Immunity, Inflammation and Disease ( IF 2.493 ) Pub Date : 2020-10-05 , DOI: 10.1002/iid3.357 Stefani Röseler 1, 2 , Friederike Leufgens 2, 3 , Hans F Merk 2 , Jens M Baron 2 , Silke Moll-Slodowy 2 , Gerda Wurpts 2 , Galina Balakirski 2, 4
Glatiramer acetate (GA; trade name: Copaxone®) is a mixture of synthetic polypeptides that is used for the immunomodulatory treatment of relapsing‐remitting multiple sclerosis (RRMS).1 While some mechanisms of action of GA are still not completely understood, it has been shown to bind to major histocompatibility complex molecules and to induce an in vivo change of the cytokine secretion pattern of CD4+ and CD8+ T cells.1
Injection site reactions and immediate post‐injection systemic reactions (IPISR) are adverse events caused by GA that are most frequently described in the literature.2 The latter are characterized by flushing, chest tightness, palpitations, and shortness of breath, and may occur several minutes after the injection, but resolve spontaneously, usually within 1 h. IPISR can take the form of a single episode or recurrent event. The mechanism of this reaction is still unclear.2 Moreover, as the use of GA became more common in clinical practice, a number of reports on possible type I hypersensitivity reactions to this drug were released.3-13 In most cases, a positive skin prick test, an intradermal test, or the basophil activation test (BAT) led to the diagnosis of an immediate‐type hypersensitivity reaction to GA and to a subsequent cessation of the therapy.5, 7, 8, 13, 12
At the present time, there are no generally accepted recommendations on how allergy diagnostic testing should be carried out to evaluate these reactions to GA. Skin prick and intradermal tests are performed at dilution ratios of 1:10000, 1:1000, 1:100, and sometimes 1:10 or with the undiluted substance.3, 5, 7, 9, 11-13 However, this procedure is not validated or standardized with respect to irritation or false‐positive reactions.
Herein we report a case of a 38‐year‐old man who was examined at our allergology clinic due to complaints of intermittent generalized pruritic skin lesions. Having received the diagnosis of RRMS in 2009, he was prescribed 20 mg GA per day (changed to 20 mg three times per week starting from 2015). From the onset of the immunomodulatory therapy, he regularly developed itchy erythematous skin reactions at the injection site and, from time to time, solitary skin lesions, which could clearly be identified as hives in the photos taken by the patient. Starting from 2016, an almost daily appearance of hives could be observed, regardless of the time of the GA injections. In addition, angioedema of the lips, tongue, and genital area occurred twice. Since cutaneous reactions have been described as possible side effects of GA, the therapy was discontinued. Despite the discontinuation of GA, the symptoms persisted with undiminished intensity. The patient presented to our allergological department approximately 18 months after the onset of the symptoms (and 2 months after the discontinuation of GA). The patient denied any known allergies. Apart from the RRMS, his medical history was remarkable for hypothyroidism, which was being treated with l‐thyroxin 75 µg once daily.
After obtaining informed consent from the patient, we performed a skin prick test with undiluted GA, which was negative. We then proceeded to perform the next diagnostic step recommended in the currently available literature: an intradermal test, which was positive at a dilution of 1:100. To rule out a false‐positive reaction, intradermal tests with the same concentrations of GA were carried out in two healthy volunteer persons (SR and GB), who had not previously been exposed to GA. The two subjects also exhibited a positive reaction at the dilution of 1:100. To complete the allergology workup, the CD63 BAT with GA was performed. At the dilution of 1:100, there was a significant activation of the basophilic granulocytes of the patient. To rule out nonspecific basophil degranulation, the CD63 BAT was performed in five more volunteers, including the two individuals who previously had the positive results in the intradermal test. All these persons tested positive in the CD63 BAT with GA at a dilution of 1:100, the same as the patient. At the same time, a skin prick test, an intradermal test, and the CD63 BAT with mannitol, which is a component of injection solutions of GA, were negative in the patient and the two controls.
To identify other similar cases, a search of Medline via PubMed and Google Scholar was conducted using the following search strings: “glatiramer acetate” AND “allergy” or “hypersensitivity” or “sensitization” or “urticaria.” The search was restricted to scientific literature published up to February 2020 in English, German, and French; full texts were systematically retrieved. The bibliographical references of the articles were screened to identify further studies for possible inclusion.
