Neonatal Lupus Erythematosus

Etiology

Neonatal lupus erythematosus is an autoimmune disease that takes place due to the passive maternal transfer of autoantibodies of Sjogren 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. So far there is no specific epitope responsible for neonatal lupus erythematosus, but some animal models have suggested a greater role of anti Ro52.[1][3]

Epidemiology

The incidence of neonatal lupus erythematosus approximates to 2% in offspring of mothers with autoantibodies of Sjogren syndrome autoantigen type A (Ro/SSA) or B (La/SSB) with an 18% to 20% recurrence rate in the following pregnancies. It affects equally males and females, and less than 5% of infants with this condition will develop systemic lupus erythematosus in late adolescence or early adulthood. Neonatal lupus erythematosus causes 80% to 95% of the cases of severe atrioventricular block in the neonatal period (younger than 28 days of life), after this period it is a less frequent cause of AV block (5% of the cases). Presentation of cutaneous manifestations ranges between 7% to 16% of mothers with positive autoantibodies type A (Ro/SSA) or B (La/SSB). These autoantibodies are present in 0.1% to 1.5% of healthy pregnant women, 90% of patients with Sjogren, 20% to 30% with systemic lupus erythematosus and 3% with rheumatoid arthritis. Approximately 25% of the mothers of neonates with neonatal lupus are asymptomatic at the time of delivery, of which 50% will become symptomatic within three years. Another 25% have an undifferentiated autoimmune syndrome, 20% Sjogren syndrome, 15% systemic lupus erythematosus, 15% systemic lupus erythematosus associated with Sjogren syndrome and 1% Rheumatoid arthritis.[1][2][4]

Pathophysiology

One mechanism that have been proposed to explain atrioventricular heart block postulate that from the 18 to the 26 weeks of pregnancy 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 mechanism that has been postulated 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. AV heart block is often seen if the mother has higher autoantibodies titers. Nevertheless, there is overlapping between affected and unaffected cases that a high titer alone is not indicative of heart involvement. Another maternal factor that has been linked with neonatal lupus cutaneous manifestations is anti-U1 RNP (small nuclear ribonucleoprotein-associated with U1 spliceosomal RNA) antibodies.[1][2][3]

History and Physical

Neonatal lupus erythematosus presents with reversible manifestations including cutaneous lesions in 40% of the cases, 35% hepatic dysfunction and 35% hematological abnormalities; a 25% of neonates present with irreversible cardiac arrhythmias, the most distinctive and dangerous feature.

Cutaneous Manifestations

Lesions resemble those seen in children and adolescents with systemic lupus erythematosus. Eruptions are often misdiagnosed as birth trauma, skin infection or eczema, especially if the mother is asymptomatic. 80% of the lesions are not clear at birth developing during the first month of life in only 20% of the affected newborns. Neonates present with photosensitivity usually within the first 2 days of sun exposure in 90% of the cases. Cutaneous lesions characterized by a superficial inflammatory coalescent rash with raised active margins, described as macular annular or elliptic erythema that involves the head (with or without the scalp or neck) in 95%, scalp in 60%, trunk (with or without groin) in 25%, extremities in 25% and can involve the whole body in 10% of the cases. Sometimes it can manifest as papular or plaque-like lesions, and 30% can present with a central clearing lesion or a fine scale. The classic rash remits within 4 months of life in 50% of the cases, 80% within 7 months and 100% within a year. Twenty percent of neonates can present with persisting skin rash characterized by telangiectasia, hyperpigmented skin areas, and atrophy. On histological examination, granular depositions of immunoglobulin G at the dermo-epidermal junction and vacuolar alteration at the interface and adnexal structures can be observed.

Hematological and Hepatobiliary Involvement

These manifestations are transient and rarely present as an isolated sign. Regarding the hematological aspect, newborns with neonatal lupus syndrome can present with anemia, neutropenia or thrombocytopenia. In 20% of the cases, aplastic anemia has been reported. There is an asymptomatic elevation of aminotransferases, cholestasis, or hepatomegaly/splenomegaly in 15% to 25% of the cases.

Neurological Involvement

This is a self-remitting phenomenon that can manifest as macrocephaly with or without associated hydrocephalus.

