International Consensus Guidance for Management of Myasthenia Gravis
2020 Update
國際共識指導方針：重症肌無力的管理
2020 年更新

Based on the availability of new clinical trial data that the panel co-chairs determined may affect previous recommendations or lend themselves to new recommendations, the following interventions were selected: thymectomy, rituximab (RTX) in MG with antibodies to acetylcholine receptors (AChRs) and muscle-specific kinase (MuSK), eculizumab, and methotrexate (MTX). Recommendations were also developed to inform early immunosuppression in ocular MG, the role of physical training/exercise in MG, and the management of MG associated with immune checkpoint inhibitor treatment. Physical training/exercise was excluded after review because of the low quality of evidence informing recommendations.
根據小組共同主席所確定的新臨床試驗數據的可用性，這些數據可能影響先前的建議或促成新的建議，因此選擇了以下介入措施：胸腺切除術、對抗乙醯膽鹼受體（AChRs）和肌肉特異性激酶（MuSK）抗體的利妥昔單抗（RTX）、依庫珠單抗和甲氨蝶呤（MTX）。還制定了建議，以指導眼部重症肌無力的早期免疫抑制、重症肌無力中身體訓練/運動的角色，以及與免疫檢查點抑制劑治療相關的重症肌無力的管理。經過審查後，因為支持建議的證據質量低，身體訓練/運動被排除在外。

The RAND/UCLA appropriateness method for formal consensus was used to obtain consensus, with the same a priori assumptions regarding treatment availability and costs as in the initial guidance document.^1,2 All voting was conducted by e-mail and the responses returned only to the methodologist to avoid the potential for panel members' opinions and votes being influenced by others. Topics were voted on sequentially, although rounds of voting for different topics frequently overlapped for efficiency. All recommendation statements were edited after the first round of voting by the co-chairs and methodologist in response to the panel's suggestions for changes and depending on whether consensus was reached or not. The edited recommendations were sent by e-mail to the panel along with collated panel comments from the previous round for voting. The process was repeated for up to 3 rounds of voting, as needed. Recommendations that did not achieve consensus after 3 rounds of voting were discarded. The panel rated each recommendation for appropriateness on a 9-point scale (1–3: inappropriate, 4–6: uncertain, and 7–9: appropriate). Median and range were calculated for each recommendation to assess appropriateness and agreement per the RAM method. Tables e1-e10, doi:10.5061/dryad.6hdr7sqxx, summarize all the recommendations of the original guideline that are still current plus those from the present update. Table 1 provides an update of drugs to avoid or use with caution in MG.
RAND/UCLA 的適當性方法用於正式共識的獲得，與初始指導文件中的治療可用性和成本的先驗假設相同。所有投票均通過電子郵件進行，回覆僅發送給方法學家，以避免小組成員的意見和投票受到他人影響。主題是依序投票，儘管不同主題的投票回合經常重疊以提高效率。所有建議聲明在第一次投票後由共同主席和方法學家根據小組的變更建議進行編輯，並根據是否達成共識進行調整。編輯後的建議通過電子郵件發送給小組，並附上來自前一回合的整理小組意見以供投票。該過程根據需要重複進行最多 3 回合的投票。經過 3 回合投票後未達成共識的建議將被捨棄。小組對每項建議的適當性進行 9 分制評分（1–3：不適當，4–6：不確定，7–9：適當）。 中位數和範圍是根據 RAM 方法計算每項建議的適當性和一致性。表 e1-e10，doi:10.5061/dryad.6hdr7sqxx，總結了所有仍然有效的原始指導方針建議以及本次更新的建議。表 1提供了在 MG 中應避免或謹慎使用的藥物更新。

