Version July 2025
INTRODUCTION —
Eosinophilic granulomatosis with polyangiitis (EGPA), previously called Churg-Strauss syndrome (CSS) or allergic granulomatosis and angiitis, is a multisystem disorder characterized most commonly by asthma/obstructive lung disease, rhinitis, nasal polyps, and prominent peripheral blood and tissue eosinophilia [1-8]. EGPA is classified as a vasculitis of the small- and medium-sized arteries, although the vasculitis, when present, may be difficult to diagnose depending on the ability to obtain biopsies off treatment or in locations where affected vessels can be obtained.
Other than the allergic manifestations, the most commonly involved organs are the lungs, the skin, and the peripheral nervous system. However, EGPA can affect almost any organ system, including the cardiovascular, gastrointestinal, kidney, and central nervous systems. Vasculitis of extrapulmonary organs can result in significant morbidity and mortality.
The goals of therapy are to achieve rapid resolution of organ-threatening manifestations, maintain a long disease 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, as is the approach to patients with unexplained peripheral or pulmonary eosinophilia.
●(See "Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis".)
●(See "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA)".)
●(See "Approach to the patient with unexplained eosinophilia".)
●(See "Overview of pulmonary eosinophilia".)
ASSESSING DISEASE SEVERITY —
The treatment approach to patients with EGPA depends in part on whether the patient has developed organ- or life-threatening manifestations (severe EGPA) or has less severe disease [9].
●Organ-threatening or life-threatening disease – Organ- or life-threatening disease includes (but is not limited to) patients with any of the following organ- or life-threatening features [9] (table 1):
•Active glomerulonephritis
•Pulmonary hemorrhage
•Cerebral vasculitis
•Progressive peripheral or cranial neuropathy
•Gastrointestinal bleeding due to vasculitis
•Cardiac involvement (coronary vasculitis, pericarditis, or myocarditis)
•Mesenteric ischemia
•Limb/digital arterial or venous insufficiency
●Nonsevere disease – Patients with nonorgan- or nonlife-threatening disease have no evidence of "active glomerulonephritis" (ie, normal serum creatinine and no red cell casts or proteinuria) and none of the organ-threatening or life-threatening manifestations listed above. Patients with nonsevere disease most frequently present with a combination of rhinosinusitis, asthma, mild systemic symptoms, rash, and/or inflammatory arthritis. Patients with nonsevere disease are frequently still very symptomatic, particularly with respect to asthma and sinus symptoms.
A separate scoring system, the five-factor score (FFS), which was initially devised in 1996 [10] and subsequently revised in 2011 (table 2) [11], has previously been used to guide therapy in EGPA and other vasculitides. Although less frequently a part of therapeutic management today, it may be helpful for identifying patients in need of more aggressive treatment [9,11]. The FFS is also used to define low- and high-risk subgroups in clinical trials and as a prognostic factor. (See 'Prognosis' below.)
DEFINING THERAPEUTIC RESPONSE —
The goal of therapy in patients with EGPA is to achieve long-term quiescence of active disease in all organ systems, termed remission. Treatment with immunomodulators typically includes an initial induction phase aimed to achieve remission followed by a maintenance phase intended to extend remission and prevent recurrence of active disease (relapse).
●Complete remission – Complete remission is defined by the absence of active disease (ie, the absence of any clinical manifestation arising from ongoing vasculitis) [12]. Complications of prior disease activity, such as kidney injury, peripheral neuropathy, or cardiac insufficiency, may still be present even in the absence of active inflammation. However, for patients with EGPA, mild residual upper and lower airway disease that can be managed by topical therapies is tolerated.
The Birmingham Vasculitis Activity Score (BVAS) is frequently used by clinicians in research and sometimes used in clinical practice to assess vasculitis activity of patients and to define remission [12-14]. The score includes both general symptoms (arthralgia, arthritis, and fever) and involvement of eight major organ systems (skin, mucous membranes, ear/nose/throat [ENT], cardiovascular, pulmonary, gastrointestinal, kidney, nervous system) [12]. In each system, persistent symptoms or manifestations (eg, sensorineural hearing loss, pulmonary nodules, 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. Asthma and allergic ENT symptoms are not necessarily vasculitic and not fully reflected in the BVAS, though they are impactful on patients’ quality of life. Nonsystemic therapies are an important part of their management. (See "Overview of the management of vasculitis in adults", section on 'Monitoring'.)
●Relapse – Relapse is defined as the recurrence of signs or symptoms of active vasculitis in any organ system after initial remission has been achieved. Relapsing disease necessitates an escalation or initiation of therapy.
INDUCTION THERAPY —
Systemic glucocorticoids act quickly against the eosinophilic inflammation of EGPA and are helpful in inducing remission [9]. An additional immunomodulatory agent is typically added, guided by disease severity and specific organ involvement [9,15]. (See 'Assessing disease severity' above and 'Defining therapeutic response' above.)
In addition to induction therapy, asthma symptoms are managed separately according to current guidelines, as discussed elsewhere. (See "An overview of asthma management in children and adults".)
Organ- or life-threatening disease — For patients with EGPA who present with organ- or life-threatening disease, we recommend initiation of both high-dose intravenous (IV) glucocorticoids and either cyclophosphamide or rituximab, rather than glucocorticoids alone. We also suggest starting anti-interleukin (IL)-5/5R therapies to reduce eosinophils as early as possible to help minimize side effects and toxicity from induction agents. Patients who have already been receiving anti-IL-5/5R agents for asthma and/or sinus disease do not need to hold them during induction therapy.
Use of additional immunosuppression in addition to glucocorticoids for induction is driven by several clinical trials and prospective series demonstrating improved survival in higher-risk patients (five-factor score [FFS] ≥1 (table 2)) in those who received cyclophosphamide in addition to glucocorticoids [10,16-19]. Several case series in EGPA [20-22], as well as randomized trials in other antineutrophil cytoplasmic antibody (ANCA)-vasculitides [23,24], suggest rituximab likely has similar efficacy as cyclophosphamide in inducing remission. The use of cyclophosphamide or rituximab in addition to corticosteroids is also recommended by the American College of Rheumatology/Vasculitis Foundation (ACR/VF) guidelines [9].
The choice between cyclophosphamide and rituximab depends on organ manifestations, side-effect profile, and availability.
●Patient selection for cyclophosphamide – Because there are more robust clinical trial data associated with cyclophosphamide, this treatment is preferred by some clinicians in patients with very high mortality risk, such as those with active cardiac involvement or severe pulmonary hemorrhage. In addition, cyclophosphamide may be preferable in patients who are ANCA-negative and have severe neurologic or gastrointestinal manifestations.
