A three-arm, multicenter, open-label randomized controlled trial of hydroxychloroquine and low-dose prednisone to treat recurrent pregnancy loss in women with undifferentiated connective tissue diseases: protocol for the Immunosuppressant regimens for LIving FEtuses (ILIFE) trial

Abstract

Background Undifferentiated connective tissue disease (UCTD) is known to induce adverse pregnancy outcomes and even recurrent spontaneous abortion (RSA) by placental vascular damage and inflammation activation. Anticoagulation can prevent pregnancy morbidities. However, it is unknown whether the addition of immune suppressants to anticoagulation can prevent spontaneous pregnancy loss in UCTD patients. The purpose of this study is to evaluate the efficacy of hydroxychloroquine (HCQ) and low-dose prednisone on recurrent pregnancy loss for women with UCTD. Methods The Immunosuppressant for Living Fetuses (ILIFE) Trial is a three-arm, multicenter, open-label randomized controlled trial with the primary objective of comparing hydroxychloroquine combined with low-dose prednisone and anticoagulation with anticoagulation alone in treating UCTD women with recurrent spontaneous abortion. The third arm of using hydroxychloroquine combined with anticoagulant for secondary comparison. A total of 426 eligible patients will be randomly assigned to each of the three arms with a 1:1:1 allocation ratio. The primary outcome is the rate of live births. Secondary outcomes include adverse pregnancy outcomes and progression of UCTD. Discussion This is the first multi-center, open-label, randomized controlled trial which evaluates the efficacy of immunosuppressant regimens on pregnancy outcomes and UCTD progression. It will provide evidence on whether the immunosuppressant ameliorates the pregnancy prognosis in UCTD patients with RSA and the progression into defined connective tissue disease. Trial registration ClinicalTrials.gov NCT03671174. Registered on 14 September 2018.

Long Noncoding RNA RP11-115N4.1 Promotes Inflammatory Responses by Interacting With HNRNPH3 and Enhancing the Transcription of HSP70 in Unexplained Recurrent Spontaneous Abortion

“…Previous studies reported that recurrent miscarriage was related to rheumatoid immune-related diseases, such as undifferentiated connective tissue diseases, antiphospholipid syndrome, antinuclear autoantibodies (24)(25)(26). Our previous study also found that mixed lymphocyte reaction-blocking factors is related to high expression of some rheumatoid biomarkers (27).…”

Undifferentiated Connective Tissue Disease in Pregnancy: A Topic Yet to be Explored

“…It was shown that pregnancy and puerperium may trigger disease flares and evolution to a definite CTDs ( Castellino et al, 2011 ; Yang et al, 2020 ). Severe disease activity was reported in about 2% of pregnant women with UCTD, which typically show a more benign course compared to other CTDs, such as SLE ( Kaufman et al, 2021 ).…”

“…Moreover, endothelial dysfunction ( Laczik et al, 2014 ) and cytokine imbalance ( Nakken et al, 2015 ) were found in pregnant women with UCTD, playing a role in causing defective placentation. Therefore, ANA and inflammation may affect platelet function, imbalance coagulation/anticoagulation mechanisms promoting a prothrombotic state, cause endothelial dysfunction and, ultimately, may impair spiral arteries remodeling and placenta development, increasing the risk of PE, FGR, SGA and RPL in pregnant women with UCTD ( Yang et al, 2020 ).…”

“…Immunotherapy may also prevent placental insufficiency by regulating immune system and vascular function. Therefore, immunosuppressant do not only improve symptoms and prevent disease recurrence and progression, but may also decrease adverse pregnancy outcomes ( Yang et al, 2020 ). However, the treatment efficacy in pregnant women with UCTD has been poorly studied.…”

“…Preliminary data have suggested good pregnancy outcomes and high birth rates when UCTD patients with RPL were treated with a combination of HCQ, low-dose prednisone and anticoagulation. An ongoing three-arm, multicenter, open-label randomized controlled trial (NCT03671174) is studying pregnancy outcomes and disease course of UCTD patients with RPL using HCQ combined with low-dose prednisone, aspirin and Low Molecular Weight Heparin (LMWH) versus aspirin and LMWH alone or hydroxychloroquine combined with ASA and LMWH ( Yang et al, 2020 ).…”