Immuno-Rheumatology Center, St. Luke's International Hospital, 9-1 Akashi-Cho, Chuo-Ku, Tokyo, Japan.
Department of Rheumatic Diseases, Tokyo Metropolitan Tama Medical Center, Tokyo, Japan.
Arthritis Res Ther. 2024 Jan 4;26(1):15. doi: 10.1186/s13075-023-03256-8.
Tacrolimus is one of the major treatment options for systemic lupus erythematosus (SLE) and is considered to be a pregnancy-compatible medication. Since little is known about tacrolimus safety during pregnancy complicated by SLE, this study was designed.
We included SLE pregnant patients who were followed up at two Japanese tertiary referral centers. We performed multivariate logistic regression analysis to assess each adverse pregnancy outcome (APO) risk. Moreover, we assessed the influence of tacrolimus on the APO ratio in pregnant patients with lupus nephritis, and the impact of combined tacrolimus-aspirin therapy on the APO ratio relative to patients exclusively administered tacrolimus.
Of the 124 pregnancies, 29 were exposed to tacrolimus. Multivariate analysis showed no statistical difference in APO ratio. (overall APO: adjusted odds ratio [aOR], 0.69; 95% confidence interval [CI], 0.23-2.03; p = 0.50; maternal APO: aOR, 1.17; 95% CI, 0.36-3.83; p = 0.80; neonatal APO: aOR, 1.10; 95% CI, 0.38-3.21; p = 0.86; PROMISSE APO: aOR, 0.50; 95% CI, 0.14-1.74; p = 0.27). Blood pressure and estimated glomerular filtration rate (eGFR) during pregnancy and after delivery did not differ between the two groups. Receiver operating characteristic (ROC) curve showed that tacrolimus concentration > 2.6 ng/ml was related to reduced preterm birth rate. (AUC = 0.85, 95% CI: 0.61-1.00, sensitivity: 93% and specificity: 75%). Regarding effect of tacrolimus on lupus nephritis during pregnancy, tacrolimus showed no increased risk of APO, blood pressure or eGFR during pregnancy and after delivery. (overall APO: OR, 1.00; 95% CI, 0.25-4.08; p = 0.98; maternal APO: OR 1.60, 95% CI, 0.39-6.64; p = 0.51; neonatal APO: OR, 0.71; 95% CI, 0.17-3.03; p = 0.65, PROMISSE APO: OR, 0.50; 95% CI, 0.08-3.22; p = 0.47). Tacrolimus-aspirin combination therapy showed a protective tendency against hypertensive disorders during pregnancy, preeclampsia and low birth weight.
Tacrolimus use during pregnancy with SLE and lupus nephritis showed no significant influence on APO, blood pressure, or renal function; therefore tacrolimus may be suitable for controlling lupus activity during pregnancy. In addition, when using tacrolimus during pregnancy, we should aim its trough concentration ≥ 2.6 ng/ml while paying careful attention to possible maternal side effects of tacrolimus.
Retrospectively registered.
他克莫司是治疗系统性红斑狼疮（SLE）的主要治疗方案之一，被认为是一种妊娠期适用的药物。由于人们对妊娠期合并 SLE 患者使用他克莫司的安全性知之甚少，因此开展了本研究。
我们纳入在日本两家三级转诊中心接受随访的 SLE 妊娠患者。我们进行了多变量逻辑回归分析，以评估每种不良妊娠结局（APO）的风险。此外，我们评估了他克莫司对狼疮性肾炎妊娠患者 APO 比值的影响，以及他克莫司-阿司匹林联合治疗对 APO 比值的影响，与仅接受他克莫司治疗的患者相比。
在 124 例妊娠中，有 29 例接受了他克莫司治疗。多变量分析显示 APO 比值无统计学差异。（总体 APO：调整后的优势比[aOR]，0.69；95%置信区间[CI]，0.23-2.03；p=0.50；母亲 APO：aOR，1.17；95%CI，0.36-3.83；p=0.80；新生儿 APO：aOR，1.10；95%CI，0.38-3.21；p=0.86；PROMISSE APO：aOR，0.50；95%CI，0.14-1.74；p=0.27）。两组妊娠和产后的血压和估算肾小球滤过率（eGFR）无差异。受试者工作特征（ROC）曲线显示，他克莫司浓度>2.6ng/ml 与早产率降低有关。（AUC=0.85，95%CI：0.61-1.00，敏感性：93%，特异性：75%）。关于他克莫司对妊娠期狼疮性肾炎的影响，他克莫司对妊娠和产后的 APO、血压或 eGFR 无增加风险。（总体 APO：OR，1.00；95%CI，0.25-4.08；p=0.98；母亲 APO：OR 1.60，95%CI，0.39-6.64；p=0.51；新生儿 APO：OR，0.71；95%CI，0.17-3.03；p=0.65，PROMISSE APO：OR，0.50；95%CI，0.08-3.22；p=0.47）。他克莫司-阿司匹林联合治疗对妊娠期高血压疾病、子痫前期和低出生体重有保护作用。
SLE 和狼疮性肾炎妊娠患者使用他克莫司对 APO、血压或肾功能无明显影响；因此，他克莫司可能适合妊娠期控制狼疮活动。此外，在妊娠期间使用他克莫司时，我们应将其谷浓度目标设定为≥2.6ng/ml，同时密切关注他克莫司可能产生的母体副作用。
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