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Takayasu arteritis (TAK) is an idiopathic large vessel vasculitis, which occurs most commonly in women of reproductive age. During pregnancy, TAK is associated with adverse pregnancy outcomes, including hypertensive disorders, preterm delivery and fetal growth restriction.1 Hence, controlling the disease activity before conception and during pregnancy is highly important for women with TAK who wish to have children. Although prednisolone (PSL) is the first-line drug for TAK, remission is sustained in only 28% of patients with TAK for more than 6 months when PSL is reduced to 10 mg/day or less.2
Tocilizumab (TCZ) is a recombinant humanised anti-interleukin-6-receptor monoclonal IgG antibody with stable or improved activity against TAK. The steroid-sparing effects of TCZ were demonstrated in a randomised, placebo-controlled, double-blind study.3 However, the safety and efficacy of TCZ in pregnancies complicated with TAK are unclear.
Herein, we describe the cases of three primiparous women with refractory TAK (table 1). TCZ treatment combined with PSL was required before pregnancy. The cardiovascular risks during pregnancy were very high in all cases: severe stenosis of the ostial right coronary artery in case 1, pulmonary hypertension resulting from bilateral pulmonary artery stenosis in case 2, and type V TAK of Numano scale and chronic hypertension in case 3. Therefore, TCZ treatment was maintained through pregnancy. All three women delivered vaginally at term without TAK relapse or adverse cardiovascular events. They also kept in good condition for the 1-year follow-up after delivery. Their neonates showed no signs of congenital anomalies or immunological disorders at birth and progressed with no physical or developmental problems for 1 year after birth.
Long-term use of high-dose glucocorticoids and the aggravation of maternal autoimmune disease itself may pose risks of adverse pregnancy outcomes. The American College of Rheumatology guideline strongly recommends a dose reduction of glucocorticoids to <20 mg/day of prednisone before trying to conceive. The three women in the report achieved well-controlled remission of TAK without adverse pregnancy outcome while using TCZ and 5–10 mg of PSL before and after conception.
Very few reports describe TCZ use during pregnancy, and the existing reports mainly include patients with rheumatoid arthritis. Nakajima et al reported the cases of 61 pregnant women exposed to TCZ, including two patients who continued TCZ throughout pregnancy.4 They found no significant increases in miscarriage or congenital anomalies. Of the 36 live births, 5 (13.9%) neonates had birth weights <2500 g. However, in four of these five cases, TCZ was discontinued at the first trimester. Hoeltzenbein et al also reported no substantial increase in congenital anomalies (4.5% with co-medications included methotrexate in 21.1%), but increase in preterm birth (31.2%) in a study of 288 pregnant women exposed to TCZ.5 In pregnancies complicated with rheumatoid arthritis, high disease activity increases the risk of preterm birth. The author speculated that TCZ treatment was discontinued in the majority of study patients after recognition of pregnancy, which might have led to increased disease activity and resulted in increased preterm birth, although the effects of TCZ exposure could not be excluded due to the lack of data. Moreover, a recent analysis of the WHO pharmacovigilance database reported no significant increase of fetal and neonatal adverse reactions to TCZ taken during pregnancy by women with autoimmune diseases.6
Based on the outcomes of these previous reports and our case series, the benefits of using TCZ during pregnancy in women with refractory TAK include preventing relapses and sparing PSL doses and may outweigh any possible harm, such as immunosuppression of neonates. Therefore, TCZ throughout pregnancy may lead to favourable clinical courses and pregnancy outcomes in patients with refractory TAK.
Patient consent for publication
Contributors CAK and YNa conceived the idea of the report. NK and CAK drafted the original manuscript. TK and YNa supervised the contents of the manuscript. All authors reviewed the manuscript draft and revised it critically for intellectual content. All authors approved the final version of the manuscript to be published.
Funding This report was supported by the Japan Agency for Medical Research and Development (grant number 22ek0109578h0001).
Competing interests YNa has received consulting fees, speaker’s fees and research grants from Chugai Pharmaceutical Co.
Provenance and peer review Not commissioned; externally peer reviewed.