Approach

The prognosis of this disease has improved dramatically since the introduction of corticosteroids, and they remain the first line of therapy of EGPA. Severe disease is treated in a similar manner to other anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (granulomatosis with polyangiitis [GPA; formerly known as Wegener's granulomatosis] and microscopic polyangiitis [MPA]).

Management remains a challenge, with limited clinical trials on well-defined cohorts of patients. Treatment needs to be tailored to the severity of disease. Management of patients with potentially life-threatening multi-system disease should be carried out in conjunction with a consultant who has appropriate experience and expertise.

The American College of Rheumatology and the Vasculitis Foundation guideline on the management of anti-neutrophil cytoplasmic antibody-associated vasculitis differentiates initial treatment of EGPA by defining two patient groups.[34]

Severe EGPA is defined as vasculitis with life- or organ-threatening manifestations, such as:

  • alveolar haemorrhage

  • glomerulonephritis

  • central nervous system vasculitis

  • mononeuritis multiplex

  • cardiac involvement

  • mesenteric ischaemia

  • limb/digit ischaemia.

Non-severe EGPA is defined as vasculitis without life- or organ-threatening manifestations, such as:

  • rhinosinusitis

  • asthma

  • mild systemic symptoms

  • uncomplicated cutaneous disease

  • mild inflammatory arthritis.

The guideline notes that although the definitions of severe and non-severe EGPA are not based on the Five-Factor Score (FFS), the components of the FFS can serve as markers of severe disease that require more aggressive treatment.[34] Due to the lack of randomised trials, the quality of evidence the recommendations are based on is low to very low.[34]

The FFS stratifies patients into low-risk and high-risk categories.[37][39] Those with a FFS ≥1 require an escalation in immunosuppressant therapy similar to that required in severe GPA. See Diagnostic criteria.

Although remission is achieved in >80% of patients, EGPA is commonly a relapsing disease (10% to 43%). Flares secondary to vasculitis must be distinguished from asthmatic flares, because they require different treatment.[37][39]

Minimising adverse effects of treatments is a further important goal of therapy.

Non-severe EGPA

Remission induction

An oral corticosteroid plus mepolizumab is the preferred initial treatment for patients with active non-severe EGPA.[34] A corticosteroid alone may be appropriate for patients with mild asthma, allergic symptoms, use during pregnancy, or with other individual patient factors.[34]

The clinical profile of non-severe EGPA includes predominantly asthma, sinus disease, and non-severe vasculitis.[34]

Mepolizumab, an interleukin (IL)-5 receptor antagonist monoclonal antibody, is approved in the US and Europe for the treatment of EGPA. IL-5 is important for eosinophilic maturation, chemotaxis, and adhesion to vascular endothelium. Elevated levels of IL-5 are found in active EGPA.[40][41] Approval was based on a multicentre randomised controlled trial (RCT) of mepolizumab versus placebo as an add-on agent to corticosteroids with or without other immunosuppressants in patients with relapsing or refractory EGPA. Patients who had had organ or life-threatening manifestations in the previous 3 months were excluded. Its use was associated with more weeks in remission (a combined vasculitis and asthma endpoint) and corticosteroid reduction.[42] Based on the data from this trial, it is reasonable to consider mepolizumab as a corticosteroid-sparing agent in patients without severe active vasculitic manifestions or in whom such manifestations have been brought under control. Its optimal place in therapy is yet to be established.

If mepolizumab is contraindicated, a corticosteroid plus methotrexate, azathioprine, or mycophenolate should be considered.[34] There is significant clinical experience with these treatments, but few data from clinical trials regarding their efficacy.[34] One study has shown that treatment of this group with a corticosteroid and azathioprine, versus a corticosteroid alone, did not lead to superior outcomes and was associated with no significant reduction in relapse rates or any corticosteroid-sparing effect.[43]

Rituximab (an anti-CD20 monoclonal antibody) in addition to a corticosteroid may be considered for patients with active non-severe EGPA if other agents are ineffective.[34]

Remission maintenance

For patients who achieve remission with corticosteroids alone, based on symptoms and laboratory markers of inflammation, corticosteroids can be slowly tapered over several months. Patients may need to be maintained on low-dose (≤10 mg/day) prednisolone long term.[44] This may be required to control asthma symptoms.

For patients who achieve remission with mepolizumab, methotrexate, azathioprine, or mycophenolate plus a corticosteroid, continuation of the same treatment is conditionally recommended.[34] Corticosteroid tapering should be guided by the clinical response, as tolerated by the patient.[34]

For patients who achieve remission with rituximab, treatment with methotrexate, azathioprine, or mycophenolate are conditionally recommended for maintenance of remission.[34]

Severe EGPA

Remission induction

A corticosteroid (intravenous pulse dose or high-dose oral) plus either cyclophosphamide or rituximab may be considered for remission induction in patients with active severe EGPA.[34][45]

Treatment should be individualised; for example, cyclophosphamide would be the preferred treatment for patients with cardiac involvement, as cardiomyopathy is the main independent predictor of death in EGPA, and there is more evidence to support this treatment. Cyclophosphamide is also preferred if patients are ANCA-negative and have severe neurological or gastrointestinal manifestations.[34] Rituximab may be preferred for patients with positive ANCA results, active glomerulonephritis, prior cyclophosphamide treatment, or those at risk of gonadal toxicity from cyclophosphamide.[34]

Cyclophosphamide

Cyclophosphamide can be given intravenously or orally. The CYCLOPS trial (daily oral versus intravenous pulse dose cyclophosphamide for renal vasculitis) in GPA suggested that intravenous pulse dosing is preferable because efficacy seems similar and it may be safer due to lower total cyclophosphamide dose received, although whether this may lead to a higher relapse rate has yet to be determined.[46] While patients with EGPA were excluded from this and other multicentre randomised ANCA vasculitis trials, the recommendation is to treat EGPA with severe manifestations in the same way as GPA and MPA.

