Long-term Safety and Efficacy of Benralizumab for Eosinophilic Granulomatosis with Polyangiitis Complicated with Severe Neuropathy

Abstract

The efficacy of benralizumab, as well as mepolizumab, to granulomatosis with polyangiitis (EGPA) involved with mononeuritis multiplex remains unclear. We experienced a case of EGPA presenting neuropathy with severe asthma. Muscle weakness due to neuropathy involved with gait disturbance was partly ameliorated by intravenous immunoglobulin therapy. Mepolizumab (100 mg/day) did not promote further improvement of neuropathy. However, the administration of benralizumab instead of mepolizumab improved neuropathy quickly and enabled walking alone. The efficacy of benralizumab for EGPA and its complication has been maintained for over four years. Benralizumab may be a possible treatment for EGPA presenting neuropathy with severe asthma.

Introduction

The anti-interleukin (IL)-5 antibody mepolizumab may be useful for treating eosinophilic granulomatosis with polyangiitis (EGPA). However, there are a few reports of clinical studies regarding the efficacy of the anti-IL-5α receptor antibody benralizumab for EPGA. Indeed, 2 small clinical studies have reported the efficacy and safety of benralizumab against EGPA for 24-48 weeks (1,2).

Most cases of mononeuritis multiplex complicated with EGPA are refractory to oral corticosteroid (OCS) therapy. Patients with neuropathy due to EGPA frequently develop disabilities in activities of daily living. The efficacy of these biologics for EGPA with mononeuritis multiplex has yet not been elucidated. Furthermore, the long-term efficacy of benralizumab against the mononeuritis multiplex feature of EGPA remains unclear.

We herein report a case of EGPA presenting with mononeuritis multiplex in a patient with severe asthma effectively treated with mepolizumab (100 mg/day) followed by benralizumab for more than 4 years. Written informed consent was obtained from the patient for the publication of this issue.

Case Report

A 65-year-old woman was admitted to our hospital for severe asthma without motion dysfunction. The patient had been administered high-dose inhaled corticosteroids (ICS)/long-acting β-antagonists (LABA) and leukotriene antagonists. She had a history of asthma for over eight years without any smoking history. Her peripheral eosinophil count and IgE level were elevated to 3,500 /μL and 524 IU/mL, respectively, at the initial admission. Despite high-dose ICS/LABA therapy, the patient developed frequent asthma exacerbations that required short-term OCS administration.

Two years after the initial admission, the patient developed a high fever and general fatigue in combination with neuropathic foot pain. Blood eosinophil counts were elevated at 34,000 /μL, and the serum anti-myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) was negative, as seen at initial admission. Parasitic infection was excluded. Although a nerve biopsy could not be performed, a diagnosis of EGPA with remarkable eosinophilia, mononeuritis multiplex, and a history of asthma was made. There were no cardiac or sinus complications and no abnormal pulmonary infiltrates.

Methylprednisolone pulse therapy followed by maintenance therapy with OCSs (prednisolone: PSL 60 mg/day) decreased the peripheral eosinophil count and improved the fever and fatigue symptoms. However, muscle weakness due to neuropathy persisted and deteriorated the gait disturbance despite maintenance treatment with OCSs. Periodic administrations of intravenous immunoglobulin (IVIG) partly ameliorated neuropathy, but gait disturbance was sustained. The patient fell easily and walked by lifting her thighs consciously due to her dropped foot. Azathioprine treatment was stopped shortly due to liver dysfunction.

Subsequently, we administered mepolizumab (100 mg/month) in 2017 for 6 months against severe asthma, followed by benralizumab. Treatment of mepolizumab (100 mg/day) did not improve the neuropathy. At this time, mepolizumab (300 mg/day) was not yet approved for refractory EGPA. Administration of benralizumab under treatment with OCSs (PSL 6 mg/day) improved neuropathy within 1 month and enabled the patient to walk smoothly. It should be noted that the peripheral eosinophil count had been normalized since methylprednisolone pulse therapy.

We monitored the effects of benralizumab on mononeuritis multiplex using a questionnaire for patients with disturbances of the motor and sensory nervous systems due to EGPA after the second IVIG treatment (3). We obtained a patient-reported outcome (PRO) from the questionnaire. The maximum scores of motor and sensory evaluations are 48 and 40, respectively (3). In this PRO, a higher motor score indicates a better motor function as assessed by the patient, whereas a higher sensory score indicates a lower sensation function as assessed by the patient. To visualize the effect of biologics on neuropathy, the variation from the initial score of PRO is shown in Figure. The effect of benralizumab on mononeuritis multiplex was quick to take place, persisted for longer than four years with a stable asthma condition, and depleted peripheral eosinophils. There were no adverse events during the administration of either mepolizumab or benralizumab. The patient is currently able to work like normal since the administration of benralizumab.