The multicenter, randomized, rater-blinded trial of thymectomy in MG (MGTX) enrolled patients younger than 65 years with AChR-positive (AChR-Ab+) generalized nonthymomatous MG of <5 years duration.³ Sixty-six subjects underwent extended transsternal thymectomy and received prednisone using a standard dosing schedule, whereas 60 subjects received the standardized prednisone dosing schedule alone. An effect favoring thymectomy was seen in both of the coprimary outcome measures: reductions in the time-weighted average quantitative MG (QMG) score and the time-weighted average alternate-day prednisone dose. Secondary outcome measures, including azathioprine use, intravenous immunoglobulin (IVIg) use, and hospitalizations for MG exacerbations, also favored thymectomy plus prednisone. Benefits were seen within the first year and were sustained through year 3. In a post hoc analysis, neither the prednisone dose nor QMG scores were significantly different between the 2 treatment groups in patients 50 years or older.³ An extension of the MGTX trial followed 68 (61%) participants from the original trial for 2 additional years. At 60 months, lower time-weighted average QMG scores and a reduction in average time-weighted prednisone dose favored thymectomy plus prednisone.⁴ A recent AAN Practice Advisory recommended that clinicians should discuss thymectomy with patients with AChR-Ab+ generalized MG and should counsel patients considering minimally invasive thymectomy techniques that it is uncertain whether the benefit attained by extended transsternal thymectomy will also be attained by minimally invasive approaches (level B).⁵
多中心、隨機、評估者盲法的胸腺切除術在重症肌無力（MG）中的試驗（MGTX）招募了 65 歲以下的 AChR 陽性（AChR-Ab+）廣泛性非胸腺瘤型重症肌無力患者。六十六名受試者接受了擴大型經胸骨胸腺切除術，並按照標準劑量計劃接受了類固醇（潑尼松）的治療，而 60 名受試者則僅接受標準化的潑尼松劑量計劃。兩項主要結果指標均顯示出胸腺切除術的有利效果：時間加權平均的重症肌無力量表（QMG）得分和時間加權平均的隔日潑尼松劑量均有所減少。次要結果指標，包括使用硫唑嘌呤、靜脈免疫球蛋白（IVIg）使用及因 MG 惡化住院的情況，也顯示出胸腺切除術加潑尼松的優勢。這些好處在第一年內顯現，並持續到第三年。在事後分析中，對於 50 歲或以上的患者，兩個治療組之間的潑尼松劑量和 QMG 得分並無顯著差異。MGTX 試驗的延伸研究隨後追蹤了 68 名（61%）來自原始試驗的參與者，持續了額外的兩年。 在 60 個月時，較低的時間加權平均 QMG 分數和平均時間加權的類固醇劑量減少使得胸腺切除術加上類固醇更具優勢。⁴ 最近的美國神經學會實務建議指出，臨床醫師應與 AChR-Ab+廣泛性重症肌無力的患者討論胸腺切除術，並應告知考慮微創胸腺切除技術的患者，尚不確定延長經胸骨胸腺切除術所獲得的益處是否也能通過微創方法獲得（B 級）。⁵

A small RCT comparing prednisone with placebo in patients with 11 ocular MG who had previously failed to achieve minimal manifestation (MM) status after 4–6 weeks of pyridostigmine found that 5 of 6 participants (83%) in the prednisone group achieved the primary end point of sustained MM status at a median of 14 weeks on prednisone (median dose 15 mg/d), compared with none of 5 in the placebo group.⁶ Three of the 5 placebo participants switched to prednisone (60 mg/d) with rapid taper; 2 attained sustained MM status. A prospective cohort study of 13 consecutive ocular and 76 generalized MG patients evaluated the effect of IS agents on ophthalmoparesis.⁷ Fifty-nine percent of patients had complete resolution of ophthalmoparesis within 12 ± 2 months of initiation of IS agents. Patients with milder ophthalmoparesis had greater odds of symptom resolution in the first year of treatment. Median time to resolution was 7 months after IS agents were started.
一項小型隨機對照試驗比較了在接受 4 至 6 週的吡啶斯的明治療後未能達到最小表現（MM）狀態的 11 名眼型重症肌無力患者中，使用類固醇（潑尼松）與安慰劑的效果。結果顯示，在潑尼松組中，6 名參與者中有 5 名（83%）在接受潑尼松治療的中位數 14 週後達到了持續的 MM 狀態（中位劑量 15 毫克/天），而安慰劑組的 5 名參與者中則無人達到此目標。⁶ 5 名安慰劑參與者中有 3 名轉換至潑尼松（60 毫克/天）並迅速減量；其中 2 名達到了持續的 MM 狀態。一項前瞻性隊列研究評估了 13 名連續眼型及 76 名全身型重症肌無力患者中免疫抑制劑對眼肌麻痺的影響。⁷ 59%的患者在開始使用免疫抑制劑後的 12 ± 2 個月內完全解決了眼肌麻痺。眼肌麻痺較輕的患者在治療的第一年中，症狀解決的機率較高。從開始使用免疫抑制劑到症狀解決的中位時間為 7 個月。

Evidence for the efficacy of thymectomy in ocular MG is limited by the retrospective design of most published studies. In a case-control study of 47 patients with nonthymomatous ocular MG who underwent thymectomy matched to 67 patients who refused surgery, there was no difference in the proportion of patients achieving stable remission at a median follow-up of 100–116 months.⁸ A retrospective analysis of 236 patients with thymomatous and nonthymomatous MG reported no improvement after thymectomy in 25 patients, of whom 17 (68%) were ocular or predominantly ocular, over 12 months of follow-up.⁹ In another retrospective case series of 52 patients with MG, only 2 of 11 patients with ocular MG (18%) achieved remission after thymectomy, in contrast to 28%–50% of patients with generalized MG.¹⁰
對於眼型重症肌無力（MG）中胸腺切除術的療效證據，受到大多數已發表研究的回顧性設計限制。在一項針對 47 名接受胸腺切除術的非胸腺腫瘤眼型 MG 患者與 67 名拒絕手術的患者進行的病例對照研究中，經過 100 至 116 個月的中位隨訪，兩組患者達到穩定緩解的比例並無差異。⁸ 對 236 名胸腺腫瘤及非胸腺腫瘤 MG 患者的回顧性分析報告顯示，在 25 名患者中，胸腺切除術後並未改善，其中 17 名（68%）為眼型或以眼型為主的患者，隨訪 12 個月後結果相同。⁹ 在另一項針對 52 名 MG 患者的回顧性病例系列中，只有 11 名眼型 MG 患者中的 2 名（18%）在胸腺切除術後達到緩解，與 28%至 50%的全身型 MG 患者相比，結果相差甚遠。¹⁰

