天疱疮是一种慢性、复发性、严重的表皮内棘刺松解性大疱性皮肤病。患者体内存在针对Ca[sup]2+[/sup]依赖的细胞间粘连分子——钙粘蛋白的抗体,因此,在正常皮肤或黏膜上出现松弛性水疱,尼氏征阳性。
病因
本病病因尚未完全明确,现认为是一种自身免疫性疾病。天疱疮的抗原主要是桥粒,抗体主要是IgG,可见四种IgG亚型,少数为IgA。抗体结合到表皮细胞上,导致棘刺松解。天疱疮抗原的cDNA序列与钙粘蛋白有明显的同源性,故天疱疮抗体也损害了表皮细胞间的粘连功能,导致棘刺松解。
临床表现
发病年龄差别很大,平均发病年龄是50~60岁,男女发病率相近。我国传统上将天疱疮分为四型:寻常型、增殖型、落叶型、红斑型。
1.寻常型天疱疮
是天疱疮中最常见的一型,半数以上患者先是口腔黏膜发生水疱和糜烂,而后出现皮肤损害,经久不愈。以后在外观正常的皮肤出现黄豆至核桃大的水疱,疱液清或稍浑,疱壁薄而松弛易破,尼氏征阳性。水疱破裂显露潮红糜烂面,有少许渗液或结痂,创面愈合慢,自觉灼痛,愈后留色素沉着和粟丘疹。水疱可以发生于全身任何部位,常见于头面、颈、胸背、腋下、腹股沟等处。可有甲营养不良和急性甲沟炎、甲下出血。妊娠期严重的天疱疮可出现早产、死胎。
2.增殖型天疱疮
发病年龄较年轻。皮损好发于脂溢部位,如头面、腋下、脐窝、胸背、阴股部等处。初起为松弛性水疱,极易破裂形成糜烂面和蕈样、乳头状增生,在摩擦部位尤为明显。损害表面有浆液或脓液渗出,覆有厚痂,周围有炎性红晕。损害聚集成群或扩大融合成片,有腥臭。皮肤损害可发生于黏膜损害前或损害后。自觉症状不明显。病程中由于继发细菌感染,有时有高热等症状。病变时重时轻,病程较寻常型长。
本病分两型:
(1)重型(Neumann型) 皮损为水疱和大疱,破裂后肥厚性颗粒状的糜烂面,很容易出血,所形成的增殖性斑块处有血清和脓液渗出,四周围小脓疱。边界处糜烂形成新的增殖斑块,最后这些增殖性损害变得干燥、角化过度、皲裂。本型病程长,在糖皮质激素应用前很难自行缓解。
(2)轻型(Hallopeau型) 早期皮损以脓疱而不是水疱为特征。疱破后形成增殖性斑块。斑块四周有小脓疱。在损害内可培养出多种细菌。本病慢性经过,病情轻,能自行缓解,预后良好。
3.落叶型天疱疮
多在头面、躯干外观正常皮肤上发生松弛大疱,尼氏征阳性,疱壁菲薄,极易破裂,很快干燥,结黄褐色薄痂,痂皮中心附着,边缘游离,痂下湿润,渐发展至全身。皮肤暗红,覆大量叶片状痂皮,有恶臭。有时无明显水疱而似剥脱性皮炎。口腔损害少见,毛发稀疏,常可脱光。指甲可见营养不良改变。自觉瘙痒或灼痛,全身症状轻重不一,可有发热、畏寒、精神障碍等。病程可持续10年以上,预后较好,易被糖皮质激素控制,部分患者可完全缓解。
4.红斑型天疱疮
又称Senear-Usher综合征。皮损发生于头部、前额、鼻、两颊、耳壳,有时胸背部、腋窝、腹股沟也可被侵犯,但很少累及四肢。头面部皮损类似盘状或系统性红斑狼疮、脂溢性皮炎。局限性红斑上有脂性鳞屑、黄痂。上述皮损出现一至数月后,胸背部和四肢突然发生松弛性大疱,疱壁薄,易破,糜烂面渐扩大,渗液较多,表面常结成污秽色、黑褐色痂和脂性厚痂,不易脱落,预后留棕褐色色素沉着。水疱此起彼伏,尼氏征阳性。一般无黏膜损害。自觉瘙痒,全身症状不明显。
诊断
诊断要点为皮肤上有松弛大疱,尼氏征阳性,常伴有黏膜损害,水疱基底涂片可见天疱疮细胞,组织病理改变有特征性,表皮内有棘刺松解。间接免疫荧光检查血清中有天疱疮抗体,水疱周围正常皮肤或新皮损直接免疫荧光检查,表皮细胞间有IgG和C3沉积。