Figure.

Time-course of the motor and sensory evaluation scores in EGPA-induced neuropathy after the second IVIG administration based on the patient-reported outcome. The motor and sensory evaluation scores in EGPA-induced neuropathy were obtained from the patient-reported outcome (PRO) determined in a questionnaire (3). The maximum scores of the motor and sensory evaluations are 48 and 40, respectively. The scores for the motor and sensory nervous systems were evaluated after the second IVIG treatment. The relative change from the baseline score over time was monitored. Mepolizumab (100 mg) did not improve neuropathy. The introduction of benralizumab promoted a significant improvement in both motor and sensory neuronal dysfunctions within one month. The effect of benralizumab was sustained for over four years with depletion of peripheral eosinophils. AZP: azathioprine, PSL: prednisone, IVIG: intravenous immunoglobulin, OCS: oral corticosteroid

Discussion

Neuropathy due to EGPA is usually refractory to OCS mono-therapy (4). IVIG is a possible treatment for refractory neuropathy due to EGPA (5). The efficacy of IVIG in the treatment of neuropathy due to EGPA typically alleviates neuronal function gradually and the mechanism of improvement for neurologic dysfunction of IVIG has not been clarified (6). Currently, mepolizumab (300 mg/day) is covered by insurance for the treatment of EGPA. The benefit of anti-IL-5 therapy for EGPA-induced neuropathy has not been clarified. The two EGPA phenotypes have been suggested to be treated regardless of anti-ANCA antibody positivity. Sinico et al. reported that the characteristic histological finding in ANCA-negative patients was massive eosinophilic tissue infiltration, whereas eosinophil-abundant necrotizing small-vessel vasculitis was found in ANCA-positive patients (7). Furthermore, neuronal biopsies revealed substantial eosinophilic infiltration in the epineurium of 5 out of 14 MPO-ANCA-negative patients and no eosinophilic infiltration in the epineurium of any of the 8 MPO-ANCA-positive patients (8). Eosinophilic infiltration in the epineurial vessels, considered to be microvasculitis, was often seen in the ANCA-negative patients. Oka et al. suggested a potential toxic eosinophilic effect on the nerve fibers that was independent of ANCA (8).

Recently, Drake et al. reported an interaction between eosinophilic inflammation and the change in the airway nerve structure in patients and mice with eosinophilic asthma (9). The prevention of eosinophil recruitment to the airway nerves is thought to preserve the nerve function and prevent neuronally mediated airway hypersensitivity in animal models (10). In this regard, anti-IL-5 antibodies might be useful for preventing the eosinophil-nerve interaction in the tissues. Consistently, anti-IL-5 antibodies prevented vagal hyperreactivity by depleting eosinophils in animal models (11). In our ANCA-negative patient, benralizumab may have been effective at improving neuronal dysfunction by promoting a reduction in the eosinophil count in the epineurium through antibody-dependent cellular cytotoxicity. The human eosinophil blood-to-tissue ratio is approximately 1.14:100. Eosinophils are distributed to tissues via systemic circulation (12). Decreased blood eosinophils do not necessarily result in decreased tissue eosinophils. Mepolizumab (100 mg/month) might therefore not have been sufficient to suppress tissue eosinophil infiltration.

Interestingly, the present patient showed a rapid improvement in neuropathy one month after benralizumab administration. Although the effect of the preceding IVIG treatment could not be ruled out, there are reports that benralizumab rapidly improved EGPA-induced neuropathy within one or two months (13,14). Mepolizumab (300 mg/day) was not approved for refractory EGPA at the time of treating this patient. High-dose (300 mg/day), but not low-dose (100 mg/day), mepolizumab may be useful for treating neuropathy due to EGPA.

Although the efficacy of benralizumab for mepolizumab-refractory EGPA has been reported previously (2,15-17), the long-term efficacy of benralizumab on EGPA and its complications has not been reported (18). Since EGPA is an intractable disease that is prone to recurrence, it is important to elucidate the long-term safety and efficacy of biologics. To our knowledge, this is the first report describing the long-term efficacy of benralizumab for mononeuritis multiplex due to EGPA. Further cases involving nerve biopsies are required to elucidate the mechanism underlying the effects of anti-IL-5 targeting therapy on EGPA-induced neuropathy.

In conclusion, benralizumab may be a potential treatment for EGPA with neuronal dysfunction in patients with severe asthma.

The authors state that they have no Conflict of Interest (COI).