Eosinophilic granulomatosis with polyangiitis present and future

There is now a scientific rationale for biologic therapies based on our understanding of the pathogenesis of EGPA. Anti-IL5 therapy is improving outcomes in refractory and relapsing EGPA as evidenced by data with mepolizumab from the MIRRA trial. Rituximab has demonstrated efficacy in retrospective studies for relapsing and refractory disease and may be more effective in the ANCA-positive EGPA subgroup. Cyclophosphamide and GC therapy remain the therapy of choice for life or organ-threatening disease. An 18-year-old Caucasian woman presented with cough, wheeze, fatigue, general malaise, epigastric discomfort and intermittent tingling of the left foot. She had been diagnosed with asthma two years previously. Recent frequent asthma exacerbations were being treated with recurrent courses of antibiotics and prednisolone. Her medical history included atopic eczema and severe recurrent nasal polyposis, in spite of surgical treatment. Her medications were montelukast and a corticosteroid/β-agonist inhaler. Physical examination revealed mild wheeze but was otherwise unremarkable. Blood results demonstrated peripheral eosinophilia (4.5 *103/μl, white blood count (WBC) 10.7 *103/μl) and mildly raised IgE (175 kU/l, reference <114), with a negative radioallergosorbent (RAST) test. Renal function and urinary dipstick testing were normal. Autoantibody (anti-nuclear and anti-neutrophil cytoplasmic antibody) screens were negative. Chest radiography reported patchy non-fixed lung infiltrates, with computerized tomography demonstrating bronchial wall thickening and scattered ground-glass opacities (Fig. 1A and B). Gastroscopy, nerve conduction study and cardiac MRI were within limits. (A) Medial segment RML ground glass on CT chest imaging; (B) bronchial wall thickening right side compared with left on CT chest imaging; (C) eosinophil count (103/ul) over time reduced from high to normal values Fractional exhaled nitric oxide (FeNO) (parts per billion) which was elevated during episodes of airway inflammation, normalized upon therapy with anti-IL5 therapy. Lung function test—FEV1 (% of expected) improved with the introduction of mepolizumab. Intramuscular (IM) glucocorticoid (GC) therapy was discontinued after mepolizumab therapy. (A) Medial segment RML ground glass on CT chest imaging; (B) bronchial wall thickening right side compared with left on CT chest imaging; (C) eosinophil count (103/ul) over time reduced from high to normal values Fractional exhaled nitric oxide (FeNO) (parts per billion) which was elevated during episodes of airway inflammation, normalized upon therapy with anti-IL5 therapy. Lung function test—FEV1 (% of expected) improved with the introduction of mepolizumab. Intramuscular (IM) glucocorticoid (GC) therapy was discontinued after mepolizumab therapy. Asthma, peripheral eosinophilia, pulmonary infiltrates and sinus abnormality supported the diagnosis of eosinophil granulomatosis with polyangiitis (EGPA). A weaning treatment course of prednisolone (40 mg/day) was commenced, and partial responses of sinus symptoms and eosinophilia were recorded (Fig. 1C). Adjuvant immunosuppressive agents were introduced as steroid-sparing agents due to ongoing symptoms that prevented the reduction of the daily prednisolone dosage below 20 mg. Methotrexate was introduced and discontinued after 6 months, due to lack of benefit. MMF was not tolerated due to gastrointestinal side effects. Rituximab was trialed (1 g ×2 for induction, followed by 1 g 6-monthly). After 6 months on rituximab, there was no improvement in disease control. Peripheral eosinophilia persisted and exacerbations of asthma became more frequent and severe, making it impossible for the patient to maintain her employment. A course of azathioprine was discontinued shortly after its introduction due to intolerance. At this time-point, there was variable prednisolone absorption on random testing and subsequent profile testing. Poor compliance was considered but excluded given the oral prednisolone prescription refill rate was 94%. Ongoing abdominal pain and weight loss raised the possibility of eosinophilic enteritis affecting absorption. Hence, prednisolone was switched to intramuscular triamcinolone to overcome this. Symptoms improved, the eosinophil count decreased, exhaled nitric oxide—a marker of eosinophilic airway inflammation—reduced to within normal levels (Fig. 1C). As a steroid sparing intervention, the patient was commenced on mepolizumab (MEPO) (subcutaneous [s/c] 100 mg every 4 weeks) as part of the NHS severe asthma pathway. Subsequently, asthma and sinus symptoms remained well controlled, FEV1(%) improved (Fig. 1C) facilitating progressive weaning of steroids, with complete discontinuation over