治疗
1.一般支持治疗
极为重要,对损害广泛者应给予高蛋白饮食,补充多种维生素。注意水、电解质平衡,禁食者应由静脉补充。全身衰竭可多次小量输血或血浆。加强护理,注意皮肤清洁卫生,以减少创面继发感染,并防止发生压疮。
2.全身治疗
(1)糖皮质激素 为治疗本病首选药物,尽量做到及时治疗,足量控制,正确减量,继用最小维持量。病情严重者可采用冲击疗法。应用糖皮质激素的患者,近半数死于糖皮质激素的并发症,如呼吸道感染、肺栓塞、糖尿病和消化道溃疡,故必须随时警惕其不良反应的发生,及时采取相应措施处理。
(2)免疫抑制剂 可抑制自身抗体的形成,是本病主要的辅助治疗方法,与糖皮质激素联合应用,可提高疗效,减少激素用量。常用者为硫唑嘌呤和环磷酰胺。
(3)金制剂 使用糖皮质激素控制病情后,可加用金制剂治疗。
(4)血浆交换疗法 适用于病情严重、糖皮质激素和免疫抑制剂联合治疗无效、血中天疱疮抗体滴度高的患者,大剂量糖皮质激素治疗有副作用或疗效不明显时可选用。每周1或2次,每次交换1~2L,根据病情可连续进行4~10次。如与小剂量的糖皮质激素或免疫抑制剂并用效果最好。
(5)其他 少数病例用以下药物治疗有效,如氨苯枫、磺胺吡胺、烟酰胺、四环素,单纯或与糖皮质激素联合使用。大剂量免疫球蛋白可是天疱疮很快缓解,但持续时间短。阿维A联合泼尼松治疗增殖型天疱疮。
3.局部治疗
注意口腔卫生,治疗牙周疾病。口腔糜烂可用2%硼酸溶液或1%过氧化氢每3~4小时漱口一次。疼痛明显时可在进食前涂用3%苯唑卡因硼酸甘油溶液,或1%普鲁卡因液含漱。皮损少时,糜烂面外用锌氧油、2%甲紫锌氧油。红斑损害可外用糖皮质激素霜。损害广泛时,注意避免条件致病菌感染,如渗液结痂较多,病人一般情况好,可采取药浴,如1:10000高锰酸钾液进行药浴。外用抗生素、抗真菌制剂。
患者应积极配合医生的治疗,定期复查,监测病情。
患者应遵从医嘱按时定量服用药物,切忌擅自停药或换药,也不要随意改变药物剂量。
有口腔损害的患者应注意口腔卫生和护理。
家庭护理
家属应做好患者的心理工作,帮助患者积极治疗。应按医生的建议,对患者的皮损进行护理。
日常生活管理
患者应注意个人卫生,保持皮肤清洁。
忌大蒜。治疗期间饮食宜清淡,食用易消化、营养丰富的食物。
注意口腔卫生,有口腔损害的,应避免坚硬、辛辣刺激类食物。使用漱口水清洁口腔。
长期服用糖皮质激素的患者由于骨质疏松
,应避免持重物,尤其是弯腰持重。
生活规律、劳逸结合,避免过劳。
日常病情监测
患者应密切注意皮肤黏膜情况,如有否新出水疱,口腔黏膜是否易破等。
特殊注意事项
治疗过程中应严格遵照医嘱用药,不要擅自停药或换药、减药,也不可随意改变药物剂量,尤其在使用糖皮质激素过程中,随意加减药物或骤然停药可能造成病情反复、甚至加重。
预防
天疱疮并无明确的诱因,无法进行有效的预防。
天疱疮是个重症、慢性的自身免疫性疾病,经过3~5年治疗,是可以达到临床治愈, 甚至完全停药的。改善本病预后的关键是早诊断、早治疗。
此外,以下因素可能影响预后:开始治疗时疾病的严重程度,病损范围,进展快慢;控制病情所需皮质激素剂量;天疱疮类型,以寻常型最重;高龄;基础疾病,如糖尿病
、高血压
等;合理减药,长期维持治疗;长期服用激素或免疫抑制剂可能产生的不良反应。
天疱疮应由专科医生诊治,并定期复诊,长期随访。
危害性
