Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Changhua Christian Hospital, 135 Nanxiao St., Changhua City, 500-06, Taiwan.
Department of Allergy, Immunology, and Rheumatology, Tungs' Taichung MetroHarbor Hospital, 699, Sec. 8, Taiwan Blvd., Taichung City, 43503, Taiwan.
Adv Rheumatol. 2021 Apr 8;61(1):22. doi: 10.1186/s42358-021-00173-9.
Hepatitis B virus (HBV) reactivation consequent to immunosuppressive therapy is an increasingly prevalent problem with serious clinical implications. Treatment with biologic agents conduces to the loss of protective antibody to HBV surface antigen (anti-HBs), which significantly increases the risk of HBV reactivation. Hence, we investigated the risk factors for losing anti-HBs in patients with rheumatic diseases and HBV surface antigen negative/anti-HBs positive (HBsAg-/anti-HBs+) serostatus during treatment with biologic disease-modifying anti-rheumatic drugs (DMARDs).
Using a nested case-control design, we prospectively enrolled patients with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis/psoriasis, or juvenile idiopathic arthritis, who were treated with biologic DMARDs at Changhua Christian Hospital, Taiwan, from January 2013 to June 2019 and had HBsAg-/anti-HBs+ serostatus; the analytic sample excluded all patients with HBsAg+ or anti-HBs- serostatus. Anti-HBs titers were monitored 6-monthly and cases were defined as anti-HBs < 10 mIU/ml during follow-up. Cases were matched one-to-all with controls with anti-HBs ≥ 10 mIU/ml on the same ascertainment date and equivalent durations of biologic DMARDs treatment (control patients could be resampled and could also become cases during follow-up). Between-group characteristics were compared and risk factors for anti-HBs loss were investigated by conditional logistic regression analyses.
Among 294 eligible patients, 23 cases were matched with 311 controls. The incidence of anti-HBs loss was ~ 2.7%/person-year during biologic DMARDs treatment. Besides lower baseline anti-HBs titer (risk ratio 0.93, 95% CI 0.89-0.97), cases were significantly more likely than controls to have diabetes mellitus (risk ratio 4.76, 95% CI 1.48-15.30) and chronic kidney disease (risk ratio 14.00, 95% CI 2.22-88.23) in univariate analysis. Risk factors remaining significantly associated with anti-HBs loss in multivariate analysis were lower baseline anti-HBs titer (adjusted risk ratio 0.93, 95% CI 0.88-0.97) and chronic kidney disease (adjusted risk ratio 45.68, 95% CI 2.39-871.5).
Besides lower baseline anti-HBs titer, chronic kidney disease also strongly predicts future anti-HBs negativity in patients with HBsAg-/anti-HBs+ serostatus who receive biologic DMARDs to treat rheumatic diseases. Patients with low anti-HBs titer (≤ 100 mIU/ml) and/or chronic kidney disease should be monitored during biologic DMARDs therapy, to enable timely prophylaxis to preempt potential HBV reactivation.
免疫抑制治疗后乙型肝炎病毒（HBV）再激活是一个日益普遍的问题，具有严重的临床意义。生物制剂治疗会导致对 HBV 表面抗原（抗-HBs）的保护性抗体丧失，这显著增加了 HBV 再激活的风险。因此，我们研究了在接受生物疾病修正抗风湿药物（DMARDs）治疗时，HBV 表面抗原阴性/抗-HBs 阳性（HBsAg-/抗-HBs+）血清状态的风湿性疾病患者中，导致抗-HBs 丧失的危险因素。
使用巢式病例对照设计，我们前瞻性招募了 2013 年 1 月至 2019 年 6 月在台湾彰化基督教医院接受生物 DMARDs 治疗的类风湿关节炎、强直性脊柱炎、银屑病关节炎/银屑病或幼年特发性关节炎患者，且 HBsAg-/抗-HBs+血清状态；分析样本排除了所有 HBsAg+或抗-HBs-血清状态的患者。每 6 个月监测抗-HBs 滴度，随访期间抗-HBs < 10 mIU/ml 定义为病例。病例与在同一确定日期和等效生物 DMARDs 治疗时间（对照患者可以重新采样，并且在随访期间也可以成为病例）的抗-HBs ≥ 10 mIU/ml 的对照患者进行一对一匹配。比较组间特征，并通过条件逻辑回归分析探讨抗-HBs 丧失的危险因素。
在 294 名符合条件的患者中，23 例与 311 例对照匹配。在生物 DMARDs 治疗期间，抗-HBs 丧失的发生率约为 2.7%/人年。除了较低的基线抗-HBs 滴度（风险比 0.93，95%置信区间 0.89-0.97）外，病例组与对照组相比，糖尿病（风险比 4.76，95%置信区间 1.48-15.30）和慢性肾脏病（风险比 14.00，95%置信区间 2.22-88.23）的发生率显著更高。多变量分析中与抗-HBs 丧失显著相关的危险因素仍为较低的基线抗-HBs 滴度（调整风险比 0.93，95%置信区间 0.88-0.97）和慢性肾脏病（调整风险比 45.68，95%置信区间 2.39-871.5）。
除了较低的基线抗-HBs 滴度外，慢性肾脏病也强烈预示着 HBsAg-/抗-HBs+血清状态患者在接受生物 DMARDs 治疗风湿性疾病时未来的抗-HBs 阴性。抗-HBs 滴度较低（≤100 mIU/ml）和/或慢性肾脏病的患者应在接受生物 DMARDs 治疗期间进行监测，以便及时进行预防以预防潜在的 HBV 再激活。
