Getting to the heart of neonatal lupus erythematosus
By Warren R. Heymann, MD, FAAD
July 21, 2021
Vol. 3, No. 29
I have found that rendering the diagnosis of neonatal lupus erythematosus (NLE) is fraught with emotional challenges. Not only are mothers concerned for their children, frequently they are unaware of the fact that they are also at risk for potential complications of autoimmune disease.
It has been more than 60 years since NLE has been recognized. The incidence is approximately 1 in 12,500 to 20,000 live births, being slightly higher in girls and premature newborns. Approximately 40-60% of mothers are asymptomatic when NLE is diagnosed. Some mothers may have systemic lupus erythematosus, Sjögren syndrome, rheumatoid arthritis, or another undifferentiated autoimmune disease. (1)
NLE presents with cutaneous lesions in about 40% of cases; 35% display hepatic dysfunction and 35% demonstrate hematological abnormalities. Most importantly, irreversible cardiac arrhythmias are observed in 25% of cases. This commentary will be limited to cutaneous and cardiac features, as the hepatic and hematologic abnormalities are characteristically mild and transient. NLE is due to the passive maternal transfer of autoantibodies of Sjögren syndrome autoantigen type A (Ro/SSA) or B (La/SSB) to the fetus. Autoantibodies against antigen type A recognize 2 cellular proteins, Ro52/52kD (localized in the nucleus and cytoplasm) and Ro60/60kD (localized in the nucleus and nucleolus). Autoantibodies against antigen type B target a 47kD protein localized between the nucleus and the cytoplasm. Based on animal models there appears to be a greater role of anti Ro52 in being pathogenic. Less frequently, for patients with cutaneous NLE, anti-U1 RNP (small nuclear ribonucleoprotein-associated with U1 spliceosomal RNA) antibodies have been implicated as pathogenic. Mechanistically, it has been postulated that atrioventricular heart block occurs during the 18 to the 26 weeks of pregnancy, when auto-antigens type A or B translocate to the cardiomyocyte surface, after which maternal autoantibodies bind to the fetal cardiac conduction tissue, triggering atrioventricular node fibrosis. Another hypothesis is based on mimicry, linking a cross-reaction between L- and T-type calcium channels and autoantibodies that subsequently cause an imbalance with calcium homeostasis, crucial for the propagation of the action potential and conduction in the AV and SA node. (2)
Cutaneous lesions of NLE are not apparent at birth in 80% of cases, and usually develop after the first month of life. (3) Lesions may be congenital (4), rarely presenting with scars at birth (5). Photosensitivity occurs in most cases. The cutaneous hallmark of NLE is a superficial inflammatory rash affecting the upper eyelids and the scalp, usually presenting as macular annular or elliptic erythema. Papular or plaque-like lesions may also be observed. A central clearing or a fine scale is observed in about 30% of cases. Lesions, which may coalesce and form larger erythematous areas in the periorbital area, frequently give rise to the typical “eye mask” or “raccoon-like” appearance (this term is entrenched in the literature, but I suggest not using it). Head, scalp, and trunk or extremities are affected in decreasing order of frequency. The differential diagnosis of NLE includes seborrheic dermatitis, tinea faciei/corporis, congenital syphilis, annular erythema of infancy, and aplasia cutis congenita. (6) Histologic examination reveals interface dermatitis, with direct immunofluorescence demonstrating granular deposition of IgG at the dermo-epidermal junction.
According to Vanoni et al, the typical rash remits in 80% of cases within 7 months, although multiple reports document the persistence of telangiectasias, hyperpigmentation, and atrophy in 20% of the cases. (3) Recent reports reach variable conclusions regarding cutaneous sequelae of NLE. Levy et al found that at the last follow-up visit, 34% of 106 NLE patients (mean age 4 years) had cutaneous sequelae — 13% had telangiectasia, 17% had dyspigmentation, and 9% had atrophic scarring. Scarring at the last follow-up was significantly associated with the presence of skin lesions at birth (P < .001). In a smaller study of 13 NLE patients, Wang et al reported that of the 9 that had follow-up appointments (seen at a mean of 229 days), none had residual cutaneous lesions, regardless of therapy. (8) Based on my personal experience and review of the literature, I think it is reasonable to be optimistic that the majority of patients will have minimal or no cutaneous sequelae, although those presenting with extensive, early disease — especially with scars — are more likely to have residual lesions.