We identified 47 scientific publications. In all, 36 publications were excluded as they were deemed irrelevant. The 11 included publications reported 44 cases of possible immediate hypersensitivity (Table 1). In most cases, positive reactions in the intradermal test occurred at a dilution of 1:100, similarly to our case, or at 1:10.3, 7, 9, 11-13 In 12 cases, these results were the basis of a diagnosis of type I hypersensitivity.7, 9, 11-13 Only some authors tested healthy volunteers3, 5, 7, 9, 11, 13 or performed drug provocation testing in affected patients.3, 9 In the study of Amsler et al.,3 after a series of positive cutaneous reactions, a drug provocation test was performed, in which 16 of the 18 test subjects tolerated GA well. We also recommended drug provocation testing to our patient, who, however, refused it. Our hypothesis was that the patient suffered from chronic spontaneous urticaria that had been initially mistaken for a drug allergy. A similar constellation of conditions was reported by Amsler et al.3 in 5 out of 18 patients. Our patient was treated with a fourfold dose of oral fexofenadine 180 mg, as recommended in the national guideline on the treatment of chronic spontaneous urticaria. There was a moderate response to the treatment. The symptoms ceased approximately 26 months after the onset (and 10 months after the discontinuation of the GA therapy). At that time, the patient was being followed up at the neurological clinic and did not require treatment for multiple sclerosis.
| Literature/reference | Number of patients | Clinical symptoms | Time to onset of symptoms after injection | Emergency treatment required | Skin prick test (SPT), dilution, and results | Intradermal test (IDT), dilution, and results | In vitro diagnostics | Control persons | Outcome/drug provocation test (DPT) |
|---|---|---|---|---|---|---|---|---|---|
| Amsler E et al., 2017 (3) | 18 | 10/18: urticaria only; 3/8: facial erythema and edema, dizziness; 4/8: chest tightness; 3/8: heat sensations; 2/8: abdominal pain; 2/8: tachycardia or palpitations; 3/8 itching or rash | 8/18: immediately to a few minutes; 1/18: 30 min; 5/18: 1 to a few hours; 4/18: unknown | 14/18: none; 2/18: emergency consultation, no treatment; 2/18: emergency consultation, corticosteroid with/without antihistamines | 16/18: negative with undiluted GA; 2/18: not performed | 1/18: positive with undiluted GA; 2/18: positive and 1/18: inconclusive at dilution of 1:10; 7/18: positive and 1/18: inconclusive at dilution of 1:100; 4/18: positive at dilution of 1:1000; 1/18: positive at dilution of 1:10,000; 1/18: negative at all tested dilutions | Not performed | Two controls (who had never received GA) had a positive IDT (at dilution 1:100 or 1:10) | 16/18: tolerated DPT without reaction; 1/18: reoccurrence of IPISR; 1/18: not performed |
| Syrigou E et al., 2015 (4) | 1 | Injection site redness and swelling followed by generalized urticaria | Unknown | Levocetirizine 5 mg × 4/24 h and corticosteroid therapy (methyl‐prednisolone 60 mg/24 h) | Borderline reaction to undiluted GA | Positive at dilution of 1:10,000 | Not performed | Not performed | Successful desensitization and continuation of the drug |
| Corominas M et al., 2014 (5) | 3 | Patients 1 and 2: generalized urticaria, nausea, and hypotension; Patient 3: facial angioedema | Patients 1 and 2: upon the first administration of GA (exact time after injection not specified); Patient 3: 20 min after injection | Not reported | 3/3 patients tested positive with undiluted GA | Not performed | Specific IgE to GA was determined in the serum of patients and controls using ImmunoCAP Technology, Thermo Fisher Scientific; 3/3 patients had elevated sIgE to GA | 10/10 control subjects tested negative in SPT with undiluted GA; 6 patients with MS treated with GA and 10 healthy controls had negative sIgE to GA | Not specified, possibly discontinuation of the drug |
| Crestani E et al., 2014 (6) | 1 | Severe shortness of breath, dizziness with shivering, tachycardia, flushing, perioral cyanosis, and brief loss of consciousness | Immediately after injection | By the time of arrival of emergency personnel, the symptoms subsided, and no treatment was needed | Negative with undiluted GA | Positive at dilution of 1:100,000 | Not performed | 1/1 negative at dilution of 1:100000 | Successful desensitization and continuation of the drug |
| Soriano Gomis V et al., 2012 (7) | 3 | Patient 1: generalized itching, weals, facial angioedema, dyspnea, and near unconsciousness; Patient 2: facial angioedema, dyspnea, abdominal cramps, and vomiting; Patient 3: generalized itching | Immediately or a few minutes after injection | All patients received epinephrine, dexchlorpheniramine, and methylprednisolone | Patient 1 tested positive in SPT (dilution not specified) | Positive in all three patients at dilution of 1:100 | Specific IgE to GA were determined using ELISA, Patients 1 and 2 had elevated levels compared to 10 controls; Patients 2 and 3 tested positive in BAT at 1:100 and 1:400, respectively | 3/3 control persons had negative IDT results (dilution not specified); 1/10 controls had elevated sIgE to GA; 1/6 controls had positive BAT result at dilution of 1:20 | Not specified, possibly discontinuation of the drug |
