青岛市胸科医院-外阴白癜风-专家在线问诊-京东健康互联网医院

简介:

青岛市胸科医院是青岛市结核病归口定点治疗医院，同时承担着青岛市非典、禽流感、甲型H1N1流感等突发公共卫生事件定点收治任务。医院位于青岛市重庆中路896号，占地2万平方米，建筑面积1.4万平方米，编制人员368人，开放病床320张,拥有中高级专业技术人员120余人。青岛胸科医院是青岛地区结核病治疗的定点医院，技术力量雄厚，经多年临床实践总结出一整套治疗各种结核病及难治、复治、耐药结核病正规方案。近年来医院坚持“以优质服务求生存，以专科特色求发展”的战略方针，对胸内科进行了心血管、内分泌、消化、肾内科、鉴别诊断专业二级分科，成立了结核病临床实验室，设置了特色专科资助基金，逐步形成了集内科治疗、外科治疗、介入治疗、中西医结合治疗、康复、科研为一体的结核病诊疗体系。2003年医院被青岛市政府指定为青岛市“非典”定点收治单位，为青岛市“非典”防治工作出了应有贡献，医院党委先后被授予全国、山东省、青岛市“非典”防治工作先进基层党组织。2004年被指定为人禽流感突发公共卫生定点收治单位。医院先后被授予2008年奥帆赛、残奥帆赛突出贡献单位、山东省卫生系统先进集体、青岛市先进基层党组织、青岛市文明单位、青岛市卫生系统文明单位标兵、青岛市卫生系统廉洁勤政先进集体、青岛市卫生系统目标绩效考核优秀单位等荣誉称号。2004年8月，青岛市政府出台优惠政策，对青岛市辖区（七区五市）和驻青高校在校学生及外地来青暂住人员中的结核病人到市胸科医院就诊，住院病人其住院总费用减免30%，门诊病人检查费用减免20%。为满足周边居民就医需求，医院已开设综合业务科室安排专家坐诊。同时，针对周围厂矿企业众多，居民密集，是道路交通事故及意外伤害事故的高发路段的特点，组建了创伤急救中心。为适应青岛市经济和社会发展需要，进一步完善青岛市突发公共卫生事件应急救治能力建设，青岛市委、市政府决定对青岛市胸科医院进行整体迁建。规划新院占地约450亩，编制床位2000张。届时，医院将建设成为集传染病救治、科研、教育、应急工作于一体的青岛市公共卫生医疗救治中心。外阴长白癜风是生活上常见的一种皮肤病,发病后无痛无痒,发病症状主要以皮肤白斑为主，不确定，女性生殖器官，科学治疗,加强白癜风护理,保持乐观的心态,树立正确的治疗观,科学饮食,小心忌口,辅助治疗。，无，不建议吃辛辣刺激的东西,如辣椒、泡椒等,也不要吃寒凉的食物，阴道镜,活检及组织病理学检查，。

true 李琴珂主治医师

二级甲等青岛市胸科医院

好评率：99% 接诊量：7.6万平均响应：-

擅长:止咳，止咳化痰，化痰，嗓子哑，清火，咽喉肿痛，儿童鼻塞，退烧，肺炎，支气管炎，感冒，上呼吸道感染，慢性阻塞性肺病，肺结核，胸膜炎，气胸，哮喘，呼吸衰竭，肺结节等呼吸道疾病艾滋病阻断，乙肝，睡眠障碍，失眠

false 邹悦副主任医师

二级甲等青岛市胸科医院

好评率：98% 接诊量：61 平均响应：-

结核病，肺结核，结核性胸膜炎，淋巴结核等结核性疾病。

false 付伟住院医师

二级甲等青岛市胸科医院

好评率：100% 接诊量：5 平均响应：-

待补充

true 王宝千主治医师

二级甲等青岛市胸科医院

好评率：100% 接诊量：3912 平均响应：-

高血压，冠心病，高脂血症，心肌缺血，动脉硬化，感冒，支气管炎，肺炎，肺结核，慢性阻塞性肺疾病，肺气肿，艾滋病阻断，艾滋病诊断，乙肝诊断

接诊医生：

2024-11-01 00:23:56

科普文章

白癜风治疗最新进展

北京医院皮肤科葛蒙梁

白癜风(vitiligo) 是一种获得性、特发性色素脱失性疾病，病程慢性。全球发病率0.5%~2%[1]。病因不明，其发病与遗传性和非遗传性多因素有关。白癜风的发病主要有如下假说：①遗传因素，双胞胎和家系的研究表明遗传因素在白癜风发病中起重要作用，但不同人种具有显著的遗传异质性。研究发现了与白癜风相关的许多候选基因，并已确定在染色体17p的一个白癜风易感基因NALP1[2]。②黑素细胞自身免疫损伤学说，白癜风病人血清中有抗黑素抗体或同时患甲状腺疾病等自身免疫性疾病。③黑素细胞内在结构和功能缺陷学说。④自由基学说，体内自由基产生过多或自由基清除系统受损，导致黑素细胞代谢障碍。⑤神经化学物质损伤黑素细胞学说，如自主神经的某些产物（乙酰胆碱、正肾上腺素、肾上腺素、褪黑素）干扰酪氨酸酶的活性。⑥黑素细胞生长因子缺乏学说，研究发现，角质形成细胞能分泌多种细胞因子，如碱性成纤维细胞生长因子、神经生长因子等，它们对黑素细胞生长起重要作用。另外劳累和精神创伤与白癜风发病或加重关系密切。

【诊断要点】

一、临床特点：白癜风是皮肤或黏膜突然出现的色素脱失斑点或斑片。斑片大小不等，形态不一，数目不定。皮损颜色通常为牛奶白或粉笔白，但无萎缩或脱屑。一般无自觉症状，少数人皮损出现前有局部痒感或皮肤发红，逐渐出现白斑。白斑可发生于皮肤任何部位，可沿神经单侧或对称分布。好发于面、手背、肘、膝、乳头、腋下、骶尾部、腹股沟和生殖器等易受摩擦部位。病变部位毛发色泽正常或变白。白斑境界清楚，其周围皮肤可有色素增加现象。但初发皮损可为轻度色素减退斑，边界模糊。

2011年国际色素细胞大会白癜风欧洲学组专家会议达成共识，将白癜风临床分为节段型、非节段型和未定类型[3]。节段型白癜风多发生于儿童，皮损发展迅速，并较早累及毛囊毛发，以后病情大多稳定不再发展，一般不伴发自身免疫疾病。非节段型白癜风多数在成人期发病，病情缓慢进展，累及毛囊毛发较晚，且常伴发自身免疫性疾病。非节段型白癜风又分为肢端型、黏膜型、散发型、泛发型、混合型和少见变异型。要正确判断白癜风进展期、消退期和稳定期来选择治疗方案，但文献对稳定期的定义从3个月至2年不等。进展期白癜风患者外伤后容易发生同形反应，不适合做外科手术治疗。

不典型白癜风诊断需Wood灯检查，白癜风皮损在暗室中用Wood灯照射呈瓷白色，而其它炎症后暂时性色素脱失斑因有一些黑素，能吸收光线，因此不像白癜风那样白，而可与这类白斑鉴别。白癜风患者脉络膜和视网膜的色素上皮内常有散在的色素脱失区。

二、实验室检查：白癜风诊断一般很少做化验检查，但有些检查可了解患者是否有自身免疫性疾病。可检查抗核抗体（ANA）、全血细胞检查、血糖、促甲状腺素(TSH)和甲状腺自身抗体。

【治疗】

白癜风是一种难治性皮肤病，虽然目前的治疗方法很多，但治疗效果因人而异，很难令人满意。一般来说初发或病程较短者、皮损位于头面部者、年龄小者治疗效果要好些。要根据不同类型、部位、病情是否稳定及对治疗的反应确定治疗方案，让患者充分了解该病知识，树立治疗信心，坚持长期治疗才能获得较好疗效。

一、白癜风治疗方案的选择[4]：

（一）、节段型白癜风或局限性非节段型（<2-3%体表面积）

一线治疗：避免诱因，局部外用糖皮质激素或钙调神经酶抑制剂

二线治疗：窄波UVB治疗，308准分子激光最好。也可联合局部外用糖皮质激素或钙调神经酶抑制剂。

三线治疗：如果面部等部位的白癜风经上述治疗复色不理想，可考虑外科手术。

（二）、大于体表面积3%的非节段型白癜风

一线治疗：窄波UVB治疗3个月，如果有效，继续治疗9个月。

还可加用局部外用糖皮质激素或钙调神经酶抑制剂治疗。

二线治疗：如果N-UVB治疗无效，可系统应用糖皮质激素。

三线治疗：如经上述治疗1年无效，且病情稳定，可考虑外科手段治疗，

四线治疗：如果皮损面积>50%，或面手部皮损较多，经上述治疗无效者，可考虑脱色治疗。

二、白癜风治疗方法

（一）、局部药物治疗

1. 糖皮质激素对小面积的局限型白癜风，外用糖皮质激素有效。外用糖皮质激素制剂有溶液、软膏、霜剂等，如0.05%卤美松乳膏，每日2次，对非节段型白癜风皮损有较好疗效。长期应用可出现毛细血管扩张、色素沉着和皮肤萎缩等副作用。可与其他类外用药物轮流使用，减少副作用的发生。如果外用糖皮质激素2个月没有明显效果，要停用或换用其他治疗。

2. 钙调磷酸酶抑制剂面部和外阴白癜风避免较长时间外用糖皮质激素，可以用他克莫司（0.1%、0.03%）或吡美莫司软膏（1%）局部外用，每天2次，疗效较好，且没有糖皮质激素外用的副作用。局部可出现短暂烧灼感。

3. 维生素D衍生物卡泊三醇软膏外用有效，每天2次，2-4个月。

4. 氮芥酒精盐酸氮芥50mg溶于95%酒精100ml中，每日2次外涂，药物进入人体形成乙烯亚胺基，与巯基起作用，激活酪氨酸酶，加速黑素合成。副作用有局部刺激或因用药范围过大致白斑周围正常皮肤色素加深。

（二）、紫外线治疗：

1．光化学疗法（补骨脂素加长波紫外线，PUVA）常用的光敏剂补骨脂素是8甲氧补骨脂素（8-MOP）。8-MOP不能直接产生黑素，而是加强紫外线的作用，一方面使还原黑素氧化为黑素并促其扩散，另一方面皮肤产生炎症，破坏皮肤中的疏基化合物，激活酪氨酸酶活性，催化黑素的形成。因其副作用大现基本被窄波UVB替代。

2. 窄谱UVB（NB-UVB） NB-UVB是能量主要分布在311nm的中波紫外线，可以在不依赖光敏剂的情况下产生光化学反应，从而发挥治疗作用。并且NB-UVB减少了宽谱UVB中容易产生红斑效应的小于300nm的波长成分，因而可以应用较大的治疗剂量而不产生红斑反应。首次照射剂量使用0.6J/cm2，后续治疗根据皮疹反应递增，每次增加10%或20%。在白斑部位出现轻微红斑反应后，维持剂量不变，每周2-3次，坚持2-3个月，如局部出现点状色素再生，需要继续坚持至6个月的疗程，多数患者均有不同程度的色素再生。患者对于治疗的耐受性良好。主要的不良反应为治疗后皮肤干燥，轻度瘙痒感，可以通过外用润肤剂改善。

3． 308准分子激光准分子激光使用308nm单一波长，将高剂量的光能直接照射到白癜风皮损上，较NB-UVB疗效好，副作用少，是目前市场上治疗白癜风疗效最好的光疗仪器[5]。且36×14 cm2的治疗头特别适合治疗各种特殊部位的白癜风。局限性白癜风皮损每周治疗2次，平均约24-48次。部分病人在治疗1-2周就可以出现明显复色。

（三）、系统应用糖皮质激素适用于进展期及泛发型白癜风，尤其是伴发自身免疫性疾病的患者。小剂量治疗，安全有效。泼尼松每日15mg，连服2个月。见效后每2-4周递减5mg，直至隔日服5-10mg，维持3-6个月。有效率可达74%-90%。应用时要注意禁忌症及可能出现的副作用。

