A successful pregnancy in a patient with Takayasu's arteritis under tocilizumab treatment: A longitudinal case study.

Abstract

Dear Editor, Takayasu's arteritis (TA) is a chronic disease characterized by inflammation of large vessels.1, 2 TA is eight times more common in women and the mean time of onset is between the 2nd and 3rd decades. It is possible to observe TA at the age of 10 but rarely occurs after age 40.2, 3 The six American College of Rheumatology (ACR) TA classification criteria are as follows: age of onset <40, claudication of an extremities, decreased brachial artery pulse, difference in systolic blood pressure between arms greater than 10 mm Hg, a bruit over the subclavian arteries or the aorta, and typical angiography findings (Table 1). The presence of three of these six criteria is sufficient to meet the ACR classification.4 Methotrexate or azathioprine as well as corticosteroids are the first and most commonly used agents in treatment. Other than these standard treatments, a few studies showed that cyclophosphamide, leflunomide, mycophenolate mofetil and cyclosporin could be effective in some cases.5-10 Today, tumor necrosis factor-α blockers anti-TNF-α) are more frequently selected for resistant cases.11 In recent years, tocilizumab (TCZ) has been used as an alternative option in patients who are unresponsive or intolerant to anti-TNF-α treatment due to potential side effects.12 Similar to systemic lupus erythematosus (SLE), TA is a disease occurring especially in women of reproductive age and also sometimes patients may want to be pregnant or have established pregnancy when they come to the hospital. As it is a less common disease compared to SLE, data on the progress and treatment of TA during pregnancy are limited.13 There are very few published studies on patients who became pregnant while they were receiving TCZ therapy in clinical settings. In their study on four pregnant patients with active RA refractory to anti-TNF agents, Kaneko et al used TCZ for their patients. They reported that three patients delivered full-term infants without any adverse outcomes and one patient had a partial molar pregnancy and miscarried in the gestational week.14 In another research, Nakajima et al presented research outcomes on 50 pregnant patients who used TCZ during conception, pregnancy or lactation and TCZ was continued during lactation in two patients, and no adverse events were reported in new-born infants. Their findings revealed that the rates of natural abortion, congenital abnormalities, and other pregnancy outcomes were similar to those seen in the general population in the previous studies.15, 16 To our knowledge, there is no research that showed a case of pregnancy in a patient with TA diagnosis who was on TCZ treatment and had healthy delivery. We present a case of pregnancy in a patient with TA diagnosis who was on TCZ treatment, followed up for 12 years and had a healthy delivery outcome. In the present research, we report on a 34-year-old female patient initially presenting with weakness and easy fatigue in the left arm and elevated sedimentation rate in 2004. Physical examination revealed 2/6 bilateral carotid bruits, no pulse and blood pressure were present on the left brachial artery and radial artery. Right arm blood pressure was 110/70. The patient with normal biochemistry and whole blood analysis had erythrocyte sedimentation rate (ESR) 42 mm/h, C-reactive protein (CRP) 1.2 mg/dL (normal < 0.5). Computed tomography angiogram revealed occlusion starting from the origin of the left common carotid artery and subclavian artery. Considering the findings of the angiography, physical examination and a large number of acute-phase reactants, the patient was diagnosed with TA based on the criteria stated by ACR.4 The treatment was initiated on prednisolone 1 mg/kg, methotrexate 15 mg/wk and aspirin. The patient, whose complaints regressed, had to discontinue methotrexate in the 6th month of the treatment due to the gastric intolerance and took azathioprine 100 mg/d. In 2009, with a planned pregnancy without any complication and on the term, she gave birth to a healthy baby boy weighing 2780 g, via caesarean section under general anesthesia. No medicine was used other than prednisolone 5 mg during the pregnancy and lactation for 8 months. In 2010, prednisolone dose was increased to 30 mg and azathioprine was initiated again due to the activation. The patient, whose prednisolone dose could not be reduced below 15 mg, was administered infliximab for 2 years and adalimumab for 1 year respectively between 2011 and 2014. In December 2014, the patient under adalimumab treatment presented with pain in the left arm, fatigue, fever, dizziness and fainting and had ESR 82 mm/h, CRP 3.6 mg/dL. After obtaining informed consent and pharmacy committee approval, intravenous TCZ (8 mg/kg/mo) was initiated. The patient was in remission with this treatment and, unexpectedly, an unplanned pregnancy occurred after the 3rd infusion. TCZ was administered until the 6th gestational week. TCZ was discontinued, and the pregnancy progressed on low-dose prednisolone and aspirin (discontinued in the 32nd week). Delivery occurred in the 38th week by caesarean section under general anesthesia without any adverse maternal or fatal events. No postpartum complications were observed in mother and baby. TA, although not a very common disease, is likely to be a problem for rheumatologists and gynecologists because TA occurs especially in women of reproductive age. Pregnant cases with TA diagnosis who