| Baumgartner A et al., 2011 (8) | 6 | Patient 1: generalized pruritic lesions; Patient 2: generalized cutaneous lesions, hypotension, and dyspnea; Patient 3: generalized erythema, dyspnea, nausea, orthostatic dysregulation, and abnormal fatigue; Patient 4: nausea, facial edema, paresthesia, and bronchial spasm; Patient 5: scalp pruritus, nausea, vomiting, and severe hypotension; Patient 6: heat sensations, facial edema, generalized skin lesions, and bronchial spasm | Immediately to a short time after injection | Patients 1, 2, and 3: none; Patient 4: administration of steroids; Patient 5: administration of dimetindene, dexamethasone, cimetidine, and adrenaline; Patient 6: injection of steroids and clemastine | Not performed | Not performed | Not performed | Not performed | Discontinuation of the drug in all patients |
| Sánchez‐López J et al., 2010 (9) | 3 | Patient 1: weals at the injection site and tachycarida; Patient 2: weals at the injection site; Patient 3: weals at injection site, generalized pruritus, and dermographism | Immediately or a few minutes after injection | None | From 1:10,000 to undiluted: negative in all patients | From 1:10,000 to 1:100: positive in patient 1 at 1:10,000; positive in Patient 2 at 1:1000; positive in Patient 3 at 1:100 | Sera of patients and controls were examined using ELISA to detect specific IgE to GA; Patient 1 had elevated levels compared to other subjects | 5 healthy subjects who had never received the drug and 5 patients with RRMS who tolerated GA: SPT negative in all controls; IDT with dilutions ≤1:100 positive in all controls | Patients 2 and 3 tolerated DPT well, and the treatment with GA was continued; DPT was considered to be too dangerous for Patient 1, therefore, GA was discontinued |
| Sheth SS et al., 2010 (10) | 1 | Localized urticaria, nasal congestion, palpitations, diffuse flushing, and hoarseness | Few minutes after injection | Not reported | Undiluted: positive | Not performed | Not performed | 1/1 negative in SPT with undiluted GA | Successful desensitization and continuation of the drug |
| Bains SN et al., 2010 (11) | 6 | Patients 1 and 2: generalized urticaria without other symptoms; Patient 3: facial swelling, palpitations, throat constriction, and shortness of breath; Patient 4: chest tightness, difficulty breathing, facial flushing, headache, and pruritic skin lesions; Patient 5: development of local hives and swelling at the injection site; Patient 6: local injection site erythema, swelling, and tenderness | Patient 1: 5 h after the first injection; Patient 2: 30 min after injection; Patient 3: immediately after injection; Patient 4: few minutes after injection; Patient 5: few hours after injection; Patient 6: unknown | Patients 1, 3, 5, and 6: none; Patient 2: emergency consultation, administration of epinephrine, diphenhydramine, and a nebulized bronchodilator; Patient 4: oral diphenhydramine | Patient 1: skin testing not performed due to dermographism | Patient 1: skin testing not performed due to dermographism; 3/5 patients positive in IDT with dilution of 1:10 and 2/5 positive in IDT with dilution of 1:100 | Not performed | 1/9: positive in SPT with undiluted GA, 8/8 positive in IDT with dilution of 1:10 and 6/8 positive in IDT with dilution of 1:100; 4/5 positive in IDT with dilution of 1:1000, and 2/5 positive in IDT with dilution of 1:10,000 | Successful desensitization and continuation of the drug |
| Rauschka H et al., 2005 (12) | 1 | Generalized flushing, itching urticarial lesions, dyspnea, abdominal cramps, vomiting, and circulatory collapse with unconsciousness for several minutes | 2 min after injection | Intravenous (i.v.) adrenalin and antihistamine | Positive with undiluted GA | Positive at dilution of 1:100 | Specific IgE was found in serum (laboratory methods were not specified) | Not performed | Discontinuation of the drug |
| Bayerl C et al., 2000 (13) | 1 | Nausea, heat sensation, generalized erythema and weals, circulatory collapse, gastric spasms, and diarrhea | Immediately after injection | None | 1:10 and undiluted: negative | 1:10 and undiluted: both positive after 24 h | Not performed | 5/5 control persons were negative in in vivo tests (tests not specified) | Not specified, probably discontinuation of the drug |
- Abbreviations: GA, glatiramer acetate; IgE, immunoglobulin E; IPISR, immediate post‐injection systemic reaction; MS, multiple sclerosis; RRMS, relapsing‐remitting multiple sclerosis; sIgE, specific immunoglobulin E.