Cardiac Manifestations

Newborns with neonatal lupus erythematosus usually have a structurally normal heart. The classic and distinctive cardiac manifestation is a congenital atrioventricular block that can present as first, second, and especially third-degree AV block. Commonly presents between 18 to 24 weeks of gestation. Other cardiac manifestations include sinus bradycardia, QT-interval prolongation, cardiomyopathy, congestive heart failure, myocarditis and structural or valvular abnormalities (ventricular septal defects, ostium secundum type atrial septal defects, patent foramen ovale, patent ductus arteriosus, pulmonary stenosis, pulmonary valve dysplasia, fusion of the chordae tendineae of the tricuspid valve). Second- and third-degree AV block present in utero with fetal bradycardia, with a ventricular rate between 40 and 80 per minute. Postnatally the heart rate is found to be less than 100 per minute, rarely associated with signs of congestive heart failure (diaphoresis, pallor, peripheral edema, prominent jugular veins and crackles on auscultation of the lungs). On cardiac auscultation, there can be an appreciation of nonspecific signs such as intermittent gallops, variability with the intensity of the first heart sound, intermittent cannon waves, and murmurs. Five percent to 10% of infants present with a severe AV block that precipitates myocardial dysfunction due to endocardial fibroelastosis and myocardial fibrosis, associated with right ventricular pacing and subsequent ventricular asynchrony and dysfunction.[1][2]

Evaluation

Fetal echocardiography is a helpful tool for the assessment of the heart structure, rhythm, and function. Commonly after the 18 weeks of pregnancy arrhythmias can be diagnosed, but there have been few cases reported at 16 to 17 weeks. Thus serial screening is advised at 16 weeks of gestation in women who tested positive for autoantibodies to Sjogren syndrome auto-antigens types A or B or with a previous history of an infant with neonatal lupus erythematosus. Less than 20% of cases are detected after 26 weeks of gestation; thus if there is no diagnosis of atrioventricular block, echocardiography screening frequency can be reduced after 26 weeks of gestation. Two percent of AV block cases are detected postnatally in the neonate period, the reason why observing newborns at risk for the first month of life should be done. However, after 28 days of life heart monitoring screening is not advised, unless already diagnosed with a heart abnormality. A pediatric cardiologist must closely monitor first- and second-degree AV block identified after birth. ECG and echocardiogram should be obtained at 1 year of age if there is a history of transient first-degree AV block in utero and within the first 3 months of life with a history of a transient second-degree block that reverted to normal sinus rhythm at birth.

Mothers with affected offspring and that tested positive for autoantibodies to Sjogren syndrome auto-antigens types A or B, should be assessed for an underlying autoimmune disease. Mothers should be counsel about the 2% risk of having an affected newborn, and if there is a history of a previous offspring with neonatal lupus, the risk increases to 20% with the subsequent pregnancies. The risk of AV block is higher if there is a history of previous infants with cardiac manifestations.[1][2][4]

Treatment / Management

Non-cardiac reversible manifestations resolve spontaneously. Therefore, observation is advised of these clinical symptoms. Photoprotection is the key to management of cutaneous manifestations. Topical corticosteroids and antimalarial drugs are not indicated, and if there are residual telangiectasia laser therapy can be used. Anemia and thrombocytopenia that become symptomatic can be managed with blood and platelets transfusion, glucocorticoids or intravenous immunoglobulin have shown to be effective in certain cases.

Atrioventricular heart block has high morbidity and mortality rates and should be approached by an interprofessional team, and should address parental counseling, serial fetal echocardiograms, maternal screening, and management. Therapy with fluorinated steroid betamethasone/dexamethasone was used aiming for prevention of the development of AV heart block due to previous reports, but more recent studies have not confirmed this benefit. There have also been reports of the beneficial use of intravenous immunoglobulin regarding prevention and management of neonatal lupus, but results are still inconclusive. Studies that involved the use of hydroxychloroquine 400 mg daily starting between the 6 and 10 weeks of gestation have shown a decreased risk of developing neonatal cardiac lupus, especially in women with the previous history of an affected infant. Beta-receptor agonist improves the heart rate and stroke volume in utero but not a decreased risk of developing AV block.

A ventricular rate is less than 55 per minute, hydrops fetalis, cardiomegaly, atrioventricular valve regurgitation or low aortic flow velocity indicate poor fetal prognosis and outcome. There are limited treatment options for AV block in utero, and management is mainly to monitor closely and follow up. If signs of fetal distress developed early delivery is indicated with emergency pacing. Permanent pacemaker insertion is the crucial treatment option with the need of determining the right time for the procedure.[1][2][4](B2)

Differential Diagnosis

The differential diagnosis of cutaneous manifestations of neonatal lupus erythematosus includes neonatal rashes with no associated congenital heart block or maternal autoantibodies type A (Ro/SSA), B (La/SSB) or anti-U1 RNP. These rashes include acute annular urticaria, tinea corporis, seborrheic dermatitis, annular erythema of childhood, cutis marmorata telangiectasia congenita, Langerhans cell histiocytosis and some auto-inflammatory syndromes (CANDLE syndrome, APLAID syndrome, SAVI syndrome and C1q deficiency).

Other causes of fetal bradycardia or heart block include congenital heart block related to congenital heart defects such as L-transposition of the great arteries, endocardial cushion defects, Holt-Oram syndrome; and idiopathic, familial congenital heart block.[1][2]