（四）、手术治疗适用于面积小、非瘢痕体质、药物治疗效果不理想的稳定期白癜风。

1.黑素细胞自体移植：选择色素正常的非暴露部位皮肤作供皮区，白癜风部位及供皮区均采用负压（300-500mmHg）抽吸2-3小时产生水疱，将受区疱顶弃去，再将供皮区疱顶移植于白癜风受区创面上，敷料包扎固定，7天后移植片成活，半个月至1个月色素恢复。此法简单易行，无痛苦，亦不会形成疤痕，色素不易消退。

2.自体小片植皮：用1-1.5mm钻孔器打孔，孔间距约5mm，使其自然止血，将供区小片游离皮片植于孔内，加压包扎15天成活，恢复色素，并向周围产生色素。

3.自体或同种异体黑素细胞培养移植：取患者或同种异体正常皮肤，分离黑素细胞在培养基中进行人工培养，细胞达到一定浓度，将黑素细胞混悬液注入到用负压法产生的水疱中。水疱吸收后，移植区逐渐恢复色素。

4.毛囊移植: 适用于眉毛、睫毛小面积白癜风。取一小条带有毛发的枕部区头皮,以单个毛囊分离,利用毛发移植器,间隔5-10mm，对皮损进行毛发毛囊移植，色素自毛囊处恢复，扩展融合而逐渐复色。

5.单纯皮肤磨削术适合于面积小的白斑，一般1-2cm2的稳定期皮损。磨削机或砂纸擦破皮损至轻微出血，然后每天用5%氟尿嘧啶涂布后用聚乙烯封包，7-10天后改用5%磺胺吡啶钠聚乙烯二醇，每日一次，至上皮形成，1个月内色素沉着出现。

6.文身使用一种非变应原性的三氧化二铁色素对皮损区进行纹身，形成永久的微色素形成。

7.外科手术切除直接切除皮损后缝合或应用局部皮瓣转移。适用于面积较小、晕痣、特别是毛发区域、经规范用药无效而白斑稳定的患者。

（五）遮盖剂（化妆）安全方便，但停药数天就开始褪色，故每2-4天需重复应用。

1. 5%二羟基丙酮重复外用，直至形成正常皮肤相似的色素。停药2-3天开始褪色，2周后色素完全消退。

2. 青核桃提取液重复外用，可形成正常皮肤相似的色素。停药2-3天开始退色，部分患者皮损中出现正常色素岛，并逐渐扩大，可恢复色素。

3. 高锰酸钾液：2.4mg高锰酸钾溶于250ml水中，涂于患处，干燥后形成暂时性着色。

4. 化妆品商店的各种肤色的遮盖霜局部外涂，可以遮盖白斑，起到较好的美容效果。

（六）脱色剂对于皮损面积大于50%，对现有疗法无效者，或暴露部位皮损面积远多于正常肤色的患者，可采用10%～20%氢醌进行脱色治疗，将残留的色素区色素脱失以达到美容的目的。

白癜风是一个慢性病，维持一段时间的治疗非常重要，有研究表明，维持治疗5年以上，患者复发的可能性明显减少。在积极配合医生治疗的同时，要做到充足睡眠，心情舒畅，均衡饮食，适当运动。要记得多晒太阳，但不要暴晒。

白癜风出现瘙痒怎么回事？

白癜风出现瘙痒症状是怎么回事？

白癜风是一种由于黑色素缺失所引起的皮肤病，一般情况下不痛不痒。然而，任何事都不是绝对的。比如在临床上我们就发现，有少数患者在白斑出现前会有局部痒感症状，当白斑出现后痒感就会消失。

白斑处瘙痒症状的出现，很可能是由于外界的一些不良刺激所导致的，比如阳光暴晒、皮肤过敏、病菌感染或者用药不当等因素所引起。还有一种可能就是，白斑正处于快速发展期，因为研究发现，有些患者在发展期会伴随皮肤瘙痒症状。因此，要想缓解这种瘙痒症状，就需要弄清楚发痒的原因，然后针对性地进行护理。

白斑处出现瘙痒怎么办？

白斑处出现瘙痒症状，千万不要老是挠抓，也不要随便抹药，一定要及时找正规的皮肤病专科专业医生咨询。深圳肤康皮肤病专科门诊部张庆果医师温馨提示，以下几点需要注意：

切莫经常抓挠

当患处皮肤出现瘙痒的情况时，建议患者不要用力用手抓挠，以免把患处皮肤抓破，进而引起白斑处皮损的感染，或者发生同行反应，使得皮肤组织的免疫力下降，从而使白癜风的病情更加严重。

要慎用外用药

很多白癜风患者往往会使用外涂药，如果外用药物涂抹太多，一旦经紫外线照射，很容易对皮肤造成一些不利刺激，或引起一些过敏性不良反应。另外，白斑处出现瘙痒后，也别胡乱使用一些止痒膏，一定要在医师的指导下使用。

少用化妆品

对于习惯化妆的面部患者来说，如果皮损部位出现瘙痒症状，建议还是少接触各种各样的护肤品为好，以免引起皮肤过敏，导致白斑蔓延。因为很多化妆品里含有铅、汞、砷等重金属成分，可能会堵塞毛孔，影响皮肤的呼吸。

平时要加强护理

患者在日常生活中也要勤讲卫生，在使用一些化学物品时也要有所注意，比如在使用洗衣粉、肥皂等洗涤用品时，要避免让这些物质接触到皮损部位和瘙痒部位，以免带来一些不良的刺激。

医生眼中看男性隐私部位（外生殖器）的白斑(白癜风)

一旦身上出现白斑，往往会引起惊慌，担心患了白癜风；其实白斑≠白癜风。患者对于“白”的畏惧是可想而知的，发生在不同部位的白斑对患者带来的影响也是不一样的，一般来说发生在头面部、颈部、双手部等暴露部位的白癜风可能对患者的影响更大，因为这些部位是要直接见人的，这些部位的白斑的治疗往往需要比较快速而激进的治疗方法，而其他部位的白斑你可以通过衣物去遮盖，但对于比较隐私部位或者私密部位的白斑呢？患者一般是怎样一种态度，而大夫往往推荐怎样的治疗方案呢？在这里我们将进行尽可能详尽的分解。

首先我们谈谈男性私密部位白斑给患者带来哪些影响？

男性私密部位一般来说是指阴囊、阴茎及肛周在内的肚脐以下穿三脚裤的区域。该部位的白斑虽然说可以通过内衣内裤遮盖，但也存在其他问题。对于未婚男女的话，可能会担心自己因为该部位的白斑而被将来的另一半所嫌弃而产生自卑的心理，对于已婚男女的话，可能这方面的影响会稍微小一点，但或多或少也会有一定的影响，因此针对男性私密部位发生的白斑，患者迫切治疗的愿望依然是相当强烈的。

白斑可以是先天性的，也可以是获得性的。也可以是其他疾病的表现。白斑一定是白癜风吗？还包括哪些病呢？

下面主要谈谈白癜风：

病理学上，白癜风主要影响表皮的黑素细胞，毛球内黑素细胞也有一定程度的受累，表现为表皮、粘膜内黑素细胞及黑素颗粒的减少或消失。

一.白癜风诊断标准为：①通常在儿童期或青春期发病，表现为大小和形状各异的脱色性白斑，周围颜色正常或有色素增加；②亦常见于外伤部位，白斑部位的毛发通常也变白；③排除其他白斑性皮肤病；④在wood灯下白斑区见亮白色荧光。Wood灯:皮损颜色呈灰白色，边界欠清，Wood灯下皮损面积大于目测面积，提示是进展期。皮损颜色是白色，边界清，wood灯下皮损面积≤目测面积，提示是稳定期。以上3条符合任何一条即可考虑病情进展。

二.治疗原则

（一）进展期自癜风

1.未定类型(原称局限型):可外用糖皮质激素(简称激素)或钙调神经磷酸酶抑制剂(他克莫司软膏、吡美莫司乳膏)等，也可外用低浓度的光敏药，如浓度＜0.1%的8-甲氧沙林(8-MOP)；维生素D3衍生物；局部光疗可选窄谱中波紫外线(NB-UVB)、308 nm准分子激光及准分子光。对于快速进展期，可系统用激素。

2.非节段型与混合型:VIDA积分＞3分考虑系统用激素，中医中药、NB-UVB、308 nm准分子光及准分子激光。快速进展期采用光疗可联合系统用激素或抗氧化剂，避免光疗引起的氧化应激而导致皮损扩大。局部外用药治疗参考进展期未定类型。

3.节段型:参考进展期未定类型治疗。

（二）稳定期白癜风

1.未定类型(原称局限型):外用光敏剂(如呋喃香豆素类药物8-MOP等)、激素、氮芥、钙调神经磷酸酶抑制剂、维生素D3衍生物等；自体表皮移植及黑素细胞移植；局部光疗参考进展期未定类型。

2.非节段型与混合型:光疗(如NB-UVB，308 nm准分子光及准分子激光等)、中医中药、自体表皮移植或黑素细胞移植(暴露部位或患者要求的部位)。局部外用药参考稳定期未定类型。

3.节段型:自体表皮移植或黑素细胞移植(稳定6个月以上)，包括自体表皮片移植，微小皮片移植，刃厚皮片移植，自体非培养表皮细胞悬液移植，自体培养黑素细胞移植等。参考稳定期未定类型治疗。

三.治疗细则

(一)激素治疗

1.局部外用激素:适用于白斑累及面积＜2%～3%体表面积的进展期皮损。超强效或强效激素，可连续外用1～3个月或在皮肤科医师的指导下使用，或予强弱效或弱中效激素交替治疗。成人推荐外用强效激素。如果连续外用激素治疗3～4个月无复色，则表明激素疗效差，需更换其他治疗方法。

2.系统用激素:适用于VIDA＞3分的白癜风患者。口服或肌内注射激素可以使进展期白癜风尽快趋于稳定。成人进展期白癜风，可小剂量口服泼尼松0.3mg·kg-l·d-l，连服1～3个月，无效中止。见效后每2～4周递减5 mg，至隔日5 mg，维持3～6个月。或复方倍他米松针l ml，肌内注射，每20～30 d 1次，可用1～4次或由医生酌情使用。

(二)光疗

1.局部光疗:NB-UVB每周治疗2～3次，根据不同部位选取不同的初始治疗剂量，或者在治疗前测定最小红斑量(MED)，起始剂量为最小红斑量的70%。下次照射剂量视前次照射后出现红斑反应情况而定：如未出现红斑或红斑持续时间＜24 h，治疗剂量增加10%～20%，直至单次照射剂量达到3.0J/cm2(Ⅲ型、Ⅳ型皮肤)。如果红斑超过72 h或出现水疱，治疗时间应推后至症状消失，下次治疗剂量减少10%～20%。如果红斑持续24～72 h，应维持原剂量治疗。308 nm单频准分子光、308 nm准分子激光：每周治疗2～3次，治疗起始剂量及下一次治疗剂量参考NB-UVB。

2.全身NB－UVB治疗:适用于皮损散发或泛发的非节段型或混合型白癜风。每周治疗2～3次，初始剂量及下次治疗剂量调整与局部NB-UVB相同。光疗治疗次数、频率、红斑量和累积剂量并非越多越好，累积剂量大易形成皮肤干燥、瘙痒、光老化等不良反应大。治疗次数、频率、红斑量和累积剂量与光耐受(平台期)的出现有关。①如出现平台期(连续照射20～30次后，无色素恢复)应停止治疗，休息3～6个月，起始剂量以最小红斑量开始；②在治疗3个月无效应停止治疗；③只要有持续复色，光疗可继续；④不建议进行维持性光疗；⑤快速进展期，联合系统用激素治疗，可避免光疗诱发的同形反应，起始剂量＜70％的最小红斑量。病程短、非节段型疗效优于病程长、节段型；面颈、躯干疗效优于肢端。