At the present time, there are still no commercially available kits for measuring specific immunoglobulin E (sIgE) antibodies to GA. The presence of these immunoglobulin E (IgE) antibodies can be detected only in specialized laboratories and, therefore, is not a routinely available standardized diagnostic tool. The BAT might be available at a larger number of research facilities, as it is widely used in allergy testing. The diagnostic tools that are widely available are in vivo tests: the skin prick test and the intradermal test. In the report of Amsler et al.,3 13 out of 14 persons who tested positive for GA in the intradermal test tolerated the substance well in the drug provocation test. Thus, false‐positive in vivo test results might not be uncommon. Additionally, in our case, healthy volunteers with no previous exposure to GA tested positive both the in vivo test and the in vitro one. Similar findings have also been reported by other authors.11, 13 This case highlights that the above‐described symptoms caused by GA may have underlying mechanisms other than IgE‐mediated hypersensitivity, despite the positive allergy test results. Furthermore, the drug does not automatically need to be discontinued based on a positive result in the skin prick test or the intradermal test, as they might be false‐positive due to nonallergic histamine release, which could also explain IPISR. In questionable cases, a drug provocation test appears to be the most reliable of the widely available diagnostic tools at the moment.
中文翻译：
诊断醋酸格拉替雷过敏的假阳性结果：病例报告和系统文献综述
醋酸格拉替雷（GA；商品名：Copaxone®）是一种合成多肽混合物，用于复发缓解型多发性硬化症 (RRMS) 的免疫调节治疗。1虽然 GA 的一些作用机制仍未完全了解，但已显示它与主要组织相容性复合物分子结合并诱导 CD4+ 和 CD8+ T 细胞的细胞因子分泌模式在体内发生变化。1
注射部位反应和注射后即刻全身反应 (IPISR) 是 GA 引起的不良事件，在文献中最常见。2后者的特点是潮红、胸闷、心悸和气短，可能在注射后数分钟发生，但通常在 1 小时内自行消退。IPISR 可以采取单次发作或反复发作的形式。该反应的机制尚不清楚。2此外，随着 GA 在临床实践中的使用变得越来越普遍，发布了一些关于可能对这种药物产生 I 型超敏反应的报告。3-13在大多数情况下，皮肤点刺试验、皮内试验或嗜碱性粒细胞活化试验 (BAT) 阳性可诊断出对 GA 的速发型超敏反应并随后停止治疗。5、7、8、13、12
