patients after treatment failure with glucocorticoids alone; five subsequently achieved remission [11]. A small trial that included 51 patients with EGPA with nonsevere disease and a five-factor score (FFS) of 0 (table 1) evaluated the addition of azathioprine or placebo to standard daily glucocorticoid therapy [52]. Among patients with EGPA, approximately 52 percent had sustained remission at 24 months, but no difference was noted between azathioprine and placebo groups in rates of attaining remission, risk of relapse, or cumulative dose of glucocorticoids over 24 months.

Methotrexate — Methotrexate is sometimes used in EGPA to maintain a remission after induction with cyclophosphamide or as a glucocorticoid-sparing agent. However, azathioprine may be preferred over methotrexate because it is difficult to monitor for methotrexate pneumonitis in a patient with other causes of dyspnea, such as asthma and pulmonary eosinophilia.

Data regarding the use of methotrexate for maintenance of remission in EGPA are limited. In a case series of 25 patients with EGPA, methotrexate was associated with relapse rate of 48 percent, when used for maintenance [56]. On the other hand, the prednisone dose was decreased by an average of 50 percent in these patients.

Methotrexate is occasionally used as an alternative to cyclophosphamide to induce a remission in patients with an FFS of 1 and mild disease. (See 'Methotrexate, azathioprine, mycophenolate as alternative agents' above.)

Dosing and administration – The dosing regimen for methotrexate comes from the larger experience using this medication in patients with granulomatosis with polyangiitis (GPA). Methotrexate is typically initiated at a dose of 15 mg/week orally with increases in dose of 5 mg/week every two to eight weeks up to 25 mg/week, if tolerated. Most patients prefer oral over parenteral therapy, although gastrointestinal toxicities may be reduced by weekly subcutaneous administration. Patients are also treated with daily folic acid 1 mg/day or leucovorin (2.5 to 5 mg) once per week given 24 hours after methotrexate. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Maintenance therapy' and "Major side effects of low-dose methotrexate".)

Methotrexate should be avoided in patients with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 and is contraindicated during pregnancy.

Mycophenolate mofetil — The ACR/VF guidelines view mycophenolate as an acceptable agent for remission maintenance in EGPA based on experience with GPA and case reports of success in EGPA [1]. A few case reports have described successful use of mycophenolate mofetil in EGPA [21,57-60]. In one case report, mycophenolate mofetil plus oral glucocorticoids was used to treat a patient with EGPA manifest by asthma, chronic rhinosinusitis, cutaneous vasculitis, and a positive ANCA (pANCA with antibodies to myeloperoxidase [MPO]) [57]. Dosing and potential side effects of mycophenolate are discussed separately. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases".)

Mepolizumab and other anti-IL-5 agents — Preparations of anti-interleukin (IL)-5 monoclonal antibodies (mepolizumab, reslizumab) and an anti-IL-5 receptor antibody (benralizumab) are approved for use in severe asthma, and accumulating evidence supports a role in EGPA.

Mepolizumab – For patients who have achieved remission with mepolizumab and systemic glucocorticoids, we suggest continuing mepolizumab. Long-term maintenance therapy for EGPA with mepolizumab has not been formally examined.

Preliminary evidence suggests that reslizumab and benralizumab may also be of benefit in EGPA:

Reslizumab – In a cohort of nine EGPA patients with severe eosinophilic asthma requiring continuous glucocorticoids to maintain disease control, 48 weeks of treatment with intravenous reslizumab (3 mg/kg every four weeks) was associated with a reduction in glucocorticoid use and improvements in patient-reported outcomes [61]. An open-label study of the safety and efficacy of intravenous reslizumab (3 mg/kg) in 10 subjects found it to be generally safe and effective as treatment for EGPA [62]. (See "Treatment of severe asthma in adolescents and adults", section on 'Reslizumab'.)

