Rituxan Scores in Rare Vasculitis Both neuropathic and kidney manifestations cleared with anti-B-cell drug. by Nancy WalshSenior Staff Writer, MedPage Today 04.04.2015 Rituximab (Rituxan) may be a useful treatment option for patients with the rare vasculitis now known as eosinophilic granulomatosis with polyangiitis -- formerly termed Churg-Strauss syndrome -- a case report and literature review suggested. A patient with refractory eosinophilic granulomatosis and polyangiitis (EGPA) who had severe neuropathy and necrotizing glomerulonephritis and received two cycles of rituximab had a full resolution of his neuropathic symptoms and normal renal function by 20 months, according to Antonis Fanouriakis, MD, of University Hospital of Heraklion in Greece, and colleagues. In addition, among cases identified in the literature, rituximab was effective for a broad spectrum of disease manifestations, including involvement of the kidney, lung, skin, liver, and heart as well as the peripheral nervous system, the researchers reported online in Seminars in Arthritis and Rheumatism. Eosinophilic granulomatosis and polyangiitis is the rarest of the antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides, a group that also includes granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). It shares certain characteristics with GPA and MPA, but also is distinct in featuring high levels of eosinophils in the circulation and tissue, an association with asthma, and cardiac involvement. The B-cell depleting agent rituximab has been approved for the treatment of GPA and MPA, but thus far has not been evaluated in clinical trials for EGPA. Experience has been limited to case reports and series.
The Case The patient was a 51-year-old man who reported a 10-day history of arthralgias and numbness in his arms and legs. He had a history of nasal polyps without asthma, and had received treatment with antibiotics and inhaled beta-agonists for a presumed respiratory tract infection 2 weeks before the extremity symptoms began. At the time of admission, he was wheezing, hypoxic, tachycardic, and had polyarthritis of the hand joints. Muscle strength was reduced in the extremities. Laboratory tests revealed eosinophilia, with a level of 10,300/mcL (the upper limit of normal is 700/mcL), a serum creatinine of 1.1 mg/dL, and glomerular hematuria with cellular casts. He was positive for ANCA and had high titers of anti-myeloperoxidase antigen, at 89.8 U/mL, but was negative for rheumatoid factor and anti-cyclic citrullinated peptide antibody. Nerve conduction studies confirmed the presence of sensorimotor axonal mononeuritis, and renal biopsy showed segmental necrotizing glomerulonephritis with cellular crescents, and numerous eosinophils within the renal infiltrates. Other potential causes of the eosinophilia, such as parasitic infection, were ruled out, and he was diagnosed with EGPA. His Birmingham Vasculitis Activity Score (BVAS) was 22. His initial treatment plan was intended to be pulsed methylprednisolone followed by oral prednisone in dosages of 0.5 mg/kg/day and monthly pulses of intravenous cyclophosphamide in dosages of 0.75 mg/m2. However, his neurologic symptoms worsened, and by day 10 following the first dose of cyclophosphamide he had lost all motor function in one hand and was having gait difficulties. The eosinophilia persisted, and additional nerve conduction studies showed ongoing axonal degeneration. He then was given rescue therapy with rituximab, with two doses of 1,000 in a 2-week period, and two additional pulses of methylprednisolone. By 6 months, his neurologic symptoms had improved and laboratory values had normalized. He was given another course of rituximab, followed by maintenance therapy with methotrexate, 25 mg/week, and 20 months after symptom onset his extremity strength and renal function were normal. His BVAS was zero, indicating complete remission. "An interesting observation from the present case is the dramatic response of peripheral neuropathy to B-cell depletion with a full recovery of motor strength following initial paralysis," Fanouriakis and colleagues noted.
The Literature The researchers then identified 73 cases of EGPA treated with rituximab in the literature. The sexes were represented equally, and ages ranged from 31 to 72. The most common disease manifestations were asthma and involvement of the kidney, skin, ear, nose, and throat, and PNS. Previous treatments included cyclophosphamide, azathioprine, mycophenolate mofetil (CellCept), methotrexate, and alemtuzumab (Lemtrada). The most common rituximab regimen was that used in rheumatoid arthritis (2 × 1,000 mg) rather than that used in lymphoma (4 × 375 mg/m2). In the largest case series, which included 41 patients, 83% had improved by 6 months and 34% were in remission, while median BVAS had fallen by 12 months from 11 to 1. The authors of that study wrote, "We have shown that rituximab is a safe and important alternative to standard therapy in EGPA, both for refractory and relapsing disease, especially for ANCA-positive patients, and also for newly diagnosed patients in whom traditional cytotoxic drugs are contraindicated or undesirable." Fanouriakis and colleagues also looked at the published cases to see if other EGPA patients with peripheral neuropathy responded as well as theirs. They found that almost half did have neurologic involvement, and for a median duration of 12 months before receiving rituximab. In the large case series, 12 patients had peripheral nervous system involvement, and in eight of these the BVAS was zero at the end of follow-up and three patients were in partial remission. "Although the authors do not specify whether ongoing disease activity in partial responders was attributed to peripheral nerve disease, complete response in eight of 12 patients indicates significant efficacy of rituximab in EGPA neuropathy," stated Fanouriakis and colleagues. They also noted that, while in the controlled trials of rituximab for GPA and MPA no specific data were included for the PNS component, in other observational studies the response rates for neurologic manifestations were almost 90%."Rituximab seems to be effective in cases of severe EGPA, with both renal and peripheral nervous system manifestations, refractory to standard of care immunosuppressive treatment," the authors concluded. "Prospective, controlled studies are now needed to document rituximab short- and long-term efficacy and assess its safety," they added.