●Patient selection for rituximab – Due to its reduced toxicity, rituximab is frequently used in the following situations: patients with concerns about fertility, alopecia, and malignancy; those who have been previously treated with a course of cyclophosphamide; in children; and in frail or older adults. Due to its demonstrated efficacy in trials of those with ANCA-positive vasculitides (including EGPA), rituximab may be preferred in patients with a positive ANCA or active glomerulonephritis; however, some series have demonstrated remission after rituximab administration even in ANCA-negative patients [25,26]. International consensus guidelines do not recommend treatment decisions based on ANCA status [27].
Systemic glucocorticoids (for all patients) — In patients with rapidly progressive vasculitis with multiple affected organs, severe neurologic complications, or actively life-threatening disease (eg, respiratory failure, cardiac failure, optic neuritis, or acute limb ischemia), IV glucocorticoid (eg, methylprednisolone 500 to 1000 mg IV daily for three to five days) is used for initial therapy. This can be followed by 1 mg/kg (typically up to 80 to 120 mg) per day of IV methylprednisolone or equivalent oral therapy [3,4,9,28].
For the remainder of patients with organ-threatening disease (see 'Assessing disease severity' above), systemic glucocorticoids are typically initiated at a dose of 1 mg/kg of intravenous methylprednisolone (up to 80 to 120 mg) or its oral equivalent per day [9,28], although higher doses are also occasionally used in more severe cases.
Similar to other patients with EGPA receiving glucocorticoids in combination with a glucocorticoid-sparing agent, those who respond well to the initial combined therapy (including cyclophosphamide or rituximab) can begin a reduced-dose glucocorticoid tapering regimen rather than a slower taper (table 3). (See 'Glucocorticoid dosing and taper during maintenance' below.)
Glucocorticoids are associated with significant immunosuppressive and metabolic side effects that require monitoring or management, which is discussed separately. (See "Major adverse effects of systemic glucocorticoids".)
Pneumocystis jirovecii prophylaxis is appropriate for patients using high-dose glucocorticoids, particularly those receiving regimens that include additional immunosuppressants. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)
Cyclophosphamide-based regimen — Both oral and IV cyclophosphamide are effective with systemic glucocorticoids in inducing remission for adults with organ- or life-threatening EGPA. Some clinicians prefer IV cyclophosphamide given the lower cumulative dose associated with this administration and theoretical subsequent lower risk of toxicity. After a maximum six-month treatment course, cyclophosphamide should be replaced by a medication with a lower risk of toxicity. (See 'Remission maintenance' below.)
●Dosing and administration – Cyclophosphamide 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 appropriate dose reductions for older patients (age ≥60 years) and those with reduced kidney function, as described for granulomatosis with polyangiitis (GPA) [9,17]. Insufficient data are available for EGPA to make a clear recommendation between oral and IV therapy. Extrapolating from GPA, outcomes with oral and IV regimens are similar; a slightly greater risk of bladder toxicity with the oral regimen and a slightly greater risk of relapse with the IV 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 [3,9,29]. (See "Cyclophosphamide in rheumatic diseases: General principles of use and toxicity", section on 'Intermittent (pulse) cyclophosphamide (most common)'.)
The duration of cyclophosphamide therapy remains controversial. When used to treat GPA, a six-month regimen is typically 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 "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Cyclophosphamide-based regimen' and "Cyclophosphamide in rheumatic diseases: General principles of use and toxicity", section on 'Adverse effects'.)
●Efficacy – The efficacy of cyclophosphamide in EGPA is supported by the following studies:
•In a meta-analysis of 278 patients with EGPA, microscopic polyangiitis (MPA), and polyarteritis and an FFS of 2 (table 2), 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 [10,17,19] (table 2). 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) [10]. (See 'Prognosis' below.)
Rituximab-based regimen — Rituximab is an anti-CD20 monoclonal antibody directed against B cells that is licensed for the treatment of GPA and MPA in the United States and Europe. Evidence of similar efficacy to cyclophosphamide has been best demonstrated in these diseases, but similar dosing is accepted for EGPA. Risks of adverse effects, particularly infection, are discussed in detail separately. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Induction therapy' and "Rituximab: Principles of use and adverse effects in rheumatologic disease".)
●Dosing and administration [9]:
•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 ≤1.5 m2 or 750 mg/m2 for patients with body surface area >1.5 m2 with a typical maximum of 1 g per infusion, administered on days 1 and 15.
•The decision to retreat patients following B-cell repopulation is individualized, accounting for the patient's preferences, the likelihood of relapse, and the potential for irreversible damage due to disease flare. When a second dose is given for maintenance, it is usually given after four to six months. (See 'Remission maintenance' below.)
•No data on use of other anti-CD20 biologics have been reported. In theory, they could be used in the event of intolerance or reactions to rituximab.
●Efficacy – Several case reports and case series have described improvement in refractory or relapsing EGPA [20,25,30-41]:
•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 [42].
•Response to rituximab was assessed in a retrospective study of 41 patients seen at four highly specialized vasculitis centers [20]. 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.
•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 [21].
Single-center studies have also suggested efficacy for rituximab in relapsing EGPA [26] and for those with myocardial or endocardial involvement [22]. In one report, rituximab appeared to cause immediate and severe bronchospasm in two patients with ANCA-negative EGPA [43].
Early initiation of anti-IL-5/5R therapy — For adults with organ- or life-threatening EGPA demonstrating improvement after high-dose glucocorticoids and cyclophosphamide or rituximab, we suggest early initiation of anti-IL-5/5R therapy to facilitate the transition from cyclophosphamide or rituximab and tapering of glucocorticoids. There is not any clinical trial evidence to date regarding the efficacy of these agents for induction; however, their impact on eosinophilic inflammation may reduce relapse and facilitate removal/taper of agents with more toxicities and adverse effects. The efficacy of anti-IL-5/5R agents in the induction phase and early maintenance has been demonstrated in those with nonsevere disease. (See 'Anti-IL-5 or anti-IL-5R agents' below.)
Adjunctive therapies for persistent organ-threatening disease — It is unusual for EGPA to not respond to the recommended regimen of high-dose glucocorticoids and either cyclophosphamide or rituximab. In rare cases where severe organ-threatening disease manifestations persist despite therapy, the following adjunctive approaches may be of benefit:
●Intravenous immunoglobulin – Several case series have reported improvement in disease control in patients with refractory disease after addition of high-dose IV immune globulin to glucocorticoids with or without cyclophosphamide [13,44,45]. (See "Overview of intravenous immune globulin (IVIG) therapy".)