3.光疗的联合治疗:光疗联合疗法疗效优于单一疗法。联合治疗主要有：光疗+激素口服或外用；光疗+钙调神经磷酸酶抑制剂外用；光疗+口服中药制剂；光疗+维生素D3衍生物外用；光疗+光敏剂外用；光疗+移植治疗；光疗+口服抗氧化剂；光疗+点阵激光治疗；光疗+皮肤磨削术等。

4.局部光化学疗法及口服光化学疗法:由于其疗效并不优于NB-UVB，不良反应多，已被NB-UVB取代。

(三)移植治疗

适用于稳定期白癜风患者(稳定6个月以上)，尤其适用于稳定期的未定类型和节段型白癜风患者，其他型别白癜风的暴露部位皮损也可以采用。选择移植方法需考虑白斑的部位和面积，进展期白癜风及瘢痕体质患者为移植禁忌证。常用的移植方法包括：自体表皮片移植、微小皮片移植、刃厚皮片移植、自体非培养表皮细胞悬液移植、自体培养黑素细胞移植、单株毛囊移植等。移植治疗与光疗联合治疗可提高疗效。

(四)钙调神经磷酸酶抑制剂

包括他克莫司软膏及吡美莫司乳膏。治疗时间连续应用3～6个月，间歇应用可更长，复色效果最好的部位是面部和颈部。特殊部位如眶周可首选应用，黏膜部位和生殖器部位也可使用，无激素引起的不良反应，但要注意可引起局部感染如毛囊炎，痤疮出现或加重等。

(五)维生素D3衍生物

外用卡泊三醇软膏及他卡西醇软膏可治疗白癜风，每日2次外涂。维生素D3衍生物可与NB-UVB、308 nm准分子激光等联合治疗。也可以与外用激素和钙调神经磷酸酶抑制剂联合治疗。局部外用卡泊三醇软膏或他卡西醇软膏可增强NB-UVB治疗白癜风的疗效。

(六)中医中药

分为进展期和稳定期2个阶段，形成与之相对应的4个主要证型(风湿郁热证、肝郁气滞证、肝肾不足证、瘀血阻络证)。进展期表现为风湿郁热证、肝郁气滞证，稳定期表现为肝肾不足证、瘀血阻络证。儿童常表现为脾胃虚弱。治疗进展期以驱邪为主，疏风清热利湿，疏肝解郁；稳定期以滋补肝肾、活血化瘀为主，根据部位选择相应中药。

(七)脱色治疗

主要适用于白斑累及面积＞95%的患者。已证实对复色治疗的各种方法抵抗，在患者要求下可接受皮肤脱色。脱色后需严格防晒，以避免日光损伤及复色。1．脱色剂治疗：20％氢醌单苯醚，每日2次外用，连用3～6周；也可用20%4-甲氧基苯酚乳膏(对苯二酚单甲醚)。开始用10%浓度的脱色剂，以后每1～2个月逐渐增加浓度。每天两次外用，先脱色曝光部位再脱色非曝光部位，1～3个月出现临床疗效。注意减少皮肤对脱色剂的吸收，身体涂药后2～3 h禁止接触他人皮肤。2．激光治疗：可选Q755 nm、Q694 nm、Q532 nm激光。

(八) 遮盖疗法

用于暴露部位皮损，用含染料的化妆品涂搽白斑，使颜色接近周围正常皮肤色泽。

(九) 儿童白癜风

局限性白斑：＜2岁的儿童，可外用中效激素治疗，间歇外用疗法较为安全；＞2岁的儿童，可外用中强效或强效激素。他克莫司软膏及吡美莫司乳膏可用于局限性儿童白癜风的治疗。快速进展期的儿童白癜风皮损可采用小剂量激素口服治疗，推荐口服泼尼松5～10 mg/d，连用2～3周。如有必要，可以在4～6周后再重复治疗一次。

(十) 辅助治疗

应避免诱发因素如外伤、暴晒和精神压力，特别是在进展期。治疗伴发疾病。心理咨询，解除顾虑、树立信心、坚持治疗。

(十一)外科治疗

不管是哪个部位的白癜风，当明确诊断之后，首先仍然是积极的皮肤内科治疗，就是大家通常理解的吃药和涂药，这个过程至少要持续半年的时间，尽可能的让白斑肤色，由于外阴部位的皮肤比较薄嫩，所以这个部位的用药跟其他部位又有明显的差别，不能太刺激，又不能太弱，所以需要把握好这个度。经过半年到1年的治疗之后，如果白斑完全肤色，那么你只需要定期专科复诊随访就可以了。基本上70%的患者通过药物及物理治疗无法达到满意的效果，你说通过这些内科的联合物理治疗的方法有效吗？有效的，但有效率非常低，有很大一部分人只能控制住不再继续发展，或者说原来的白斑面积有缩小，但缩小到一定的程度就“定死”在哪里了，接着吃药、涂药抹药根本没有效果，这是因为这个部位白斑下面的黑色细胞完全死了，死的很彻底，所以这时候你的任何内科治疗都是“无用功”，这时候我们往往需要用外科的方法来处理白癜风。阴囊部的白癜风经过药物治疗后白斑没法再好转时，如果面积小，可以将其直接切除。

五.白癜风患者最关心的几个问题

（一）白癜风会传染吗？

白癜风不会传染。白癜风是色素代谢障碍而发病，不是由病原体引起，无传染性。患者及其周围的人都应对此有所认识，不应歧视白癜风患者。在日常人际交往中，白癜风患者常有一种自卑感，不愿接触熟人，尤以暴露部位发病者更加严重。作为患者的家人、同事或朋友，要主动和患者交往，理解他们，帮助他们树立生活的信心、早日康复。患者则更应该理性看待疾病，消除自卑恐慌心理，正常生活和社交。

（二）白癜风会遗传吗？

父母亲患了白癜风，最担心会遗传给下一代。临床中观察发现白癜风有一定的遗传性，在同一个家族中会有多人患白癜风。进一步的研究提示白癜风可能是多基因遗传，伴有不同的外显率。这也就是说即使家族中有人患有白癜风，与患者有血缘关系的人不一定都会的白癜风，是否发病还受到环境、精神状况、工作种类、生活方式的影响。故白癜风虽有一定的遗传倾向，但并非所有患者子女都会患白癜风。

（三）得了白癜风需要做什么检查？

大部分白癜风通过皮肤科医生临床看诊就可以做出诊断，有些患者的白斑不典型，可以通过特殊的紫外线灯（伍德氏灯）检查来帮助明确诊断。此外，一些患者可能伴随其他的自身免疫相关疾病，医生会建议抽血进行相关检查。遇到诊断十分困难的，可能还需要在白斑部位取皮肤活检，在显微镜下进行病理检查辨认。

其他白斑还有

1.粘膜白斑：

男性生殖器白斑多见于包皮内侧、冠状沟、龟头部位，边界不清、形状不规则白斑。肛门粘膜白斑常伴瘙痒。与局部刺激、神经血管营养失调、代谢紊乱等局部因素以及感染、自身免疫、性激素、遗传、氧化与抗氧化等因素有关。该白斑黑素细胞数量正常，表面粗糙，有过度角化，触之韧硬感可区别于阴部白癜风。

2.硬化萎缩性苔藓:

硬化性萎缩性苔藓是一种慢性炎症性皮肤病。皮损大多是非对称性的呈粉红色、象牙白色，融合性的斑疹或斑片，边界清楚。后期斑片上出现羊皮纸样萎缩。此病病理改变有特异性，表现为淋巴细胞浸润，毛囊角栓，棘层萎缩，基底细胞液化变性，真皮浅层呈纯一化改变。

3.无色素性色素失禁症：

即伊藤色素减少症，为常染色体显性遗传，先天性神经皮肤病，50%以上的病例在出生时或婴幼儿期发病，常伴有智力发育障碍和癫痫。本病单侧（偶尔双侧）形态奇异的白斑，无自觉症状，或伴有其他系统疾病，且出生后不久发病，不伴有脉络膜黑素消失，可区别于白癜风和白化病。病理表现为基底细胞层内黑素颗粒减少，部分完全缺如。

4.炎症后色素减退：

很多炎症性皮肤病，如扁平苔藓的白色Wickham纹、红斑狼疮、银屑病、玫瑰糠疹、湿疹、神经性皮炎、烧伤后瘢痕、带状疱疹和药疹等炎症后，出现继发性黑素减退，多为暂时的，不需治疗，可自行恢复。

5.无色素痣（nevusdepigmententosus,ND）:

即脱色素痣，是一种少见、稳定、局限、先天性黑素减退性疾病，分为孤立型、节段型和系统型。临床诊断一直沿用Coupet提出的诊断标准：①白斑出生时或出生后不久发生；②白斑分布终生不变；③皮损部位无组织学改变和感觉变化；④白斑边缘无黑素沉着。在Wood灯下是黄白色，没有荧光。DP下白斑边界不清，无色素加深，个别呈锯齿状，有时可见白毛。

罹患双癌，依然有办法治疗！“海外二诊”为客户快速链接全球权威专家资源！

病症：胃癌恶性黑色素瘤

患者：李女士

年龄：70岁

罹患癌症，毫无疑问对每个人都是重大打击。而如果一位患者不幸同时罹患两种癌症，我们可以想象得出他的心情会是怎样的沉重。

但时至今日，癌症早已不再是什么“不治之症”，很多良好的治疗方法，可帮助患者迈过重重困境，预后得到极大提升。

不仅如此，在医疗全球化的今天，中国患者也能通过“海外二诊”服务，快速触达到国际权威专家资源，为自己的治疗保驾护航！

今天的案例主人公李女士，正是一位“海外二诊”的受益者。我们来一起看看她的故事。*为保护隐私，文中患者个人信息均已经脱敏处理。

70岁的李女士在去年年底，因脚底疼痛去医院看病，结果发现脚后跟有一个1厘米的黑色肿物。医生判断是冻疮，于是开了点外用药，李女士也就没有再放在心上。

大概4个月后，真正的噩梦降临：李女士通过影像检查，被诊断为胃癌，而且有了淋巴结转移。她还出现了多次呕血，病情非常危急。很快,医生为她实施了全胃切除。令人意想不到的是，几天后通过检查，医生发现李女士后脚跟的肿物竟然也是癌症——恶性黑色素瘤。于是大概2个月后，医生又切除了她的足底肿瘤。

为了降低复发风险，李女士开始了3个周期的化疗联合免疫治疗（替吉奥联合纳武单抗）。

虽然该做的都已做完，但对于李女士来说，恐惧感还远未被消除。因为癌症最令人恐惧的，是其具有“复发转移”的能力。一旦癌症再次袭来，李女士不知道自己该如何应对。另外，两种癌症的治疗以及术后辅助药物治疗，也让李女士遭遇了一些副作用。比如腹泻、味觉障碍还有体重明显下降的问题。这些对于已经70岁的李女士来说，都很影响生活质量，所以迫切需要解决。

在本次的国际专家“海外二诊”服务中，李女士预约的是来自日本某知名综合性医院肿瘤中心的外科部长医生，他的专长领域既包括肿瘤外科，又包括各类癌症药物疗法、姑息治疗，是一位“内外兼修”的权威专家。在充分了解了李女士既往的病情和治疗经过后，医生很快通过远程会诊的方式，为患者详细解答了当前她的所有问题。

