ABSTRACT
OBJECTIVE: To determine whether blocking the neonatal Fc receptor (FcRn) during gestation with an anti-FcRn monoclonal antibody (mAb) reduces transfer of pathogenic maternal antibodies in utero and decreases the likelihood of maternal antibody-mediated neonatal disease in the offspring. METHODS: Using a previously established maternal-to-fetal transfer mouse model of arthrogryposis multiplex congenita (AMC), we assessed the effect of 4470, an anti-FcRn mAb, on the transfer of total human immunoglobulin G (IgG) and specific acetylcholine receptor (AChR)-antibodies from mother to fetus, as well as its effect on the prevention of neurodevelopmental abnormalities in the offspring. RESULTS: Offspring of pregnant dams treated with 4470 during gestation showed a substantial reduction in total human IgG and AChR antibody levels compared with those treated with the isotype mAb control. Treatment with 4470 was also associated with a significant reduction in AMC-IgG-induced deformities (limb or spinal curve malformations) when compared with mAb control-exposed embryos and a nonsignificant increase in the percentage of fetuses showing spontaneous movements. 4470 exposure during pregnancy was not associated with changes in general parameters of maternal well-being or fetal development; indeed, male neonates showed faster weight gain and shorter time to reach developmental milestones. CONCLUSIONS: FcRn blockade is a promising therapeutic strategy to prevent the occurrence of AMC and other human maternal autoantibody-related diseases in the offspring.
Subject(s)
Antibodies, Blocking/administration & dosage , Antibodies, Monoclonal/administration & dosage , Arthrogryposis/prevention & control , Autoantibodies/drug effects , Histocompatibility Antigens Class I/drug effects , Maternal-Fetal Exchange , Receptors, Fc/drug effects , Animals , Animals, Newborn , Disease Models, Animal , Female , Humans , Immunoglobulin G , Mice , Mice, Inbred ICR , Pregnancy , Receptors, Cholinergic/immunologyABSTRACT
Neonatal mysthenia gravis (NMG) is a rare cause of arthrogryposis multiplex congenita (AMC) due to diaplacental transfer of maternal acetylcholine receptors (AChR) antibodies. 2 cases of severe NMG complicated by chronic lung disease and pulmonary arterial hypertension are reported. With respect to the severe course of the index patient, prenatal diagnosis and immunomodulation treatment were offered during the 2nd pregnancy. The combination of prenatal immunoadsorption (IA) therapy, administration of intravenous immunoglobulin (IVIG) and prednisolone failed. Failure may be partly explained by immaturity of the infant. However, considering the successful treatment of fetal/neonatal alloimmune thrombocytopenia (AIT) reported in literature, a treatment approach with IVIG doses up to 1-2 g/kg per week plus prednisone/prednisolone at a higher dose up to 1 mg/kg/d might be more effective.
Subject(s)
Arthrogryposis/embryology , Arthrogryposis/prevention & control , Immunologic Factors/therapeutic use , Myasthenia Gravis, Neonatal/drug therapy , Myasthenia Gravis, Neonatal/embryology , Prednisone/therapeutic use , Prenatal Care/methods , Arthrogryposis/diagnosis , Fatal Outcome , Female , Humans , Myasthenia Gravis, Neonatal/diagnosis , Pregnancy , Pregnancy Outcome , Prenatal Diagnosis , Treatment Outcome , Young AdultABSTRACT
Arthrogryposis (multiple congenital joint contractures) is an uncommon problem. Because there are many causes, correct diagnosis is important to predict the natural history and determine appropriate treatment. Inconsistent terminology has caused confusion about both diagnosis and treatment. Amyoplasia, the most common type of arthrogryposis, is characterized by quadrimelic involvement and replacement of skeletal muscle by dense fibrous tissue and fat. Early physical therapy and splinting may improve contractures, but surgical intervention is often necessary. Aggressive soft-tissue releases in addition to casting may improve joint position. In more severe contractures, osseous surgery also may be needed. Deformity recurrence is common, particularly in skeletally immature patients.