●Plasma exchange – Plasma exchange should only be considered for patients with EGPA presenting with rapidly progressive glomerulonephritis or diffuse alveolar hemorrhage [28]. Much of the data are from patients with GPA or MPA, but the appropriate role for this therapy remains uncertain. One meta-analysis of 140 patients with glomerulonephritis due to EGPA or MPA found that it did not add benefit to treatment with glucocorticoids, with or without cyclophosphamide [46]. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Role of plasma exchange' and "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology".)
●Interferon-alpha – Several patients with disease unresponsive to glucocorticoids and cyclophosphamide have improved with a regimen of glucocorticoids and interferon-alpha [47,48]. 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) [49]. 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 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 hypereosinophilic syndrome, although discontinuation for adverse effects is common (50 percent). (See "Hypereosinophilic syndromes: Treatment", section on 'Interferon alfa'.)
For patients who have initial improvement in organ-threatening or life-threatening vasculitis symptoms but who fail to achieve remission or have an early relapse, we typically add an anti-IL-5/5R agent, if this has not already been done. The glucocorticoid taper may need to be slowed, and higher doses reinstituted, to regain control.
Nonsevere disease — For patients without life- or organ-threatening manifestations of EGPA (see 'Assessing disease severity' above), we suggest initial induction therapy with moderate to high doses of glucocorticoids alone rather than using additional immunomodulatory agents. For those unable to achieve remission or who have an early relapse on glucocorticoid therapy, we suggest the addition of anti-IL-5/5R agents. We prefer these anti-eosinophilic biologics because they are effective for most patients with limited toxicities. Methotrexate, azathioprine, or mycophenolate are reasonable alternative add-on agents.
First-line therapy (glucocorticoids) — Systemic glucocorticoid therapy is the mainstay of induction therapy for nonsevere EGPA. We typically initiate treatment with prednisone (or equivalent) at a dose of 0.5 mg/kg (up to 60 mg) per day [9,28]. For those receiving reinduction after a relapse, the dose is guided by their previous response and is typically the last dose that clearly achieved remission.
If an effective response to the initial regimen over the first one to two weeks occurs, tapering can begin; we typically use a four- to six-month taper such as the example provided in the table (beginning at week 2 for those using 0.5 mg/kg dosing) (table 3). During the initial taper, it is useful to monitor symptoms and eosinophil counts closely and adjust the taper to avoid more clinically severe relapses. Remission usually occurs within a few weeks of initiating therapy. Patients who have had relapses should begin the taper based on their most recent remission-achieving dose, but they may require a slower taper or a halt to the taper prior to completion.
Most patients with nonsevere EGPA who do not have poor prognostic factors achieve remission with glucocorticoid therapy alone, although relapses are common during tapering [50]. In a study of 72 patients without poor prognosis factors (ie, no cardiac, kidney, or central nervous system involvement) followed for five years or longer, 93 percent achieved remission with glucocorticoid therapy alone [50]. However, patients with more significant involvement of the heart, kidney, gastrointestinal tract, or central nervous system frequently either have severe disease or require additional immunosuppressive therapy to achieve remission, as described below. (See 'Glucocorticoid dosing and taper during maintenance' below and 'Cyclophosphamide-based regimen' above.)
Glucocorticoids are associated with significant immunosuppressive and metabolic side effects that are discussed separately. (See "Major adverse effects of systemic glucocorticoids".)
Pneumocystis jirovecii prophylaxis is appropriate for patients using prolonged medium-dose glucocorticoids. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)
Resistant disease or early relapse — Patients with nonsevere EGPA who are unable to achieve remission or have a relapse early in their glucocorticoid taper require additional therapy to achieve induction. This involves an adjustment in their glucocorticoid regimen and initiation of additional immunomodulators, usually anti-IL-5/5R therapies.
Glucocorticoid management — For patients unable to achieve remission despite initial dosing of glucocorticoids, the typical approach is to increase the dose to 1 mg/kg of oral prednisone (up to 80 to 120 mg daily) in addition to adding a second-line agent. For those who have experienced an early relapse, it is appropriate to increase the glucocorticoid dose back up to the previous level that achieved remission while adding a second-line agent. A slower taper than previously instituted is usually appropriate for the first month of therapy due to the relatively slower onset of these second-line agents.
Anti-IL-5 or anti-IL-5R agents — For adults with nonsevere EGPA who are not in remission, we suggest adding mepolizumab or benralizumab to systemic glucocorticoids rather than other agents [9].
IL-5 is a potent mediator of eosinophil hematopoiesis and contributes to eosinophilic inflammation. Mepolizumab and reslizumab are anti-IL-5 monoclonal antibodies, while benralizumab is an anti-IL-5 receptor alpha monoclonal antibody. These biologic agents were first studied and approved for use in the treatment of severe asthma, but they are increasingly found to be useful in other diseases mediated by eosinophilic inflammation, including EGPA. 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-5/5R antibodies' 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 United States Food and Drug Administration (FDA), is 300 mg every four weeks for those aged ≥12 years; this dose is higher than the dose of 100 mg every four weeks approved by the FDA for severe asthma [51]. 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 [52]. 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 [53,54]. The two doses have not been compared in the setting of a controlled trial. For children aged 6 to 11 years, 40 mg every four weeks may be used.
Benralizumab 30 mg subcutaneously every four weeks was compared with mepolizumab 300 mg every four weeks in a noninferiority trial (MANDARA). Benralizumab dosing was continued every four weeks, in contrast to the every-eight-week dosing approved for severe asthma [55]. Monthly dosing was chosen for this study based on preliminary data on monthly dosing used for hypereosinophilic syndrome in a phase 2b clinical trial [14]; 10 mg dosing every four weeks is appropriate for children weighing <35 kg. Preexisting helminth infections should be treated prior to initiating benralizumab. Rare hypersensitivity reactions may occur. (See "Overview of infections associated with immunomodulatory (biologic) agents" and "Treatment of severe asthma in adolescents and adults", section on 'Anti-IL-5/5R antibodies'.)
●Efficacy – The efficacy of anti-IL-5 and IL-5 receptor agents in patients with EGPA has been assessed in randomized trials [56,57] and in case reports and series [58-60]. For example:
•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 [56]. Mepolizumab led to significantly more accrued weeks of remission (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 participants 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. Differences in response to mepolizumab were not seen based on vasculitic phenotype [61], and glucocorticoid sparing was seen in patients receiving mepolizumab in post-hoc analyses [62]. For 100 patients who continued an open-label extension, long-term use (average of 39 months) was well tolerated; worsening of asthma and EGPA occurred in 6 and 3 percent of patients, respectively [63]. Twenty-eight percent of patients were able to discontinue systemic glucocorticoids, and an additional 40 percent tapered to less than 7.5 mg of prednisone-equivalent daily.
