Onset of eosinophilic granulomatosis with polyangiitis in a patient treated with an IL-5 pathway inhibitor for severe asthma

DearEditor, Eosinophilic inflammation represents a common background of several diseases, including severe asthma. Two monoclonal antibodies targeting eosinophils by blocking IL-5 (mepolizumab) and its receptor (benralizumab) have been approved for subcutaneous administration as a treatment option for eosinophilic severe asthma [1]. Especially when associated to chronic rhinosinusitis with nasal polyps (CRSwNP), severe asthma is often part of the clinical picture of eosinophilic granulomatosis with polyangiitis (EGPA) and may precede its onset by many years [2]. The US Food and Drug Administration has recently approved mepolizumab at the dose of 300 mg/4 weeks (vs 100 mg/4 weeks for asthma) for the treatment of EGPA. A phase II trials including benralizumab for EGPA and a head to head trial with mepolizumab [1, 3] are currently ongoing.

We report on a case of EGPA acute onset in a patient treated with benralizumab for severe asthma.

A 55-year-old, non-smoker, non-atopic woman was referred to our centre for CRSwNP and a 20-year-long mild to moderate asthma history. About 2 years before our evaluation she experienced severe respiratory symptom worsening, refractory to inhaled maximal therapy and requiring chronic treatment with oral steroids. An extensive diagnostic work-up was performed revealing blood eosinophils ranging from 10% (750/mm³) to 15% (1130/mm³) of the white blood cells, normal renal and hepatic function and negative ANA and ANCA. No other relevant comorbidities or lung abnormalities were detected. In order to optimize nasal and bronchial disease control and modulate oral steroid dependence, the patient was prescribed benralizumab (30 mg/4 weeks for the first three injections, then 30 mg/8 weeks). Since the start of the anti-IL-5 treatment, she experienced a fast and significant improvement of lung function and asthma clinical control, and therefore a gradual oral steroid withdrawal was carried out. Two weeks after the third injection and the complete oral steroid stop, she was admitted to the emergency room for acute onset of fever, arthritis, purpura, hypoesthesia and paraesthesia of hands and feet and asthma worsening. Blood exams showed increased inflammation indexes, blood eosinophilia (12% of leukocytes, 900/mm³ rising to 2.800/mm³ in the following days) and a strong P-ANCA positivity. No abnormalities were revealed by chest X-ray, ECG, echocardiography and brain MRI (except for paranasal sinuses involvement), whilst electromyography detected symmetric peripheral polyneuropathy involving sensory nerves of the distal portion of upper and lower limbs. The patient was finally diagnosed with EGPA [4] and immunosuppressive therapy with i.v. methylprednisolone 1000 mg/day for the first 3 days, then tapered to oral administration, and i.v. cyclophosphamide (overall 6 g) was provided [5, 6]. Ten days after a complete clinical remission, excepting from mild paraesthesia, and blood parameter normalization was observed.

Oral steroid (prednisone) was gradually tapered over a period of 4 months, but at the dose of 10 mg/day, despite cyclophosphamide infusion (500 mg/4 weeks) being still ongoing, asthma started to exacerbate. The clinical picture was characterized on one hand by the complete remission of systemic vasculitis, defined as absence of laboratory (including ANCA negativity) and clinical signs suggesting systemic inflammation and organ involvement, and on the other hand by the persistence of steroid-dependent asthma. Taking that into consideration, mepolizumab treatment at the asthma dose (100 mg/4 weeks) was initiated. The patient rapidly experienced an optimal symptoms and lung function control and over 5 months both oral steroid and i.v. cyclophosphamide were discontinued. In the past 3 months mepolizumab and inhaled steroid represented the only ongoing treatments and no relapse has been observed so far.

To our knowledge we report the first unexpected case of EGPA onset during IL-5 receptor inhibitor treatment for severe asthma successfully treated with mepolizumab in the remission phase. In light of the anti-IL-5 treatment mechanism and of the evidence supporting the ongoing trials on its use in EGPA [1, 3], it is unlikely that benralizumab caused the systemic vasculitis; more reasonably its steroid sparing effect contributed to ‘unmask’ an underlying unpredictable condition. In fact, predicting the potential disease evolution from severe asthma to EGPA before the systemic vasculitis phase occurs cannot count up to now on prodromal reliable biomarkers or specific clinical signs [1, 2]. It remains unclear why direct interaction with IL-5 was apparently more effective than IL-5 receptor blockade, despite a very similar mechanism of action and the currently available evidence in favour of a potential role of both mepolizumab and benralizumab in the management of EGPA [1–3]. In our report benralizumab treatment was ongoing at the time of EGPA acute phase, whilst mepolizumab was started during the remission phase. The place of anti-IL-5 treatment in comparison with the traditional therapeutic options in the management of EGPA is currently under debate, as well as the best responder phenotype [2, 5, 6]. In fact many variables may account for a dis-homogeneous response to anti-IL-5 treatment in different patients, including type and entity of organ involvement at the onset, patients’ comorbidities or characteristics (ANCA status), and timing of anti-IL-5 treatment start in respect of EGPA acute phase. The currently available evidence on anti-IL-5 treatment in EGPA is too little to allow a phenotype-driven cluster analysis of treated patients, but further investigation on the topic is needed for optimizing the use of anti-IL-5 treatment options in clinical practice.

Our observation highlights that a proper timing of anti-IL-5 treatment is essential and suggests that anti-IL-5 monoclonal antibodies should be considered as immunosuppressive-sparing agents in the maintenance phase only, once the systemic vasculitis is in remission. Furthermore, although mepolizumab has been recently approved as a treatment option for EGPA at the dose of 300 mg/4 weeks [2], in patients with systemic vasculitis in remission phase and persisting severe steroid-dependent asthma, an ‘asthma-tailored’ dose of the anti-IL-5 drug (100 mg/4 weeks) may be considered in the long-term management of EGPA.

Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript.

Disclosure statement: The authors have declared no conflicts of interest.

References