目前，对于如何进行过敏诊断测试以评估对 GA 的这些反应，还没有普遍接受的建议。皮肤点刺和皮内试验以 1:10000、1:1000、1:100 和有时 1:10 的稀释比例或使用未稀释的物质进行。3, 5, 7, 9, 11-13但是，该程序在刺激或假阳性反应方面未经验证或标准化。
在本文中，我们报告了一例 38 岁男性，由于主诉间歇性全身性瘙痒性皮肤病变而在我们的变态反应科诊所接受检查。2009 年被诊断为 RRMS，他每天服用 20 毫克 GA（从 2015 年开始改为每周 3 次 20 毫克）。从免疫调节治疗开始，他经常在注射部位出现发痒的红斑皮肤反应，并且不时出现孤立的皮肤病变，在患者拍摄的照片中可以清楚地识别为荨麻疹。从 2016 年开始，无论 GA 注射的时间如何，几乎每天都可以观察到荨麻疹。此外，嘴唇、舌头和生殖器区域的血管性水肿发生了两次。由于皮肤反应被描述为 GA 可能的副作用，因此停止治疗。尽管停止了 GA，但症状仍然没有减弱。患者在症状出现后大约 18 个月（和停用 GA 后 2 个月）就诊于我们的过敏科。患者否认任何已知的过敏反应。除了 RRMS 之外，他的甲状腺功能减退症病史非常显着，目前正在接受治疗l -甲状腺素 75 µg 每天一次。
在获得患者的知情同意后，我们用未稀释的 GA 进行了皮肤点刺试验，结果为阴性。然后我们继续执行当前可用文献中推荐的下一个诊断步骤：皮内试验，在 1:100 稀释时呈阳性。为了排除假阳性反应，对之前未接触过 GA 的两名健康志愿者（SR 和 GB）进行了相同浓度的 GA 皮内测试。两名受试者在1:100稀释时也表现出阳性反应。为了完成过敏学检查，进行了 GA 的 CD63 BAT。在 1:100 的稀释度下，患者的嗜碱性粒细胞显着活化。为了排除非特异性嗜碱性粒细胞脱颗粒，在另外五名志愿者中进行了 CD63 BAT，包括之前在皮内试验中获得阳性结果的两个人。所有这些人在 1:100 稀释的 GA 中的 CD63 BAT 检测呈阳性，与患者相同。同时，皮肤点刺试验、皮内试验和含有甘露醇的 CD63 BAT 是 GA 注射液的成分，在患者和两个对照中均为阴性。
为了识别其他类似病例，使用以下搜索字符串通过 PubMed 和 Google Scholar 搜索 Medline：“醋酸格拉替雷”和“过敏”或“超敏反应”或“致敏”或“荨麻疹”。搜索仅限于截至 2020 年 2 月以英语、德语和法语出版的科学文献；全文被系统地检索。对文章的参考书目进行了筛选，以确定可能纳入的进一步研究。
我们确定了 47 篇科学出版物。总共有 36 篇出版物被排除在外，因为它们被认为是不相关的。纳入的 11 篇出版物报告了 44 例可能的即刻超敏反应（表 1）。在大多数情况下，皮内试验的阳性反应发生在 1:100 的稀释度，类似于我们的案例，或在 1:10。3, 7, 9, 11-13在 12 例中，这些结果是诊断 I 型超敏反应的基础。7, 9, 11-13只有一些作者测试了健康志愿者3, 5, 7, 9, 11, 13或在受影响的患者中进行了药物激发测试。3, 9在 Amsler 等人的研究中，3在一系列皮肤反应呈阳性后，进行了药物激发试验，其中 18 名受试者中有 16 名对 GA 耐受良好。我们还向我们的患者推荐了药物激发试验，但他拒绝了。我们的假设是，患者患有最初被误认为是药物过敏的慢性自发性荨麻疹。Amsler 等人报告了类似的条件星座。318 名患者中有 5 名。按照国家慢性自发性荨麻疹治疗指南的建议，我们的患者接受了四倍剂量的非索非那定 180 mg 口服治疗。对治疗有中等反应。症状在发病后约 26 个月（和停止 GA 治疗后 10 个月）停止。当时，患者正在神经科门诊接受随访，不需要治疗多发性硬化症。
| 文献/参考 | 患者人数 | 临床症状 | 注射后症状出现的时间 | 需要紧急治疗 | 皮肤点刺试验 (SPT)、稀释和结果 | 皮内试验 (IDT)、稀释和结果 | 体外诊断 | 控制人 | 结果/药物激发试验 (DPT) |