•Benralizumab was compared with mepolizumab in a randomized, double-blind, double-dummy, noninferiority trial that included 140 patients with EGPA receiving glucocorticoids with or without other immunosuppressants (azathioprine, methotrexate, or mycophenolate mofetil) for relapsing or refractory disease despite glucocorticoid doses more than 7.5 mg of prednisone or equivalent daily [57]. Rates of remission (BVAS 0 and prednisone ≤4 mg/day) after 48 weeks were 59 percent with benralizumab and 56 percent with mepolizumab (difference 3 percent, 95% CI -13 to 18). Complete withdrawal of glucocorticoids could be achieved in 41 percent of patients on benralizumab and 26 percent receiving mepolizumab after one year. Thirty percent of patients in each group had a relapse during therapy. Serious adverse events were uncommon and not different between groups. In a one-year extension trial, remission and oral glucocorticoid discontinuation rates were maintained, and only 23 percent of patients experienced a relapse [64].
Patients with nonsevere disease who do not develop remission despite treatment with high-dose glucocorticoids and anti-IL-5/5R therapy may require cyclophosphamide- or rituximab-based regimens like those with organ-threatening disease. (See 'Organ- or life-threatening disease' above.)
Alternative therapies — Alternative induction regimens for patients with nonsevere EGPA resistant to initial glucocorticoids include initial treatment with glucocorticoids plus methotrexate or mycophenolate [9,65,66]. These agents are preferred over cyclophosphamide or rituximab in patients with nonsevere EGPA because of lower toxicity [9] 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 [65]. 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. Separately, a single-center open-label study compared methotrexate and cyclophosphamide in ANCA-associated vasculitis, including 30 participants with EGPA [67]. There were no differences in relapse rates, or time to relapse, in those receiving cyclophosphamide as compared with methotrexate.
Data are less robust for other alternative agents. An open label trial evaluated azathioprine in 10 patients after treatment failure with glucocorticoids alone; five subsequently achieved remission [50]. A small trial that included 51 patients with EGPA with nonsevere disease and a FFS of 0 (table 2) evaluated the addition of azathioprine or placebo to standard daily glucocorticoid therapy [68]. Among patients with EGPA, approximately 52 percent had sustained remission at 24 months, but no difference was noted between azathioprine and glucocorticoid alone in rates of attaining remission, risk of relapse, or cumulative dose of glucocorticoids over 24 months. Longer term outcomes were also similar over a median follow-up of 6.3 years [69]. Given these data, induction with azathioprine is less preferred.
Additional information on the use of these agents for maintenance of remission can be found below:
●Methotrexate – Methotrexate 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 a maximum of 25 mg/week. Subcutaneous therapy has greater bioavailability and often decreased gastrointestinal side effects.
Because methotrexate inhibits the binding of dihydrofolic acid to dihydrofolate reductase, folic acid (1 to 2 mg per day), or folinic acid (5 to 10 mg per week, 24 hours after methotrexate) should be given concurrently to reduce potential toxicity.
Given the risk of methotrexate toxicity in patients with reduced kidney function, this drug should not be used in patients with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 or evidence of active renal vasculitis. It should also be avoided in patients who are contemplating becoming pregnant. Alcohol intake should be avoided while using methotrexate.
Additional information on pharmacology, mechanism of action, precautions, and dosing (including alternative dosing regimens) are discussed in detail separately. (See "Use of methotrexate in the treatment of rheumatoid arthritis" and "Major adverse effects of low-dose methotrexate".)
●Mycophenolate – The ACR/VF guidelines include mycophenolate as an alternative induction agent, but data in EGPA are limited [9]. Dosing of mycophenolate mofetil in EGPA follows 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".)
●Azathioprine (less preferred) – If thiopurine methyltransferase (TPMT) testing is performed prior to the initiation of therapy and is normal, azathioprine can be initiated at 2 mg/kg per day and can be increased to 3 mg/kg/day in those with an insufficient response after three months; the maximum dose should generally not exceed 200 mg/day. If TPMT testing has not been performed prior to initiation of therapy, azathioprine is typically initiated at a dose of 50 mg/day. If this dose is tolerated well at one week, the daily dose can be increased over several weeks to 2 to 3 mg/kg per day (maximum 200 mg/day). A lower target dose is appropriate in patients with kidney insufficiency. A complete blood count (CBC) and platelet count should be monitored every two weeks during dose escalation and every four to six weeks after a stable dose is achieved. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases".)
Patients with nonsevere disease who do not develop remission despite treatment with high-dose glucocorticoids and additional immunosuppressant therapy may either require a different agent (eg, anti-IL-5/5R therapies) or cyclophosphamide- or rituximab-based regimens like those with organ-threatening disease. (See 'Anti-IL-5 or anti-IL-5R agents' above and 'Organ- or life-threatening disease' above.)
REMISSION MAINTENANCE —
After attaining remission with induction immunosuppressive therapy, patients are switched to a maintenance regimen to facilitate tapering of glucocorticoids. For most patients, anti-IL-5/5R therapies will be the most appropriate maintenance therapy of choice. Other options include maintenance methotrexate, mycophenolate, azathioprine, and rituximab.
When to begin maintenance therapy — Most patients achieve remission within six to twelve weeks of initiation of therapy; this is a good time to shift to a regimen that facilitates long-term remission with minimal toxicity. Patients who have not achieved remission in this timeframe should escalate or change their induction regimen. (See 'Adjunctive therapies for persistent organ-threatening disease' above and 'Resistant disease or early relapse' above.)
Many patients begin agents appropriate for maintenance of remission (eg, anti-IL-5/5R agents, methotrexate, mycophenolate) as part of their induction regimen. Based on effectiveness, tolerability, and side effects, these agents can either be continued or modified after achieving remission. For those using cyclophosphamide- or rituximab-based regimens, timing of transition to other therapies is as follows:
●For patients treated with rituximab for induction of remission, maintenance therapy with alternative immunosuppressants typically begins between months four and six after the last induction dose, regardless of the maintenance agent that is used. However, anti-IL-5/5R therapies can be initiated concomitantly. (See 'Early initiation of anti-IL-5/5R therapy' above.)
●For patients treated with intravenous (IV) cyclophosphamide for induction of remission, alternative immunosuppressant maintenance therapy may be started two to four weeks after the last dose of cyclophosphamide if the white blood cell count is >3500 cells/microL and the absolute neutrophil count is >1500 cells/microL. For patients using daily oral cyclophosphamide, maintenance therapy can be started as soon as the above white blood cell criteria are met. Anti-IL-5/5R therapies can be initiated concomitantly with cyclophosphamide. It is reasonable to bridge therapy with either glucocorticoids and/or cyclophosphamide for four to six weeks after initiating anti-IL-5/5R therapy until steady state is achieved. (See 'Early initiation of anti-IL-5/5R therapy' above.)