BenralizumabBenralizumab, a fully humanized monoclonal antibody that binds with high affinity to the alpha-chain of the interleukin-5 receptor and mediates antibody-dependent eosinophil depletion, reduced glucocorticoid intake and improved clinical manifestations and patient-reported outcomes in patients with EGPA [63-65]. (See "Treatment of severe asthma in adolescents and adults", section on 'Benralizumab'.)

A clinical trial is in progress to compare benralizumab and mepolizumab in EGPA (clinicaltrials.gov NCT04157348).

Rituximab — The dose of rituximab used for remission maintenance is 500 to 1000 mg IV every four to six months in adults and 250 mg/m2 IV every six months in children [1]. For remission maintenance in GPA and MPA, the ACR/VF guidelines advise redosing based on a schedule rather than based on ANCA levels; this may be extrapolated to EGPA.

Adjunctive topical therapy for asthma and chronic rhinosinusitis — Adjunctive therapies, such as inhaled glucocorticoids, long-acting bronchodilators, and leukotriene modifying agents, are typically used to help control upper and lower respiratory tract disease, as described separately. (See "An overview of asthma management", section on 'Initiating pharmacologic treatment' and "Treatment of severe asthma in adolescents and adults", section on 'Adjusting controller therapy' and "Chronic rhinosinusitis: Management", section on 'Intranasal corticosteroids'.)

LESS COMMON THERAPIES — Second-line treatment options may be considered when patients have disease refractory to the above-described conventional therapy or have therapy-limiting side effects. The data in support of these agents are limited to case reports and case series.

Leflunomide — Leflunomide, an inhibitor of pyrimidine synthesis, is considered an alternate agent for remission maintenance in EGPA after induction with cyclophosphamide or as a glucocorticoid-sparing agent [1,20]. The American College of Rheumatology/Vasculitis Foundation (ACR/VF) guidelines prefer methotrexate or azathioprine over leflunomide for remission maintenance as data in support of leflunomide for EGPA are limited [1]. The dose of leflunomide used in one case series was 10 to 30 mg/day [20]. This is within the range of dosing used to treat rheumatoid arthritis where there is a greater experience. The dosing and adverse effects of leflunomide in patients with rheumatoid arthritis are described separately. (See "Pharmacology, dosing, and adverse effects of leflunomide in the treatment of rheumatoid arthritis".)

Anti-IgE therapy — Several observational reports have described a beneficial effect of omalizumab (anti-IgE) on certain manifestations of EGPA, such as asthma and sinonasal disease. While omalizumab may have an indirect apoptotic effect on eosinophils, it would not be expected to impact vasculitis. Further studies of safety and efficacy are needed before this approach can be recommended for routine treatment of EGPA. (See "Anti-IgE therapy".)

In a retrospective series of 17 patients with steroid-dependent asthma and refractory or relapsing EGPA, omalizumab was associated with a decrease in prednisone dosage to ≤7.5 mg/day without asthma or sinonasal exacerbation in six (35 percent), prednisone dose >7.5 mg/day but no asthma or sinonasal exacerbations in five (30 percent), and no improvement in six (35 percent) [66]. Approximately half of the patients received another immunosuppressive agent in addition to prednisone. Prednisone doses were able to be tapered from a mean of 16 mg/day to 10 mg/day after three months and continued at this level for the 12 months of the study. Mean eosinophil counts did not decrease during omalizumab therapy in this study. While omalizumab may have a steroid-sparing effect, reducing the prednisone dose was associated with disease flares in some patients.

A case report described a patient with EGPA and nonallergic asthma, whose asthma was refractory to systemic and inhaled glucocorticoid and long-acting beta agonists; asthma control improved with anti-IgE (omalizumab) therapy [67].

Another report described improvement in asthma control and a reduction in eosinophil counts with anti-IgE in two patients whose EGPA was not controlled by systemic glucocorticoid [68].  

An observational study of five patients showed that during the 36 months of omalizumab treatment asthma progressively improved and the eosinophilia decreased. The oral prednisone dose was reduced or withdrawn during treatment [69].