A retrospective case series of 110 patients with ocular MG who underwent extended transsternal thymectomy reported that at a median follow-up of 33.5 months, 26% achieved complete remission (defined as asymptomatic without medications for 12 months).¹¹ Five patients had a thymoma.¹¹ A retrospective case series of 49 nonthymomatous ocular MG and 12 ocular MG with thymoma undergoing thymectomy followed for a mean duration of 9 years reported a cure defined as asymptomatic without the need for medications in 51%.¹² In yet another retrospective case series of transcervical thymectomy in MG, 57% of 12 patients with ocular MG achieved MGFA postintervention status (PIS) of complete stable remission (CSR)¹³ at 5 years.¹⁴ A subsequent case series of 151 patients with MG who underwent transcervical thymectomy followed for 5 years showed a higher odds ratio for remission in ocular MG compared with generalized MG without controlling for other variables (analysis performed by P.N.).¹⁵ In 12 patients with ocular MG undergoing thymectomy because of an abnormal chest CT scan, all but one required additional immunosuppression after thymectomy; 6 achieved remission at a mean follow-up of 81 months.¹⁶ In a retrospective analysis of 50 patients with juvenile MG undergoing thymectomy, of whom 46% were ocular, 50% showed improved PIS at a mean of 3.5 years of follow-up.¹⁷ There was no difference between ocular and generalized MG. In a meta-analysis of 26 studies of thymectomy in nonthymomatous MG, the pooled CSR rate was 0.51.¹⁸ There was high heterogeneity in the meta-analysis model, indicating substantial differences among the included studies.
一項回顧性病例系列研究報告了 110 名接受擴展性胸骨前胸腺切除術的眼型重症肌無力患者，經過中位數 33.5 個月的隨訪，26%達到完全緩解（定義為無症狀且無需用藥 12 個月）。¹¹ 其中五名患者有胸腺瘤。¹¹ 另一項回顧性病例系列研究報告了 49 名非胸腺瘤性眼型重症肌無力患者及 12 名有胸腺瘤的眼型重症肌無力患者接受胸腺切除術，平均隨訪 9 年，報告顯示 51%達到治癒，定義為無症狀且無需用藥。¹² 在另一項針對重症肌無力的經頸胸腺切除術的回顧性病例系列中，12 名眼型重症肌無力患者中有 57%在術後 5 年達到重症肌無力功能評估（MGFA）完全穩定緩解（CSR）狀態。¹³ 隨後的一項病例系列研究顯示，151 名接受經頸胸腺切除術的重症肌無力患者在 5 年隨訪中，眼型重症肌無力的緩解機率比全身型重症肌無力高，未控制其他變數（分析由 P.N.進行）。在 12 名因胸部 CT 掃描異常而接受胸腺切除手術的眼型重症肌無力患者中，除了 1 人外，皆需在手術後進行額外的免疫抑制治療；6 名患者在平均 81 個月的隨訪中達到緩解。在對 50 名接受胸腺切除手術的青少年重症肌無力患者的回顧性分析中，其中 46%為眼型，50%在平均 3.5 年的隨訪中顯示 PIS 改善。眼型與全身型重症肌無力之間沒有差異。在對 26 項非胸腺瘤重症肌無力胸腺切除手術的研究進行的綜合分析中，合併 CSR 率為 0.51。該綜合分析模型中存在高度異質性，顯示所納入研究之間存在顯著差異。

Most studies of RTX are retrospective, and some combine patients with AChR-Ab, MuSK-Ab, and seronegative MG. A multicenter blinded prospective review of MuSK-Ab + MG patients demonstrated that 14 of 24 (58%) patients treated with RTX achieved MM status and required only low-dose IS therapy, compared with 5 of 31 (16%) of the non-RTX group.¹⁹
大多數對 RTX 的研究都是回顧性的，有些將 AChR-Ab、MuSK-Ab 和血清陰性 MG 的患者合併在一起。一項多中心盲法前瞻性回顧 MuSK-Ab + MG 患者的研究顯示，24 名接受 RTX 治療的患者中有 14 名（58%）達到 MM 狀態，且僅需低劑量的免疫抑制療法，相較於非 RTX 組的 31 名患者中只有 5 名（16%）。¹⁹