1、未来如果转移或复发了该怎么办？

医生：假如您未来不幸出现转移或复发，那么化疗是核心治疗手段。对于单发的孤立转移灶，可以选择手术、放疗来进行局部治疗。

具体化疗方案选择，我按使用的先后顺序列出了3类，当前面的方案失效后，可更换为后面的方案。

一类方案：化疗联合/不联合免疫方案

CAPOX (卡培他滨+奥沙利铂)±O药（即免疫药物纳武单抗）

SOX (替吉奥+奥沙利铂)±O药

FOLFOX (5-FU+奥沙利铂)±O药

二类方案：化疗联合/不联合抗血管药物方案

Taxane (紫杉醇/白蛋白结合型紫杉醇/多西紫杉醇)±雷莫芦单抗

三类方案：化疗方案

曲氟尿苷/盐酸替吡嘧啶

伊立替康

2、N K细胞疗法是否对我有帮助？副作用是否可控？ X医生：目前尚没有证据表明NK细胞疗法对癌症有效，因此不予推荐。

3、口服替吉奥会腹泻，是否需要调整方案？ II/III期胃癌患者术后采用辅助治疗方案，分别为：

替吉奥口服 1 年（口服 4 周，停药 2 周，共 8 个疗程或口服 2 周，停药 1 周，共 16个疗程）

CAPOX (卡培他滨+奥沙利铂) 共半年（每 3 周一次，共 8 个疗程）

SOX (替吉奥+奥沙利铂) 共半年（每 3 周一次，共 8 个疗程）

这三种方案中，替吉奥方案和CAPOX方案等效，但SOX要优于替吉奥。另外，胃癌术后直接使用纳武单抗免疫治疗无意义。

替吉奥确实会出现腹泻等代表性不良反应，患者可以考虑对症治疗，比如调节肠道的药物、止泻药等缓解副作用。如果副作用太严重，那么可以考虑减少药物剂量。

替吉奥的标准用药剂量为120mg，但用量低于80mg无法达到预期效果。如果当前患者用药为100mg，那么为了降低副作用，可以减少剂量到80mg；但如果目前剂量已经是80mg，则无法进一步降低剂量，此时考虑更换方案为CAPOX方案替代。如果不良反应严重到干扰日常生活，则患者可以选择停药，持续观察病情变化。

对于无淋巴结转移的II期B和II其C的患者，可选择使用1年帕博丽珠单抗免疫治疗。

4 、术后患者很瘦，味觉障碍，如何调理改善？通常，手术后患者体重会减轻20%左右。这是患者消化吸收能力低下、促食欲的胃肠激素减少引起的。大约6个月到1年时间，患者可以恢复正常。

味觉障碍可能是抗癌药的副作用引起的，也可能是饮食减少导致缺乏锌等微量元素引起的。建议患者采用少食多餐的方式饮食，每天分5-6次吃饭。在日本，我们有时也会给患者用一些营养补充剂。

另外，也可以考虑采用中草药的对症治疗，改善症状，比如十全大补汤、六君子汤。会诊结束后，李女士的心情得到了极大的平复。她对自己未来要走的路更清晰了，也对日本专家的细致指导和会诊的快速响应非常满意。

高龄+多基础病，该手术还是姑息治疗？日本专家为7旬胃癌患者一锤定音！

中国是消化道癌症发病数量较多的国家，根据国家癌症中心发布的《2022年中国恶性肿瘤疾病负担情况》数据，2022年我国胃癌新发病例约为35.87万例，死亡人数26.04万人。

总体来说，胃癌属于严重威胁我国国民生命健康的蕞常见癌症之一。胃癌如能在早、中期发现，还是有很大机会通过手术实现根治的，患者仍有一定机会得到临床治愈（术后5年不复发即为临床治愈）。

但在胃癌患者中，一部分人会因为【年龄较高】、伴有诸多【基础病】等问题，对手术存有疑虑，担心“下不来手术台”，甚至会放弃手术机会，选择吃药等姑息治疗。这样的选择真的正确吗？现如今的技术能否支持这类老年患者安全手术呢？接下来，我们一起看一个真实案例。

01七旬老人遭遇中期胃癌

一位七十多岁的“老胃病”项女士，因短时间体重骤降（8斤）前往就医。血液检测显示，她有一项指标异常升高。进一步检查发现，她的食道和胃连接的地方（贲门）以及胃的“外墙”（胃壁）都变得异常的厚，而且形状不均匀——这正是胃癌常见的表现。

医生随后通过胃镜检查和病例活检（取一小块组织观察上面的细胞），确诊了老人患有胃癌。由于还没有出现胃以外的远处其他器官的转移，也没有附近淋巴结转移，因此项女士的胃癌分期为中期。虽不是早期，但中期胃癌通常是可以手术的。为项女士提供诊疗的医生也表示，可以通过全胃切除手术实现根治。

但一来项女士已经七十多岁，二来她有20多年的糖尿病（手术伤口会更慢愈合、感染风险高、术后并发症风险高）、右肺还有一枚1.2厘米的肺结节。种种问题让老人和家人们都比较犹豫，担心扛不住治疗，最终“越治越糟”。在这样的背景下，项女士决定找一位足够权威的外科专家，来为自己进行全面评估，看看能不能兼顾好肿瘤根治以及手术的安全性。

不久后，项女士预约了来自日本癌研有明医院消化中心胃外科部长布部创也医生为自己提供指导。

02日本专家咨询内容分享

在充分了解了项女士的病情信息和全部资料后，布部创也医生给出了如下指导建议：首先，患者此前接受的是普通CT而非增强CT，胃镜也没有清晰展示食道上肿瘤具体侵犯的程度，因此很难得出精准的分期判断。

后面患者来癌研有明医院就医时，医疗团队会在治疗前为她做一套非常精细、全面的检查，此后就可以明确肿瘤情况了。届时如果发现患者的分期、肿瘤侵犯的范围确实和现在的结果相同，那么可以通过一个腹腔镜微创手术实现根治，损伤会非常小；如果届时发现肿瘤侵犯食道过多，则需要消化道联合食道外科共同进行胸腔镜手术治疗。

但无论是哪一种情况，患者都可以耐受手术，并且保留一部分胃。癌研有明医院是一家极为擅长肿瘤微创手术的知名癌症专科医院。在胃癌方面，2005年，医院开始导入腹腔镜，2019年又引入了达芬奇手术机器人，患者术后并发症更少了。如今，癌研有明医院98%的外科手术都采用微创。

受益于此，很多在别的医院需要胃全切的胃癌患者，到癌研有明后可以保留一部分胃，还能兼顾临床治愈。这对于术后患者的长期营养摄入和体重维持都很有帮助。布部创也医生所在科室的主要目标之一，正是在做到根治性切除的前提之下，将原本的胃全切术式变为次全胃切除术，尽可能为患者保留一些胃，让他们未来的生活质量得到提升。

那么项女士的糖尿病问题，会不会影响到手术呢？对此，布部创也医生认为完全不必担心，因为对于这类患者，癌研有明医院会进行详细的术前评估，并且有专业团队介入，从生活方式调整和专业治疗入手，帮助患者控制好血糖，让血糖水平达到符合手术的标准，从而降低术后愈合不良风险。

关于肺部的1.2厘米结节，布部医生认为可以暂不处理，无论它到底是良性还是恶性。因为这枚结节属于纯磨玻璃结节，即便是恶性，进展也非常缓慢，并不会快速出现转移扩散。而胃癌根治手术虽然会采用微创方式，但依然会给患者带来一定的负担，如果同时处理肺结节，会导致负担过重、患者难以承受。所以当前蕞好的处理办法，是先集中精力解决胃癌肿瘤，术后安排呼吸科专家为患者进行肺结节诊断，给出随访或手术或根治性放疗的建议。

03项女士术后，是否需要化疗来降低复发风险、争取更大治愈希望？

对此，布部创也医生表示，是否化疗现在还不能判断。因为术后患者能获得蕞精准的分期判断，有可能患者术前被认为是2期，但实际上术后成了1期（无需化疗）；有时也可能患者术前是1期，但术后成了2-3期。假如是2-3期，则患者术后需要坚持1年的辅助化疗，大概可以降低10%的复发风险。

有效减少不良反应，AD新药改良给药方案来了

当地时间10月29日礼来宣布了Ⅲb期临床试验（TRAILBLAZER-ALZ 6）的积极结果，对于早期症状性阿尔茨海默病成人患者，用改良滴定方案接受donanemab治疗的患者在24周主要终点时，伴水肿/积液的淀粉样蛋白相关影像学异常（ARIA-E）有所减少。

donanemab这个新药在今年7月获批于美国，又在之后获日本厚生劳动省、英国药品和医疗产品监管局批准，用于轻度阿尔茨海默病、轻度认知功能障碍的治疗。donanemab在国内2023年取得突破性治疗药物认定，并纳入优先审评审批程序，目前还在审评审批过程中。

CDE官网截图

但在FDA说明书中有黑框警告，大意是应用该药时应注意淀粉样蛋白相关影像学异常（ARIA），表现为ARIA-E和ARIA伴含铁血黄素沉积（ARIA-H），通常发生在治疗早期，且无症状，很少发生严重和危及生命的事件。本次试验的积极结果和这个黑框警告相关。一起来看详情。

FDA说明书截图

给药方式有哪些改变？会不会影响效果？

TRAILBLAZER-ALZ 6是一项多中心随机双盲Ⅲb期研究，主要研究donanemab的不同给药方案对早期症状性AD患者ARIA-E和淀粉样蛋白清除率的影响，这里的早期AD指的是轻度认知障碍（MCI）和轻度痴呆疾病阶段。

给药方式和既往不同，既往标准给药方案是在前三次输注时接受2瓶（700mg）donanemab，然后再接受4瓶（1400mg）；改良滴定方式是患者第一次输注1瓶（350mg），第二次输注2瓶（700mg），第三次输注3瓶（1050mg），此后每次输注4瓶（1400mg）。

研究的主要终点是第24周时患者出现ARIA-E占总参与者的比例，结果显示接受改良滴定方式的患者ARIA-E发生率为14%，而标准给药方案为24%，相对风险降低41%。载脂蛋白E（APOE）是已知的阿尔茨海默病遗传风险因素的携带者，在这些患者中，19%患者在改良滴定时患有ARIA-E，而标准给药方案中为57%，相对风险降低67%。

看到这里你或许也有疑问，虽然ARIA-E的发生风险降低了，但改良滴定方案会不会影响疗效？答案是不会。

与接受标准给药方案的患者相比，改良滴定患者淀粉样斑块和p-tau217减少。改良滴定的患者的淀粉样斑块水平较基线平均降低 67%，而标准给药组患者为69%。

参考来源

1.Modified Titration of Donanemab Demonstrated Reduction of ARIA-E in Early Symptomatic Alzheimer's Disease Patients in Phase Ⅲb study.

2.CED官网.

3.A Study of Different Donanemab (LY3002813) Dosing Regimens in Adults With Early Alzheimer's Disease (TRAILBLAZER-ALZ 6).

重磅！白血病一线新药获FDA加速批准

当地时间10月29日，阿西米尼（asciminib）获美国食品药品管理局（FDA）加速批准^[1] ，用于慢性期新诊断的费城染色体阳性慢性粒细胞白血病（Ph+CML）成年患者。CML是一种骨髓和血细胞癌症，通常由费城染色体的异常染色体引起。在一线治疗中，约1/3的患者会出现下列问题：由于不良反应或者治疗无效而停止酪氨酸激酶抑制剂（TKI）治疗。

为了解决这一问题，需要开发新的药物，asciminib就是解决这一困境的新药。早在2022年8月，加拿大药物和卫生技术局（CADTH）建议^[2] ：“若满足条件，可通过公共药物计划报销asciminib用于治疗费城染色体阳性慢性粒细胞白血病。”

asciminib为何得到FDA的青睐？

本次获批基于一项III期多中心随机研究，研究目的是比较每日80mg的asciminib与TKI治疗的疗效。TKI治疗是接受伊马替尼、尼洛替尼、达沙替尼或博舒替尼任意一种治疗。

共有405名患者被随机分配（1:1）进两组治疗。主要疗效结局指标是48周时的主要分子反应（MMR）率。这个指标是慢性髓性白血病的关键指标，这个比例越高，说明该治疗在基因水平上对疾病的控制效果越好，能够更有效地抑制疾病相关基因的表达，进而有望更好地控制疾病的进展、改善患者的症状和预后。

研究结果显示，48周时MMR率方面，asciminib组中为68%（95% CI: 61, 74)，TKI组为49%（95% CI: 42, 56），二者相差19%。细看具体的TKI，入组伊马替尼和其他TKI药物入组比例为1:1；asciminib组的MMR率为69%（95% CI: 59, 78），而伊马替尼组为40%（95% CI: 31, 50），相差近30%（95% CI: 17, 42）。