Conversely, a temporal association between omalizumab use and the development of EGPA has been reported, although sometimes in the context of tapering of systemic glucocorticoids [70-72].

Hydroxyurea — Hydroxyurea, an agent that is used in the treatment of the hypereosinophilic syndrome, was found to be beneficial as a glucocorticoid-sparing agent in a patient with EGPA [73]. Hydroxyurea has relatively few side effects compared with other chemotherapeutic agents, although hematological toxicity and gastrointestinal side effects may occur at higher doses. (See "Hypereosinophilic syndromes: Treatment".)

Interferon-alpha — Several patients with disease unresponsive to glucocorticoids and cyclophosphamide have improved with a regimen of glucocorticoids and interferon-alpha [6,54]. However, high rates of adverse effects and relapses limit utility of this agent for EGPA. In a retrospective series of 30 patients with EGPA and a medium Birmingham Vasculitis Activity Score (BVAS) of 6 at baseline, interferon-alpha was added to ongoing prednisolone (mean dose 17.5 mg/day) [74]. After initiation of interferon-alpha, the mean prednisolone dose was decreased to 5.5 mg/day. By six months, 16 patients (53 percent) achieved remission, while nine (30 percent) had a partial response. However, only nine patients (36 percent) experienced a sustained remission at a median follow-up of 31 months; 16 patients experienced relapses and 13 experienced major adverse events requiring treatment discontinuation.

Interferon-alpha has also been used as a second-line agent for certain patients with the hypereosinophilic syndrome, although discontinuation for adverse effects is common (50 percent). (See "Hypereosinophilic syndromes: Treatment", section on 'Interferon alfa'.)

Intravenous immune globulin — Several case series have reported improvement in disease control in patients with refractory disease after addition of high-dose intravenous immune globulin to glucocorticoids with or without cyclophosphamide [5,75,76]. (See "Overview of intravenous immune globulin (IVIG) therapy".)

Plasma exchange — Plasma exchange occasionally has been used in conjunction with other therapies, but a meta-analysis involving 140 patients with glomerulonephritis due to EGPA or microscopic polyangiitis found that it added no benefit to treatment with glucocorticoids, with or without cyclophosphamide [77]. It should only be considered for patients with EGPA presenting with rapidly progressive glomerulonephritis or diffuse alveolar hemorrhage [8]. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology".)

MONITORING — Monitoring responsiveness to treatment and the development of recurrence is best achieved by following symptoms, the eosinophil count, spirometry, and any previously abnormal laboratory parameters. Radiographic manifestations may remain stable or may rapidly regress with glucocorticoid treatment. Kidney function should be monitored by urinalysis and measurement of serum creatinine. We typically reassess patients at three-month intervals, sooner if they experience any change in clinical status.

Persistence of antineutrophil cytoplasmic antibody (ANCA) positivity in EGPA may be a marker of an underlying disease process but does not appear to adequately reflect disease activity and, thus, cannot be used by itself to determine changes in therapy [78,79]. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Management of relapsing disease", section on 'Monitoring for relapse'.)

INFECTION PREVENTION — All patients should receive age-appropriate vaccination against Pneumococcus, influenza, and SARS-CoV-2 (Coronavirus disease 2019 caused by SARS-CoV-2 virus). (See "Pneumococcal vaccination in adults" and "Pneumococcal vaccination in children" and "Seasonal influenza vaccination in adults" and "Seasonal influenza in children: Prevention with vaccines" and "COVID-19: Vaccines".)