In a prospective open-label study of 22 refractory AChR-Ab+, MuSK-Ab+, and seronegative MG, MG manual muscle testing (MMT) scores revealed significant improvement from baseline at a mean follow-up of 29 ± 19 months in the AChR-Ab+ and MuSK-Ab+ groups.²⁰ Another prospective open-label study of 14 patients with refractory AChR-Ab+, MuSK-Ab+, and seronegative MG reported improvement in MMT scores at a mean follow-up of 22 months.²¹ The time to peak response after a single cycle of RTX was 4.5 ± 1 months. A retrospective multicenter study of MuSK-Ab + MG reported that RTX given in the dose of 375 mg/m² weekly for 4 weeks and then monthly for the next 2 months was associated with lower relapse rates (18%) compared with a regimen of two 1 g infusions separated by 2 weeks (80%).²² A retrospective Austrian nationwide study of 56 patients with AChR-Ab+ and MuSK-Ab + MG reported that 26% of patients were in remission 3 months after treatment with varying dosing protocols of RTX. At a median of 20 months, 43% were in remission and 25% achieved MM status.²³ A single-center retrospective study of 21 AChR-Ab+, 3 MuSK-Ab+, and 4 patients with double-seronegative MG found that muscle strength improved significantly from baseline at 6 months and then stabilized up to 36 months, and PIS was improved in 43% at 6 months.²⁴ A retrospective combined analysis of previously published case reports of 169 patients between January 2000 and August 2015 reported that 72% of MuSK-Ab + MG and 30% of AChR-Ab+ MG patients treated with RTX achieved MM status or better.²⁵ The number of cycles of RTX varied but did not have an effect on the response. A recent systematic review of previous studies of 165 patients with AChR-Ab+ MG treated with RTX concluded that despite heterogeneous outcome measures, significant clinical improvement was seen in 113 patients (68%), with 36% achieving remission.²⁶ A phase II RCT of RTX (Beat-MG) enrolled 52 patients with generalized nonthymomatous AChR-Ab+ MG on a stable regimen of prednisone for 4 weeks or prednisone plus another IS agent for 6 months.²⁷ Two cycles of RTX 6 months apart were compared to placebo with the primary outcome being a steroid-sparing effect (≥75% reduction in mean daily prednisone requirements in the 4 weeks before week 52 compared with the 4-week period before randomization). The study was designed to assess futility (nonsuperiority). Preliminary results reported that the area under the curve for prednisone was not significantly different between RTX and placebo groups, with 60% on RTX and 56% on placebo achieving the primary outcome. There were no significant differences in mean QMG or MG-composite (MGC) changes between the groups. The study suggests that in mildly to moderately symptomatic generalized AChR-Ab+ MG, RTX is unlikely to have a clinically meaningful steroid-sparing effect over 12 months.
在一項前瞻性開放標籤研究中，22 名難治性 AChR-Ab+、MuSK-Ab+及血清陰性 MG 患者的 MG 手動肌肉測試（MMT）分數顯示，在平均隨訪 29 ± 19 個月後，AChR-Ab+和 MuSK-Ab+組別的基線有顯著改善。²⁰ 另一項針對 14 名難治性 AChR-Ab+、MuSK-Ab+及血清陰性 MG 患者的前瞻性開放標籤研究報告，在平均隨訪 22 個月後，MMT 分數有所改善。²¹ 單次 RTX 療程後的峰值反應時間為 4.5 ± 1 個月。一項回顧性多中心研究顯示，對於 MuSK-Ab+ MG 患者，使用 375 mg/m²的 RTX 劑量，每週 4 週後再每月一次，與兩次 1 g 的輸注（間隔 2 週）相比，復發率較低（18%對 80%）。²² 一項針對 56 名 AChR-Ab+和 MuSK-Ab+ MG 患者的回顧性奧地利全國研究報告，26%的患者在接受不同劑量方案的 RTX 治療後 3 個月內達到緩解。在中位數 20 個月時，43%的患者達到緩解，25%的患者達到 MM 狀態。²³ 一項單中心回顧性研究對 21 名 AChR-Ab+、3 名 MuSK-Ab+及 4 名雙陰性 MG 患者進行了分析，發現肌肉力量在基線時於 6 個月顯著改善，並在 36 個月時穩定，且在 6 個月時有 43%的患者的 PIS 有所改善。²⁴ 一項對 2000 年 1 月至 2015 年 8 月期間 169 名患者的已發表病例報告進行的回顧性綜合分析報告指出，72%的 MuSK-Ab+ MG 患者和 30%的 AChR-Ab+ MG 患者在接受 RTX 治療後達到 MM 狀態或更好。²⁵ RTX 的療程數量各異，但對反應沒有影響。最近對 165 名接受 RTX 治療的 AChR-Ab+ MG 患者的研究進行的系統性回顧得出結論，儘管結果指標異質性，但有 113 名患者（68%）顯示出顯著的臨床改善，其中 36%達到緩解。²⁶ 一項 RTX 的二期隨機對照試驗（Beat-MG）招募了 52 名接受穩定的類固醇治療 4 週或類固醇加其他免疫抑制劑治療 6 個月的廣泛性非胸腺瘤性 AChR-Ab+ MG 患者。²⁷ 兩個 RTX 療程相隔 6 個月與安慰劑進行比較，主要結果為類固醇節省效果（在第 52 週之前的 4 週內，平均每日類固醇使用量減少≥75%與隨機分配前的 4 週期間相比）。該研究旨在評估無效性（非優越性）。初步結果報告顯示，RTX 和安慰劑組在類固醇使用量的曲線下面積並無顯著差異，60%的 RTX 組和 56%的安慰劑組達成主要結果。兩組之間在平均 QMG 或 MG 綜合指數（MGC）變化上也沒有顯著差異。該研究表明，在輕度至中度症狀的全身性 AChR-Ab+重症肌無力患者中，RTX 在 12 個月內不太可能具有臨床上有意義的類固醇節省效果。