had TCZ exposure are under-researched. Most of the published studies in the medical literature are not in favor of using TCZ in pregnancy and TCZ should be discontinued at least 3 months before conception.3 For TA patients, worsening of existing hypertension, increased risk of arterial occlusion, aortic aneurysm development, preeclampsia, eclampsia, and renovascular hypertension are important complications for the mother. For the fetus, the risk of abortus, intrauterine loss, growth retardation, and low birth weight are more frequently seen compared to normal pregnancies. Comarmond et al reported in a pool of French patients, in which during 98 pregnancies in 52 patients, complications were present because of TA 13 times higher regardless of disease activity.17 More than 5% of pregnant patients with TA diagnosis may experience life-threatening maternal complications. Therefore, pregnancies with TA diagnosis must be considered high risk and followed up in close contact with obstetricians.18 Tocilizumab is a biologic agent which is approved for RA patients. TCZ has been approved for large vessel arteritis recently. Giant cell arteritis (GCA) was approved in the USA and GCA and TA were approved in Japan. Many case series and 1 large nationwide retrospective survey recommend that TCZ could be an alternative for treating refractory TA patients.19-22 A French nationwide survey, showed the long-term outcomes of 49 patients with TA who were treated with TNF-α antagonists and TCZ.19 In another randomized controlled trial, 36 patients with TA in Japan, found a significant difference for TCZ versus placebo.22 The 2018 update of the European League Against Rheumatism recommendations call for the management of large vessel vasculitis, and TCZ or TNF inhibitors can be taken into account in case of relapsing or refractory disease although conventional therapy is administered.23 Rheumatoid arthritis course is generally good in pregnancy, and the need for conventional or biologic treatment is lower. Therefore, while there is limited data about anti-TNF-α treatments, indeed, there is very little data about TCZ use in pregnancy and limited to RA patients only, and remains to be researched. Notably, when the relevant literature is examined, there is no pregnancy case with TA diagnosis with TCZ exposure. The current convention is not to use TCZ in pregnancy and that it should be discontinued at least 3 months before conception for patients planning pregnancy.24 Tocilizumab is a human monoclonal immunoglobulin G1 (IgG1) antibody which was developed against the interleukin-6 receptor. There is limited data on the use of TCZ. In animal studies, teratogenic/ dismorphogenetic effects have not been reported in any dose.25 When high-dose intravenous TCZ (50 mg/kg/d) was administered to pregnant monkeys, the death rate increased but no malformation was observed.24 Due to its high molecular weight, placental transfer of TCZ is not expected in the 1st trimester but is considered in the 2nd and 3rd trimester as an IgG1 antibody. Because treatment was not ongoing during pregnancy, no risk assessments have been performed.26 All of the clinic data regarding safety of TCZ during pregnancy rely on RA patients. To our knowledge, this is the first case report showing the safety of TCZ during pregnancy. Our patient received two cycles of TCZ until the 6th gestational week. Rubbert-Roth et al (2010) reported that among the 33 pregnancies in 32 RA patients (26 patients were on TCZ + MTX, six patients were on TCZ monotherapy or disease-modifying antirheumatic drugs), 13 patients had therapeutic abortus, seven had spontaneous abortus (three patients were aged ≥35) and 11 had healthy deliveries. One infant died of acute respiratory distress syndrome after emergency caesarean section for intrapartum fetomaternal hemorrhage due to placenta previa on the 3rd day and two pregnancy outcomes were unknown.27 Among pregnancies in 2072 RA patients, six patients were exposed to TCZ over 8 years. Only one patient developed spontaneous abortus, the other five pregnancies had healthy deliveries.28 It should be kept in mind that RA and TA may have different pregnancy outcomes. Thus, pregnancy safety in RA cannot be generalized to TA. There is limited data on TCZ use in pregnancy, but treatment is recommended to be discontinued in men and women 3 months before the conception.24, 29 Cases with TCZ exposure during pregnancy must be followed up using prenatal ultrasound with a multidisciplinary approach. If exposed during early pregnancy, elective termination is not considered necessary.26 It is unknown whether TCZ is excreted in human breast milk.25 Pregnancy must be planned after a long remission period to prevent complications. Detailed maternal ultrasound should be performed during pregnancies which occurred while on a biologic treatment. The findings of our research suggest that TCZ should not be administered apart from necessary health conditions due to the limited evidence in light of empirical research. Patients should be followed up by rheumatologists and obstetricians with a multidisciplinary approach during pregnancy. Data on TCZ exposure during pregnancy is limited and almost all are in RA patients. Our case is striking as it is a case that reported on a pregnant patient while on TCZ treatment and had a healthy delivery. This interesting finding calls for future research on the use of TCZ during pregnancy. The authors report no conflicts of interest. Written informed consent was obtained from the patient by the corresponding author.