CASE REPORT. Abstract. Introduction. Case Reports

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1 CASE REPORT Efficacy of Early Intravenous Immunoglobulin for Eosinophilic Granulomatosis with Polyangiitis with Drastically Progressive Neuropathy: A Synopsis of Two Cases Takeshi Matsumoto 1, Kojiro Otsuka 1, Michi Kawamoto 2, Kazuma Nagata 1, Ryo Tachikawa 1, Yukihiro Imai 3, Nobuyuki Oka 4 and Keisuke Tomii 1 Abstract Two women, 66-year-old and 63-year-old, were admitted for drastically progressive neuropathy, and diagnosed with eosinophilic granulomatosis with polyangiitis (EGPA). Steroid pulse therapy failed to exert effect upon neuropathy, so we administered early intravenous immunoglobulin (IVIG) for fear of immobilization of neuropathy. This resulted in marked improvement in neuropathy without apparent side effects. Recent evidence suggests the efficacy of IVIG for steroid refractory neuropathy associated with EGPA, but has previously been administered during the chronic phase resulting in slow improvement. Our two successfully treated cases indicate the efficacy of early IVIG in preventing the immobilization of neuropathy, especially in progressive cases. Key words: eosinophilic granulomatosis with polyangiitis (EGPA), Churg-Strauss syndrome (CSS), intravenous immunoglobulin (IVIG), neuropathy, early administration (Intern Med 52: , 2013) () Introduction Eosinophilic granulomatosis with polyangiitis (EGPA), formerly known as Churg-Strauss syndrome (CSS), is characterized by the presence of asthma, hypereosinophilia and small-to medium-sized vessel vasculitis with granuloma (1). Peripheral neuropathy, usually mononeuritis multiplex, is seen in up to 75 percent of patients with EGPA (2). For the treatment of EGPA, systemic steroids are the predominant choice, and the majority of EGPA patients respond well to such treatment. However, some patients suffer from neuropathy refractory to steroid treatment resulting in a marked and longstanding reduction in the ability to perform ADLs. Recently, the efficacy of intravenous immunoglobulin (IVIG) in treating the neuropathy of EGPA has been reported; however, the administration of such treatment is generally considered in the chronic phase, usually more than four weeks after the first administration of steroids, resulting in only a slow improvement in neuropathy. Since EGPA involves aspects of ischemic disorders, it is important to treat such cases as quickly as possible in the acute phase, especially rapidly progressive cases, before fixed neuropathy becomes established. We herein report two cases of EGPA with drastically progressive neuropathy refractory to steroids that were successfully treated with the early administration of IVIG in addition to steroids. Case 1 Case Reports A 66-year-old woman diagnosed with EGPA was admitted to our hospital due to drastically progressive neuropathy. Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Japan, Department of Neurology, Kobe City Medical Center General Hospital, Japan, Department of Clinical Pathology, Kobe City Medical Center General Hospital, Japan and Department of Neurology, Minami-Kyoto National Hospital, Japan Received for publication August 30, 2012; Accepted for publication January 11, 2013 Correspondence to Dr. Takeshi Matsumoto, t.matsumoto@kcho.jp 913

2 Figure 1. (a) Purpura on the left lower leg in case 1. (b) The result of purpura biopsy with Giemsa stain shows eosinophilic infiltration in extravascular areas. (c) Hematoxylin and Eosin (H&E) staining shows eosinophilic infiltration in extravascular areas. (d) The result of sural nerve biopsy in case 2 with H&E staining shows occlusion of epineurium vessel (arrow), with mononuclear cell infiltration. (e) CD68 staining shows macrophage infiltration. (f) Toluidine blue staining shows broad axonal degeneration of internal sheath of nerve. She had been treated for uncontrolled bronchial asthma for three years. One year before admission, she noticed plantar paresthesia, which gradually worsened for one month prior to admission. The paresthesia rapidly progressed, extending to the extremities, and muscle weakness appeared in the patient s left arm three days before admission. Since the symptoms drastically progressed and the patient became unable to stand, she was conveyed by ambulance to our emergency unit. On physical examination, she exhibited purpura on her left lower leg (Fig. 1a). No abnormalities were found in the chest or abdomen. Neurological examinations showed muscle weakness of the left arm and fingers, with a score of 2 on a manual muscle test (MMT), and the lower legs, with a score of 4 on the MMT, in addition to deep sensation disturbance, particularly on both soles, that prevented the patient from standing. Chest radiography showed no abnormalities. Laboratory studies revealed the following values: white blood cell count, 36,000/mm 3 with 70% eosinophils; C- reactive protein, 3.8 mg/dl; myeloperoxidase-specific antineutrophil cytoplasmic antibody ( MPO-ANCA) and proteinase-3 specific antineutrophil cytoplasmic antibody (PR3-ANCA), negative; immunoglobulin E (IgE), 3,574 U/ ml; and occult blood in urine, 5-9/high-power field (HPF). A skin biopsy of the purpura disclosed eosinophilic infiltration around the capillary vessels, indicating vasculitis (Fig. 1b, c). The patient therefore fulfilled the American College of Rheumatology (ACR) criteria for CSS with a history of asthma, hypereosinophilia, mononeuritis multiplex and histological evidence of eosinophilic infiltration in extravascular areas (3). We commenced steroid pulse therapy (methylprednisolone (mpsl), 500 mg for three days) on the day of admission, followed by mpsl at a dose of 80 mg daily. Although the patient s subjective view of muscle weakness slightly improved, the MMT scores did not change. In addition, no differences were observed in sensory disturbance, and the patient was unable to stand alone. For fear of future impending reductions in the QOL as a result of immobilization due to neuropathy, we administered IVIG at a dose of 400 mg/ kg/day for five days starting on day 5. The deep sensation disturbance improved quickly, and the patient was able to stand on day 8. The muscle weakness in the left arm also gradually improved, and the patient was able to walk with a walker on day 14. However, improvements in paresthesia in both soles achieved a plateau, and during the course of treatment, the paresthesia slightly deteriorated on day 29. A nerve conduction test performed on day 31 showed axonal changes (Table 1). Since the first course of IVIG was effective, we administered a second course of IVIG on day 36. The paresthesia and muscle weakness subsequently improved, enabling the patient to walk alone without a walker on day 43. The MMT scores of the left arm and fingers ultimately improved from 2 to 4 +. The patient was discharged on day 62 (Fig. 2). Case 2 A 63-year-old woman who was treated for bronchial asthma for 23 years first noticed a steppage gait and paresthesia in her left lower leg three years before admission. These symptoms fluctuated but gradually worsened. She noticed paresthesia of both soles one month before admission, and found it difficult to walk one week before admission. She was admitted to our hospital for further investigation. 914

3 Table 1. A Nerve Conduction Test in Case 1 Figure 2. Clinical course of case 1. IgE: Immunoglobulin E, IVIG: intravenous immunoglobulin, mpsl: methylprednisolone, MMT: manual muscle test Table 2. A Nerve Conduction Test in Case 2 On physical examination, no abnormalities were found in the chest, abdomen or skin. Neurological examinations showed muscle weakness in both lower legs, with MMT scores of 2; however, the MMT scores of the proximal muscles were 5. Severe deep sensation disturbance was seen, particularly in both legs, which prevented the patient from standing. Laboratory studies showed the following values: white blood cell count, 15,100/mm 3 with 49% eosinophils; C-reactive protein, 1.2 mg/dl; MPO-ANCA and PR3- ANCA, negative; IgE, 692 U/mL; and occult blood in urine, 0-1/HPF. A sural nerve biopsy was performed on day 5, which showed infiltration of mononuclear cells within the vessel walls and around the capillaries, indicating vasculitis. The infiltrates were composed of macrophages and lymphocytes. Most of the myelinated fibers exhibited axonal degeneration (Fig. 1d, e, f). Although no eosinophilic infiltration was seen, most likely due to the administration of steroids before the nerve biopsy, we diagnosed the patient with EGPA on the grounds of the above findings. A nerve conduction test performed on day 15 showed axonal changes Figure 3. Clinical course of case 2. IgE: Immunoglobulin E, IVIG: intravenous immunoglobulin, mpsl: methylprednisolone, MMT: manual muscle test (Table 2). In this case, we also started steroid pulse therapy (mpsl, 500 mg for three days) followed by mpsl at a dose of 80 mg daily for drastically progressive neuropathy. The muscle power of the patient s lower legs and the deep sensation disturbance did not exhibit a prompt response to steroid treatment, preventing the patient from standing. Therefore, we administered IVIG at a dose of 400 mg/kg/day for five days starting on day 13. The paresthesia and deep sensation disturbance gradually improved, enabling the patient to stand on day 17, walk with a walker on day 23 and walk alone on day 36. The MMT scores of both lower legs improved from 2 to 4. The patient was discharged on day 38 (Fig. 3). Discussion The first step in the management of EGPA is to assess the disease severity according to the five-factors score based on 915

4 the presence of five clinical factors: gastrointestinal disorders, renal dysfunction, severe proteinuria, myocardial disorders and central nerve system disorders, all of which are associated with the poor prognosis of EGPA (4). Although not strongly associated with mortality, peripheral neuropathy is closely related to the QOL and often remains unimproved (5). The principle of treatment of EGPA is to provide early diagnosis and treatment. Steroids are the mainstay of treatment for EGPA. Although over half of patients exhibit immediate improvements following the administration of steroids, other cases are refractory (6). For patients with severe multiorgan disease, especially those with poor prognosis factors, cyclophosphamide is typically used in combination with steroids (7). Despite the use of combination therapy, a large proportion of patients with EGPA suffer from long-lasting neuropathies that lead to a marked reduction in the ability to perform ADLs. In addition, cyclophosphamide causes serious adverse effects such as hemorrhagic inflammation of the bladder, testicular and ovary