Three cases of progressive multifocal leukoencephalopathy have been reported in MG. One was RTX related, although the patient had previously received other IS agents,²⁸ another patient was on azathioprine and prednisone,²⁹ and the third patient was on prednisolone, IVIg, and azathioprine.³⁰
在 MG 中已報告三例進行性多灶性白質腦病。其中一例與 RTX 有關，儘管該患者之前已接受其他免疫抑制劑，另一位患者則使用了硫唑嘌呤和類固醇，第三位患者則使用了潑尼松龍、靜脈注射免疫球蛋白和硫唑嘌呤。

Studies on the use of MTX in MG are limited, and the available data do not provide convincing evidence of efficacy. In a retrospective case series of 16 patients with MG treated with MTX, (abstract only) 8 patients reduced pyridostigmine doses and 6 showed “clinical improvement.”³¹ A prospective open-label case series published only as an abstract reported that 14 of 16 patients with MG treated with MTX had an improved PIS on a mean follow-up of 20.6 months.³² In a single-blinded trial, 24 patients with generalized MG on prednisone were randomized to MTX (11) or azathioprine (13).³³ At 24 months, the average prednisone dose required to achieve and maintain MM status was lower in both MTX- and azathioprine-treated patients but was not different between the groups. At months 10 and 12, the prednisone dose was lower in the MTX group, but the confidence interval includes clinically meaningful and nonmeaningful effects. Similar proportions of both groups achieved MM status, and there were no differences in QMG or MG-activity of daily living (MG-ADL) scores between the groups.³³ An RCT enrolled 50 patients with AChR-Ab+ MG taking prednisone at a dose of ≥10 mg/d.³⁴ Patients were randomized 1:1 to MTX 20 mg/wk or placebo. There was no difference in the primary outcome measure, the area under the prednisone dose-time curve between months 4 and 12, and the mean 12-month change in QMG, MMT, MG-Quality of life, MG-ADL, and MGC was no different between treatment groups.
對於使用 MTX 治療重症肌無力（MG）的研究有限，現有數據並未提供令人信服的療效證據。在一項回顧性病例系列中，16 名接受 MTX 治療的 MG 患者中，8 名患者減少了吡啶斯的明劑量，6 名顯示出「臨床改善」。一項僅以摘要形式發表的前瞻性開放標籤病例系列報告指出，在接受 MTX 治療的 16 名 MG 患者中，有 14 名在平均 20.6 個月的隨訪中 PIS 有所改善。在一項單盲試驗中，24 名接受類固醇治療的廣泛性 MG 患者被隨機分配至 MTX（11 名）或硫唑嘌呤（13 名）。在 24 個月時，為了達到並維持完全緩解（MM）狀態所需的平均類固醇劑量在 MTX 和硫唑嘌呤治療的患者中均較低，但兩組之間並無差異。在第 10 和第 12 個月，MTX 組的類固醇劑量較低，但信賴區間包括臨床上有意義和無意義的效果。兩組達到 MM 狀態的比例相似，且在 QMG 或 MG 日常生活活動（MG-ADL）得分方面兩組之間沒有差異。³³ 一項隨機對照試驗招募了 50 名接受≥10 mg/d 的類固醇治療的 AChR-Ab+重症肌無力患者。³⁴ 患者以 1:1 的比例隨機分配至每週 20 mg 的美克氯噻噻或安慰劑組。主要結果指標，即在第 4 個月至第 12 個月之間的類固醇劑量-時間曲線下面積，兩組之間沒有差異，而 12 個月的 QMG、MMT、MG 生活品質、MG-ADL 和 MGC 的平均變化在治療組之間也沒有差異。

