Rheumatology: Current Research
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A Case of Eosinophilic Granulomatosis with Polyangiitis with Severe Peripheral Neuropathy Refractory to Standard Treatment Successfully Treated by Mepolizumab

Seika Terashima, Makoto Yamaguchi, Takayuki Katsuno, Hirokazu Sugiyama, Shiho Iwagaitsu, Hironobu Nobata, Hiroshi Kinashi, Shogo Banno and Yasuhiko Ito^{* *}Correspondence: Yasuhiko Ito, Department of Nephrology and Rheumatology, Aichi Medical University, 1-1 Karimata, Yazako, Nagakute 480-1195, Japan, Tel: +81-0561-62-3311, Fax: +81-0561-63-158, Email:

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Introduction

Eosinophilic Granulomatosis with Polyangiitis (EGPA) is a type of Anti-Neutrophil Cytoplasmic Antibody (ANCA) Associated Vasculitis (AAV), characterized by small to medium-sized vessel vasculitis, and is typically associated with eosinophilic granulomatous inflammation [1-3]. EGPA is the rarest among AAV, and studies have reported that the annual incidence and prevalence of EGPA were 0.9-2.4 per million and 10.7-17.8 per million, respectively [4,5].

EGPA is generally responsive to glucocorticoids, however, the relapses are common [6-8], and some refractory cases have been reported [9,10]. The clinical benefits of administering mepolizumab to patients with EGPA for prolonging the remission period of the disease have been reported [11-14]. However, it has not yet been elucidated when mepolizumab should be started or what clinical characteristics are the best indicators for mepolizumab treatment.

Herein, we present a case of ANCA-negative EGPA with severe peripheral neuropathy refractory to standard therapy. The patient was administered with a high-dose steroid, intravenous cyclophosphamide, intravenous immune globulin, and finally mepolizumab, which resulted in marked clinical improvement of nervous symptom without any adverse effects.

Case Presentation

A 57-year-old man presented to our hospital with a 1 week history of fever, deteriorating bilateral leg pain and numbness, and difficulty in walking due to progressive weakness in the bilateral lower extremities. He was subsequently admitted. He had been diagnosed with bronchial asthma and eosinophilic sinusitis 2 years prior to this case, at which time he was treated with anti-leukotrienes, inhaled steroids, and theophylline. His body temperature was 38.4°C. Neurological examination showed touch-temperature-pain hypoesthesia in a stocking and glove distribution. Weakness in the distal muscle groups in the lower limbs was also observed, resulting in bilateral foot drop and weakened hand grip motion, indicating sensorimotor polyneuropathy. No skin rash was observed. Laboratory data revealed leucocytosis (31800/μL) with eosinophilia (52.5%) and increased C-reactive protein level (11.6 mg/dl).

Kidney function was normal, with no haematuria or proteinuria. Both proteinase-3 (PR-3)/myeloperoxidase (MPO)-ANCA and indirect immunofluorescence ANCA were negative. Computed tomography revealed sinusitis, but not pulmonary lesion. His motor nerve conduction study (NCS) showed decreased amplitude of Compound Motor Action Potentials (CMAP) in bilateral tibial nerves. The sensory NCV study showed absence of Sensory Nerve Action Potentials (SNAP) in the bilateral sural nerves, and mildly decreased amplitude of SNAP in bilateral median and ulnar nerves. Head and spinal magnetic resonance imaging showed no abnormal findings. Sural nerve biopsy could not be performed; however, based on clinical features, including the history of sinusitis and bronchial asthma, peripheral eosinophilia, and peripheral neuropathy, EGPA was diagnosed. Ultrasound cardiography revealed normal cardiac function. The 2009 Five Factor Score was zero [15].

Methylprednisolone pulse therapy and administrations of methylprednisolone 60 mg/day, intravenous cyclophosphamide 500 mg biweekly, and intravenous immune globulin (0.4 g/kg/day × 5 days) were started as an induction treatment (Figure 1).

Figure 1: Clinical course of this case. Mepolizumab was effective for improving the clinical symptoms and decreasing CRP levels in this case. CRP: C-reactive protein; EOSI: Eosinophils; IVCY: Intravenous Cyclophosphamide; IVIg: Intravenous Immune Globulin; mPSL: methylprednisolone, MPZ: Mepolizumab; PSL: Prednisolone.

Although the patient’s peripheral eosinophil count decreased to within the normal range 10 days after admission, neurologic symptoms had not improved; severe pain, numbness, hypoesthesia, and paraesthesia in both the upper and lower extremities continued. At 22 days after starting initial treatment, the prednisolone dose was tapered to 40 mg/day, and intravenous administrations of cyclophosphamide were started biweekly for three times; however, the neurological symptoms (pain and numbness in the upper and lower extremities) deteriorated with elevated peripheral eosinophil count (5590/μL), resulting in the difficulty of moving the lower extremities.

