Rheumatology key message Tocilizumab concentrations in breast milk were 1/500–1/1000 of those in serum. Sir, Tocilizumab is an IL-6 receptor blocker that has been approved for RA . According to previous reports, tocilizumab is effective in patients with an inadequate response to TNF-α inhibitors , and does not require co-administration of MTX . The demand for biologics has been increasing in female patients with active RA who wish to bear children. Women with RA often show remission during pregnancy and disease exacerbation during the post-partum period , and it is therefore desirable to ensure that drug treatment is compatible with breastfeeding. To achieve this goal, more data must be accumulated about the safety of anti-rheumatic drugs during pregnancy and breastfeeding . In this study, we measured tocilizumab concentrations in the breast milk of two nursing mothers with RA and evaluated the safety of their breastfed infants. This study was approved by the ethics committee of the National Center for Child Health and Development and both participants provided written informed consent. The first case was a 43-year-old female. Before pregnancy she had received tocilizumab at a dose of 400 mg (8 mg/kg) once a month for 2 years. At 5 weeks’ gestational age, tocilizumab was discontinued and the patient was switched to bi-weekly dosing of etanercept, a TNF-α inhibitor known to have lower transplacental transfer . Etanercept was continued throughout gestation, and the Clinical Disease Activity Index (CDAI) showed persistent remission. A healthy male infant was born by normal vaginal delivery at 37 weeks’ gestational age, with a birth weight of 2516 g. The mother experienced a flare of RA despite etanercept therapy, and monthly dosing of tocilizumab was resumed 5 weeks after delivery. Overall, RA was well controlled during breastfeeding. If symptoms worsened briefly, the patient received 3–6 mg/day of prednisolone and 120 mg/day of loxoprofen sodium hydrate. The patient’s infant was exclusively breastfed until the present day (at the age of 9 months), and experienced no health problems. Routine vaccinations, including the BCG vaccine, were administered without any adverse effects such as infection or immunoreaction. Maternal serum and breast milk tocilizumab concentrations were measured after the third, fourth and fifth tocilizumab treatments (13, 18 and 22 weeks after delivery, respectively). The steady-state serum concentration prior to each dose ranged from 3214 to 4512 ng/ml. Tocilizumab concentrations in breast milk were measured frequently after injections, as shown in Fig. 1A, reaching a peak ∼3 days after each injection and decreasing gradually thereafter. The maximum and minimum tocilizumab concentrations in breast milk were 68.2 ng/ml after 3 days and <2.0 ng/ml after 34 days, respectively. The milk to serum concentration ratios at these time points were 0.0015 (4.8/3214.0) and 0.0057 (19.7/3477.0), respectively. Fig. 1 View largeDownload slide Tocilizumab concentrations in the serum and breast milk (A) Case 1, (B) case 2. X-axis, post-partum weeks. Closed squares indicate the concentrations of tocilizumab in breast milk (left axis). Open circles indicated the concentrations of tocilizumab in serum (right axis). Fig. 1 View largeDownload slide Tocilizumab concentrations in the serum and breast milk (A) Case 1, (B) case 2. X-axis, post-partum weeks. Closed squares indicate the concentrations of tocilizumab in breast milk (left axis). Open circles indicated the concentrations of tocilizumab in serum (right axis). The second case was a 35-year-old female. Due to an inadequate response to a TNF-α inhibitor, she had been treated with monthly intravenous tocilizumab for 2 years until the pregnancy with her second child. Prednisolone had also been administered, and RA activity was well controlled, with low CDAI scores. At 9 days’ gestational age, tocilizumab was discontinued, leading to an exacerbation of RA and an increase in prednisolone dosage (5–8 mg/day) until delivery. A healthy female infant was born naturally at 36 weeks’ gestational age, with a birth weight of 2350 g. Nine days after delivery, tocilizumab was resumed. The patient achieved CDAI remission, and prednisolone was tapered then discontinued 2 months later. Her infant was exclusively breastfed for at least 11 months while tocilizumab was administered, with no serious infections that required hospitalization. As of 13 months of age, there has been no developmental delay. Routine vaccinations, including BCG and rotavirus vaccines, were administered without any adverse effects such as infection or immunoreaction. Maternal serum and breast milk tocilizumab concentrations were measured after the 9th and 12th tocilizumab treatments (35 and 49 weeks after delivery, respectively). The steady-state serum concentration prior to each dose ranged from 14881.6 to 24125.6 ng/ml. Tocilizumab concentrations in breast milk were measured frequently after injections, as shown in Fig. 1B. As in case 1, concentrations reached a peak ∼3 days after each injection and decreased gradually thereafter. In this case, the maximum and minimum tocilizumab concentrations in breast milk were 148.2 ng/ml after 3 days and 9.0 ng/ml after 28 days, respectively. The milk to serum concentration ratios at these time points were 0.00045 (9.0/19874.5) and 0.00082 (12.2/14881.6), respectively. Our patients were treated with tocilizumab until 9 days and 5 weeks’ gestational age, respectively, and achieved clinical RA remission after delivery without any risk to their infants. Breast milk levels of tocilizumab ranged from 1/500 to 1/1000 of those in serum. Further studies are needed to elucidate the impact of tocilizumab exposure on the breastfeeding infant. Funding: This work was supported by the Research Program from the Japanese Agency for Medical Research and Development awarded to A.M. Disclosure statement: The authors have declared no conflicts of interest. References 1 Mihara M , Kasutani K , Okazaki M et al. Tocilizumab inhibits signal transduction mediated by both mIL-6R and sIL-6R, but not by the receptors of other members of IL-6 cytokine family . Int Immunopharmacol 2005 ; 5 : 1731 – 40 . Google Scholar CrossRef Search ADS PubMed 2 Dougados M , Kissel K , Sheeran T et al. Adding tocilizumab or switching to tocilizumab monotherapy in methotrexate inadequate responders: 24-week symptomatic and structural results of a 2-year randomised controlled strategy trial in rheumatoid arthritis (ACT-RAY) . Ann Rheum Dis 2013 ; 72 : 43 – 50 . Google Scholar CrossRef Search ADS PubMed 3 Emery P , Keystone E , Tony HP et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial . Ann Rheum Dis 2008 ; 67 : 1516 – 23 . Google Scholar CrossRef Search ADS PubMed 4 Ostensen M , Husby G. A prospective clinical study of the effect of pregnancy on rheumatoid arthritis and ankylosing spondylitis . Arthritis Rheum 1983 ; 26 : 1155 – 9 . Google Scholar CrossRef Search ADS PubMed 5 Nakajima K , Watanabe O , Mochizuki M et al. Pregnancy outcomes after exposure to tocilizumab: a retrospective analysis of 61 patients in Japan . Mod Rheumatol 2016 ; 26 : 667 – 71 . Google Scholar CrossRef Search ADS PubMed 6 Murashima A , Watanabe N , Ozawa N , Saito H , Yamaguchi K. Etanercept during pregnancy and lactation in a patient with rheumatoid arthritis: drug levels in maternal serum, cord blood, breast milk and the infant’s serum . Ann Rheum Dis 2009 ; 68 : 1793 – 4 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: firstname.lastname@example.org This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)
Rheumatology – Oxford University Press
Published: Apr 4, 2018
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