We suggest Pneumocystis prophylaxis for patients who are on a combination of high-dose glucocorticoid (eg, prednisone 20 mg/day or more) and another immunosuppressive agent. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)

SPECIAL CONSIDERATIONS

Upper airway involvement — Nasal and otologic complications of EGPA typically require intranasal glucocorticoids and intermittent courses of antibiotics and systemic glucocorticoids [80,81]. Some patients will also require more long-term systemic glucocorticoid therapy and sometimes also immunosuppressive therapy. In addition, surgical approaches, such as functional endoscopic sinus surgery for nasal polypectomy or myringotomy with ventilation tube placement for refractory otitis, may be necessary. When possible, we try to manage the upper airway complications of EGPA with local therapy (saline lavage and topical glucocorticoids), intermittent courses of systemic glucocorticoids, and addition of mepolizumab for persistent nasal obstruction due to nasal polyposis, as described separately. (See "Chronic rhinosinusitis: Management", section on 'CRS with nasal polyposis'.)

The role of leukotriene modifying agents (LTMA) in the management of asthma and nasal polyposis in patients with EGPA is unclear, due to the reports of EGPA developing in the context of LTMA therapy. In patients with asthma, nasal polyposis, and EGPA who have not previously taken an LTMA, we often add an LTMA to the regimen, as described for patients with aspirin-exacerbated respiratory disease. (See "Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)", section on 'Association with medications' and "Aspirin-exacerbated respiratory disease", section on 'Leukotriene-modifying agents'.)

Pregnancy — EGPA is rare during the child-bearing years, so little is known about the effect of pregnancy on the course of EGPA or the effect of EGPA on gestation. The fetal death rate may be slightly increased among pregnancies occurring in patients with EGPA. As an example, one review reported a fetal death rate of approximately 15 percent among 22 pregnancies [9]. A separate review of 16 pregnancies in patients with EGPA noted vasculitic flares (eg, radiographic opacities, sinusitis, or neuropathy) in four pregnancies (25 percent), one maternal death, and five fetal deaths (one due to maternal death, one spontaneous abortion, one intrauterine death, and two elective terminations of pregnancy) [82]. The effect of EGPA on the placenta is not known.

Treatment of vasculitis during pregnancy is complicated due to adverse fetal effects of immunosuppressive medications. As examples, cyclophosphamide and azathioprine are teratogenic and methotrexate is an abortifacient. Systemic glucocorticoids are relatively safer, but may not control active vasculitis. Approaches to the treatment of vasculitis and the use of biologic agents for asthma during pregnancy are discussed separately. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Pregnant patients' and "Management of asthma during pregnancy", section on 'Anti-immunoglobulin E' and "Management of asthma during pregnancy", section on 'Anti-interleukin 5'.)

PROGNOSIS — The prognosis of patients with EGPA has improved significantly since the widespread use of systemic glucocorticoids and selected use of immunosuppressant agents for patients with more severe disease [20,21,53,83]. Prior to the use of glucocorticoids, for example, the disease was uniformly fatal, with 50 percent of untreated patients dying within three months of the onset of vasculitis. In comparison, most modern clinical series suggest a much improved survival rate (70 to 90 percent at five years) [20,21,84-86].

Most deaths result from complications of the vasculitic phase of the disease, and are most commonly due to:

Cardiac failure and/or myocardial infarction

Cerebral hemorrhage

Renal failure

Gastrointestinal bleeding

Status asthmaticus

The presence or absence of the features that make up the five-factor score (FFS) has been used to predict survival in EGPA (table 1), although the components of the FFS have changed over the years [4,18]. In the 1990s, an FFS of ≥1 was associated with 25 to 45 percent mortality at five years [4]. Subsequently, survival has improved. One case series followed 118 patients for six years and found a mortality of 14 percent among 44 patients with an FFS ≥1 and an overall mortality of 10 percent [21]. In a separate series, 150 patients with EGPA (of whom 71 percent had received cyclophosphamide) had a 10-year estimated mortality of 11 percent [20].

Of the five factors, cardiac involvement, gastrointestinal disease, and age ≥65 appear to be the strongest indicators of poor prognosis [20,21,84]. In the case series of 118 patients noted above, an age ≥65 years was the only factor associated with a significantly higher risk of death on multivariate analysis [2,21]. The role of serial antineutrophil cytoplasmic antibody (ANCA) measurements in predicting outcome is not known. However, patients with baseline positive anti-myeloperoxidase (MPO) ANCA had a higher risk of relapse compared with anti-MPO negativity [21,87,88]. The duration of disease-free survival was significantly longer for patients with negative anti-MPO ANCA at entry, although overall survival was not different [21].

