Immunology Outpatient Clinic, Vienna, Austria.
Harvard Medical School, Massachusetts General Hospital, Boston, MA, United States.
Front Immunol. 2020 Oct 21;11:574738. doi: 10.3389/fimmu.2020.574738. eCollection 2020.
Vasculitis can be a life-threatening complication associated with high mortality and morbidity among patients with primary immunodeficiencies (PIDs), including variants of severe and combined immunodeficiencies ((S)CID). Our understanding of vasculitis in partial defects in recombination activating gene (RAG) deficiency, a prototype of (S)CIDs, is limited with no published systematic evaluation of diagnostic and therapeutic modalities. In this report, we sought to establish the clinical, laboratory features, and treatment outcome of patients with vasculitis due to partial RAG deficiency. Vasculitis was a major complication in eight (13%) of 62 patients in our cohort with partial RAG deficiency with features of infections and immune dysregulation. Vasculitis occurred early in life, often as first sign of disease (50%) and was complicated by significant end organ damage. Viral infections often preceded the onset of predominately non-granulomatous-small vessel vasculitis. Autoantibodies against cytokines (IFN-α, -ω, and IL-12) were detected in a large fraction of the cases tested (80%), whereas the majority of patients were anti-neutrophil cytoplasmic antibodies (ANCA) negative (>80%). Genetic diagnosis of RAG deficiency was delayed up to 2 years from the onset of vasculitis. Clinical cases with sole skin manifestation responded well to first-line steroid treatment, whereas systemic vasculitis with severe end-organ complications required second-line immunosuppression and/or hematopoietic stem cell transplantation (HSCT) for definitive management. In conclusion, our data suggest that vasculitis in partial RAG deficiency is prevalent among patients with partial RAG deficiency and is associated with high morbidity. Therefore, partial RAG deficiency should be included in the differential diagnosis of patients with early-onset systemic vasculitis. Diagnostic serology may be misleading with ANCA negative findings, and search for conventional autoantibodies should be extended to include those targeting cytokines.
血管炎可导致原发性免疫缺陷（PID）患者发生危及生命的并发症，这些患者的死亡率和发病率较高，包括严重和联合免疫缺陷（(S)CID）的变异型。我们对部分重组激活基因（RAG）缺陷患者（S)CID 的典型疾病）血管炎的认识有限，尚无关于诊断和治疗方式的系统评估。在本报告中，我们旨在确定部分 RAG 缺陷患者血管炎的临床、实验室特征和治疗结果。在我们的部分 RAG 缺陷患者队列中，有 8 例（13%）患有血管炎，其特征为感染和免疫失调。血管炎是主要并发症，发生于生命早期，通常是疾病的首发表现（50%），并伴有严重的终末器官损伤。病毒感染常先于主要为非肉芽肿性小血管血管炎的发生。经检测，在很大一部分病例中检测到针对细胞因子（IFN-α、-ω 和 IL-12）的自身抗体（80%），而大多数患者抗中性粒细胞胞质抗体（ANCA）阴性（>80%）。RAG 缺陷的基因诊断直到血管炎发病后 2 年才延迟。仅有皮肤表现的临床病例对一线类固醇治疗反应良好，而伴有严重终末器官并发症的系统性血管炎需要二线免疫抑制和/或造血干细胞移植（HSCT）进行明确治疗。总之，我们的数据表明，部分 RAG 缺陷患者中血管炎较为常见，且发病率较高。因此，部分 RAG 缺陷应纳入早期系统性血管炎患者的鉴别诊断中。诊断性血清学可能具有误导性，出现 ANCA 阴性结果，应扩大对传统自身抗体的检测，包括针对细胞因子的自身抗体。