这个新药安全吗？每周需要打几次药？

根据FDA数据显示，在新诊断和既往接受过治疗的患者，应用新药最常见的不良反应（≥20%）是肌肉骨骼疼痛、皮疹、疲劳、上呼吸道感染、头痛、腹痛和腹泻。若只看新诊断的患者，最常见的实验室异常（≥40%）是淋巴细胞计数降低、白细胞计数降低、血小板计数降低、中性粒细胞计数降低等。

根据FDA已批准的asciminib说明书，用药期间还需要注意一下事项：

1.骨髓抑制：用药期间可能因出现骨髓抑制，发生血小板减少症、中性粒细胞减少症和贫血。用药应在治疗的前3个月，需要每两周进行一次全血细胞计数，此后每月进行一次检测，从而判断患者有无骨髓抑制症状。根据严重程度，咨询医生是否需要停药。

2.胰腺毒性：患者可能出现血清脂肪酶和淀粉酶无症状升高，每月需评估血清脂肪酶和淀粉酶水平，如果您有胰腺炎，则注意主动告知医生，需要进行频率更高的检测。

3.高血压风险：可能出现3级或4级高血压风险，应注意检测血压。

4.超敏反应：可能出现3级或4级超敏反应，包括皮疹、水肿和支气管痉挛。如果出现这些症状，需及时反馈医生，医生会根据超敏反应的体征和症状，开始适当的治疗。

5.心血管毒性：如果您有心血管病史，需要告知医生；对于3级或更高级别的心血管毒性，医生会考虑暂停用药、减少剂量或永久停药。

6.胚胎/胎儿毒性：若您在怀孕期间用药或在服用药物期间怀孕，可能对孩子有潜在风险。这个新药是口服药，需要根据不同的给药剂量（80mg或40mg）每天/或每两天用药。

近些年来，还有哪些白血病药物获批FDA？

根据FDA肿瘤学/血液系统恶性肿瘤批准通知，白血病相关新药整理如下表。

另外可以看出21年时asciminib已获批白血病治疗，但限定既往接受过两种或更多TKIs治疗，本次获批属于扩大适应证。

参考来源：

1.FDA grants accelerated approval to asciminib for newly diagnosed chronic myeloid leukemia. 2.Asciminib(Scemblix):CADTHReimbursementRecommendation:Indication:ForthetreatmentofadultpatientswithPhiladelphiachromosome-positivechronicmyeloidleukemia(Ph+CML)inchronicphase(CP)previouslytreatedwith2ormoretyrosinekinaseinhibitors.Ottawa(ON):CanadianAgencyforDrugsandTechnologiesinHealth;2022Aug.PMID:38713779. 3.AStudyofOralAsciminibVersusOtherTKIsinAdultPatientsWithNewlyDiagnosedPh+CML-CP. 4.Product information：SCEMBLIX-asciminibtablet,filmcoated.UpdatedAugust7,2024. 5.Oncology(Cancer)/HematologicMalignanciesApprovalNotifications.

病例31-2023：一名79岁男性，身体不自主运动，一过性反应迟钝

以下内容来源于新英格兰医学杂志。

Presentation of Case

Dr. Carrie Chui (Neurology): A 79-year-old man was admitted to this hospital because of involuntary movements on the left side and transient unresponsiveness.

The patient had been in his usual state of health until 9 months before admission, when involuntary movements of the left shoulder and left side of the face developed. The movements were described by the patient as twitching, were not associated with a change in the level of consciousness, and resolved after 1 to 2 minutes. During the next 6 months, the patient had similar episodes approximately once per month, but the episodes increased in duration, lasting 5 to 6 minutes.

Three months before admission, the episodes of involuntary movements increased in frequency, and the patient was evaluated by his primary care physician. The physical examination was normal. Results of kidney-function tests were normal, as were blood levels of glucose and electrolytes, except for the sodium level, which was 129 mmol per liter (reference range, 135 to 145). There was a history of inappropriate antidiuretic hormone secretion, and the sodium level was similar to levels obtained during the past 4 years. Magnetic resonance imaging (MRI) of the head (Figure 1A), performed before and after the administration of intravenous contrast material, revealed a focus of enhancement in the right middle frontal gyrus that was thought to be a small vascular anomaly. Electroencephalography (EEG), performed with the patient in awake and drowsy states, revealed rare, brief, focal slowing in the left temporal lobe during drowsiness; no epileptiform abnormalities were present.

Figure 1

MRI of the Head and CT Angiogram of the Head and Neck.

Two months before admission, the patient was evaluated in the epilepsy clinic affiliated with this hospital. He reported that the episodes of involuntary movements had increased in both frequency and duration, occurring once or twice per day and lasting approximately 10 minutes. Episodes began with tingling and numbness in the left leg that prompted the patient to voluntarily stomp the left foot to relieve the uncomfortable sensation. Then, the patient had involuntary movements that he described as an uncontrollable invisible force moving the left leg and arm, with hyperextension of the arm backward and pronation of the wrist. There was associated numbness in the distal portions of the left third, fourth, and fifth fingers and involuntary movement of the left cheek. No prodromal symptoms occurred. The patient had awareness during the episodes, and after the episodes, he felt fatigued but had a normal level of consciousness, without confusion. The examination in the epilepsy clinic was normal. A diagnosis of seizure disorder was considered, and treatment with levetiracetam was started.

Three weeks before admission, the patient was again evaluated in the epilepsy clinic. He reported that the episodes of involuntary movements still occurred on a daily basis but had decreased in duration and involved only the left leg, without abnormal movements of the arm or face. Dizziness, headache, and weakness had developed and were attributed to the use of levetiracetam. The patient’s family had recorded a video of one of the episodes of involuntary movements. After reviewing the video, the patient’s neurologist thought that the episodes were less likely to be caused by seizures and more consistent with choreoathetoid movements. Cross-tapering of medications — with the simultaneous administration of levetiracetam in decreasing doses and clobazam in increasing doses — was initiated, and the patient was referred to the movement disorders clinic affiliated with this hospital.

On the morning of admission, an episode of involuntary movements of the left leg and left shoulder occurred and persisted for 1 hour. Several hours after the symptoms abated, the patient’s wife found the patient to be unresponsive; he was sitting in a chair. Emergency medical services were called, and when they arrived, the patient was responsive. The fingerstick blood glucose level was 180 mg per deciliter (10.0 mmol per liter) and the blood pressure 110/80 mm Hg. The patient was transported to the emergency department of this hospital for further evaluation.

In the emergency department, the patient reported dysuria and increased urinary frequency. The patient’s daughter noted that he had been more anxious during the past 3 years and occasionally had trouble with memory. Other medical history included Barrett’s esophagus, benign prostatic hypertrophy, chronic hepatitis B virus infection, eczema, gastroesophageal reflux disease, hypertension, nonischemic cardiomyopathy, and osteoporosis. There was no history of head trauma or extended loss of consciousness. Medications included aspirin, atorvastatin, doxazosin, finasteride, omeprazole, metoprolol, sacubitril, and valsartan. There were no known drug allergies. The patient was a lifelong nonsmoker and drank alcohol rarely; he did not use illicit drugs. His mother had had gastric cancer, and his sister had had esophageal cancer; there was no family history of seizures.

On examination, the temporal temperature was 36.8°C, the blood pressure 152/97 mm Hg, the pulse 65 beats per minute, the respiratory rate 16 breaths per minute, and the oxygen saturation 96% while the patient was breathing ambient air. The body-mass index (the weight in kilograms divided by the square of the height in meters) was 21.7. The blood pressure decreased to 130/63 mm Hg with standing. The patient was alert and interactive. The lower jaw was held to the left, but the nasolabial folds and smile were symmetric with activation. There were nonrhythmic, nonstereotyped, writhing movements of the left arm. Tone was normal, and strength was assessed as 5 out of 5 in the arms and legs. Results of liver-function and kidney-function tests were normal, as were blood levels of glucose and electrolytes, except for the sodium level, which was 125 mmol per liter. The lactate level was 2.1 mmol per liter (19 mg per deciliter; reference range, 0.5 to 2.0 mmol per liter [5 to 18 mg per deciliter]). The urinalysis was normal. Intravenous fluids were administered. Imaging studies were obtained.

Dr. Rajiv Gupta: Computed tomographic (CT) angiography of the head and neck (Figure 1B) revealed extensively calcified plaque with severe stenosis of the distal right common carotid artery (CCA), extending into the proximal right internal carotid artery (ICA), as well as stenosis of the right and left paraclinoid ICAs and the left vertebral artery at its origin. There was no vascular abnormality on the CT angiogram that corresponded to the abnormality in the right middle frontal gyrus seen on the previous MRI.

Dr. Chui: The patient was admitted to the hospital. On the second hospital day, the sodium level had increased to 130 mmol per liter, and the lactate level was normal. Additional imaging studies were obtained.

Dr. Gupta: MRI of the head showed no evidence of acute infarction. The focus of enhancement in the right frontal lobe that had been noted previously was not seen on the current MRI.

Dr. Chui: Blood levels of thyrotropin, cobalamin, and glycated hemoglobin and results of coagulation tests were normal. Screening tests for Lyme disease, tuberculosis, and syphilis were negative, as were tests for antibodies to cardiolipin and β₂-glycoprotein. A test for antinuclear antibodies was positive, at a titer of 1:160 in a homogeneous pattern. During a physical therapy session, the patient had abnormal movements of the left leg, left arm, and left side of the face. The abnormal movements diminished when the patient used distraction techniques, such as thigh tapping, finger snapping, and walking while holding a glass of water.

The transient unresponsiveness that led to the patient’s admission was attributed to a combination of sedation from clobazam and hypovolemia. Treatment with clobazam was stopped, and hydration was encouraged. A diagnosis of functional neurologic disorder was considered; outpatient physical therapy with continued use of distraction techniques was recommended. The patient was discharged home on the third hospital day.

Episodes of involuntary movements continued to occur on a daily basis at home. Two weeks after discharge, when the patient was doing exercises while sitting in a chair and having a conversation with his wife, he suddenly stopped talking. She found him slumped in the chair with his eyes closed, no longer exercising. When she asked him questions, he repeatedly said “yes.” Emergency medical services were called, and when they arrived, the patient was alert, diaphoretic, and nonverbal. He had a facial droop on the left side and a right gaze preference. The fingerstick blood glucose level was 130 mg per deciliter (7.2 mmol per liter) and the blood pressure 120/60 mm Hg. The patient was transported to the emergency department of this hospital for further evaluation.

In the emergency department, the temporal temperature was 36.6°C, the blood pressure 143/63 mm Hg, the pulse 66 beats per minute, the respiratory rate 18 breaths per minute, and the oxygen saturation 98% while the patient was breathing ambient air. He was alert and interactive. There was a facial droop on the left side. There was no effort against gravity in the left arm. The patient was able to lift the left leg off the bed for 1 to 2 seconds. He had a right gaze deviation that could not be overcome and mild dysarthria. The remainder of the examination was normal. A diagnosis of stroke was considered, and emergency CT angiography was performed.

Dr. Gupta: CT angiography showed no evidence of acute territorial infarction and no changes in cerebrovascular disease.

Dr. Chui: On repeat physical examination performed after CT angiography, the gaze deviation and dysarthria had resolved, and strength was normal. Mild facial paralysis was present.

A diagnosis was made.

Differential Diagnosis

Dr. Albert Y. Hung: This 79-year-old man initially presented with involuntary movements of the left shoulder and face without associated loss of consciousness. Diagnosis of an unusual movement disorder, especially one that is present episodically, can be challenging. Videos brought in by the patient can be very useful.¹ Most movement disorders result from abnormal functioning of extrapyramidal circuits involving the basal ganglia, rather than a specific neuroanatomical lesion, and the first step toward diagnosis is to identify the type of abnormal movements.²

Four salient aspects of this patient’s involuntary movements can help in characterizing the movement disorder before generating a differential diagnosis. First, the movements were paroxysmal, lasting for short periods of time with resolution between episodes. Second, the movements were nonstereotyped, appearing randomly and variably. Third, the movements were restricted to the left side of his body throughout the course, localizing the disease process to the right cerebral hemisphere. Finally, the symptoms were progressive, increasing in both duration and frequency.

