科普文章
慢性喘息性支气管炎是一种慢性炎症性疾病，导致气道狭窄和呼吸困难，可根据患者的症状和病情，合理采用支气管扩张剂、类固醇激素、镇咳药物、免疫调节剂等。
1.支气管扩张剂：支气管扩张剂是最常用的药物治疗慢性喘息性支气管炎的类别。可以通过舒张支气管平滑肌，减轻气道狭窄，以改善呼吸。常见的支气管扩张剂包括短效β2-激动剂（如沙丁胺醇）、长效β2-激动剂（如沙美特罗）和长效抗胆碱能药物（如噻托溴铵）。
2.类固醇激素：类固醇激素可以减轻气道炎症和控制症状，主要是通过减少气道炎症和黏液分泌来减轻气道狭窄。常见的类固醇激素包括口服或吸入的糖皮质激素，如布地奈德、氟替卡松等。
3.镇咳药物：对于出现剧烈咳嗽的患者，可采用镇咳药物，帮助清除气道中的痰液。常见的镇咳药物包括川贝枇杷膏、复方甘草片等。
4.免疫调节剂：对于严重的慢性喘息性支气管炎患者，可考虑使用免疫调节剂，如甲基泼尼松龙、环孢素等，以控制炎症反应。
具体药物的使用，需在专业医生的指导下，根据患者病情采用合适的药物进行治疗。
咳痰是呼吸道内病理性分泌物，凭借支气管黏膜上皮细胞的纤毛运动，支气管肌肉的收缩及咳嗽时的气流冲动，将呼吸道内的分泌物从口腔排出的动作。
痰潴留在呼吸道对人体是有害的，它不仅促进呼吸道的微生物长繁殖，使本身存在的炎症扩散，还可引起断发感染。
咳痰是机体的一种保护性生理功能，痰是气管、支气管的分泌物或肺泡内的渗出物，咳痰常见于肺炎、慢性咽炎、慢性支气管炎、支气管扩张、肺脓肿与空洞型肺结核等疾病，观察痰的量，色，气味，性状常可提示诊断。
咳嗽、咳痰不仅见于上述疾病中，还可作为一个独立的症状出现。不论是何种原因的咳嗽、咳痰，都应及早到医院就诊。以免延误病情，产生不良后果。
患者有支气管哮喘、慢性喘息性支气管炎、 慢性阻塞性肺病 等缓解喘息症状，或者 心功能不全 和心源性哮喘，医生经常会给加上氨茶碱相关药物，那么氨茶碱有什么作用呢？
氨茶碱为茶碱与乙二胺复盐，其药理作用主要来自茶碱，乙二胺使其水溶性增强。氨茶碱其药理作用主要来自茶碱，乙二胺使其水溶性增强。本品对呼吸道平滑肌有直接松弛作用。其作用机理比较复杂，过去认为通过抑制磷酸二酯酶，使细胞内 cAMP 含量提高所致。
近来实验认为茶碱的支气管扩张作用部分是由于内源性肾上腺素与去甲肾上腺素释放的结果，此外，茶碱是嘌呤受体阻滞剂，能对抗腺嘌呤等对呼吸道的收缩作用。
茶碱能增强膈肌收缩力，尤其在膈肌收缩无力时作用更显著，因此有益于改善呼吸功能。本品尚有微弱舒张冠状动脉，外周血管和胆管平滑肌作用。有轻微增加收缩力和轻微利尿作用。
喘息性支气管炎是发生于儿童的一种急性支气管炎，好发于两岁左右的儿童。常见的临床症状有，咳嗽，发热，咳痰，由于患儿痰不易咳出而出现气管的喘鸣音，还有一少部分儿童会出现胸闷、呼吸困难等。
临床上对于喘息性支气管的治疗主要以抗感染以及对症治疗为主。首先需要明确感染的病原菌一般是常见的有腺病毒、甲乙型流感病毒，鼻病毒，单纯疱疹病毒等感染引起。常见的细菌感染有肺炎链球菌，卡他莫拉菌的等。针对感染的病原菌可以选择大环内酯类，青霉素，头孢菌素类抗生素，同时应用奥司他韦等抗病毒治疗。对症治疗主要是给予止咳，化痰，平喘等，积极的对症治疗可以减轻患儿支气管痉挛，从而缓解临床症状。同时建议多饮水，注意休息，饮食上加强营养，多吃高蛋白，高热量饮食来增强体质。从治疗效果上来看，喘息性支气管炎一般是可以达到根治的，但是有极少部分体弱的患者，可能由于长时间不愈而发展成为慢性支气管炎或者支气管哮喘。
总而言之，喘息性支气管炎在临床上的起病是比较急的，积极的应用药物治疗，一般在4-5天左右患者的症状可以明显减轻。后续在应用巩固治疗一般是可以达到根治的，但是也有一部分患者可能会出现长期迁延不愈。所以在药物治疗喘息性支气管炎同时要积极辅助以加强营养来增强患者的体质，有利于病情的尽早恢复。
喘息性支气管炎在临床上也是属于常见病，一般以婴幼儿的发病率比较高，在临床上属于急性支气管炎的范畴。主要见于秋冬季节和季节的更替、环境温度的下降有明显的关系。主要的临床症状有咳嗽、胸闷、憋喘、咳痰，严重的可以出现呼吸困难、全身乏力等。