Eculizumab is a humanized monoclonal antibody against the terminal C5 complement molecule.³⁵ Eculizumab prevents the formation of the membrane attack complex and reduces damage caused by complement-fixing AChR antibodies.³⁶ In a phase II crossover RCT of 14 patients with refractory generalized AChR-Ab + MG, at the end of the first treatment period, 6/7 (86%) of eculizumab-treated patients achieved the primary end point of a 2-point reduction in the QMG score, compared to 57% with placebo.³⁷ A repeated measures mixed model of data from all visits revealed significant differences in the QMG score favoring eculizumab. Eculizumab was well tolerated. In a phase III international multicenter RCT of 125 patients with refractory generalized nonthymomatous AChR-Ab+ MG (REGAIN), the primary outcome measure of change in the MG-ADL score from baseline to week 26, measured by worst-rank analysis of covariance, was not significantly different (p = 0.0698) between eculizumab and placebo arms.³⁸ However, QMG score change on worst-rank analysis of covariance, all prespecified secondary endpoints (changes in QMG, MGC, and MG-QOL15 scores and responder analyses of QMG and MG-ADL scores), and multiple sensitivity analyses showed a significant benefit for eculizumab. Participants who completed the 26-week REGAIN study were followed in an open-label extension (OLE) within 2 weeks of completing REGAIN.³⁹ A preplanned interim analysis of the OLE at 22.7 months of median follow-up found a reduction in MG exacerbations by 75% compared with the year before REGAIN. In addition, 56% (65/116) of patients achieved MM status or pharmacologic remission. The magnitude of response on all clinical measures for the placebo patients in REGAIN who crossed over to receive eculizumab in the OLE was similar to the eculizumab-treated patients in REGAIN. A clinically meaningful response in MG-ADL and QMG scores was seen in 55% and 39.7% of patients, respectively. Eculizumab was well tolerated. One case of meningococcal meningitis occurred, despite vaccination in the OLE and the patient was successfully treated.
Eculizumab 是一種針對末端 C5 補體分子的人體化單克隆抗體。Eculizumab 可防止膜攻擊複合體的形成，並減少由補體固定的 AChR 抗體所造成的損害。在一項針對 14 名難治性全身性 AChR-Ab + MG 患者的第二期交叉隨機對照試驗中，在第一次治療期結束時，接受 eculizumab 治療的患者中有 6/7（86%）達成了 QMG 分數降低 2 分的主要終點，而安慰劑組則為 57%。對所有訪視數據進行的重複測量混合模型顯示，QMG 分數在 eculizumab 組中有顯著差異。Eculizumab 的耐受性良好。在一項針對 125 名難治性全身性非胸腺瘤 AChR-Ab+ MG 患者的第三期國際多中心隨機對照試驗（REGAIN）中，基線到第 26 週的 MG-ADL 分數變化的主要結果測量，經最差秩分析協方差檢驗，顯示 eculizumab 與安慰劑組之間並無顯著差異（p = 0.0698）。³⁸ 然而，根據最差排名的協方差分析，所有預先指定的次要終點（QMG、MGC 和 MG-QOL15 分數的變化以及 QMG 和 MG-ADL 分數的應答者分析）以及多項敏感性分析顯示，eculizumab 有顯著的益處。完成 26 週 REGAIN 研究的參與者在完成 REGAIN 後 2 週內進入開放標籤延伸研究（OLE）。³⁹ 在中位隨訪 22.7 個月的 OLE 預先計劃的中期分析中，發現與 REGAIN 前一年相比，MG 加重減少了 75%。此外，56%（65/116）的患者達到了 MM 狀態或藥物緩解。在 REGAIN 中轉為接受 eculizumab 的安慰劑患者在 OLE 中的所有臨床指標反應程度與 REGAIN 中接受 eculizumab 治療的患者相似。在 MG-ADL 和 QMG 分數中，分別有 55% 和 39.7% 的患者顯示出臨床上有意義的反應。eculizumab 耐受性良好。儘管在 OLE 中接種了疫苗，但仍發生了一例腦膜炎球菌性腦膜炎，該患者成功接受治療。

Vaccination against Neisseria meningitidis (both meningococcal conjugate Men ACWY and serogroup B or MenB) is required at least 2 weeks before starting treatment with eculizumab. The conjugate ACWY vaccines available in the United States include Menveo (1 dose, GlaxoSmithKline Biologicals, Inc.) and Menactra (1 dose, single booster 4 years after initial dose if needed, Sanofi Pasteur, Inc.). The 2 brands of MenB vaccine are Bexsero (2 dose series, GlaxoSmithKline Biologicals, Inc.) and Trumenba (3 dose series, Pfizer, Inc.). The brands are not interchangeable, and a course should be completed with the same brand of the vaccine for all doses. The vaccine does not confer absolute protection against meningococcal meningitis. Antibiotic coverage, for at least 4 weeks after immunization, is recommended if eculizumab is started before the 2-week period after vaccination. The recommendations for antibiotic coverage vary. Penicillin VK 250–500 mg every 12 hours is usually the first-line chemoprophylaxis.^40,41 Erythromycin 500 mg twice daily, azithromycin 500 mg daily, or ciprofloxacin 500 mg daily are alternatives for penicillin-allergic patients.^40–42 However, both fluoroquinolones and macrolides can worsen MG. Chemoprophylaxis of meningococcal infections in penicillin-allergic patients can therefore be challenging, and infectious disease consultation may be required.
接種奈瑟氏腦膜炎球菌（包括腦膜炎球菌結合疫苗 Men ACWY 和 B 型腦膜炎球菌或 MenB）必須在開始使用 eculizumab 治療前至少 2 週進行。美國可用的 ACWY 結合疫苗包括 Menveo（1 劑，葛蘭素史克生物科技公司）和 Menactra（1 劑，若需要可在初次接種後 4 年進行單次加強接種，賽諾菲巴斯德公司）。兩種 MenB 疫苗品牌為 Bexsero（2 劑系列，葛蘭素史克生物科技公司）和 Trumenba（3 劑系列，輝瑞公司）。這些品牌不可互換，所有劑量應使用相同品牌的疫苗完成接種。該疫苗並不提供對腦膜炎球菌性腦膜炎的絕對保護。如果在接種後的 2 週內開始使用 eculizumab，建議在接種後至少 4 週內使用抗生素預防。抗生素預防的建議有所不同。青黴素 VK 250–500 毫克每 12 小時通常是首選的化學預防藥物。紅黴素 500 毫克每日兩次、阿奇黴素 500 毫克每日一次，或環丙沙星 500 毫克每日一次是對青黴素過敏患者的替代選擇。然而，氟喹諾酮類和大環內酯類藥物可能會加重重症肌無力。因此，對青黴素過敏患者進行腦膜炎球菌感染的化學預防可能會面臨挑戰，可能需要傳染病專家的諮詢。