Movement Disorders

This patient had abnormal involuntary movements, symptoms indicative of a hyperkinetic movement disorder. Tremor, the most common hyperkinetic disorder, is unlikely because the patient did not have rhythmic movements. Dystonia is also unlikely, because he did not have sustained muscle contractions that were causing twisting or abnormal postures of the legs, arms, head, neck, or face. Although the patient initially described the movements as twitching, his later descriptions are not suggestive of myoclonus or tics, which manifest as sudden, rapid, recurrent movements.

This patient’s neurologist described the involuntary movements as “choreoathetoid” after reviewing a video of an episode. Chorea, athetosis, and ballism make up a spectrum of involuntary movements that often occur in combination. Chorea refers to involuntary movements that are “dancelike” — irregular, random, unintended, and flowing from one body part to another. When these movements are slow and writhing (with a lower amplitude) and involve the distal limbs, the term athetosis is used. The presence of both chorea and athetosis in the same patient is referred to as choreoathetosis. When the movements are fast and flinging (with a higher amplitude) and involve the proximal limbs, the term ballism is used. Although the description of this patient’s movements was not clearly suggestive of ballism, hemichorea and hemiballismus often occur together.

The term dyskinesia can refer to any abnormal movements and is often used to describe hyperkinetic disorders that are induced by specific drugs, such as tardive dyskinesia induced by dopamine antagonists or dyskinesia induced by levodopa in patients with Parkinson’s disease. Often, dyskinesia manifests as chorea or choreoathetoid movements, but chorea and dyskinesia are not synonymous. This patient appears to have involuntary dyskinesia with choreoathetosis as the primary phenomenology. Before constructing a differential diagnosis for dyskinesia in this patient, I will consider two conditions that mimic dyskinesia: seizures and functional movement disorder.

Seizures

Various movement disorders may be mistaken for seizures, although these movement disorders are not associated with EEG abnormalities during the episode. Patients with some forms of epilepsy may present with abnormal movements without other features that are typically associated with seizures, such as aura, change in responsiveness, incontinence, or a postictal state.^3,4 Seizures were initially suspected in this patient, and he was referred to the epilepsy clinic. Recurrent focal seizures were probably suspected because of the transient nature of the episodes. Initial MRI had shown a small abnormality in the right middle frontal gyrus, but this finding was not seen on follow-up imaging, which makes it unlikely to be related to the overall presentation. Baseline EEG had shown only brief left temporal slowing, without epileptiform abnormalities. The EEG was an interictal study, so the findings do not rule out seizures. However, the slowing was ipsilateral to the abnormal movements, so it is unlikely to be related to the episodes. In addition, the patient’s involuntary movements were nonstereotyped and nonrhythmic, which makes his presentation unlikely to be due to a seizure disorder.

Functional Movement Disorder

Because this patient’s movements diminished with the use of distraction techniques, a diagnosis of functional movement disorder was considered. Most cases of functional movement disorder begin abruptly after a trigger, such as a mild physical injury or illness; a psychological stressor can be present but is not required for diagnosis. Symptoms are typically most severe around the time of onset and may wax and wane over time. Although distractibility is a finding associated with functional disorders, abnormal movements that occur with nonfunctional syndromes can sometimes be suppressed by action or incorporated into voluntary movements in a manner that may appear distractible. Several clinical features in this patient make a diagnosis of functional disorder unlikely. Functional movement disorder is more common in women than in men, and the average age at onset is 40 years.⁵ In addition, tremor is the most common clinical phenotype seen in patients with functional movement disorder; chorea or choreoathetosis, which was seen in this patient, is very unusual in patients with functional movement disorder. Overall, functional movement disorder is unlikely to explain this patient’s presentation.

Dyskinesia

Primary paroxysmal dyskinesia refers to a group of heterogeneous syndromes characterized by recurrent involuntary movements that occur episodically and abruptly, without loss of consciousness.⁶ These disorders usually begin in childhood or young adulthood. Both the age of this patient and the described phenomenology make a diagnosis of primary paroxysmal dyskinesia unlikely.

The differential diagnosis in this case is therefore focused on causes of secondary dyskinesia, of which there are many.⁷ MRI ruled out the presence of a mass lesion suggestive of cancer. The patient had no history of acute illness suggestive of a viral or other infectious encephalitis, and there was no history of trauma or exposure to drugs or other toxins. Although his daughter mentioned trouble with memory, there was no compelling history suggestive of a neurodegenerative disease.

A common metabolic cause of secondary dyskinesia is diabetic striatopathy, a syndrome involving the acute-to-subacute onset of chorea and ballism in the context of hyperglycemia.⁸ This syndrome can occur as the initial manifestation of type 2 diabetes mellitus or as a complication of poorly controlled diabetes. Diabetic striatopathy is more likely to develop in women than in men, and the average age at onset is 70 years. Most patients present with hemichorea and hemiballismus, rather than bilateral symptoms. CT shows hyperdensity, and T1-weighted MRI shows hyperintensity, in the contralateral basal ganglia. However, this patient had no history of diabetes and had a normal blood glycated hemoglobin level, features that rule out a diagnosis of diabetic striatopathy.

Choreiform movements can also be a manifestation of autoimmune conditions.⁹ This patient’s initial presentation with unilateral shoulder and face movements would have suggested the possibility of faciobrachial dystonic seizures associated with anti–leucine-rich, glioma-inactivated 1 (anti-LGI1) encephalitis.¹⁰ This condition is often associated with hyponatremia, which was present in this patient. However, as the case evolved, leg involvement and sensory changes developed that would be atypical for anti-LGI1 encephalitis.

One key clue in this case is that the patient did not have an isolated movement disorder. In addition to motor symptoms, he had a variety of sensory symptoms involving both the left arm and the left leg. His first hospital admission was precipitated by an episode of unresponsiveness. The clinical event that led to his second presentation to the emergency department was distinctly different: an acute onset of speech difficulty accompanied by left hemiparesis and right gaze deviation that was worrisome for an acute right middle cerebral artery (MCA) syndrome. The symptoms resolved without intervention, which indicates that he may have had an acute transient ischemic attack (TIA). The most relevant imaging finding was severe cerebrovascular disease, including severe stenosis of the distal right CCA and proximal right ICA. Could this patient’s movement disorder be explained by a vascular lesion?

Limb-Shaking TIAs

Limb-shaking TIAs were first described by C. Miller Fisher in 1962.¹¹ In most case reports, these episodes are associated with high-grade stenosis of the ICA, which was seen in this patient.^12,13 The mechanism is thought to be cerebral hypoperfusion, and changes in posture or head position that decrease cerebral blood flow can precipitate these episodes. In this patient, the first episode of unresponsiveness that led to hospital admission occurred when he was sitting. He then had an acute episode involving right gaze preference that was provoked by exercise and was very suggestive of a TIA in the right MCA territory. These findings are highly suggestive of a diagnosis of limb-shaking TIAs, and I would refer this patient for emergency carotid endarterectomy.

Clinical Impression and Initial Management

Dr. Scott B. Silverman: When I evaluated this patient, his transient right gaze preference and left hemiparesis were consistent with a right MCA syndrome due to a TIA from symptomatic severe stenosis of the right ICA. The mechanism of this event was either artery-to-artery embolism or hypoperfusion. His previous, recurrent episodes of transient choreoathetosis on the left side that had occurred mainly while he was sitting, standing, or exercising were consistent with limb-shaking TIAs from hypoperfusion or low flow.

The pathogenesis of a low-flow state related to severe carotid stenosis resulting in limb-shaking TIAs is described in a small case series.¹⁴ In six out of eight patients, the transient, stereotyped, involuntary movements were eliminated with carotid artery revascularization. Positional cerebral ischemia in patients without orthostatic hypotension has been described.¹⁵

Treatment with atorvastatin was continued, the dose of aspirin was increased to 325 mg per day, and an intravenous heparin infusion was started. The strategy of permissive hypertension was used, with high blood pressure allowed to a maximum systolic blood pressure of 180 mm Hg. The patient was admitted to the stroke service, and carotid artery duplex ultrasonography was performed.

Dr. Gupta: Doppler ultrasonography of the carotid arteries (Figure 2) revealed markedly elevated Doppler flow velocities within the proximal right ICA. There was a parvus et tardus waveform in the distal right ICA, a finding indicative of low flow related to the more proximal high-grade stenosis. The Doppler waveform contours had poststenotic turbulence.

Figure 2

Doppler Ultrasound Image.

Dr. Silverman: The vascular surgery service was consulted, and the patient underwent right carotid endarterectomy.

Clinical Diagnosis

Limb-shaking transient ischemic attacks.

Dr. Albert Y. Hung’s Diagnosis

Limb-shaking transient ischemic attacks due to severe carotid stenosis, with secondary paroxysmal dyskinesia.

Pathological Discussion

Dr. Caroline F. Hilburn: The endarterectomy specimen included the carotid bifurcation and was notable for firm arterial walls, a finding consistent with calcification. On gross examination (Figure 3A), a large plaque was centered at the carotid bifurcation and protruded into the lumen, resulting in a maximal luminal stenosis of 80%. The plaque had an irregular and focally friable surface. On microscopic examination (Figure 3B), the plaque was characterized by extensive calcification. Some regions of the plaque had a smooth, healed fibrous cap, whereas other regions had an irregular surface suggestive of ulceration, which indicated potential sites of plaque rupture. Multiple smaller calcified plaques were present, affecting both branches of the artery.

Figure 3

Endarterectomy Specimen.

Pathological Diagnosis

Complex atherosclerotic plaque with portions of attached media.

Additional Management

Dr. Silverman: After the procedure, the patient had an uneventful recovery and was discharged home on the fifth hospital day. He was seen 1 month after discharge in the stroke prevention clinic. There had been no further episodes of involuntary movements or choreoathetosis and no stroke or TIA. The patient continues to take aspirin, atorvastatin, and antihypertensive medications.

Final Diagnosis

Limb-shaking transient ischemic attacks.

病例28-2024：一名75岁女性，患有水肿、关节炎和蛋白尿

以下内容来源于新英格兰医学杂志。

Presentation of Case

Dr. Christine M. Parsons (Medicine): A 75-year-old woman was evaluated at this hospital because of arthritis, abdominal pain, edema, malaise, and fever.

Three weeks before the current admission, the patient noticed waxing and waning “throbbing” pain in the right upper abdomen, which she rated at 9 (on a scale of 0 to 10, with 10 indicating the most severe pain) at its maximal intensity. The pain was associated with nausea and fever with a temperature of up to 39.0°C. Pain worsened after food consumption and was relieved with acetaminophen. During the 3 weeks before the current admission, edema developed in both legs; it had started at the ankles and gradually progressed upward to the hips. When the edema began to affect her ambulation, she presented to the emergency department of this hospital.

A review of systems that was obtained from the patient and her family was notable for intermittent fever, abdominal bloating, anorexia, and fatigue that had progressed during the previous 3 weeks. The patient reported new orthopnea and nonproductive cough. Approximately 4 weeks earlier, she had had diarrhea for several days. During the 6 weeks before the current admission, the patient had lost 9 kg unintentionally; she also had had pain in the wrists and hands, 3 days of burning and dryness of the eyes, and diffuse myalgias. She had not had night sweats, dry mouth, jaw claudication, vision changes, urinary symptoms, or oral, nasal, or genital ulcers.

The patient’s medical history was notable for multiple myeloma (for which treatment with thalidomide and melphalan had been initiated 2 years earlier and was stopped approximately 1 year before the current admission); hypothyroidism; chikungunya virus infection (diagnosed 7 years earlier); seropositive erosive rheumatoid arthritis affecting the hands, wrists, elbows, and shoulders (diagnosed 3 years earlier); vitiligo; and osteoarthritis of the right hip, for which she had undergone arthroplasty. Evidence of gastritis was reportedly seen on endoscopy that had been performed 6 months earlier. Medications included daily treatment with levothyroxine and acetaminophen and pipazethate hydrochloride as needed for cough. The patient consumed chamomile and horsetail herbal teas. She had no known allergies to medications, but she had been advised not to take nonsteroidal antiinflammatory drugs after her diagnosis of multiple myeloma.