Heart involvement is a leading cause of EGPA-associated deaths [20]; consequently, the possibility of heart transplantation has been considered. A case series showed that heart transplantation is feasible in EGPA, but patients have a poor outcome and more data are needed to improve patient care in this setting [89]. (See "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)", section on 'Cardiovascular'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Vasculitis".)

SUMMARY AND RECOMMENDATIONS

Goals of therapy – The goals of therapy for eosinophilic granulomatosis with polyangiitis (EGPA; Churg-Strauss) are to achieve rapid onset of remission, followed by a long remission without relapse, and to minimize complications of therapy. (See 'Introduction' above.)

Assessment of vasculitis severity – Initial therapy is selected based on disease severity, so the first step is determining whether the patient has severe EGPA, defined as organ or life-threatening disease, or nonsevere EGPA. Organ or life-threatening features include, but are not limited to, active glomerulonephritis, pulmonary hemorrhage, cerebral vasculitis, progressive peripheral or cranial neuropathy, gastrointestinal bleeding due to vasculitis, pericarditis, or myocarditis.  

The five-factor score (FFS) is no longer used for initial determination of disease severity, but can help identify patients in need of more aggressive treatment (table 1). (See 'Assessing vasculitis severity' above.)

Remission induction

Glucocorticoids are a key component of treatment for EGPA; typical initial doses are the equivalent of prednisone 0.5 to 1 mg/kg (up to 80 mg) per day. (See "Treatment of severe asthma in adolescents and adults".)

For patients with severe EGPA (organ or life-threatening disease), we recommend remission induction with a combination of systemic glucocorticoids and either cyclophosphamide or rituximab, rather than glucocorticoids alone or combined with mepolizumab (Grade 1B). (See 'Severe EGPA' above.)

For patients with severe EGPA and cardiac or central nervous system involvement, we typically select cyclophosphamide rather than rituximab. In contrast, for patients with severe EGPA who have previously received cyclophosphamide or are at risk of gonadal toxicity, we select rituximab. (See 'Choice of agent' above.)

For patients with nonsevere EGPA, we suggest remission induction with a combination of systemic glucocorticoids and mepolizumab rather than glucocorticoids alone or induction regimens containing cyclophosphamide or rituximab (Grade 2B). The usual dose of mepolizumab for EGPA is 300 mg subcutaneously every four weeks. An alternative would be to add methotrexate, azathioprine, or mycophenolate, although the evidence in favor of these agents is less robust.

Remission maintenance

For patients who received cyclophosphamide for induction, we recommend a transition to maintenance therapy with azathioprine, methotrexate, or mycophenolate to sustain the remission, rather than transitioning to rituximab (Grade 2C). While experience with mycophenolate in EGPA is limited, it is considered an acceptable alternative based on its use in other antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides. (See 'Remission maintenance' above.)

For patients who received rituximab for induction, we suggest continuing rituximab, rather than switching to another agent, and redosing every four to six months (Grade 2C). (See 'Rituximab' above.)

For patients who achieved remission with mepolizumab, we suggest continuing mepolizumab, rather than switching to an immunosuppressive agent (Grade 2C). Mepolizumab has demonstrated benefits in controlling severe asthma, although long-term studies in EGPA are lacking. (See 'Mepolizumab and other anti-IL-5 agents' above.)

The glucocorticoid dose is gradually tapered to the lowest dose required for control of symptoms and signs of active EGPA. (See 'Glucocorticoid dosing and taper' above.)

Maintenance immunosuppressive therapy is typically continued for 12 to 18 months. Longer-term or indefinite maintenance therapy may be warranted in patients with multiple relapses. (See 'Remission maintenance' above.)

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Topic 4346 Version 38.0

References