the following 18 months. This coincided with a significant improvement in quality of life, enabling the patient to enrol at university. The patient remains on mepolizumab for more than two and a half years, symptom free, with eosinophil counts in the normal range. Anti-IL5 therapy has enabled complete withdrawl of steroid therapy. In 1951, the defining paper by Churg and Strauss observed mortality in 11 of 13 patients for the disease they called ‘allergic granulomatosis and angiitis’ (Churg Strauss syndrome) [1], latterly known by the 2012 Chapel Hill nomenclature as ‘eosinophilic granulomatosis with polyangiitis’ (EGPA) [2]. The presence of pulmonary infiltrates, rhinosinusitis, asthma and eosinophilia supports the diagnosis of EGPA in this case. Differentials of hyper-eosinophilia include eosinophilic asthma, eosinophilic pneumonia, hyper-eosinophilic syndrome or eosinophilic leukaemia [3]. While the overall prognosis has improved significantly, the natural history of the disease is one of regular relapse, with damage accrual. To date, steroids have played a major role in the treatment of EGPA due to their rapid efficacy for asthma flares, eosinophilic and vasculitic manifestations [3]. The French Factor Five Score (FFS) prognostic tool (2009) predicts poor outcome based upon age (>65years), presence of cardiomyopathy, gastrointestinal, central nervous system, renal (raised creatinine >150μmol/l) involvement and absence of ear, nose and throat disease. More intensive remission-induction therapy such as cyclophosphamide and glucocorticoid (GC) are recommended for FFS ≥1 [3]. In non-severe disease, oral immunosuppressants such as azathioprine are regularly instituted [3], but with variable success. The addition of azathioprine to remission-induction glucocorticoids for EGPA (Churg Strauss syndrome), microscopic polyangiitis (MPA) or polyarteritis nodosa (PAN) without poor prognostic factors (the CHUSPAN2 trial) did not show any benefit of azathioprine for improving remission rates or lowering relapse risk [3, 4]. Clinical remission is achievable; however, ongoing dependence on steroids due to uncontrolled asthma has been a driving impetus to develop newer patho-physiologically targeted therapies and immunomodulatory strategies. Mepolizumab (MEPO), a humanized monoclonal IgG1 antibody, inhibits IL-5 eosinophilic signalling thereby minimizing eosinophilic proliferation, maturation and differentiation [5]. MEPO was demonstrated to be efficacious for relapsing and refractory EGPA in the ‘Mepolizumab in Relapsing or Refractory EGPA’ MIRRA trial [5]. In this double-blind randomized controlled trial (RCT), those receiving add-on MEPO 300 mg treatment (vs placebo) in addition to standard of care accrued longer times in remission, reduced steroid exposure and reduced relapse rates at one year. Notably, this was achieved in 53% of patients. In a further study using post-hoc analysis, additional clinical benefit over 52 weeks was achieved [6]. Ongoing clinical trials include the MANDARA trial (Clinical Trials.gov ID:NCT04157348) comparing 300 mg MEPO (anti-IL5) vs benralizumab (anti-IL5R) treatment in relapsing or refractory disease. Efficacy of eosinophilic asthma MEPO dosage (100 mg s/c every 4 weeks) for EGPA is also the subject of ongoing studies. We present a case of refractory EGPA, highly responsive to 100 mg mg s/c anti-IL5 therapy, which facilitated complete with-drawl of steroids. Rituximab (RTX), an anti-CD20 chimeric antibody, has demonstrated efficacy in retrospective studies among patients refractory to standard-of-care therapy [7]. Higher remission rates are noted in ANCA-positive patients [7]. Two ongoing prospective RCTs will help to stratify the role for RTX in EGPA. For remission-induction, REOVAS compares RTX to standard of care based on the FFS (Clinical Trials.gov ID: NCT02807103), while for maintenance therapy, MAINRITSEG compares azathioprine to scheduled RTX therapy (ClinicalTrials.gov ID NCT0316447) [8]. Rituximab and anti-IL5 therapy is a further treatment strategy undergoing evaluation in retrospective studies. Biologic therapy may evoke a paradigm shift in therapy similar to granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), with studies underway to guide recommendations. The authors would like to thank the patient for their consent to publish this manuscript for educational purposes. Funding: This paper forms part of the supplement entitled ‘EUVAS Cambridge Vasculitis Course Case-Base Supplement’. This supplement is supported by the University of Cambridge. Disclosure statement: The authors have no financial disclosures relevant to the submitted work. The data underlying this article will be shared on reasonable request to the corresponding author.

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