Choice of maintenance agent — 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 [9]. For most patients, we suggest the use of anti-IL-5/5R therapies for maintenance because they are effective, well-tolerated, and have minimal toxicities.
●Severe disease
•For patients with severe EGPA who received cyclophosphamide for remission, induction transition to an alternative maintenance agent is required. Those who have begun anti-IL-5/5R therapies during induction can continue these therapies and stop cyclophosphamide once stably in remission (typically three to six months after induction). Alternative agents have not been directly compared with each other or anti-IL-5/5R therapies; when using alternative approaches, we typically choose methotrexate or mycophenolate in those with pulmonary disease; azathioprine is also reasonable in those with other systemic manifestations. We reserve rituximab maintenance therapy for those who have relapsed despite low-dose glucocorticoids and other maintenance regimens. Immunosuppressant maintenance agents are initiated two to four weeks after the last dose of cyclophosphamide. (See 'When to begin maintenance therapy' above.)
•For patients with severe EGPA who achieved remission with rituximab, we suggest using an alternative agent rather than continuing rituximab to avoid infectious complications of long-term B-cell depletion and frequent hypogammaglobulinemia. For those who have had multiple relapses or very difficult-to-control disease, it is also reasonable to continue rituximab [9]. Those who have begun on anti-IL-5/5R therapies during induction can continue these therapies and stop rituximab once stably in remission. Other agents have not been directly compared with each other or to anti-IL-5/5R therapy. (See 'When to begin maintenance therapy' above.)
●Nonsevere disease
•For patients with nonsevere EGPA who achieved remission on glucocorticoids alone, we suggest initiating anti-IL-5/5R therapies when possible to facilitate glucocorticoid tapering to the minimal necessary dose. We prefer these agents to alternative immunosuppressants because they are effective and well-tolerated with minimal toxicities or risks for infection. (See 'Glucocorticoid dosing and taper during maintenance' below.)
•For patients with nonsevere EGPA who achieved remission with mepolizumab or benralizumab, we suggest continuing those agents and tapering prednisone (or equivalent) as tolerated. (See 'Glucocorticoid dosing and taper during maintenance' below.)
Alternative regimens include methotrexate and mycophenolate maintenance therapies; these have not been directly compared either with each other or to anti IL-5/5R agents.
•For patients with nonsevere EGPA who achieved remission with methotrexate or mycophenolate, it is reasonable to continue those agents if they are well-tolerated [9]. Transition to an IL-5/5R therapy may decrease short- and long-term adverse effects of these immunosuppressants; however, data on long-term outcomes with IL-5/5R therapies are not yet available.
Glucocorticoid dosing and taper during maintenance — Once disease manifestations have come under control and a maintenance regimen selected, the glucocorticoid dose is gradually tapered over variable time periods (ranging from 3 to 18 months) based on weight-based initial dosing, disease severity, history of relapses, patient tolerance, and symptom or laboratory monitoring. A typical tapering regimen for those without a history of relapses is shown (table 3). Historically, in the absence of maintenance therapy, most patients required low-dose oral glucocorticoid therapy. For example, in the study of 72 patients described above (see 'First-line therapy (glucocorticoids)' above), almost 80 percent of those who achieved remission required long-term, low-dose glucocorticoid therapy, mainly to control respiratory disease [50]. Based on clinical trials of anti-IL-5/5R agents, up to 40 percent of patients can be fully tapered off glucocorticoids over one year using maintenance therapy [29,56,57,62,70]; the number is likely even higher over the long term in our clinical experience. Many of the remaining patients can achieve stability on an acceptably low dose of maintenance glucocorticoids (eg, 2.5 to 5 mg of prednisone daily).
In EGPA, late relapses of systemic vasculitis after a successful response to treatment are uncommon [71]. However, premature withdrawal of treatment can result in recurrence.
Prevention of complications due to chronic systemic glucocorticoid therapy is discussed separately. (See "Major adverse effects of systemic glucocorticoids" and "Prevention and treatment of glucocorticoid-induced osteoporosis".)
Dosing and efficacy of individual agents
Anti-IL-5 and anti-IL-5 receptor therapies — For patients who have achieved remission with anti-IL-5 monoclonal antibodies (mepolizumab, reslizumab) or an anti-IL-5 receptor antibody (benralizumab), we suggest continuation of these agents as maintenance therapy. However, clinical studies of long-term maintenance therapy with these agents have not yet been reported.
●Mepolizumab and benralizumab – Mepolizumab, a monoclonal antibody to IL-5, and benralizumab, a monoclonal antibody to the alpha-chain of the IL-5 receptor, have been shown to induce remission effectively in patients with nonsevere EGPA [56,57]. In the setting of these induction therapy trials, over 50 percent of patients remained in remission after one year, and 25 to 40 percent were able to taper off systemic glucocorticoids. (See 'Anti-IL-5 or anti-IL-5R agents' above.)
In addition, one observational cohort study has evaluated effectiveness of benralizumab in both induction and remission phases of disease [72]. The study retrospectively analyzed two groups: Group A, with a stable daily glucocorticoid dose and an EGPA diagnosis for more than six months, and Group B, with a recent EGPA diagnosis and high-dose daily glucocorticoid therapy. Over 12 months, Group A showed significant reductions in glucocorticoid dose and asthma exacerbations, along with improved lung function, with 88 percent continuing benralizumab treatment. Group B tolerated benralizumab well during remission induction, with 78 percent maintaining EGPA remission after 12 months.
●Reslizumab – Preliminary evidence suggests that reslizumab may also be of benefit for maintenance therapy in EGPA. In a cohort of nine EGPA patients with severe eosinophilic asthma requiring continuous glucocorticoids to maintain disease control, 48 weeks of treatment with IV reslizumab (3 mg/kg every four weeks) was associated with a reduction in glucocorticoid use and improvements in patient-reported outcomes [73]. An open-label study of the safety and efficacy of IV reslizumab (3 mg/kg) in 10 participants found it to be generally safe and efficacious as treatment for EGPA [74]. (See "Treatment of severe asthma in adolescents and adults", section on 'Reslizumab'.)
Methotrexate — Methotrexate may be used in EGPA to maintain remission after induction with cyclophosphamide or as a glucocorticoid-sparing agent. 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 toxicity 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. Methotrexate should be avoided in patients with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 and is contraindicated during pregnancy. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Maintenance therapy' and "Major adverse effects of low-dose methotrexate" and "Use of methotrexate in the treatment of rheumatoid arthritis".)