血管炎 2015/04/02"亞東紀念醫院過敏免疫風濕科" 是一類疾病的名稱，是因為免疫系統攻擊血管組織造成 。血管炎可約略分為大血管、中小血管炎。有些血管炎只侷限於皮膚，沒有全身性的表現。而嚴重的全身性血管炎通常的表現有發燒、倦怠、表皮的紅疹、咳血、血尿、蛋白尿或神經痛等等 (神經痛與一般關節酸痛不同，主要以燒、麻、刺痛、感覺異常表現)。因為疾病的症狀多變且少見，所以診斷困難。病程反覆，治療也困難。 這類的疾病相對少見，對於醫療機構的診療水準也是一大挑戰。
侵犯大血管的血管炎 颞動脈炎/巨細胞血管炎(Temporal arteritis/Giant cell arteritis) 高安氏血管炎(Takayasu arteritis)
侵犯中小血管的血管炎 ANCA陽性 韋格納氏肉芽腫 (Wegner's granulomatosus) 顯微性多血管炎 (Microscopic polyangiitis) 過敏性肉芽腫 (Churg-Strauss syndrome)
其它 節結性多動脈硬化(Polyarteritis nodosum) 貝賽特氏病或貝雪氏病(Behcet's disease) 冷凝蛋白血症(Cryoglobulinemia) 過敏性紫斑症(Henoch-Scholein purpura) Burger's disease(thromboangiitis obliterans)
颞動脈炎/巨細胞血管炎(Temporal arteritis/Giant cell arteritis) 好發於老年人(大於五十歲)的大血管炎，一般症狀可能有發燒、倦怠、頭痛及視力模糊，嚴重時颞動脈(最明顯的部份是經過太陽穴的血管)會有鼓脹壓痛的情況。需用高劑量類固醇治療。聶動脈炎常常與風濕性多發肌痛合併發生。
高安氏血管炎(Takayasu arteritis) 好發於育齡(二十到四十歲)婦女的血管炎，又稱為無脈搏病，也是一種自體免疫疾病，會造成主動脈及其第一分支發炎且狹窄。通常表現為發燒與倦怠，理學檢查可發現四肢血壓不對稱或兩側脈搏強弱不一。治療須用到高劑量類固醇，有時血管狹窄部位須用手術整修以增加血流。
ANCA相關血管炎
韋格納氏肉芽腫(Granulomatosis with polyangiitis/Wegener's granulomatosus) 更詳細資料 一種中小血管炎，屬於健保的重大傷病，主要以發燒、慢性鼻竇炎、咳血、血尿、周邊神經麻痛等表現。 實驗室的檢驗通常有抗嗜中性球細胞質抗體(c-ANCA)陽性。治療通常需要類固醇以及其他免疫抑制劑。疾病有時會因感染而惡化。
顯微性多血管炎(Microscopic polyangiitis) 一種中小血管炎，主要以發燒、腎絲球炎、咳血、血尿、周邊神經麻痛等表現。實驗室的檢驗通常有抗嗜中性球細胞質抗體(p-ANCA)陽性。治療通常需要類固醇以及其他免疫抑制劑。
過敏性肉芽腫(Churg-Strauss syndrome) 一種中小血管炎，主要以嗜伊紅性白血球上升，氣喘，鼻竇炎，週邊神經麻痛表現。治療通常需要類固醇以及其他免疫抑制劑。
節結性多動脈硬化(Polyarteritis nodosum) 一種非常罕見的中小血管炎，主要以發燒、體重下降、腹痛、血便、高血壓或腎功能異常、週邊神經病變等表現 ，病人中約有15%與B型肝炎有關。治療通常需要類固醇以及其他免疫抑制劑。
貝雪氏病或貝塞特氏病(Behcet's disease) 更詳細資料 健保的重大傷病之一。本質也是一種慢性反覆性的自體免疫的疾病，並不是傳染病，主要表現是口腔及陰部的潰瘍(男性在陰囊，女性在陰唇)。其它的併發症也包括 皮膚病變、虹彩炎、關節炎、血管病變、腸道潰瘍及肚子疼痛等。治療上可以使用免疫調節劑與類固醇。
