Abstract：
OBJECTIVE: Juvenile arthritis caused by loss-of-function LACC1 mutations is characterized by early onset of symmetric and chronic arthritis, associated with an elevation of inflammatory markers. We aimed to describe serum cytokine levels, explore the type I interferon pathway, and evaluate the efficacy of treatment in a patient presenting with polyarthritis and anemia caused by novel compound heterozygous variations in LACC1.
METHODS: Clinical data of a patient with compound heterozygous variations in LACC1 was collected. Serum cytokine levels and IFN-stimulated cytokine genes were analyzed at diagnosis, at disease flare, and after treatment. Full-length cDNA of LACC1 was checked by RNA analysis. Single-cell RNA sequencing was performed in PBMCs.
RESULTS: Two novel variants in the LACC1 gene were identified in a patient presenting with polyarthritis and anemia. LACC1-cDNA was normally expressed in the healthy control, the target production at 1384 bp was not observed in the patient. Compared to nine patient controls with non-systemic juvenile idiopathic arthritis, serum interleukin(IL)-6 level was significantly elevated in the affected patient. The median IFN score for the patient, her mother, and controls were 118, 8, and 4.9, respectively. The combined treatment of JAK inhibitors with prednisone or tocilizumab led to a complete response, including remission of joint symptoms, resolution of anemia, reduced expression of IFN-stimulated cytokine genes, and normalized levels of inflammatory markers, including CRP, ESR, SAA, and serum IL-6.
CONCLUSIONS: LACC1 may play a crucial role in multiple inflammatory signaling pathways. The combination therapy of JAK inhibitors and tocilizumab may be effective for a subset of refractory patients.
METHODS: Clinical data of a patient with compound heterozygous variations in LACC1 was collected. Serum cytokine levels and IFN-stimulated cytokine genes were analyzed at diagnosis, at disease flare, and after treatment. Full-length cDNA of LACC1 was checked by RNA analysis. Single-cell RNA sequencing was performed in PBMCs.
RESULTS: Two novel variants in the LACC1 gene were identified in a patient presenting with polyarthritis and anemia. LACC1-cDNA was normally expressed in the healthy control, the target production at 1384 bp was not observed in the patient. Compared to nine patient controls with non-systemic juvenile idiopathic arthritis, serum interleukin(IL)-6 level was significantly elevated in the affected patient. The median IFN score for the patient, her mother, and controls were 118, 8, and 4.9, respectively. The combined treatment of JAK inhibitors with prednisone or tocilizumab led to a complete response, including remission of joint symptoms, resolution of anemia, reduced expression of IFN-stimulated cytokine genes, and normalized levels of inflammatory markers, including CRP, ESR, SAA, and serum IL-6.
CONCLUSIONS: LACC1 may play a crucial role in multiple inflammatory signaling pathways. The combination therapy of JAK inhibitors and tocilizumab may be effective for a subset of refractory patients.
摘要：
目的：由功能丧失型LACC1突变引起的幼年关节炎的特点是早期发作的对称性和慢性关节炎，与炎症标志物升高有关。我们的目的是描述血清细胞因子水平，探索I型干扰素途径，并评估由LACC1的新型复合杂合变异引起的多关节炎和贫血患者的治疗效果。
方法：收集LACC1复合杂合变异患者的临床数据。在诊断时分析血清细胞因子水平和IFN刺激的细胞因子基因，在疾病爆发时，和治疗后。通过RNA分析检查LACC1的全长cDNA。在PBMC中进行单细胞RNA测序。
结果：在一名患有多关节炎和贫血的患者中发现了LACC1基因的两个新变异。LACC1-cDNA在健康对照中正常表达，在患者中未观察到目标产量为1384bp.与9例非系统性幼年特发性关节炎患者对照相比，受影响患者的血清白细胞介素（IL）-6水平显着升高。患者的IFN评分中位数，她的母亲,对照组分别为118,8和4.9.JAK抑制剂与泼尼松或托珠单抗的联合治疗导致完全反应，包括关节症状的缓解,贫血的解决，IFN刺激的细胞因子基因表达降低，和炎症标志物的正常化水平，包括CRP,ESR,SAA,和血清IL-6。
结论：LACC1可能在多种炎症信号通路中起关键作用。JAK抑制剂和托珠单抗的联合治疗可能对一部分难治性患者有效。
方法：收集LACC1复合杂合变异患者的临床数据。在诊断时分析血清细胞因子水平和IFN刺激的细胞因子基因，在疾病爆发时，和治疗后。通过RNA分析检查LACC1的全长cDNA。在PBMC中进行单细胞RNA测序。
结果：在一名患有多关节炎和贫血的患者中发现了LACC1基因的两个新变异。LACC1-cDNA在健康对照中正常表达，在患者中未观察到目标产量为1384bp.与9例非系统性幼年特发性关节炎患者对照相比，受影响患者的血清白细胞介素（IL）-6水平显着升高。患者的IFN评分中位数，她的母亲,对照组分别为118,8和4.9.JAK抑制剂与泼尼松或托珠单抗的联合治疗导致完全反应，包括关节症状的缓解,贫血的解决，IFN刺激的细胞因子基因表达降低，和炎症标志物的正常化水平，包括CRP,ESR,SAA,和血清IL-6。
结论：LACC1可能在多种炎症信号通路中起关键作用。JAK抑制剂和托珠单抗的联合治疗可能对一部分难治性患者有效。