Approximately 5 months before the current admission, the patient had emigrated from Central America. She lived with her daughter and grandchildren in an urban area of New England. She had previously worked in health care. She had no history of alcohol, tobacco, or other substance use. There was no family history of cancer or autoimmune, renal, gastrointestinal, pulmonary, or cardiac disease.

On examination, the temporal temperature was 37.1°C, the heart rate 106 beats per minute, the blood pressure 152/67 mm Hg, and the oxygen saturation 100% while the patient was breathing ambient air. She had a frail appearance and bitemporal cachexia. The weight was 41 kg and the body-mass index (the weight in kilograms divided by the square of the height in meters) 15.2. Her dentition was poor; most of the teeth were missing, caries were present in the remaining teeth, and the mucous membranes were dry. She had abdominal tenderness on the right side and mild abdominal distention, without organomegaly or guarding. Bilateral axillary lymphadenopathy was palpable. Infrequent inspiratory wheezing was noted.

The patient had swan-neck deformity, boutonnière deformity, ulnar deviation, and distal hyperextensibility of the thumbs (Fig. 1). Subcutaneous nodules were observed on the proximal interphalangeal joints of the second and third fingers of the right hand and on the proximal interphalangeal joint of the fourth finger of the left hand. Synovial thickening of the metacarpophalangeal joints of the second fingers was noted. There was mild swelling and tenderness of the wrists. She had pain with flexion of the shoulders and right hip, and there was subtle swelling of the shoulders and right knee. Pitting edema (3+) and vitiligo were noted on the legs. No sclerodactyly, digital pitting, telangiectasias, appreciable calcinosis, nodules, nail changes (including pitting), or tophi were present. The remainder of the examination was normal.

Figure 1

Photograph of the Hands.

The blood levels of glucose, alanine aminotransferase, aspartate aminotransferase, bilirubin, globulin, lactate, lipase, magnesium, and phosphorus were normal, as were the prothrombin time and international normalized ratio; other laboratory test results are shown in Table 1. Urinalysis showed 3+ protein and 3+ blood, and microscopic examination of the sediment revealed 5 to 10 red cells per high-power field and granular casts. Urine and blood were obtained for culture. An electrocardiogram met (at a borderline level) the voltage criteria for left ventricular hypertrophy.

Table 1

Laboratory Data.

Dr. Rene Balza Romero: Computed tomography (CT) of the chest, abdomen, and pelvis, performed after the intravenous administration of contrast material, revealed scattered subcentimeter pulmonary nodules (including clusters in the right middle lobe and patchy and ground-glass opacities in the left upper lobe), trace pleural effusion in the left lung, coronary and valvular calcifications, and trace pericardial effusion, ascites, and anasarca. The scans also showed slight enlargement of the axillary lymph nodes (up to 11 mm in the short axis) bilaterally and a chronic-appearing compression fracture involving the T12 vertebral body.

Dr. Parsons: Morphine and lactated Ringer’s solution were administered intravenously. On the second day in the emergency department (also referred to as hospital day 2), the blood levels of haptoglobin, folate, and vitamin B₁₂ were normal; other laboratory test results are shown in Table 1. A rapid antigen test for malaria was positive. Wright–Giemsa staining of thick and thin peripheral-blood smears was negative for parasites; the smears also showed Döhle bodies and basophilic stippling. Antigliadin antibodies and anti–tissue transglutaminase antibodies were not detected. Tests for hepatitis A IgG and hepatitis C antibodies were positive. Tests for hepatitis B core and surface antibodies were negative. A test for human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) was negative.

Findings on abdominal ultrasound imaging performed on the second day (Fig. 2A and 2B) were notable for a small volume of ascites and kidneys with echogenic parenchyma. Ultrasonography of the legs showed no deep venous thrombosis. An echocardiogram showed normal ventricular size and function, aortic sclerosis with mild aortic insufficiency, moderate tricuspid regurgitation, a right ventricular systolic pressure of 39 mm Hg, and a small circumferential pericardial effusion. Intravenous hydromorphone was administered, and the patient was admitted to the hospital.

Figure 2

Imaging Studies of the Abdomen and Hands.

On the third day (also referred to as hospital day 3), nucleic acid testing for cytomegalovirus, Epstein–Barr virus, and hepatitis C virus was negative, and a stool antigen test for Helicobacter pylori was negative. An interferon-γ release assay for Mycobacterium tuberculosis was also negative. Oral acetaminophen and ivermectin and intravenous hydromorphone and furosemide were administered.

Dr. Balza Romero: Radiographs of the hands (Fig. 2C through 2F) showed joint-space narrowing of both radiocarpal joints and proximal interphalangeal erosions involving both hands. Radiographs of the shoulders showed arthritis of the glenohumeral joint and alignment suggestive of a tear of the right rotator cuff. A radiograph of the pelvis showed diffuse joint-space narrowing of the left hip, without osteophytosis, and an intact right hip prosthesis.

Dr. Parsons: Diagnostic tests were performed, and management decisions were made.

Differential Diagnosis

Dr. Beth L. Jonas: This patient is a 75-year-old woman who recently emigrated from Central America. She presented to this hospital with a multisystem disease involving the respiratory, gastrointestinal, renal, and musculoskeletal systems. Her medical history is notable for seropositive erosive rheumatoid arthritis and multiple myeloma, which had been treated with melphalan and thalidomide. Relevant clinical features on presentation include unintended weight loss and cachexia, axillary lymphadenopathy, serositis, cytopenia in two cell lines, hypocomplementemia, and elevated serum free kappa and lambda light-chain levels (with a normal free light-chain ratio) with no monoclonal spike. The white-cell count was elevated, but she had no eosinophilia. CT images of the chest showed scattered subcentimeter pulmonary nodules. With respect to the patient’s anemia, no schistocytes were present, the haptoglobin level was normal, and the iron studies were unremarkable. These findings, in combination with the elevated ferritin level, indicate anemia of chronic inflammation. The renal findings are most salient in the context of the patient’s hypertension, anasarca, elevated cystatin C level, active urinary sediment with proteinuria in the nephrotic range, and small, echogenic kidneys on ultrasonography.

In constructing a differential diagnosis, I will consider medication use, cancer, infectious disease, and autoimmune disease. Medications can be eliminated as the cause of this patient’s illness, since she was taking only levothyroxine, acetaminophen, and the antitussive agent pipazethate.

Cancer

The patient has a history of multiple myeloma, which may manifest with a multisystem disease involving the kidneys, but serum protein electrophoresis showed no monoclonal protein. Given the presence of nephrotic syndrome in the context of multiple myeloma, systemic immunoglobulin light-chain amyloidosis would be highest on the differential diagnosis with respect to cancer; however, the patient’s normal light-chain ratio makes this diagnosis unlikely. The development of myeloid neoplasms, such as acute myeloid leukemia, myelodysplastic syndromes, and myeloproliferative neoplasms, is important to consider in the context of previous treatment with alkylating agents,¹ which this patient had received. However, the peripheral-blood smear showed no findings that would indicate a hematologic cancer, and such a diagnosis would not explain the patient’s acute kidney injury with nephrotic-range proteinuria.

Infectious Disease

Several features of this patient’s case warrant special consideration, including her history of immunosuppression due to rheumatoid arthritis and to previously treated myeloma, along with the fact that she had emigrated from Central America, where certain infections may be prevalent. Infection with hepatitis A virus, hepatitis B virus, hepatitis C virus, HIV-1 and HIV-2, cytomegalovirus, Epstein–Barr virus, H. pylori, and M. tuberculosis can be ruled out on the basis of laboratory studies. A rapid antigen test for plasmodium species was reported to be positive, but this assay has a known cross-reactivity with rheumatoid factor.² Moreover, the thick and thin peripheral-blood smears were negative. Thus, malaria would be an unlikely diagnosis.

The patient has a history of infection with chikungunya virus, an arbovirus transmitted by a mosquito vector that has been responsible for large epidemics in the Americas since 2013.³ Acute symptoms include fever, rash, arthralgia, and myalgia. The development of a chronic arthritis that may meet the classification criteria for rheumatoid arthritis, as defined by the American College of Rheumatology and the European Alliance of Associations for Rheumatology, has been reported in up to 60% of patients infected with chikungunya virus.^4,5 In the context of this discussion, I considered whether chikungunya virus infection could be the cause of this patient’s symptoms, since this infection occurred before the diagnosis of rheumatoid arthritis. However, the degree of erosion and loss of joint space that was visible on radiographs would be most unusual for arthritis associated with chikungunya virus infection and would not explain the renal manifestations.

Strongyloidiasis is a helminth infection (caused by Strongyloides stercoralis) that is widespread in developing countries. Infection usually occurs through contact with soil, and most affected persons are asymptomatic. However, in immunosuppressed persons, strongyloides hyperinfection syndrome or a disseminated infection can develop as a consequence of accelerated autoinfection.⁶ The clinical presentation of strongyloides hyperinfection syndrome can include gastrointestinal symptoms (diarrhea, constipation, nausea, or vomiting), respiratory symptoms (cough, dyspnea, or wheezing), and rash due to migration of larvae through the subcutaneous tissues. Of note, only a minority of patients present with eosinophilia. Several case reports describe the development of nephrotic-range proteinuria, thrombotic microangiopathy, and IgA vasculitis in patients with strongyloides hyperinfection syndrome.^7-9 However, strongyloidiasis would not explain this patient’s cytopenias and hypocomplementemia.

Autoimmune Disease

The patient has a 3-year history of rheumatoid arthritis, although her clinical features of swan-neck deformity, boutonnière deformity, and joint instability suggest a longer duration of disease. We do not know whether she had received previous treatment with disease-modifying antirheumatic drugs or biologic agents, but the possible use of such treatments may be a consideration with respect to her progression of disease and overall degree of immunosuppression. The blood levels of rheumatoid factor and anti–cyclic citrullinated peptide antibodies were elevated, and radiographs of the hands showed erosive disease, although there was a relative paucity of metacarpophalangeal findings. A review of systems was negative for dry mouth, but her physical examination showed poor dentition and dry mouth — findings that make secondary Sjögren’s syndrome a consideration.

Renal disease can occur in patients with Sjögren’s syndrome. The two most typical presentations are tubulointerstitial nephritis and, less commonly, nephritic syndrome (membranoproliferative glomerulonephritis related to cryoglobulinemia). Tubulointerstitial nephritis may manifest with renal disease of varying severity, usually with a bland urinary sediment and often with abnormalities of tubular function such as distal renal tubular acidosis. Membranoproliferative glomerulonephritis caused by cryoglobulinemia is the most common glomerular disease associated with Sjögren’s syndrome. Although nephrotic-range proteinuria can occur with Sjögren’s syndrome, it is relatively uncommon.¹⁰ Renal disease is uncommon in patients with rheumatoid arthritis and is usually related to coexisting cardiovascular conditions. Medications used in the treatment of autoimmune disease — mainly nonsteroidal antiinflammatory drugs — may be associated with renal disease, but I would not expect the presence of an active urinary sediment, as was seen in this patient.

Amyloid A (AA) amyloidosis, a condition that is rare in the era of aggressive management of rheumatoid arthritis, has been described in patients with severe, long-standing seropositive erosive rheumatoid arthritis. Serum amyloid A (SAA) is a protein that is produced in the liver in response to chronic inflammation associated with interleukin-1, interleukin-6, and tumor necrosis factor α (TNF-α) in the context of chronic infections, autoimmune disease (classically rheumatoid arthritis), autoinflammatory disease, and cancers including renal cell carcinoma and non-Hodgkin’s lymphoma.¹¹ Signs and symptoms of AA amyloidosis are related to the deposition of the protein in organs, and patients often present with multisystem signs and symptoms. The kidney is the organ that is most often affected, but deposition can occur in the heart, gastrointestinal tract, nervous system, musculoskeletal system, and lungs. Proteinuria is the first clinical manifestation in almost 95% of patients with AA amyloidosis, and 50% of affected patients present with nephrotic syndrome.¹² The urinary sediment is generally bland, and complement levels in the blood are normal. AA amyloidosis remains on the differential diagnosis in this patient, but it would not completely explain her renal disease.

