Neonatal systemic lupus erythematosus syndrome (NSLES) develops as a result of passively acquired autoimmunity, when autoantibodies produced by the mother cross the placenta, affecting the developing fetus.1 The autoantibodies produced by a dysfunctional maternal immune system include anti-Sjörgen syndrome-A and -B (anti-SSA and anti-SSB, respectively), and anti-ribonuclear protein.2

NSLES is rare and can involve multiple organs in a newborn, including the skin, heart, and liver.3 In addition to a characteristic rash on the scalp and upper eyelids,4 the condition is characterized by transient cutaneous, hepatic, and hematologic abnormalities.1 A complete congenital heart block is the most serious, and irreversible, manifestation of NSLES. It is typically diagnosed in utero, but may also be detected at birth or in the first few weeks of the infant’s life.5

The management of NSLES is complicated by potential fetal toxicity and several of the syndrome’s clinical manifestations require management by different subspecialists. Since cutaneous, hepatobiliary, hematologic, and neurological manifestations most often resolve spontaneously, current therapies are mostly focused on preventing cardiac disease and congenital heart block.4

In an interview with Rheumatology Advisor, Gregorio P. Milani, MD, pediatrician in the pediatric unit at Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico and in the department of Clinical Sciences and Community Health, Università degli Studi di Milano, in Milan, Italy, and Marisa S Klein-Gitelman, MD, head of the division of pediatric rheumatology at Ann & Robert H. Lurie Children’s Hospital of Chicago and professor of pediatrics at Northwestern University Feinberg School of Medicine in Chigago, Illinois, discussed the risk factors and current therapeutic approaches to NSLES.                                        

Rheumatology Advisor: What are the most common clinical manifestations of NSLES?

Gregorio P. Milani, MD: NSLES is a syndrome that commonly presents with reversible and irreversible features. The most common reversible manifestation is cutaneous lesions. They are observed in more than 90% of cases and usually appear as a superficial inflammatory rash on the upper eyelids and scalp resembling the rash seen in older patients with systemic lupus erythematosus (SLE).

The main severe, irreversible, potentially life-threatening clinical manifestation is a congenital atrioventricular heart block, which may be detected in utero. In neonates with a structurally normal heart, congenital atrioventricular heart block due to NSLES constitutes more than 80% of severe atrioventricular block cases.

Rheumatology Advisor: What are some of the factors that complicate the management of NSLES?

Dr Milani: In addition to the cardiac involvement that is the main determinant of prognosis in affected infants, NSLES may involve other organ systems. Hematologic abnormalities are found in 20% of cases and include anemia, neutropenia, and thrombocytopenia. Hepatic involvement occurs in 15% to 25% of cases and usually presents with asymptomatic elevation of aminotransferases, cholestasis, or hepatomegaly. Rarely, infants may also present with macrocephaly with or without associated hydrocephalus. Although these phenomena usually resolve with the disappearance of maternal antibodies from the infant’s circulation, it is important to manage infants with NSLES in medical centers where they can receive care from various subspecialists.

Rheumatology Advisor: What is the long-term outlook for patients with NSLES?

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Dr Milani: Cutaneous manifestations spontaneously resolve in most cases; only avoidance of light exposure is advised. The main issue in NSLES treatment is management of the cardiac heart block. Data on preventive treatments are inconclusive. Some investigators suggest the use of hydroxychloroquine in pregnant women with autoantibodies to Sjögren syndrome antigens who have previously given birth to a child with cardiac NSLES to prevent the occurrence of heart block. The efficacy of therapeutic options for congenital heart block in utero is controversial, and management is primarily expectant. After birth, more than 90% of patients with complete atrioventricular block eventually have a pacemaker placed. Their prognosis is usually excellent.

Rheumatology Advisor: What are the most common risk factors for the development of NSLES?

Marisa S Klein-Gitelman, MD: NSLES is a disease caused by the passive transfer of autoantibodies from maternal to fetal circulation during pregnancy. The auto-antibodies are typically to ribonuclear proteins anti-SSA (Ro) and anti-SSB (La). The presence of these antibodies is required but not sufficient to cause disease. These antibodies are most commonly found in women who have autoimmune diseases such as lupus, Sjögren’s syndrome, mixed connective tissue disease, and rheumatoid arthritis. Women who are treated with certain medications such as particular antiepileptics and antiarrhythmics can also develop these auto-antibodies. It is important to note that they can be found in healthy women as well. 

Rheumatology Advisor: Which treatments are used during pregnancy to prevent cardiac disease associated with NSLES and how effective are they?

Dr Klein-Gitelman: There is an ongoing trial (ClinicalTrials.gov identifier: NCT01379573) to determine the efficacy of hydroxychloroquine in the prevention of heart block in the high-risk fetus, especially in mothers who have Ro60, Ro52 or Ro52p200 autoantibodies. Previous research has suggested that the risk is reduced.6 Trials have demonstrated some benefit of intravenous immunoglobulin, fluorinated steroids, and beta-agonists in the treatment of a fetus who has already developed heart block and is at risk for developing myocarditis and endocardial fibroelastosis. 

Rheumatology Advisor: What are the most common late complications of NSLES?

Dr Klein-Gitelman: Studies of healthy infants born to mothers with NSLES auto-antibodies found that a small percentage will develop heart block over time and should be monitored. For infants born with heart block, there is a risk for developing other conduction abnormalities. These infants, particularly infants who require pacing, should be monitored for growth restriction, neurodevelopmental problems, other conduction abnormalities, and aortic root dilation. 

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References

  1. Buyon JP. Neonatal lupus syndromes. Am J Reprod Immunol. 1992;28(3-4):259-263.
  2. Johnson B. Overview of neonatal lupus. J Pediatr Health Care. 2014;28(4):331-341.
  3. Klein-Gitelman MS. Neonatal lupus: What we have learned and current approaches to care. Curr Rheumatol Rep. 2016;18:60.
  4. Vanoni F, Lava SAG, Fossali EF, et al. Neonatal systemic lupus erythematosus syndrome: a comprehensive review. Clinic Rev Allerg Immunol. 2017;53(3):469-476.
  5. Brito-Zerón P, Izmirly PM, Ramos-Casals M, et al. The clinical spectrum of autoimmune congenital heart block. Nat Rev Rheumatol. 2015;11(5):301-312.
  6. Izmirly PM, Costedoat-Chalumeau N, Pisoni CN, et al. Maternal use of hydroxychloroquine is associated with a reduced risk of recurrent anti-SSA/Ro-antibody-associated cardiac manifestations of neonatal lupus. Circulation. 2012;126(1):76-82.