除了天疱疮本身可引起严重的皮肤黏膜损害,引起水电解质紊乱、感染等多种可危及生命的并发症之外,长期使用糖皮质激素和/或免疫抑制剂的治疗可造成诸多不良反应。
后遗症
主要为长期使用糖皮质激素和/或免疫抑制剂治疗的不良反应,如股骨头无菌坏死等。
并发症
皮肤感染:天疱疮皮损为开放性的糜烂,从而引发细菌、真菌等感染。严重时可发生脓毒血症,危及生命;
水电解质紊乱:严重天疱疮患者体表大面积的糜烂,可造成体液大量丢失,加之糖皮质激素的储钠排钾作用,可引发水电解质紊乱、低蛋白血症
;
长期服用糖皮质激素和/或免疫抑制剂治疗的不良反应,如高血压、糖尿病、易骨折
、股骨头无菌环死等;
或出现发烧、咳嗽、黑便、走路时髋部疼痛等症状,提示可能出现药物的不良反应,应请专科医生在全面评估病情后,制定新的治疗方案,包括应用利妥昔单抗等。
复发
天疱疮是复杂疾病,治疗过程中需定期随访,医生会根据病情变化及时调整治疗方案。
天疱疮是可以复发的,骤然停药、减药过快是引起复发最常见的原因。
天疱疮患者在治疗期间,若出现水疱短期内增多,糜烂面增大,表明病情有反复。
天疱疮属于自身免疫性疾病,属于慢性的、复发性的、皮肤黏膜上的疾病,一般表现在正常的皮肤黏膜上发生的松弛性的水疱,尼氏征阳性,尼氏征阳性指这个水疱往前方推动,它可以随着推移,水疱直接窜到前方,而疱壁还是正常的,但是这种水泡比较容易破裂,有的时候看不到水疱,就出现了糜烂面。分型主要有寻常型天疱疮、红斑型天疱疮、增殖型天疱疮和落叶型天疱疮。寻常型天胞疮主要好发在容易受摩擦或挤压的部位,红斑型天疱疮多发生在皮脂腺分泌比较旺盛的部位,增殖型天疱疮的表现是糜烂面之后可能出现增殖,落叶型天疱疮主要发生在头面和躯干上,水疱更薄,上面有黄褐色油腻性的斑片。
预后
天疱疮是个重症、慢性的自身免疫性疾病,经过 3~5 年治疗,是可以达到临床治愈, 甚至完全停药的。改善本病预后的关键是早诊断、早治疗。
此外,以下因素可能影响预后:
- 开始治疗时疾病的严重程度,病损范围,进展快慢;
- 控制病情所需皮质激素剂量;
- 天疱疮类型,以寻常型最重;
- 高龄;
- 基础疾病,如糖尿病、高血压等;
- 合理减药,长期维持治疗;
- 长期服用激素或免疫抑制剂可能产生的不良反应。
天疱疮应由专科医生诊治,并定期复诊,长期随访。
危害性
除了天疱疮本身可引起严重的皮肤黏膜损害,引起水电解质紊乱、感染等多种可危及生命的并发症之外,长期使用糖皮质激素和/或免疫抑制剂的治疗可造成诸多不良反应。
后遗症
主要为长期使用糖皮质激素和/或免疫抑制剂治疗的不良反应
以下内容来源于新英格兰医学杂志。
Presentation of Case
Differential Diagnosis
Movement Disorders
Seizures
Functional Movement Disorder
Dyskinesia
Limb-Shaking TIAs
Clinical Impression and Initial Management
Clinical Diagnosis
Dr. Albert Y. Hung’s Diagnosis
Pathological Discussion
Pathological Diagnosis
Additional Management
Final Diagnosis
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.
