摘要：
目的 分析症状表现为反复不明原因发热(FUO)并最终诊断为自身炎症性疾病(AUID)的成人患者的临床特点.方法 2015年4月至2017年3月北京协和医院风湿免疫科成人AUID中心前瞻性纳入反复FUO、临床拟诊单基因AUID的成人患者(≥14岁),收集其临床资料,并对其进行包含单基因AUID致病基因在内的全基因组二代测序.比较检测到单基因AUID致病基因变异的患者(基因阳性组)和未检测到单基因AUID致病基因变异的患者(基因阴性组)两组之间临床表型的差异.结果 共对51例因反复FUO临床拟诊单基因AUID的成人患者进行了基因检测,基因阳性组26例患者与基因阴性组25例.除基因阳性26例(51.0%)外,另有6例诊断周期性发热-阿弗它口炎-咽炎-淋巴结炎(PFAPA)综合征,最终确诊共32例(63.0%)成人AUID患者,其中包括家族性地中海热11例(34.4%),冷炎素相关周期性综合征5例(15.6%),NLRP12自身炎症性疾病5例(15.6%),Blau综合征2例(6.3%),YAO氏综合征2例(6.3%),肿瘤坏死因子受体相关周期性综合征1例(3.1%)以及PFAPA综合征6例(18.8%).基因阴性组25例患者中除6例诊断为PFAPA综合征外,有9例最终诊断为其他疾病,10例(40.0%)虽然临床具有AUID的表现,但是基因检测未发现与AUID相关的致病基因突变,未能获得确诊.基因阳性组与基因阴性组相比幼年起病更常见[分别为8例(30.8%),2例(8.0%),P=0.041],平均病程更长[分别为(11.2 ±10.1)年,(6.1 ± 5.9)年,P=0.031],临床症状中腹痛/腹泻更多见[分别为11例(42.3%),3例(12.0%),P=0.015],其余症状如皮疹、关节痛/炎、胸痛、眼炎、口腔溃疡等比较差异无统计学意义.51例患者中仅1例有类似疾病的家族史,最终基因检测发现NOD2基因阳性,结合临床确诊为Blau综合征.结论 AUID是成人反复FUO的主要病因之一,临床医师需要提高对AUID的认识.幼年起病、病程长、腹痛/腹泻、有AUID家族史几项临床表现与基因检测阳性率的关联更强,临床医师应对此类FUO患者警惕AUID,建议转诊至AUID专科门诊,进行基因检测并提供适宜的诊治方案.%Objective To analyze the clinical characteristics of adult patients with autoinflammatory diseases(AUID)presenting as recurrent fever of unknown origin(FUO).Methods The clinical and genetic features of 51 adult patients with recurrent FUO,who were suspected of monogenic AUID admitted in adult AUID center Department of Rheumatology,Peking Union Medical College Hospital from April 2015 to March 2017, were prospectively studied.The clinical phenotypes were compared between patients with pathogenic gene mutations and diagnosed as monogenic AUID(gene-positive group), and those without pathogenic gene mutations(gene-negative group).Results Among 51 patients,there were 26 patients with positive monogenic mutations(51.0%); in addition 6 patients were diagnosed as periodic fever-aphthous stomatitis-pharyngitis-adenitis(PFAPA)syndrome.Finally 32 patients(63.0%)were diagnosed as AUID, including 11 cases of familial Mediterranean fever(34.4%), 5 cases of cryopyrin-associated periodic syndrome(15.6%), 5 cases of NLRP12-autoinflammtory disease(15.6%), 2 cases of Blau syndrome (6.3%),2 cases of Yao syndrome(6.3%),1 case of tumor necrosis factor-receptor associated periodic syndrome(3.1%),and 6 cases of PFAPA syndrome(18.8%).Among 25 gene-negative patients except 6 cases of PFAPA syndrome, 9 were diagnosed as other diseases, and the diagnosis of AUID was not confirmed in 10 cases(40.0%).Compared with gene-negative group, gene-positive group had more common childhood-onset(30.8%vs.8.0%,P=0.041),longer disease duration(11.2 ±10.1 vs.6.1 ± 5.9,P=0.031),and more common abdominal pain/diarrhea(42.3% vs.12.0%, P=0.015).There were no significant differences in manifestations such as rash, arthralgia/arthritis, thoracic pain, eye inflammation and oral ulcers between two groups.One patient had family history of AUID, and finally diagnosed as Blau syndrome with NOD 2 gene mutation.Conclusion AUID is one of the main causes of adult patients with recurrent FUO.Childhood-onset, long disease duration, abdominal pain/diarrhea, and family history of AUID are more common in patients with AUID pathogenic gene variations.Recognizing these symptom patterns can provide the clues, leading to the initiation of gene testing for patients with recurrent FUO.Adults patients with recurrent FUO suspected of AUID should be referred to specialist physicians in adult AUID center.