Immune checkpoints (ICPs) are most often inhibitory molecules expressed on the surface of T cells, which modulate the immune response and prevent host tissue damage due to uncontrolled responses to foreign or self-antigens. The immune inhibitory cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed cell death ligand 1 (PD-L1) are the best-characterized ICPs and are targeted in cancer immunotherapy. CTLA-4 reduces T-cell activation, competing with CD28 in binding B7 molecules (CD80 and CD86) on antigen-presenting cells. PD-1 binds its ligands (PD-L1 and PD-L2) and reduces activated T-cell proliferation through the inhibition of specific phosphorylation pathways.^43,44 Monoclonal antibodies against CTLA-4, PD-1, and PD-L1 act by blocking these inhibitory ICP molecules to stimulate antitumor immunity (immune checkpoint inhibitors [ICIs]). These include the CTLA-4 inhibitor ipilimumab, PD-1 inhibitors pembrolizumab, nivolumab, and cemiplimab, and the PDL-1 inhibitors atezolizumab, durvalumab, and avelumab. Because of the upregulation of the immune response, multisystem immune-related adverse events (irAEs) such as skin rash, thyroid dysfunction, pneumonitis, colitis, hepatitis, nephritis, hypophysitis, and neurologic disorders including MG have been reported in patients receiving checkpoint inhibitors.
免疫檢查點（ICPs）通常是表現在 T 細胞表面的抑制性分子，調節免疫反應並防止因對外來或自我抗原的失控反應而造成的宿主組織損傷。免疫抑制性細胞毒性 T 淋巴細胞相關蛋白 4（CTLA-4）、程序性細胞死亡蛋白 1（PD-1）和程序性細胞死亡配體 1（PD-L1）是最具特徵的 ICPs，並在癌症免疫療法中被針對。CTLA-4 減少 T 細胞的活化，與 CD28 競爭結合抗原呈現細胞上的 B7 分子（CD80 和 CD86）。PD-1 與其配體（PD-L1 和 PD-L2）結合，通過抑制特定的磷酸化途徑來減少活化 T 細胞的增殖。針對 CTLA-4、PD-1 和 PD-L1 的單克隆抗體通過阻斷這些抑制性 ICPs 分子來刺激抗腫瘤免疫（免疫檢查點抑制劑[ICIs]）。這些包括 CTLA-4 抑制劑伊匹單抗、PD-1 抑制劑帕博利珠單抗、尼伏單抗和西美普單抗，以及 PD-L1 抑制劑阿特朱單抗、杜瓦利單抗和阿維單抗。 由於免疫反應的上調，接受檢查點抑制劑的患者報告出現多系統免疫相關不良事件（irAEs），如皮疹、甲狀腺功能障礙、肺炎、結腸炎、肝炎、腎炎、腦下垂體炎，以及包括重症肌無力在內的神經系統疾病。

The literature on irAEs of these drugs is rapidly evolving. De novo MG has been reported in patients treated with anti–CTLA-4 agents (ipilimumab),⁴⁵ PD-1 inhibitors (nivolumab or pembrolizumab),^45–47 and with combined (anti–CTLA-4 plus anti–PD-1 or PD-L1) therapy.⁴⁵ The estimated frequency of MG among patients treated with PD-1 inhibitors ranges from 0.12% to 0.2%.^48–52 Exacerbation of preexisting MG and subclinical AChR-Ab+ MG has been reported in patients treated with PD-1 inhibitors.^45,53,54
這些藥物的免疫相關不良事件（irAEs）文獻正在迅速發展。已報告在接受抗 CTLA-4 藥物（如伊匹單抗）、PD-1 抑制劑（如尼伏單抗或帕博利珠單抗）及聯合治療（抗 CTLA-4 加上抗 PD-1 或 PD-L1）治療的患者中出現新發的重症肌無力（MG）。在接受 PD-1 抑制劑治療的患者中，重症肌無力的估計發生率範圍為 0.12% 至 0.2%。在接受 PD-1 抑制劑治療的患者中，已報告加重既有的重症肌無力及亞臨床 AChR-Ab+ 重症肌無力的情況。