One potential disadvantage of methotrexate is the rare development of methotrexate-induced lung injury, which can be difficult to distinguish from pulmonary eosinophilia or hemorrhage. (See "Methotrexate-induced lung injury".)
Data regarding the use of methotrexate for maintenance of remission in EGPA are limited. In one case series of 25 patients with EGPA, methotrexate was associated with relapse rate of 48 percent when used for maintenance [75]. On the other hand, the prednisone dose was decreased by an average of 50 percent in these patients.
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 [9,70,76-79]. In one case report, mycophenolate mofetil plus oral glucocorticoids was used to treat a patient with EGPA with asthma, chronic rhinosinusitis, cutaneous vasculitis, and a positive antineutrophil cytoplasmic antibodies (ANCA; pANCA with antibodies to myeloperoxidase [MPO]) [76]. Dosing of mycophenolate mofetil in EGPA follows 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 "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases".)
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. For remission maintenance in GPA and microscopic polyangiitis (MPA), the ACR/VF guidelines advise redosing based on a schedule rather than based on ANCA levels; this may be extrapolated to EGPA [9]. Immunoglobulin levels should be checked at baseline, prior to each course, and every six months until two years following completion of therapy to detect the rare adverse side effect of hypogammaglobulinemia [80].
Less common maintenance therapies — For occasional patients with therapy-limiting side effects from multiple other options, there are highly limited data in support of the following alternative maintenance agents:
●Azathioprine – In patients with EGPA, azathioprine has been 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 [48,50]; however, its effectiveness at maintaining remission compared with glucocorticoids alone is uncertain [68,69].
Analysis of the thiopurine methyltransferase (TPMT) gene prior to the administration of azathioprine may help predict those individuals at risk for severe toxicity. When deficiency of the TPMT enzyme is found, an alternative agent should be used. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Pharmacogenetics and azathioprine toxicity'.)
Assuming TPMT status is known, initiating therapy at the target dose of 2 mg/kg lean body weight avoids relapse during the time that the patient is titrating from suboptimal doses. The direct approach was used successfully in a trial of patients with GPA [81]. A lower target dose is indicated in patients with kidney 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'.)
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 [50]. A small trial that included 51 patients with EGPA with nonsevere disease and a five-factor score (FFS) of 0 (table 2) evaluated the addition of azathioprine or placebo to standard daily glucocorticoid therapy [68]. Among patients with EGPA, approximately 52 percent had sustained remission at 24 months, but no difference was noted between azathioprine and glucocorticoids alone in rates of attaining remission, risk of relapse, or cumulative dose of glucocorticoids over 24 months. Longer term outcomes were also similar over a median follow-up of 6.3 years [69].
●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 [9,29]. The ACR/VF guidelines prefer methotrexate or azathioprine over leflunomide for remission maintenance as data in support of leflunomide for EGPA are limited [9]. The dose of leflunomide used in one case series was 10 to 30 mg/day [29]. 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 (omalizumab) – Several observational reports have described a beneficial effect of omalizumab (anti-IgE) on certain manifestations of EGPA such as asthma and sinonasal disease [82-86]. For example, in a case series of 17 patients with glucocorticoid-dependent asthma and refractory or relapsing EGPA, omalizumab was associated with a decrease in prednisone dosing 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) [82]. 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 treatment of EGPA alone. (See "Anti-IgE therapy".)
Conversely, a temporal association between omalizumab use and the development of EGPA has been reported, although, as with other associations, tends to occur in the context of tapering of systemic glucocorticoids [86-88].
Adjunctive topical therapy for asthma and chronic rhinosinusitis — Adjunctive therapies, such as inhaled or intranasal glucocorticoids or long-acting bronchodilators, are typically used to treat upper and lower respiratory tract disease, as described separately. (See "An overview of asthma management in children and adults", section on 'Initiating pharmacologic treatment' and "Treatment of severe asthma in adolescents and adults", section on 'Optimizing standard controller therapy' and "Chronic rhinosinusitis with nasal polyposis: Management and prognosis", section on 'Intranasal corticosteroids'.)
Management of relapses on maintenance therapy — Relapses are common during the treatment of EGPA, particularly during glucocorticoid tapering. Our typical approach is to increase glucocorticoids back to the last dose that achieved convincing remission and taper more slowly. For recurrent relapses, our usual strategy is as follows:
●Any relapse with organ- or life-threatening manifestations – For those who develop a severe relapse with organ- or life-threatening manifestations (see 'Assessing disease severity' above), induction therapy should be used as described above. (See 'Organ- or life-threatening disease' above.)
Those who have previously received cyclophosphamide should likely receive rituximab to avoid cumulative toxicity and the possibility of improved efficacy in this setting based on data from other ANCA-associated vasculitides [24]. Anti-IL-5/5R therapy should be continued, but other immunosuppressive agents are typically held in favor of rituximab or cyclophosphamide until remission is once again achieved.
●Recurrent relapses on low-dose glucocorticoids – For those with recurrent relapses during tapers at low doses of glucocorticoids, it is often reasonable to continue a maintenance dose of 7.5 mg of prednisone daily or less, assuming adverse effects of glucocorticoids are tolerable for the patient at these doses. Ongoing therapy should be approached cautiously in patients at high risk for osteoporosis or those with type 2 diabetes mellitus. These groups may benefit from additional steroid-sparing agents instead.
●Recurrent relapses on higher glucocorticoid doses, or glucocorticoid intolerance – For those with recurrent relapses during tapers at prednisone >7.5 mg daily (or equivalent) or who do not tolerate glucocorticoids, we suggest adjusting the maintenance regimen. For those receiving anti-IL-5/5R therapy, we add an additional immunosuppressant agent, typically methotrexate or mycophenolate. For those not already using anti-IL-5/5R therapy, one of these agents should be initiated. Rituximab can be helpful for those who have recurrent relapses despite both anti-IL-5/5R therapy and an additional immunosuppressant. The dosing and efficacy of individual agents is described above. (See 'Dosing and efficacy of individual agents' above.)
Duration of maintenance therapy — Maintenance therapy is typically continued for at least 12 to 18 months. Longer-term or indefinite maintenance therapy may be warranted in patients with multiple relapses, multi-organ involvement, or other poor prognostic factors. (See 'Prognosis' below.)
There are minimal data to guide tapering maintenance therapy. Most clinical trials have continued therapy for at least 12 months, and the American College of Rheumatology guidelines suggest at least 18 months of therapy for ANCA-associated vasculitides [9]. When tapering maintenance therapy, the first step is typically to taper any remaining maintenance glucocorticoids. Assuming remission is sustained, the dose of systemic agents other than IL-5/5R therapies (eg, methotrexate, mycophenolate) should be reduced. Rituximab can be held altogether given its long-lasting effect. Patients with persistent remission for several months on anti-IL-5/5R therapies alone are reasonable candidates for slow withdrawal of anti-eosinophilic therapies, though in our experience indefinite therapy is often required.