Hypocomplementemia

The key to this case is understanding the cause of this patient’s hypocomplementemia. Hypocomplementemia can be due to decreased complement production in the context of liver disease, congenital complement deficiency, or increased complement consumption resulting from activation of the innate immune system. This patient has no history of chronic liver disease and her laboratory test results indicated good hepatic synthetic function. Classical complement deficiency (including C4 deficiency) that begins early in life is associated with autoimmune disease, and early C3 deficiency is characterized by severe pyogenic infections. It would be unusual for a patient of this age to be deficient in both C3 and C4 without earlier clinical consequences. I therefore concluded that the hypocomplementemia in this case was related to complement consumption.

Rheumatic diseases that may be associated with prominent renal manifestations include antineutrophil cytoplasmic antibody–associated vasculitis, systemic sclerosis with renal crisis, cryoglobulinemic vasculitis, antiglomerular basement membrane disease, and systemic lupus erythematosus (SLE). Of those conditions, SLE would be the most likely to be manifested by an active urinary sediment and nephrotic-range proteinuria with consumption of both C3 and C4 in the context of fever, thrombocytopenia, and serositis. This patient’s fever, thrombocytopenia, and serositis also fit with this diagnosis.¹³

Because the patient has long-standing seropositive erosive rheumatoid arthritis, a diagnosis of AA amyloidosis is strongly suspected. Moreover, given the presence of thrombocytopenia, hypocomplementemia, and an active urinary sediment, I would recommend a kidney biopsy to evaluate for lupus nephritis and AA amyloidosis.

Dr. Beth L. Jonas’s Diagnosis

Overlap syndrome of rheumatoid arthritis and systemic lupus erythematosus with amyloid A amyloidosis.

Pathological Discussion

Dr. Claire Trivin-Avillach: Testing for autoimmune antibodies was performed. A test for antinuclear antibodies was positive at a titer of 1:5120 with a homogeneous pattern, and a test for anti–double-stranded DNA antibodies was positive at a titer of 1:2560.

The diagnostic procedure in this case was a core-needle biopsy of the kidney. Examination of the specimen with light microscopy revealed 20 glomeruli, 45% of which were globally sclerosed, along with fibrosis involving approximately 60% of the interstitium and tubular atrophy. Diffusely enlarged glomeruli with thickened capillary walls and an expanded mesangium were weakly positive on periodic acid–Schiff staining; the glomeruli stained pale blue on Masson’s trichrome staining. Congo red staining revealed metachromatic salmon-colored deposition involving the glomeruli, the blood-vessel walls, and the interstitium, which was associated with apple-green birefringence when viewed under polarized light (Fig. 3A). In addition, mesangial and endocapillary hypercellularity was identified in approximately 30% of the nonsclerosed glomeruli and was associated with karyorrhexis (Fig. 3B). One cellular crescent was also detected. These features are characteristic of active proliferative glomerulonephritis.

Figure 3

Biopsy Specimen of the Kidney.

Immunofluorescence microscopy revealed prominent granular staining for IgG (4+), IgM (4+), C3 (3+), C1q (3+), IgA (1+), kappa (3+), and lambda (3+) along the glomerular basement membranes and within the mesangium, as well as focal granular deposits of IgG and C3 along the tubular basement membrane (Fig. 3C and 3D). Additional immunofluorescence studies showed strong positivity (4+) for SAA within the glomeruli, the blood-vessel walls, and the interstitium (Fig. 3E), whereas staining for beta₂-microglobulin, transthyretin, and apolipoprotein A1 was faint.

Electron microscopy revealed the presence of subendothelial and mesangial electron-dense deposits (with no substructure identified) adjacent to randomly arranged fibrils (measuring 8.2 to 10.6 nm in diameter) within the glomerular basement membranes and the mesangium (Fig. 3F). Glomerular endothelial cells appeared reactive and contained tubuloreticular inclusions, features that were suggestive of interferon-mediated activation.

The findings on Congo red staining were characteristic of amyloidosis with typical birefringent material. The strong positivity of SAA within the deposits as compared with the faint staining of other reactants identified the type of amyloid as SAA, which is consistent with the patient’s history of rheumatoid arthritis. The biopsy also showed an immune complex–mediated proliferative glomerulonephritis with a “full house” pattern (defined as positivity for the three immunoglobulin classes IgG, IgM, and IgA and the two complement components C3 and C1q, in reference to the “full house” hand in a poker game). Immune complex–mediated proliferative glomerulonephritis has been reported in patients with rheumatoid arthritis who were receiving anti–TNF-α therapy,¹⁴ which was not the case in this patient. The positive test for hepatitis C antibodies prompted consideration of hepatitis C–related membranoproliferative glomerulonephritis. However, taken together, the negative nucleic acid test for hepatitis C virus, the full house pattern on immunofluorescence, the tubular basement membrane deposits, and the positive test for anti–double-stranded DNA antibodies favor a diagnosis of lupus nephritis of at least class III (defined as focal proliferative glomerulonephritis), according to the criteria of the International Society of Nephrology and the Renal Pathology Society, superimposed on AA amyloidosis.

Pathological Diagnosis

Proliferative lupus nephritis of International Society of Nephrology and Renal Pathology Society class III, superimposed on amyloid A amyloidosis.

Discussion of Management

Dr. Pui W. Cheung: On the basis of the finding of echogenic kidneys on ultrasonography and the findings of extensive interstitial fibrosis and tubular atrophy on kidney biopsy, we know that this patient has advanced chronic kidney disease that is unlikely to be reversible. The patient is also noted to have a markedly lower glomerular filtration rate (GFR) than that predicted by the blood creatinine level owing to the presence of cachexia, and this is substantiated by the cystatin C–based GFR and a 24-hour creatinine clearance of 22 ml per minute per 1.73 m² of body-surface area. The typical induction therapy for stage III or IV lupus nephritis consists of high-dose glucocorticoids and either mycophenolate mofetil or cyclophosphamide. Other reasonable alternatives for initial therapy include mycophenolate mofetil in combination with either a calcineurin inhibitor or belimumab, or cyclophosphamide in combination with belimumab.¹⁵ Hydroxychloroquine is also recommended as part of the therapy, since it has shown benefits in improving the response to treatment and reducing disease flare.¹⁶ Mycophenolate mofetil and cyclophosphamide have similar efficacy with respect to clinical response, which includes a reduction in proteinuria and either an improvement in renal function or stabilization of renal function; the risks of infections and adverse events associated with these medications are also similar.^17,18

Given the severity of the lupus nephritis with overlying AA amyloidosis from active rheumatoid arthritis, the treatment options proposed were high-dose glucocorticoids and rituximab with either mycophenolate mofetil or cyclophosphamide.¹⁹ After discussions with multidisciplinary consultants from rheumatology, infectious diseases, and nephrology, lingering concerns were raised about infection and patient frailty; ultimately, the decision was made to initiate high-dose glucocorticoid therapy in combination with mycophenolate mofetil, rituximab, and hydroxychloroquine.

The patient’s mycophenolate mofetil dose regimen was inconsistent owing to gastrointestinal side effects, and the treatment was eventually withheld because of pancytopenia and fever. Unfortunately, her kidney function worsened, and renal replacement therapy was initiated within 3 weeks after the start of the induction therapy. The cause of her renal failure was thought to be disease progression, compounded by hemodynamically mediated tubular injury in the context of infection. While the administration of mycophenolate mofetil was stopped, treatment with rituximab was continued, with slow tapering of the glucocorticoid dose at the direction of the rheumatologist. She remained dependent on dialysis and was deemed to have end-stage kidney disease after 3 months of dialysis.

Dr. Lisa G. Criscione-Schreiber: The patient has SLE with nephritis, seropositive erosive rheumatoid arthritis, and systemic AA amyloidosis. AA amyloidosis is rare owing to the availability of effective therapies for rheumatoid arthritis and is managed through aggressive treatment of inflammation due to rheumatoid arthritis. Reports addressing the management of rheumatoid arthritis–induced AA amyloidosis generally cite stability of end-organ damage caused by AA amyloid as evidence of effective management of the condition (through treatment of the inflammation of rheumatoid arthritis). Methotrexate, the cornerstone of treatment for rheumatoid arthritis, is contraindicated in this case owing to the presence of kidney disease. The alkylating agent cyclophosphamide has been reported to be effective for the treatment of AA amyloidosis from rheumatoid arthritis²⁰ and has known efficacy in patients with lupus nephritis, both of which make it a viable treatment option. Rituximab has also been reported to be effective for managing rheumatoid arthritis–induced AA amyloidosis,²¹ is approved for the treatment of rheumatoid arthritis, and is used for manifestations of SLE, including thrombocytopenia and nephritis. Although anti–TNF-α agents, abatacept, and Janus kinase inhibitors are reported to be effective for the treatment of AA amyloidosis in patients with rheumatoid arthritis,²² recent publications have coalesced on the ability of anti–interleukin-6 therapy to block interleukin-6–induced hepatic production of SAA.^23-25

The overlap of seropositive erosive rheumatoid arthritis and SLE (sometimes termed “rhupus”) usually resembles rheumatoid arthritis more than SLE; manifestations include thrombocytosis, leukocytosis, an elevated erythrocyte sedimentation rate, an elevated blood level of C-reactive protein, and the presence of marginal erosions on radiographs.²⁶ In contrast, SLE without seropositive erosive rheumatoid arthritis characteristically manifests with thrombocytopenia, leukopenia, and an elevated erythrocyte sedimentation rate but usually not an elevated C-reactive protein level; in addition, nonerosive inflammatory arthritis with reversible deformities is commonly observed. This patient had a mixed laboratory profile, on the basis of the results of antinuclear antibody and anti–double-stranded DNA antibody tests. The challenge of treating an overlap syndrome of rheumatoid arthritis and SLE is choosing disease-modifying antirheumatic drugs that are effective and safe in both conditions. This patient’s most severe disease manifestation is lupus nephritis; therefore, the treatment regimen must target nephritis along with the AA amyloidosis and inflammatory arthritis.

As noted earlier, current induction therapy for lupus nephritis includes either mycophenolate mofetil or cyclophosphamide. Mycophenolate mofetil may provide inadequate treatment of the rheumatoid arthritis and amyloidosis, whereas cyclophosphamide would treat the lupus nephritis, has possible efficacy for treatment of the AA amyloidosis, and would treat the rheumatoid arthritis. Rituximab could be added to cyclophosphamide or mycophenolate mofetil to treat the rheumatoid arthritis and resultant AA amyloidosis and could also possibly help treat the lupus nephritis. The addition of anti–interleukin-6 therapy to mycophenolate mofetil or cyclophosphamide is an intriguing option that may effectively treat the rheumatoid arthritis and subsequent AA amyloidosis. The addition of belimumab to mycophenolate mofetil or cyclophosphamide has been reported to improve renal response in patients with lupus nephritis,²⁷ as has the addition of voclosporin to mycophenolate mofetil.²⁸ However, belimumab is ineffective for the treatment of rheumatoid arthritis, and voclosporin has not been studied in patients with rheumatoid arthritis or in those with a GFR of 45 milliliters per minute or less. The high-dose glucocorticoids that are used in induction therapy for lupus nephritis will effectively manage this patient’s inflammatory arthritis and probably also the subsequent AA amyloidosis. Finally, it is important that every patient with lupus nephritis receive hydroxychloroquine, which improves the treatment response to induction therapy.²⁹

Follow-up

Dr. Parsons: The patient’s hospital course was further complicated by suspected immune-mediated thrombocytopenia, for which she received intravenous immune globulin. Her pancytopenia and arthritis ultimately abated. Unfortunately, she did not have renal recovery and continues to receive hemodialysis. After a prolonged hospital course, she was discharged home.

Final Diagnosis

Overlap syndrome of rheumatoid arthritis and systemic lupus erythematosus complicated by proliferative lupus nephritis, superimposed on amyloid A amyloidosis.