As previously stated, the most crucial manifestation of NLE is congenital atrioventricular (AV) block that can present as first, second, and especially third-degree AV block. This commonly presents between 18 and 24 weeks of gestation. The initial incidence of congenital heart block (CHB) in SSA/Ro-positive pregnancies is reported in about 2% and may be slightly higher in women with active disease and high antibody titers. Isolated SSB-positive titers do not appear to confer a significant risk for CHB. If a previous pregnancy has been complicated by AV block, the risk is reported to be as high as 18%. Attempts to reverse AV block in utero with IVIG or dexamethasone have been successful in only about 25% of cases. (9) In an open label trial of 54 anti-SSA/Ro-positive mothers, Izmirly et al administered hydroxychloroquine (400 mg daily) prior to completion of gestational week 10, which was maintained during pregnancy. Based on historical data (of third degree CHB having an incidence of 18%), the finding that only 4 patients (7.4%) developed CHB, suggests that hydroxychloroquine should be prescribed for prevention of fetal cardiac disease in anti-SSA/Ro-exposed pregnancies. (10)
In conclusion, as dermatologists, we can be reasonably sanguine about the ultimate appearance of patients with NLE. Mothers of children with NLE who wish to get pregnant should discuss the possibility of using hydroxychloroquine during gestation.
Point to Remember: Although there may be some residual cutaneous manifestations of NLE, for most patients, the prognosis is excellent. For mothers at risk for having children with NLE, in utero administration of hydroxychloroquine may decrease the risk of congenital heart block.
Our expert’s viewpoint
Amanda T. Moon, MD
Attending Physician, Pediatric Dermatology
Clinical Assistant Professor, Pediatrics
Perelman School of Medicine at the University of Pennsylvania
It is quite satisfying to clinch the diagnosis of neonatal lupus. When I’m working with dermatology residents, one of my favorite Kodachromes to share is a picture of an annular, facial rash in a newborn. Dermatologists tend to be expertly trained in connective tissue disease, but neonatal lupus usually isn’t the first answer I’ll get. I think this has a lot to do with the mostly transient nature of cutaneous neonatal lupus, and relatively brisk response to topical steroids, photo-protection, and “tincture of time” as the maternal antibodies decrease. Patients without cardiac involvement tend to do very well, without long term health consequences. That being said — it is critical to recognize neonatal lupus promptly and monitor, both because of the potential extracutaneous manifestations and implications for maternal health. More often than not, the diagnosis is twofold — a positive antibody result for the infant renders the mother a diagnosis as well. As Dr. Heymann cited, oftentimes the mother is asymptomatic or has mild, undiagnosed symptoms. The diagnosis is also critical for future pregnancies in particular, because maternal hydroxychloroquine can decrease the risk for heart block in future siblings. It is reassuring to see in our study and others that neurologic, hepatic, hematologic, and cutaneous abnormalities tend to improve, if not fully resolve, over time. Those observations enable us to provide mostly reassuring anticipatory guidance for families that are often quite worried about their little one.
Sato, Yamaguchi T, Muroaoka J, Taniguchi H, et al. C4d deposition in fetal vessels of the placenta in neonatal lupus syndrome. Case Rep Obstet Gynecol 2019;2019:5863476.
Diaz J, Badri T. Neonatal lupus erythematosus. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing 2020 Jan.
Vanoni, F. Lava SAG, Fossali EF, Cavalli R, et al. Neonatal systemic lupus erythematosus syndrome: A comprehensive review. Clin Rev Allergy Immunol 2017; 53: 469-476.
Sechi A, Patrizi A, Cangemi J, Galletti S, Neri I. Congenital onset of neonatal lupus erythematosus. Arch Dis Child Fetal Neonatal Ed 2020; 105: F356.
Khurana A, Maria A, Sardana K, Sjukla A, Gupta. Congenital scars: A rare presentation of neonatal lupus. Arch Dis Child Fetal Neonatal Ed 2019; 104: F630.
Mendiratta V, Yadaw A. Neonatal lupus with extensive cutaneous involvement. Indian Pediatr 2019;56(8):701-702.
Levy R. Briggs L Silverman E, Pope E, Lara-Corrales I. Cutaneous sequelae in neonatal lupus: A retrospective cohort study. J Am Acad Dermatol 2020; 83: 440-446.
Wang YA, Sibbald C, Moon AT. Retrospective, single-center case series of neonatal lupus. Pediatr Dermatol 2020;37(3):484-489.
Strasburger JF, Wacker-Gussmann A. Congenital Heart Block in Subsequent Pregnancies of SSA/Ro-Positive Mothers: Cutting Recurrence in Half. J Am Coll Cardiol 2020;76(3):303-305.
Izmirly P, Kim M, Friedman DM, Costedoat-Chalumeau N, et al. Hydroxychloroquine to Prevent Recurrent Congenital Heart Block in Fetuses of Anti-SSA/Ro-Positive Mothers. J Am Coll Cardiol 2020;76(3):292-302.
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