The Ohio State University College of Medicine, OH, Columbus, USA.
Nationwide Children's Hospital, Ohio, Columbus, USA.
Pediatr Rheumatol Online J. 2021 Jun 7;19(1):84. doi: 10.1186/s12969-021-00581-7.
Children with rheumatic diseases (cRD) receiving immunosuppressive medications (IM) are at a higher risk for acquiring potentially lethal pathogens, including Histoplasma capsulatum (histoplasmosis), a fungal infection that can lead to prolonged hospitalization, organ damage, and death. Withholding IM during serious infections is recommended yet poses risk of rheumatic disease flares. Conversely, reinitiating IM increases risk for infection recurrence. Tumor necrosis factor alpha inhibitor (TNFai) biologic therapy carries the highest risk for histoplasmosis infection after epidemiological exposure, so other IM are preferred during active histoplasmosis infection. There is limited guidance as to when and how IM can be reinitiated in cRD with histoplasmosis. This case series chronicles resumption of IM, including non-TNFai biologics, disease-modifying anti-rheumatic drugs (DMARDs), and corticosteroids, following histoplasmosis among cRD.
We examine clinical characteristics and outcomes of 9 patients with disseminated or pulmonary histoplasmosis and underlying rheumatic disease [juvenile idiopathic arthritis (JIA), childhood-onset systemic lupus erythematosus (cSLE), and mixed connective tissue disease (MCTD)] after reintroduction of IM. All DMARDs and biologics were halted at histoplasmosis diagnosis, except hydroxychloroquine (HCQ), and patients began antifungals. Following IM discontinuation, all patients required systemic or intra-articular steroids during histoplasmosis treatment, with 4/9 showing Cushingoid features. Four patients began new IM regimens [2 abatacept (ABA), 1 HCQ, and 1 methotrexate (MTX)] while still positive for histoplasmosis, with 3/4 (ABA, MTX, HCQ) later clearing their histoplasmosis and 1 (ABA) showing decreasing antigenemia. Collectively, 8/9 patients initiated or continued DMARDs and/or non-TNFai biologic use (5 ABA, 1 tocilizumab, 1 ustekinumab, 3 MTX, 4 HCQ, 1 leflunomide). No fatalities, exacerbations, or recurrences of histoplasmosis occurred during follow-up (median 33 months).
In our cohort of cRD, histoplasmosis course following reintroduction of non-TNFai IM was favorable, but additional studies are needed to evaluate optimal IM management during acute histoplasmosis and recovery. In this case series, non-TNFai biologic, DMARD, and steroid treatments did not appear to cause histoplasmosis recurrence. Adverse events from corticosteroid use were common. Further research is needed to implement guidelines for optimal use of non-TNFai (like ABA), DMARDs, and corticosteroids in cRD following histoplasmosis presentation.
接受免疫抑制药物（IM）治疗的风湿性疾病（cRD）儿童存在更高的风险，可能会感染潜在致命病原体，包括荚膜组织胞浆菌（荚膜组织胞浆菌病），这是一种真菌感染，可导致长期住院、器官损伤和死亡。建议在严重感染期间停止使用 IM，但这会增加风湿性疾病发作的风险。相反，重新开始使用 IM 会增加感染复发的风险。肿瘤坏死因子-α抑制剂（TNFai）生物疗法在流行病学暴露后感染荚膜组织胞浆菌的风险最高，因此在活动性荚膜组织胞浆菌感染期间，建议优先使用其他 IM。对于患有荚膜组织胞浆菌的 cRD 患者，何时以及如何重新开始使用 IM（包括非 TNFai 生物制剂、改善病情的抗风湿药物（DMARDs）和皮质类固醇），目前的指导意见有限。本病例系列报告了在 cRD 中重新引入 IM（包括非 TNFai 生物制剂、DMARDs 和皮质类固醇）后，发生播散性或肺荚膜组织胞浆菌病和潜在风湿性疾病（幼年特发性关节炎（JIA）、儿童发病系统性红斑狼疮（cSLE）和混合性结缔组织病（MCTD））的患者的临床特征和结局。所有 DMARDs 和生物制剂在荚膜组织胞浆菌病诊断时均停止使用，除羟氯喹（HCQ）外，患者开始使用抗真菌药物。停止使用 IM 后，所有患者在治疗荚膜组织胞浆菌病期间均需要全身或关节内皮质类固醇治疗，其中 4/9 例出现库欣样特征。4 名患者开始新的 IM 方案[2 种阿巴西普（ABA）、1 种 HCQ 和 1 种甲氨蝶呤（MTX）]，同时仍呈荚膜组织胞浆菌阳性，其中 3/4（ABA、MTX、HCQ）后来清除了荚膜组织胞浆菌，1（ABA）显示抗原血症减少。总的来说，8/9 名患者开始或继续使用 DMARDs 和/或非 TNFai 生物制剂（5 种 ABA、1 种托珠单抗、1 种乌司奴单抗、3 种 MTX、4 种 HCQ、1 种来氟米特）。在随访期间（中位数 33 个月），没有发生死亡、病情加重或荚膜组织胞浆菌复发。
在我们的 cRD 队列中，重新引入非 TNFai IM 后的荚膜组织胞浆菌病病程良好，但需要进一步研究来评估急性荚膜组织胞浆菌病和恢复期的最佳 IM 管理。在本病例系列中，非 TNFai 生物制剂、DMARD 和类固醇治疗似乎没有导致荚膜组织胞浆菌病复发。皮质类固醇治疗的不良反应很常见。需要进一步研究，以制定在 cRD 中出现荚膜组织胞浆菌病后使用非 TNFai（如 ABA）、DMARD 和皮质类固醇的最佳使用指南。