Hence, we considered the case refractory to standard treatment and began administering mepolizumab 300 mg subcutaneously at 23 days after admission. Immediately after initiating mepolizumab, clinical symptoms, such as severe pain and numbness in both the upper and lower extremities, markedly improved, which was associated with decreased eosinophilic count. Thereafter, mepolizumab 300 mg administered subcutaneously has been continued every 4 weeks. The glucocorticoid dose could have been tapered quickly. At 6 months after starting treatment, neurological symptom improved and rehabilitation enabled the patient to walk by himself, although foot drop was still present. The steroid dose was tapered to 8 mg/day, and no relapse was observed during the period when mepolizumab 300 mg was administered monthly for 5 months.

Discussion

The present case highlighted the effectiveness of mepolizumab in an ANCA-negative EGPA case with severe peripheral neuropathy refractory to standard treatment, including administration of high-dose steroid, intravenous cyclophosphamide, and intravenous immune globulin. 

Peripheral neuropathy is a common complication in patients with EGPA. In the largest published series of patients with EGPA, 51.4%-60% had peripheral neuropathy at presentation [6,16]. Once peripheral neuropathy developed, regardless of treatment, the neuronal damage recovered slowly, and many patients had neurologic sequelae [5,17]. Neurologic sequelae were especially seen in severely ill patients in whom treatment was delayed, which significantly affected their future quality of life [17-19].

Therefore, it is essential to construct the optimal treatment strategy for peripheral neuropathy in EGPA. Basically, the primary initiating therapy is systemic glucocorticoids; an additional immunosuppressive agent is typically added in patients with more advanced or refractory disease and in those whose disease flares upon tapering of systemic glucocorticoids [20,21]. Cyclophosphamide is typically used in combination with glucocorticoids for patients with severe, multiorgan disease [20,21].

Furthermore, several case series have reported improvement in disease control in patients with refractory disease after addition of intravenous administration of high-dose immune globulin to glucocorticoids [22]. Recently, a multicentre randomised trial [11], including 136 patients with relapsing or refractory EGPA cases, showed clinical benefit of mepolizumab. Namely, over 52 weeks, treatment with mepolizumab, compared with placebo, was clinically beneficial and resulted in at least two-fold increase in the proportion of patients who achieved remission (from 19% to 53%), who could reduce their oral glucocorticoid dose by ≥ 50% (from 21% to 57%), or who were relapse-free (from 18% to 44%).

However, the results should be interpreted cautiously based on the following points. First, the study included only 56 (41.2%) patients with neuropathy, and information about the severity of neurological damage in each case was unknown. Furthermore, the study did not monitor whether organ damage, including neuropathy, had improved or continued.

Thus, it is unknown whether mepolizumab is effective for neuropathy or not. Second, this study included only patients with mild-to-moderate vasculitis activity because patients with organ-threatening damage were excluded. Moreover, the baseline median eosinophil count was relatively low (mepolizumab vs. placebo: 177 vs. 172/mm3), and the baseline prednisolone dose was also low (mepolizumab vs. placebo: 11 vs. 12 mg/day), showing lower eosinophil count and lower dose of prednisolone than our case. 

Thus, the efficacy of mepolizumab for severe cases was unknown. Finally, the disease duration since diagnosis of EGPA at baseline was approximately 5 years; therefore, the effect of mepolizumab in the early phase after EGPA diagnosis was not elucidated. Considering the results, when mepolizumab should be started or what clinical characteristics are the best indicators for mepolizumab treatment it remained unclear.

To realise the optimal use of mepolizumab by evaluating the pathogenesis of peripheral neuropathy in EGPA, a retrospective study investigated the clinicopathologic features of 82 patients with EGPA-associated neuropathy who underwent sural nerve biopsy, focusing on the presence or absence of MPO-ANCA [16]. The results indicated that the pathogenesis of EGPA comprises at least two distinct mechanisms: ANCA-associated vasculitis and eosinophil-associated vascular occlusion. 

ANCA-associated vasculitis results in ischaemic effects and inflammation and is prominent in MPO-ANCA-positive patients. Eosinophil-associated vascular occlusion leads to ischaemia and eosinophil-associated tissue damage and is prominent in MPO-ANCA-negative patients. In our case, considering that neurological symptoms (i.e., lower extremity pain and numbness) improved immediately after starting mepolizumab, the nerve damage might have been predominantly due to eosinophil-associated inflammation.

Based on the results of this case report, early use of mepolizumab as an induction treatment, especially in ANCA-negative patients with peripheral neuropathy, might be a better strategy. This strategy suppresses the eosinophil-associated inflammatory reaction in the early phase, avoiding irreversible neurological damage and reducing total steroid dosage. 

Future research should focus on evaluating and constructing the best treatment strategy, including the optimal timing and dose of and indications for mepolizumab, in addition to conventional treatment (steroids or immunosuppressants). To essentially elucidate this, obtaining genomic information to determine predictive tools that might have good response for mepolizumab may be essential [22-24].

Conclusion

Early use of mepolizumab as an induction treatment might be an effective strategy, especially in ANCA-negative EGPA patients with polyneuropathy. Further studies should be undertaken to construct the best treatment strategy for EGPA.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors’ Contributions

All authors contributed to the concept and design of the study; performed data acquisition, analysis, and interpretation; drafted the manuscript; critically revised the manuscript for important intellectual content; and have read and approved the manuscript.

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