冷凝蛋白血症(Cryoglobulinemia) 通常是C型肝炎的併發症，可能有眼乾、口乾，下肢皮疹，關節酸痛，蛋白尿等 表現， 因為常常有類風濕因子的假陽性發生，所以可能被誤認為類風濕性關節炎，所以診斷類風濕性關節炎前，應詢問病人是否有肝炎家族史，以免將冷凝蛋白血症誤認為類風濕性關節炎。治療上可以用一些免疫調節劑，包括干擾素，此外類固醇的使用需小心，以免造成肝炎發作。
過敏性紫斑(Henoch-Schonlein Purpura) 一種好發在3-15歲兒童的血管炎，偶而也見於成人。主要的症狀為腹痛、關節痛與下肢的紫斑。通查在上呼吸道感染後一到兩週後發生。少數病人會有血尿與腎臟併發症。治療上可能需要到類固醇，一般為一過性的血管炎，但是少數人在減藥後有復發的可能。
Burger's disease (thromboangiitis obliterans) 一種好發在吸煙男性的血管堵塞病變，一般發病在五十歲前症狀為末梢循環堵塞，手指、腳趾末端蒼白麻木、缺血性壞死，甚至可能要截肢，唯一的改善的方法是戒菸，類固醇或其他的抗發炎藥物是無效的。
churg-strauss 综合症点击认领 变应性肉芽肿血管炎又叫Churg-Strauss综合征，是一类原因不明、主要累及中小动脉的系统性坏死性血管炎。患者常伴有哮喘或变应性鼻炎，主要累及肺、心、肾、皮肤和外周神经。一般预后较好，但侵犯重要脏器和治疗延误者预后不佳。
疾病描述 变应性芽肿血管炎（Churg—Strauss综合症）病因不明，病理变化示坏死性血管炎。血管壁及血管外肉芽肿形成，组织内嗜酸粒细胞浸润，病变累及全身，特别是肺，心和皮肤、比结节性多动脉炎更少见，各年龄均可发现，男性稍多。
症状体征 呼吸道过敏史，有过敏性鼻炎，鼻息肉，哮喘，血嗜酸粒细胞增多，组织内嗜粒细胞浸润，表现为一过性肺浸润及胃肠炎，全身性血管炎。
疾病病因 病因不明。
病理生理病理变化示坏死性血管炎。血管壁及血管外肉芽肿形成，组织内嗜酸粒细胞浸润，病变累及全身，特别是肺，心和皮肤。
诊断标准 验检测可见外周血嗜酸性粒细胞增高，经激素治疗后嗜酸性粒细胞可下降 ，但复发时又再次增高，血沉增快，Ｃ -反应蛋白阳性，ＩｇＥ升高，约 67%的患者抗白细胞浆抗体阳性。受累组织活检显示小血管的血管炎，血管周围肉芽肿及嗜酸性粒细胞浸润具有较高诊断意义。本病的诊断主要依据临床表现及病理学检查。 19 9 0年美国学者ＭＡＳＩＡＴ提出的诊断标准为：:①有反复发作的哮喘病病史 ；②外周血嗜酸性粒细胞增多；③系统性血管炎所致的单发性或多发性神经病变，如手套或袜套样分布；④Ｘ线有非固定性肺浸润性病变 ；⑤有变应性急性或慢性鼻窦炎病史 ；⑥病理检查示血管外嗜酸性粒细胞浸润，如动脉、小动脉、小静脉外周有嗜酸性粒细胞浸润。具备以上 6项标准中的 4项，或 4项以上即可诊断该病。抗白细胞浆抗体滴度显著升高者 ，亦有助于诊断。活检取材诊断血管炎可取腓肠神经、肌肉、肠、肝、肺、肾为标本。
诊断检查 变应性肉芽血管炎的分类诊断标准如下：1.哮喘史2.血嗜酸粒细胞＞10％（白细胞分类）3.单神经病，多发性单神经病，多发性神经病。4.游走性或—过性肺浸润，固定性浸润下不属于与此项。5.鼻窦病，病史有极性或者慢性鼻窦痛或压痛，或X线片示鼻窦不透明。6.血管外嗜酸粒细胞，活检示动脉，微动脉、微静脉外的组织有嗜酸粒细胞堆积，有四项阳性即可诊断为变应性肉芽肿血管炎。
治疗方案 主要是糖皮质激素及环磷胺的联合应用。
治疗预后在糖皮质激素应用之前，本病被认为是不治之症，主要死于充血性心力衰竭和心肌梗死。哮喘发作频繁及全身血管炎进展迅速者预后不佳。大剂量糖皮质激素的应用，甚至加用环磷酸胶以来使本病预后明显改善， 5 年生存率从 25% 上升 50% 以上。对重症患者可每日静脉注射甲泼尼龙 0.5~ 1g ，连用 3~5 天后改为泼尼松 40~60mg/d 口服 8 周左右，酌减其量，维持治疗。若单纯激素治疗效果不佳可加用环磷酸胶或硫唑嘌呤。
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