化脓性无菌性关节炎-坏疽性脓皮病-痤疮综合征一例并文献复习

Targeted therapy of pyogenic sterile arthritis,pyoderma gangrenosum,and acne syndrome(PAPA):a case report and literature review

目的:了解化脓性无菌性关节炎-坏疽性脓皮病-痤疮(PAPA)综合征的发病特点及诊治情况。方法:收集2017年香港大学深圳医院诊断的1例6岁男性PAPA综合征患儿的临床资料,监测生物制剂治疗前后血红细胞沉降率(ESR)、C反应蛋白(CRP)及白细胞介素(IL)1、IL-6、肿瘤坏死因子α(TNF-α)等指标改变。以“PAPA综合征”“PSTPIP1基因”为关键词在Pubmeb、万方及知网检索1997年1月至2019年12月的文献资料,对文献资料进行汇总分析。结果:患儿男,6岁,因反复关节肿痛4年余入香港大学深圳医院。治疗前血液CRP(256 mg/L),ESR(105 mm/1 h)均升高,TNF-α,IL-1正常(7.43 ng/L、<5 ng/L),IL-6增高(301 ng/L)。关节穿刺液培养微生物无阳性发现,关节液IL-6(>1000 ng/L)明显增高。磁共振成像示右侧下肢骨质改变,考虑骨髓炎。基因测序示PSTPIP1基因杂合突变(c.748G>A,p.E250K),诊断PAPA综合征,先后选择托珠单抗及英夫利昔单抗治疗,关节肿痛症状曾好转,在有效治疗1年后症状反复。后改IL-1拮抗剂治疗,关节肿痛消退,现定期随访,未再出现关节肿痛反复。末次随访复查血液CRP、ESR、TNF-α、IL-1和IL-6均下降至正常。通过文献检索及复习,共搜索文献29篇,包含本例,共有患者87例。87例患者有关节症状的58例、脓皮病33例、痤疮24例;共发现基因型13种,突变发生在p.E250位置共有47例;治疗以激素、生物制剂为主。结论:对于反复出现非感染化脓性关节炎,炎症指标增高而无明显微生物感染证据患儿,需考虑PAPA综合征,完善基因检查有助于明确诊断,生物制剂可有效控制症状。

Objective To analyze the clinical course and targeted therapy of pyogenic sterile arthritis,pyoderma gangrenosum,and acne(PAPA)syndrome.Methods The clinical history of a 6-year-old boy with PAPA syndrome,who was admitted to Hong Kong University Shenzhen Hospital in September 2017,was reviewed.His genetic diagnosis was confirmed by whole exome sequencing.The response to targeted therapy was evaluated by comparing the inflammatory markers erythrocyte sedimentation rate(ESR)and C reactive protein(CRP)and serum cytokines(interleukin(IL)-1,IL-6 and tumor necrosis factor-α(TNF-α))before and after biological agents treatment.For literature review,"PAPA syndrome"and"PSTPIP1 gene"were used as keywords to retrieve papers published from January 1997 to December 2019 from Pubmed,Wanfang and CNKI database.Results The patient was a 6-year-old boy,admitted to the hospital due to recurrent joint swelling and pain for more than 4 years.Before treatment,the CRP(256 mg/L),ESR(105 mm/1 h)and cytokines including serum TNF-α(7.43 ng/L),IL-1(<5 ng/L),IL-6(301 ng/L)were significantly elevated.Culture of the joint effusion was negative,but the IL-6 level was above 1000 ng/L.MRI showed osteomyelitis at the lower end of the right femur.Gene detection found a heterozygous variation of PSTPIP1 gene(c.748G>A,p.E250K).Arthralgia once alleviated after the initiation of tocilizumab and infliximab,but recurred after 1 year of treatment.Thereafter,the anti-IL-1 receptor antagonist(Anakinra)was commenced,followed by a significant improvement of the arthralgia,and a complete remission during the follow-up.Besides,the level of CRP,ESR,serum TNF-α,IL-1 and IL-6 were all decreased to normal on the last followed up in December 2019.Literature review found 29 articles and 87 patients in total.The initial symptoms included those of arthritis(n=58),pyoderma gangrenosum(n=33),and acne(n=24).Among all the cases,13 genotypes were confirmed,and 47 variations involved amino acid p.E250.Steroid and/or biological agents were used in most patients.Conclusions PAPA syndrome should be suspected in children with recurrent pyogenic sterile arthritis,and an early diagnosis could be achieved by genetic test.Targeted treatment with biological agent may control the symptoms effectively.Biological agents can control symptoms of this disorder effectively.