|---|---|---|---|---|---|---|---|---|---|
| Amsler E 等人，2017 (3) | 18 | 10/18：仅荨麻疹；3/8：面部红斑水肿，头晕；4/8：胸闷；3/8：热感；2/8：腹痛；2/8：心动过速或心悸；3/8 瘙痒或皮疹 | 8/18：立即到几分钟；1/18：30 分钟；5/18：1到几个小时；4/18：未知 | 14/18：无；2/18：急诊，不治疗；2/18：紧急咨询，皮质类固醇加/不加抗组胺药 | 16/18：阴性，未稀释 GA；2/18：未执行 | 1/18：未稀释 GA 阳性；2/18：阳性和 1/18：在 1:10 稀释时无定论；7/18：阳性和 1/18：在 1:100 稀释时无定论；4/18：1:1000 稀释阳性；1/18：1:10,000 稀释阳性；1/18：所有测试稀释度均为阴性 | 不执行 | 两个对照（从未接受过 GA）的 IDT 呈阳性（稀释 1:100 或 1:10） | 16/18：耐受 DPT 无反应；1/18：IPISR 再次发生；1/18：未执行 |
| Syrigou E 等人，2015 (4) | 1 | 注射部位红肿，继而出现全身性荨麻疹 | 未知 | 左西替利嗪 5 mg × 4/24 h 和皮质类固醇治疗（甲基强的松龙 60 mg/24 h） | 对未稀释 GA 的临界反应 | 1:10,000 稀释阳性 | 不执行 | 不执行 | 成功的脱敏和继续药物 |
| Corominas M 等人，2014 (5) | 3 | 患者1和2：全身性荨麻疹、恶心和低血压；患者 3：面部血管性水肿 | 患者 1 和 2：首次给予 GA 时（未指定注射后的确切时间）；患者 3：注射后 20 分钟 | 未报道 | 3/3 患者用未稀释的 GA 检测呈阳性 | 不执行 | 使用 Thermo Fisher Scientific 的 ImmunoCAP 技术在患者和对照的血清中测定了对 GA 的特异性 IgE；3/3 患者对 GA 的 sIgE 升高 | 10/10 对照受试者在使用未稀释 GA 的 SPT 中检测为阴性；6 名接受 GA 治疗的 MS 患者和 10 名健康对照者对 GA 的 sIgE 为阴性 | 未指定，可能停药 |
| 克雷斯塔尼 E 等人，2014 (6) | 1 | 严重气短、头晕、颤抖、心动过速、潮红、口周紫绀和短暂的意识丧失 | 注射后立即 | 到急救人员赶到时，症状已消退，无需治疗 | 未稀释 GA 为阴性 | 1:100,000 稀释阳性 | 不执行 | 1/1 稀释为 1:100000 时为阴性 | 成功的脱敏和继续药物 |
| 索里亚诺·戈米斯 V 等人，2012 (7) | 3 | 患者1：全身瘙痒、皮肤发红、面部血管性水肿、呼吸困难、几乎失去知觉；患者2：面部血管性水肿、呼吸困难、腹部绞痛、呕吐；患者3：全身瘙痒 | 注射后立即或几分钟 | 所有患者均接受肾上腺素、右旋氯苯那敏和甲泼尼龙 | 患者 1 的 SPT 检测呈阳性（未指定稀释） | 在 1:100 稀释时，所有三名患者均呈阳性 | 使用 ELISA 确定了对 GA 的特异性 IgE，与 10 名对照相比，患者 1 和 2 的水平升高；患者 2 和 3 分别在 1:100 和 1:400 的 BAT 检测呈阳性 | 3/3 对照者的 IDT 结果为阴性（未指定稀释度）；1/10 对照的 sIgE 升高至 GA；1/6 对照在 1:20 稀释时具有阳性 BAT 结果 | 未指定，可能停药 |
| Baumgartner A 等人，2011 (8) | 6 | 患者1：全身瘙痒性病变；患者2：全身皮肤病变、低血压、呼吸困难；患者3：全身红斑、呼吸困难、恶心、直立性失调、异常疲劳；患者4：恶心、面部水肿、感觉异常、支气管痉挛；患者5：头皮瘙痒、恶心、呕吐、严重低血压；患者6：热感、面部水肿、全身皮肤病变和支气管痉挛 | 注射后立即至短时间内 | 患者 1、2 和 3：无；患者 4：使用类固醇；患者5：给予二甲亚胺、地塞米松、西咪替丁和肾上腺素；患者 6：注射类固醇和氯马斯汀 | 不执行 | 不执行 | 不执行 | 不执行 | 在所有患者中停药 |