The choice between daily oral and pulse intravenous cyclophosphamide administration may be influenced by factors including the patient's risk of relapse, compliance with treatment and monitoring schedules, fertility issues, and potential susceptibility to other adverse effects of cyclophosphamide. If intravenous cyclophosphamide is used, the protocol should incorporate intravenous fluids and mesna (a uroprotective agent) to minimise bladder toxicity. To reduce the risk of toxicity from oral cyclophosphamide, it should be taken in the morning and a liberal fluid intake maintained throughout the day. Full blood count and urinalysis should be monitored regularly, in accordance with local protocols.

Rituximab

For patients with severe EGPA who have contraindications to cyclophosphamide, rituximab in combination with a corticosteroid is recommended as an alternative.[34][47]​​ One RCT, including 105 patients with new onset or relapsing EGPA, of which 42 patients had life-threatening or organ-threatening disease (FFS ≥1), demonstrated that rituximab was as effective as standard therapy for remission induction at 180 and 360 days.[48] Results were similar in both newly diagnosed and relapsing disease. However, the superiority design, lack of fully published results, and limited number of patients do not allow for strong conclusions regarding non-inferiority.[47] One phase 3 randomised placebo-controlled trial is ongoing.[49]

Remission maintenance

For patients with severe EGPA who achieve remission with either 3 to 6 months of cyclophosphamide or 4 weeks of rituximab plus a corticosteroid, treatment with methotrexate, azathioprine, or mycophenolate are conditionally recommended for maintenance of remission.[34] Corticosteroid tapering should be guided by the clinical response, as tolerated by the patient. 

In circumstances where disease is severe and life-threatening, plasma exchange may be used as an adjunct to corticosteroids and cyclophosphamide.[10]​ One subsequent systematic review and meta-analysis demonstrated that adjunctive treatment with plasma exchange reduced 12-month risk of end stage kidney disease, regardless of baseline kidney disease, in patients with ANCA-associated vasculitis, but had no important effect on mortality and increased the risk of serious infections.[50] ​BMJ: plasma exchange and glucocorticoid dosing for patients with ANCA-associated vasculitis: a clinical practice guideline Opens in new window

Relapsed disease

Mepolizumab is conditionally recommended for patients who have relapsed disease with non-severe disease manifestations (i.e., asthma and/or sinonasal disease), who:[34]

  • are being treated with a low-dose corticosteroid alone

  • are being treated with methotrexate, azathioprine, or mycophenolate

  • have high serum IgE levels and are being treated with methotrexate, azathioprine, or mycophenolate.

Clinical trials have demonstrated the effectiveness of mepolizumab in patients with relapsing non-severe EGPA who are receiving immunosuppressive therapy and in patients with eosinophilic asthma.[51][42] The addition of mepolizumab is preferred to the addition of systemic immunosuppressants in patients receiving corticosteroids alone, and in preference to switching to an alternative agent in patients being treated with methotrexate, azathioprine, or mycophenolate.[34]

For patients who have experienced relapse with severe disease manifestations after prior successful remission induction, rituximab is preferred for remission re-induction, as re-treatment with cyclophosphamide should be avoided if possible.[34] Evidence from retrospective studies supports the use of rituximab in patients with refractory or relapsed EGPA.[52][53]

Adjunctive therapies

Infection and bone prophylaxis during corticosteroid treatment

  • Patients taking ≥20 mg/day of prednisolone or corticosteroid-sparing agents should consider prophylaxis against Pneumocystis jirovecii.[34][54] See Pneumocystis jirovecii pneumonia.

  • Patients taking corticosteroids long term should also receive osteoporosis prophylaxis treatment depending on individual factors.[55]​ Screening and preventive measures against corticosteroid-induced osteoporosis should be instituted, along with monitoring and treatment for other complications of corticosteroid treatment (e.g., hypertension, diabetes mellitus, dyslipidaemia).[55]​ See Osteoporosis (Management approach).

Preservation of fertility

  • There is interest in trying to induce a temporary chemical menopause in young women receiving cyclophosphamide to attempt to preserve fertility. This is done with hormonal manipulation with the gonadotrophin-releasing hormone (GnRH) analogue leuprorelin. Norethisterone is started at the same time as leuprorelin and is continued until resumption of menses after the end of ovarian suppression.[56][57]

  • In men, sperm banking is recommended before starting cyclophosphamide therapy.

  • In women, embryo freezing is an option, and oocyte cryopreservation is also emerging as a potential option.

Asthma management

  • Inhaled corticosteroids are used to manage airway inflammation and may allow a more successful taper of oral corticosteroid. Patients on leukotriene receptor antagonists at the time of their EGPA diagnosis may be continued on these medications.[20][34] Standard asthma therapy may also be needed.

  • Inhaled therapy for active asthma should be optimised before increasing systemic immunosuppressive treatment in patients with non-severe disease relapse.[34]

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