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.
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.
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
Cancer
Infectious Disease
Autoimmune Disease
Hypocomplementemia
Dr. Beth L. Jonas’s Diagnosis
Pathological Discussion
Pathological Diagnosis
Discussion of Management
Follow-up
Final Diagnosis
Overlap syndrome of rheumatoid arthritis and systemic lupus erythematosus complicated by proliferative lupus nephritis, superimposed on amyloid A amyloidosis.
以下内容来源于PubMed。
Abstract
Sacituzumab govitecan (SG) significantly improved progression-free survival (PFS) and overall survival (OS) versus chemotherapy in hormone receptor-positive human epidermal growth factor receptor 2-negative (HR+HER2-) metastatic breast cancer (mBC) in the global TROPiCS-02 study. TROPiCS-02 enrolled few Asian patients. Here we report results of SG in Asian patients with HR+HER2- mBC from the EVER-132-002 study. Patients were randomized to SG (n = 166) or chemotherapy (n = 165). The primary endpoint was met: PFS was improved with SG versus chemotherapy (hazard ratio of 0.67, 95% confidence interval 0.52-0.87; P = 0.0028; median 4.3 versus 4.2 months). OS also improved with SG versus chemotherapy (hazard ratio of 0.64, 95% confidence interval 0.47-0.88; P = 0.0061; median 21.0 versus 15.3 months). The most common grade ≥3 treatment-emergent adverse events were neutropenia, leukopenia and anemia. SG demonstrated significant and clinically meaningful improvement in PFS and OS versus chemotherapy, with a manageable safety profile consistent with prior studies. SG represents a promising treatment option for Asian patients with HR+HER2- mBC (ClinicalTrials.gov identifier no. NCT04639986 ).
以下内容来源于PubMed。
Abstract
Irritable bowel syndrome with diarrhea (IBS-D) is a common and chronic gastrointestinal disorder that is characterized by abdominal discomfort and occasional diarrhea. The pathogenesis of IBS-D is thought to be related to a combination of factors, including psychological stress, abnormal muscle contractions, and inflammation and disorder of the gut microbiome. However, there is still a lack of comprehensive analysis of the logical regulatory correlation among these factors. In this study, we found that stress induced hyperproduction of xanthine and altered the abundance and metabolic characteristics of Lactobacillus murinus in the gut. Lactobacillus murinus-derived spermidine suppressed the basal expression of type I interferon (IFN)-α in plasmacytoid dendritic cells by inhibiting the K63-linked polyubiquitination of TRAF3. The reduction in IFN-α unrestricted the contractile function of colonic smooth muscle cells, resulting in an increase in bowel movement. Our findings provided a theoretical basis for the pathological mechanism of, and new drug targets for, stress-exposed IBS-D.
Keywords: AdorA2B; Lactobacillus murinus; irritable bowel syndrome with diarrhea; spermidine; stress; type I interferon; xanthine.
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