| Sánchez-López J 等人，2010 (9) | 3 | 患者 1：注射部位和心动过速愈合；患者 2：注射部位愈合；患者 3：注射部位肿胀、全身瘙痒和皮肤病 | 注射后立即或几分钟 | 没有任何 | 从 1:10,000 到未稀释：所有患者均为阴性 | 从 1:10,000 到 1:100：患者 1 在 1:10,000 呈阳性；1:1000 时患者 2 呈阳性；1:100 患者 3 阳性 | 使用ELISA检测患者和对照的血清以检测GA的特异性IgE；与其他受试者相比，患者 1 的水平升高 | 5 名从未接受过该药物的健康受试者和 5 名耐受 GA 的 RRMS 患者：所有对照的 SPT 均为阴性；IDT 稀释度≤1:100 在所有对照中呈阳性 | 2、3号患者对DPT耐受良好，继续GA治疗；DPT 被认为对患者 1 太危险，因此停用 GA |
| Sheth SS 等人，2010 (10) | 1 | 局部荨麻疹、鼻塞、心悸、弥漫性潮红和声音嘶哑 | 注射后几分钟 | 未报道 | 未稀释：阳性 | 不执行 | 不执行 | SPT 中 1/1 阴性，未稀释 GA | 成功的脱敏和继续药物 |
| 贝恩斯 SN 等人，2010 (11) | 6 | 患者1、2：全身性荨麻疹，无其他症状；患者3：面部肿胀、心悸、喉咙紧缩、气短；患者4：胸闷、呼吸困难、面部潮红、头痛、皮损瘙痒；患者5：注射部位出现局部荨麻疹和肿胀；患者6：局部注射部位红斑、肿胀和压痛 | 患者 1：第一次注射后 5 小时；患者 2：注射后 30 分钟；患者3：注射后立即；患者 4：注射后几分钟；患者 5：注射后数小时；患者 6：未知 | 患者 1、3、5 和 6：无；患者 2：紧急咨询，给予肾上腺素、苯海拉明和雾化支气管扩张剂；患者4：口服苯海拉明 | 患者 1：由于皮肤病学未进行皮肤测试 | 患者 1：由于皮肤描记未进行皮肤测试；3/5 患者在 IDT 中呈阳性，稀释度为 1:10，2/5 患者在 IDT 中呈阳性，稀释度为 1:100 | 不执行 | 1/9：未稀释GA的SPT阳性，稀释1:10的IDT阳性8/8，稀释1:100的IDT阳性6/8；1:1000 稀释的 IDT 中 4/5 阳性，1:10,000 稀释的 IDT 中 2/5 阳性 | 成功的脱敏和继续药物 |
| Rauschka H 等人，2005 (12) | 1 | 全身潮红、瘙痒性荨麻疹、呼吸困难、腹部绞痛、呕吐和循环衰竭，意识不清数分钟 | 注射后2分钟 | 静脉注射 (iv) 肾上腺素和抗组胺药 | 未稀释 GA 阳性 | 1:100 稀释阳性 | 血清中发现特异性 IgE（未指定实验室方法） | 不执行 | 停药 |
| Bayerl C 等人，2000 (13) | 1 | 恶心、热感、全身红斑和肿胀、循环衰竭、胃痉挛和腹泻 | 注射后立即 | 没有任何 | 1:10 和未稀释：阴性 | 1:10 和未稀释：24 小时后均为阳性 | 不执行 | 5/5 对照者在体内试验中呈阴性（未指定试验） | 未指定，可能停药 |
- 缩写：GA，醋酸格拉替雷；IgE，免疫球蛋白 E；IPISR，即刻注射后全身反应；MS，多发性硬化症；RRMS，复发缓解型多发性硬化症；sIgE，特异性免疫球蛋白E。
目前，仍然没有市售的试剂盒用于测量针对 GA 的特异性免疫球蛋白 E (sIgE) 抗体。这些免疫球蛋白 E (IgE) 抗体的存在只能在专业实验室中检测到，因此不是常规可用的标准化诊断工具。BAT 可能在更多的研究机构中可用，因为它广泛用于过敏测试。广泛使用的诊断工具是体内试验：皮肤点刺试验和皮内试验。在 Amsler 等人的报告中，3在皮内试验中 GA 检测呈阳性的 14 人中有 13 人在药物激发试验中对该物质耐受良好。因此，假阳性体内试验结果可能并不少见。此外，在我们的案例中，之前没有接触过 GA 的健康志愿者在体内测试和体外测试中均呈阳性。其他作者也报道了类似的发现。11、13该病例强调，尽管过敏测试结果呈阳性，但由 GA 引起的上述症状可能具有除 IgE 介导的超敏反应之外的潜在机制。此外，不会根据皮肤点刺试验或皮内试验的阳性结果自动停药，因为它们可能由于非过敏性组胺释放而呈假阳性，这也可以解释 IPISR。在有问题的情况下，药物激发试验似乎是目前广泛使用的诊断工具中最可靠的。
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