对于喘息性支气管炎的治疗主要是以对症治疗和对因治疗为主。对症治疗是积极地给予止咳、化痰、平喘等药物来减轻患者的临床症状。对因治疗主要是根据喘息性支气管炎的发病原因积极的应用药物。从临床上来看，喘息性支气管炎的发病原因主要是细菌、病毒、支原体等病原菌的感染引起的。也有一部分患者是对于花粉等过敏源过敏导致的支气管痉挛引起的。积极的给予抗生素、抗病毒药物治疗，可以从根本上控制患者疾病的发展，一般的治疗疗程在十天左右。同时在治疗过程中还建议增加营养，以高热量、高维生素、高蛋白饮食为主，可以有效的提高患者的体质；注意休息、避免剧烈活动、避免过度劳累等。
总而言之，临床上对于喘息性支气管炎的治疗主要是应用药物治疗。对于轻症的患者可以应用口服药物来缓解病情，如果患者出现严重的呼吸困难，建议积极就诊于专业医院的呼吸内科，静脉输入药物来对症治疗，尽早的控制患者的病情，防止出现感染性休克等严重的并发症。
最近一则新闻引起了我的注意，
作为一个呼吸科医生的我，自喻什么样的烂肺没见过，却完全不能把这样一个“爆米花”般的病态肺部和一个如花似玉年纪的青年人联系在一起。事实却是加拿大一名17岁青少年连续吸电子烟5年后，因为咳嗽和呼吸急促去医院就诊。起初，医生诊断少年患了肺炎，给他开了抗生素。可过了几天，少年的病症并未好转，呼吸越来越困难，住院拍片后惊讶地发现少年的肺已经成了医生们所说的“爆米花肺”（popcorn lung）。接下来的两周，患者出现了持续低氧及呼吸衰竭表现，医生不得不行气管插管，并使用呼吸机帮助其呼吸。第三周，少年被转到更大的医院，经会诊，大部分专科医生认为少年很有可能要做双肺移植手术。而通常这种手术，即使成功移植后存活率也仅有5-6年。少年及其家人听闻此消息后，受到了沉重的打击。17岁，还太年轻！家人感到心痛的同时，也很纳闷，少年平时身体健康，怎么好好的肺就成了这样？
最后经医生抽丝剥茧的问诊，发现少年从5个月前，开始接触了一个潮流"网红品"--电子烟。在这5个多月里，他越抽约多，几乎各种口味都尝试一遍，医生表明，少年因长时间大量吸食后患上了闭塞性细支气管炎，在这种情况下，肺中的小气道发炎并被阻塞，从而出现了"爆米花肺"的情况。
爆米花肺疾病学名为闭塞性细支气管炎，俗称爆米花肺。最早在美国的微波爆米花工厂工人中发现，研究后发现因长期暴露在一种叫二乙酰的化学物质中，肺就变成了这种状况。而这种二乙酰，主要是用来制作爆米花时所需的黄油添加剂。所以在后来，美国的爆米花工厂禁止使用这种添加剂。此病患者起病急、持续性干咳、发热等流感样症状，活动后呼吸困难，胸痛、关节痛、少数病人伴有哮喘、偶见咯血。体征为两侧中、下肺爆破音，少数病人可无阳性体征。影像学可见多发性两肺斑片状阴影。此病例中也被事后推测为电子烟为了增加香气，增加使用感，加入了类似物质，让年轻人上瘾，最后引起少年致命的“爆米花肺”。
正是因为过去几年开始加拿大及美国电子烟正式合法，很多厂家为了增加快感，还在电子烟中添加四氢大麻酚（THC）。THC相信大家并不陌生，是大麻的重要组成部分。同样来自美国18岁女孩Simah Herman，也开始她的噩梦，16岁之前，她还是一个健康的青年。一切都在她接触了电子烟后，发生了天翻地覆的变化。Simah表示，因为看了广告的宣传，她误以为是无害的。没想到两年后，自己刚过完18岁生日不久，就出现了呼吸困难的情况。虽然因及时求医暂时保住了这条小命，Simah却非常后悔和自责。她还在网上发起了“禁电子烟运动”，以亲身经历呼吁大家远离。
生命没有第二次，你的肺也不一定有第二次选择的机会，所以请远离“爆米花肺”，请远离电子烟，更请远离所有吸食烟草等不健康的生活习惯。
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.
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.
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 arthritis 20 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.
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