●Tapering off mepolizumab – For those with prolonged remission on mepolizumab alone without poor prognostic features, we begin tapering by reducing the dose from 300 mg to 100 mg every four weeks. If this is tolerated over three months, we space the dose to every other month for four to six months. Assuming remission is sustained, we then proceed with a trial off therapy.
●Tapering off benralizumab – For those with prolonged remission on benralizumab alone without poor prognostic features, we begin tapering by increasing the interval between 30 mg doses from every four weeks to every eight weeks, as used routinely for severe asthma. If this is tolerated over four months, we space the dose to every 12 weeks for six months. For those with sustained remission, we subsequently proceed with a trial off therapy.
Nonsevere relapses during a taper of anti-IL-5/5R therapy should lead to increasing therapy to the prior dosing that was sustaining remission and often require a short (eg, two to four week) course of glucocorticoids. In some cases, decisions to continue anti-IL-5/5R therapies may be driven by comorbid chronic rhinosinusitis with nasal polyposis or asthma.
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.
The Birmingham Vasculitis Activity Score (BVAS) is a comprehensive tool that can be used to quantify disease activity and assess for remission. (See 'Defining therapeutic response' above.)
Patients with organ- or life-threatening disease are typically admitted to the hospital for treatment with close monitoring of their clinical status and laboratory testing on a daily basis. When patients are receiving high-dose glucocorticoids for initial induction or relapse, they require close monitoring over the first two to three weeks to ensure a meaningful clinical response as the initial glucocorticoid taper is introduced. The rapidity of recovery, degree of organ involvement, and history of prior relapses affect the anticipated glucocorticoid course.
Patients on maintenance therapy should be reassessed 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 [89,90]. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Management of relapsing disease", section on 'Monitoring for relapse'.)
INFECTION PREVENTION —
All patients should receive age-appropriate vaccinations and be encouraged to stay up to date with vaccines against respiratory pathogens including pneumococcus, influenza, respiratory syncytial virus, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). (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".)
Pneumocystis prophylaxis is appropriate for patients while on moderate to high doses of glucocorticoids and for some patients who are using glucocorticoids and other immunosuppressive agents. (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 [91,92]. Some patients will also require more long-term systemic glucocorticoid therapy and other glucocorticoid-sparing therapies. 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. Adjunctive therapies such as glucocorticoid-eluting stents or exhalation delivery systems have also been used by rhinologists for recurrent polyps after surgery. (See "Chronic rhinosinusitis with nasal polyposis: Management and prognosis".)
The efficacy of leukotriene modifying agents (LTMA) in the management of asthma and nasal polyposis in patients with EGPA is uncertain. In patients with asthma, nasal polyposis, and EGPA who have not previously taken an LTMA, a trial of add-on LTMA is often appropriate. The dosing regimen is the same as that described for patients with aspirin-exacerbated respiratory disease. (See "Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis", section on 'Association with medications and toxins' and "Aspirin-exacerbated respiratory disease", section on 'Leukotriene-modifying agents'.)
Pregnancy — EGPA is relatively rare during the child-bearing years, so little is known about the effect of EGPA on gestation. Only a few case reports have been published, which probably represent less common and more severe complications. As an example, one review reported a fetal death rate of approximately 15 percent among 22 pregnancies [3]. 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) [93]. These case reports contrast with our authors’ clinical experience guiding patients successfully through pregnancy without complications. In some cases, the degree of glucocorticoid requirement decreases during the 1st and 2nd trimesters, but periparturient and postpartum relapses or increased glucocorticoid requirement may occur. Monitoring by a high-risk obstetrician is appropriate. Case reports and a registry of patients receiving anti-IL-5 therapy during pregnancy exist and are discussed in more detail elsewhere. (See "Management of asthma during pregnancy", section on 'Biologics'.)
Several agents used for the treatment of vasculitis are not appropriate during pregnancy due to adverse fetal effects. As examples, cyclophosphamide and mycophenolate are teratogenic, and methotrexate is an abortifacient. Systemic glucocorticoids are relatively safe in pregnancy and can usually control disease in those on maintenance therapy; they may be insufficient in some patients with active vasculitis. Although human data are still relatively meager, animal data and growing clinical experience suggest anti-IL-5/5R therapy may be safe during pregnancy; these agents are also often helpful postpartum to facilitate glucocorticoid tapering and prevent relapse. For patients who develop severe disease or relapse, high-dose glucocorticoids are the mainstay of therapy, but rituximab or intravenous (IV) immunoglobulin may be reasonable options. Cyclophosphamide can also be used with caution in the second or third trimester (after organogenesis is complete).
Approaches to the treatment of vasculitis and the use of asthma biologic agents, including anti-IL-5/5R therapy, during pregnancy are discussed in more detail 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' and "Safety of rheumatic disease medication use during pregnancy and lactation".)
Treatment-associated toxicities — Glucocorticoids, cyclophosphamide, rituximab, methotrexate, mycophenolate, and azathioprine are all associated with important toxicities. In addition to the toxicities discussed below, cytotoxic agents are toxic to the fetus. (See 'Pregnancy' above and "Safety of rheumatic disease medication use during pregnancy and lactation".)
Adverse effects of these drugs are discussed in separate topics:
●Glucocorticoids (see "Major adverse effects of systemic glucocorticoids")
●Cyclophosphamide (see "Cyclophosphamide in rheumatic diseases: General principles of use and toxicity", section on 'Adverse effects')
●Rituximab (see "Rituximab: Principles of use and adverse effects in rheumatologic disease" and "Infusion-related reactions to monoclonal antibodies for cancer therapy", section on 'Rituximab')
●Methotrexate (see "Major adverse effects of low-dose methotrexate")
●Mycophenolate (see "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases")
●Azathioprine (see "Pharmacology and side effects of azathioprine when used in rheumatic diseases")
PROGNOSIS —
The prognosis of patients with EGPA has improved significantly since the widespread use of systemic glucocorticoids and biologic agents as well as the selected use of immunosuppressants for patients with more severe disease [29,70,94,95]. 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 clinical series post-glucocorticoid use but prior to introduction of biologic agents demonstrate a much-improved survival rate (70 to 90 percent at five years) [6,29,70,96,97].