MG onset or exacerbation varies in severity and generally occurs in the early phase of treatment. MG can overlap with other immune-mediated peripheral and central neurologic syndromes.^48,55 In a review of the literature combined with a single-center experience, of 63 patients with MG due to ICIs, 52 had new-onset MG and 11 had a flare of preexisting MG. Most received PD-1 therapy. Concurrent myositis was diagnosed in 24 patients (37%) and myocarditis in 5 (8%); 2 had the triad of MG/myositis/myocarditis. Median time from ICI initiation to developing MG was 4 weeks (6 days–16 weeks). Respiratory failure requiring mechanical ventilation occurred in 29 patients (45%). Patients with MG/myositis/myocarditis developed respiratory failure more frequently than those with MG alone (54% vs 42%). AChR-Ab titers were elevated in 37/56 (66%) of tested patients. Three patients had AChR-Ab when tested before ICI initiation and antibody titers increased at least 2-fold after ICI initiation. Intravenous corticosteroids were used in 59 of 63 patients. Thirty-eight patients received steroids as first-line therapy and 24 (63%) improved. Four patients with ocular MG developed respiratory insufficiency after corticosteroid treatment. MG symptoms completely resolved in 12 patients (19%), improved in 34 (55%), and worsened in 16 (26%).⁵¹ In a review of 1834 patients receiving ICIs, 4 had MG, of whom 1 was AChR-Ab+. Three were associated with myositis. Three patients with MG received combined CTLA-4 and PD-1 ICIs and one received a CTLA-4 ICI. Concurrent occurrence of MG with myocarditis and thyroiditis was also noted.⁵⁰ The diagnosis of ICI-related MG can be challenging. Many patients with cancer have fatigue or generalized weakness. The recognition of the underlying neuromuscular disease may be delayed by the focus on the oncologic illness. Concurrent myositis may make MG difficult to diagnose especially when associated with ocular and bulbar weakness. Seronegative MG appears to be more frequent in these patients, making the diagnosis even more challenging.⁵⁰ The severity of the illness may be the result of multiple concurrent conditions including MG, myositis, and myocarditis. CNS involvement may occur in conjunction with MG or MG-myositis overlap.⁵⁰ Corticosteroid therapy appears to result in favorable outcomes.⁵⁰
MG 的發作或惡化程度各異，通常發生在治療的早期階段。MG 可能與其他免疫介導的周邊及中樞神經綜合症重疊。在一項結合文獻回顧及單中心經驗的研究中，63 名因免疫檢查點抑制劑（ICIs）而患有 MG 的患者中，52 名為新發 MG，11 名為既有 MG 的惡化。大多數患者接受了 PD-1 治療。24 名患者（37%）被診斷為同時合併肌炎，5 名（8%）診斷為心肌炎；2 名患者出現 MG/肌炎/心肌炎的三聯症。從 ICI 開始治療到發展為 MG 的中位時間為 4 週（6 天–16 週）。29 名患者（45%）出現需要機械通氣的呼吸衰竭。MG/肌炎/心肌炎的患者出現呼吸衰竭的頻率高於僅有 MG 的患者（54%對 42%）。在 56 名接受檢測的患者中，37 名（66%）的 AChR 抗體滴度升高。三名患者在 ICI 開始前檢測時已存在 AChR 抗體，且在 ICI 開始後抗體滴度至少增加了 2 倍。63 名患者中有 59 名使用了靜脈類固醇。38 名患者作為一線治療接受類固醇，24 名（63%）有所改善。 四名患有眼型重症肌無力的病人在接受皮質類固醇治療後出現呼吸功能不全。12 名病人的重症肌無力症狀完全緩解（19%），34 名病人改善（55%），16 名病人惡化（26%）。在對 1834 名接受免疫檢查點抑制劑（ICIs）治療的病人進行的回顧中，有 4 名病人患有重症肌無力，其中 1 名為乙醯膽鹼受體抗體陽性（AChR-Ab+）。三名病人與肌炎有關。三名重症肌無力病人接受了 CTLA-4 和 PD-1 免疫檢查點抑制劑的聯合治療，另一名則接受了 CTLA-4 免疫檢查點抑制劑。也有報告指出重症肌無力與心肌炎和甲狀腺炎同時發生。診斷與免疫檢查點抑制劑相關的重症肌無力可能具有挑戰性。許多癌症病人會出現疲勞或全身無力，對潛在神經肌肉疾病的識別可能因專注於腫瘤疾病而延遲。伴隨肌炎的情況可能使重症肌無力的診斷變得困難，尤其是當與眼部和延髓無力相關時。這些病人中無抗體的重症肌無力似乎更為常見，進一步增加了診斷的挑戰性。疾病的嚴重程度可能是多種同時存在的病症，包括重症肌無力、肌炎和心肌炎的結果。 中樞神經系統的參與可能與重症肌無力或重症肌無力-肌炎重疊同時發生。⁵⁰ 皮質類固醇治療似乎會帶來良好的結果。⁵⁰