dysfunction, myelosuppression, carcinogenicity and so on. As mentioned above, the neuropathy caused by EGPA is often refractory to steroid therapy. Hattori et al. reported that approximately 57% of patients with EGPA exhibit no response, even after four weeks of steroid administration, thus resulting in a long-lasting poor function (8). Recently, the efficacy of IVIG for treating neuropathy of EGPA refractory to steroids has been reported (9), and the drug has been revealed to exhibit steroid-sparing effects (10, 11). IVIG demonstrates efficacy in treating the neuropathy of EGPA in the chronic phase that is refractory to long-term steroid treatment (12). Danieli et al. reported that, in their study, while 44% of patients receiving steroids and cyclophosphamide achieved remission in neuropathy, all patients receiving IVIG and plasmapheresis achieved remission in neuropathy (13). The clinical backgrounds associated with the efficacy of IVIG involve pretreatment with steroids and immunosuppressants before the administration of IVIG. In addition, it has been reported that when IVIG is effective on the first administration, re-administration may also be effective; however, when the first administration of IVIG is ineffective, re-administration may also be ineffective (12). Generally, IVIG is administered during the chronic phase, predominantly starting four weeks after the first administration of steroids, thus resulting in a slow improvement of neuropathy. Since EGPA exhibits aspects of ischemic disorders, it is important to treat the condition as quickly as possible during the acute phase, especially in rapidly progressive cases, before fixed neuropathy is established, as regeneration of peripheral nerves may require months or years (12). Our two patients with drastically progressive neuropathy were first treated with steroid pulse therapy. Cyclophosphamide was not given to either patient since the fivefactors score was zero in both cases. Although rapid progression of neuropathy was retarded by steroid treatment, no further improvements were observed, leaving both patients with an impaired ability to perform ADLs. Therefore, we administered IVIG on day 5 and day 13, respectively, resulting in marked improvement of neuropathy without any apparent side effects. Due to remaining neuropathy, our first patient required a second course of IVIG, which also improved the neuropathy. One year and a half after discharge, both patients were reviewed in our hospital, and no relapse of neuropathy was observed in either case. The contribution of continuous steroid administration to the observed improvements in neuropathy cannot be ruled out. However, for both patients, the symptoms of neuropathy were apparently altered after the administration of IVIG. Furthermore, our first patient not only showed improvement of neuropathy after the first administration of IVIG, but also demonstrated further improvement after a plateau following the second administration of IVIG, which suggests the beneficial effects of IVIG on neuropathy. Considering the patients clinical courses, it seems that IVIG combination therapy played a pivotal role in the improvement of neuropathy in these cases. To the best of our knowledge, there are few case reports of the efficacy of early administration of IVIG treatment for the neuropathy of EGPA. Of the few cases, many are in the form of conference abstracts. Our two cases are valuable because the patients exhibited improvement of drastically progressive neuropathy in response to the early administration of IVIG in combination with steroids. In conclusion, early treatment with IVIG in combination with steroids during the acute phase of EGPA neuropathy may be effective, especially in rapidly progressive cases, and may prevent the establishment of fixed neuropathy. Further studies are needed to clarify the therapeutic efficacy of IVIG during the acute phase of EGPA neuropathy and to determine the optimal timing of administration. The authors state that they have no Conflict of Interest (COI). References 1. Falk RJ, Gross WL, Guillevin L, et al. Granulomatosis with polyangiitis (Wegener s): an alternative name for Wegener s granulomatosis. Arthritis Rheum 63: , Wolf J, Bergner R, Mutallib S, Buggle F, Grau AJ. 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5 Chest 136: , Hattori N, Ichimura M, Nagamatsu M, et al. Clinicopathological features of Churg-Strauss syndrome-associated neuropathy. Brain 122: , Hamilos DL, Christensen J. Treatment of Churg-Strauss syndrome with high-dose intravenous immunoglobulin. J Allergy Clin Immunol 88: , Tsurikisawa N, Taniguchi M, Saito H, et al. Treatment of Churg- Strauss syndrome with high-dose intravenous immunoglobulin. Ann Allergy Asthma Immunol 92: 80-87, Kobayashi D, Wada Y, Takata T, et al. A severe form of Churg- Strauss syndrome complicated with acute cardiac failure and rapidly progressive peripheral neuropathy: a possible effect of intravenous immunoglobulin therapy. Intern Med 50: , Taniguchi M, Tsurikisawa N, Higashi N, et al. Treatment for Churg-Strauss syndrome: induction of remission and efficacy of intravenous immunoglobulin therapy. Allergol Int 56: , Danieli MG, Cappelli M, Malcangi G, Logullo F, Salvi A, Danieli G. Long term effectiveness of intravenous immunoglobulin in Churg-Strauss syndrome. Ann Rheum Dis 63: , The Japanese Society of Internal Medicine 917