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
●Kidney failure
●Gastrointestinal bleeding
●Status asthmaticus
Developed based on recognition of these vasculitic risks, the five-factor score (FFS) has been used to predict survival in EGPA (table 2), although the components of the FFS have changed over the years [10,18]. In the current system, revised in 2011, the presence of each of the following factors is given one point:
●Age >65 years
●Cardiac insufficiency
●Gastrointestinal involvement
●Kidney 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 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. An FFS ≥1 is associated with a worse prognosis and in the past has been used to guide treatment [70].
In the 1990s, an FFS of ≥1 was associated with 25 to 45 percent mortality at five years [10]. 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 [70]. In a separate series, 150 patients with EGPA (of whom 71 percent had received cyclophosphamide) had a 10-year estimated mortality of 11 percent [29].
Of the five factors, cardiac involvement, gastrointestinal disease, and age ≥65 years appear to be the strongest indicators of poor prognosis [6,29,70]. 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 [11,70]. 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 [70,98,99]. The duration of disease-free survival was significantly longer for patients with negative anti-MPO ANCA at entry, although overall survival was not different [70].
Heart involvement is a leading cause of EGPA-associated deaths [29]; consequently, heart transplantation has been considered in severe cardiomyopathy. A case series from 2014 showed that heart transplantation is feasible in EGPA, but patients had a poor outcome. More data are needed to evaluate feasibility in EGPA with current treatments [100]. (See "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA)", 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" and "Society guideline links: Pulmonary eosinophilia".)
SUMMARY AND RECOMMENDATIONS
●Goals of therapy – The goals of therapy for new-onset eosinophilic granulomatosis with polyangiitis (EGPA) are to achieve rapid onset of remission, followed by maintenance of remission without relapse, and to minimize complications of therapy. (See 'Introduction' above and 'Defining therapeutic response' above.)
Complete remission is defined by the absence of active disease (ie, the absence of any clinical manifestation arising from ongoing vasculitis); however, for patients with EGPA, residual upper and lower airway disease may impact quality of life but can often be managed by topical therapies.
●Assessment of vasculitis severity – The treatment approach to patients with EGPA depends in part on whether the patient has developed organ- or life-threatening manifestations (severe EGPA) or has less severe disease. Organ-threatening manifestations include active glomerulonephritis, cerebral vasculitis, myocarditis, alveolar hemorrhage, and limb or mesenteric ischemia (table 1).
●Induction therapy for organ- or life-threatening disease – For patients with EGPA who present with new-onset or relapsed organ- or life-threatening disease, we recommend initiating both high-dose intravenous (IV) glucocorticoids and either cyclophosphamide or rituximab rather than glucocorticoids alone (Grade 1C). For such patients, we also suggest early initiation of anti-IL-5/5R therapy (rather than initiating postremission or not using anti-IL-5/5R therapy) (Grade 2C) to facilitate tapering off the induction regimen and to minimize the adverse effects and toxicities of induction agents.
•Choosing between cyclophosphamide and rituximab – 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, are at risk of gonadal toxicity, or are clinically frail, we select rituximab. (See 'Organ- or life-threatening disease' above.)
•Glucocorticoid dosing – In patients with rapidly progressive vasculitis with multiple affected organs, severe neurologic complications, or actively life-threatening disease (eg, respiratory failure, cardiac failure, optic neuritis, or acute limb ischemia), IV glucocorticoid (eg, methylprednisolone 500 to 1000 mg IV daily for three to five days) is used for initial therapy.
Immediately following this ultra-high-dose induction and for the remainder of patients with organ-threatening disease, systemic glucocorticoids are used at a dose of 1 mg/kg (typically up to 80 to 120 mg) per day.
•Anti-IL-5/5R therapy – The efficacy of anti-IL-5/5R agents in the induction phase and early maintenance has to date been demonstrated in those with nonsevere disease. Options include mepolizumab 300 mg every four weeks (40 mg in children aged 6 to 11 years) or benralizumab 30 mg every four weeks (10 mg in children aged 6 to 11 years weighing <35 kg). (See 'Early initiation of anti-IL-5/5R therapy' above.)
●Induction therapy for nonsevere disease – For patients without life- or organ-threatening manifestations of EGPA (table 1), we suggest therapy with moderate to high doses of glucocorticoids alone rather than glucocorticoids and additional immunomodulatory agents (Grade 2C).
For those unable to achieve remission or who have early relapse on glucocorticoid therapy, we suggest the addition of anti-IL-5/5R agents rather than higher-dose glucocorticoids alone or other immunomodulators (Grade 2B). We prefer these anti-eosinophilic biologics because they are effective for most patients with very limited toxicity. Methotrexate or mycophenolate are reasonable alternative agents.
●Remission maintenance
•Preferred glucocorticoid-sparing agent – For all patients with EGPA, we suggest the inclusion of anti-IL-5/5R therapies (mepolizumab or benralizumab) as part of maintenance regimens (Grade 2C), although long-term data on remission maintenance with these agents remain limited. Other options include maintenance methotrexate, mycophenolate, and rituximab. (See 'Remission maintenance' above.)
•Glucocorticoid taper – Once disease manifestations have come under control and a maintenance regimen selected, the glucocorticoid dose is gradually tapered over variable time periods (ranging from 3 to 18 months) based on weight-based initial dosing, disease severity, history of relapses, and patient tolerance. A typical tapering regimen for those without a history of relapses is shown (table 3). The dose is gradually tapered to the lowest dose required for control of symptoms and signs of active EGPA. (See 'Glucocorticoid dosing and taper during maintenance' above.)
•Management of relapses on maintenance therapy – Relapses are common during the treatment of EGPA, particularly during glucocorticoid tapering. (See 'Management of relapses on maintenance therapy' above.)
-Relapses with organ- or life-threatening manifestations require reinduction.
-For less severe relapses, we suggest increasing glucocorticoids back to the last dose that achieved convincing remission followed by a slower taper and/or cessation of the taper at a low maintenance dose (≤7.5 mg of prednisone) (Grade 2C).
-For those with recurrent relapses during tapers at prednisone >7.5 mg daily (or equivalent) or who do not tolerate glucocorticoids, we suggest adding an additional immunosuppressant agent to anti-IL-5/5R therapy (Grade 2C). Rituximab can be helpful for those who have recurrent relapses despite both anti-IL-5/5R therapy and an additional immunosuppressant.
•Duration of maintenance therapy – Maintenance immunosuppressive therapy is typically continued for 12 to 18 months, though no long-term studies describe the natural history of EGPA. Longer-term or indefinite maintenance therapy may be warranted in patients with multiple relapses. (See 'Remission maintenance' above.)
●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.
ACKNOWLEDGMENT —
The UpToDate editorial staff acknowledges Talmadge E King, Jr, MD, who contributed to earlier versions of this topic review.
