1. Neonatal Lupus ErythematosusProf Ariyanto Harsono MD PhD SpA(K)Dept Pediatrics, Medical Faculty, Airlangga University, Surabaya, Indonesia.1

2. IntroductionNeonatal lupus erythematosus (NLE) refers to a clinical spectrum ofcutaneous, cardiac, and systemic abnormalities observed in newborninfants whose mothers have auto antibodies against Ro/SSA, La/SSB,and, less commonly, U1-ribonucleoprotein (U1-RNP). The conditionwas first described in 1954 by McCuistion and Schoch who reported acase of transient lupus skin lesion in an infant with an ANA-positivemother. The most common presentation is a nonscarring,nonatrophic skin lesion which resemble subacute cutaneous lupuserythematosus. The infants may have no skin lesions at birth butdevelop them during the first weeks of life. Cardiac, hematological,hepatobiliary, central nervous, and pulmonary systems may also beinvolved. The condition is usually benign and self-limited butsometimes may be associated with serious sequelae.2Prof Ariyanto Harsono MD PhD SpA(K)

3. PathophysiologyA number of studies have suggested that NLE is caused bythe transplacental passage of maternal autoantibodies.These autoantibodies may cause damage to thedeveloping tissue and increase the risk of bearinginfants with NLE. Approximately 98% of affected infantshave maternal transfer of autoantibodies againstRo/SSA, La/SSB, and, less commonly, U1-RNP.However, only 1-2% of mothers with theseautoantibodies have neonates with NLE, regardless ofwhether the mothers are symptomatic or not3Prof Ariyanto Harsono MD PhD SpA(K)

4. The 52-kD Ro/SSA (Ro52) ribonucleoprotein is anantigenic target strongly linked with the autoimmuneresponse in mothers whose children haveNLE, congenital heart block, and other conductionabnormalities. Anti-Ro52/SSA autoantibodiesantagonize the serotonin-induced L-type calciumchannel activation on human fetal atrial cells andtrigger an inflammatory response, leading ultimately tofibrosis and scarring of the atrioventricular node, sinusnode, and His bundle. This may explain theelectrophysiological abnormalities in NLE and thepathogenesis of the cardiac rhythm disturbances, whichmay lead to diminished cardiac output and thesubsequent development of congestive heart failure.4Prof Ariyanto Harsono MD PhD SpA(K)

5. In a rat model, Boutjdir et al. demonstrated that IgGcontaining anti-Ro/SSA and -La/SSB antibodies inducescomplete AV block in beating hearts and in multicellularpreparations, thus implicating a preferential interactionof these autoantibodies with calcium channels and/orassociated regulatory proteins. This is consistent withthe observed inhibition of calcium channels that maybe a critical factor contributing to the pathogenesis ofcomplete heart block. These conduction defects arecaused by anti-Ro/SSA and anti-La/SSB antibodies aswell as other autoantibodies against cardiacadrenoceptors and muscarinic acetylcholine receptors.5Prof Ariyanto Harsono MD PhD SpA(K)

6. The antibodies associated with heart block andwith cutaneous disease are believed to bedifferent; antibodies against the 52/60-kDRo/SSA and 48-kD La/SSB ribonucleoproteinsare associated with heart block, whereasantibodies against the 50-kD La/SSBribonucleoprotein are associated withcutaneous disease.6Prof Ariyanto Harsono MD PhD SpA(K)

7. 7Prof Ariyanto Harsono MD PhD SpA(K)antibodies against the 50-kD La/SSB ribonucleoprotein are associated with cutaneous disease

8. On the other hand, anti-U1RNP autoantibodies are usuallyassociated with atypical cutaneous lesions without cardiac orsystemic abnormalities in a small number of NLE cases andmay play a role in the pathogenesis of thrombocytopenia. Ithas been demonstrated that the anti-U1RNP antibody frompatients with connective tissue disease can directly recognizea variety of antigens on the endothelial surface of thepulmonary artery, including the components of U1RNP orother unknown polypeptides. These results suggest thatbinding to HPAECs of this autoantibody may be one of thetriggers of endothelial cell inflammation in various connectivetissue diseases. The spectrum of cutaneous disease in U1RNPantibody-positive infants is similar to Ro/SSA antibody-positive infants with NLE. Complete heart block was not afeature of U1RNP antibody-positive NLE.8Prof Ariyanto Harsono MD PhD SpA(K)

9. It has been shown that the amount of maternalantibodies, rather than their presence, is associatedwith fetal tissue injury. However, only some neonatesexposed to these antibodies develop complications.Therefore, other factors such as titers of maternalantibodies, genetic predisposition, and environmentalfactors such as viral infection may be involved.Additionally, induction of apoptosis in culturedcardiomyocytes has been demonstrated to result in theexpression of Ro/La antigens on the cell surface forrecognition by circulating maternal antibodies. It isspeculated that in vivo such opsonized apoptoticcardiocytes promote an inflammatory response byresident macrophages with damage to surroundingconducting tissue.9Prof Ariyanto Harsono MD PhD SpA(K)

10. 10Prof DR Dr Ariyanto Harsono SpA(K)Maternal antibodies, genetic predisposition, and environmental factors such as viral infectionmay be involved.

11. In addition to its presence in the skin and heart, the Roantigen is also found in theliver, bowel, lungs, brain, and blood cellsthe tissuesthat are most often affected by NLE. Ultravioletradiation and estrogens increase Ro antigen expressionon the surface of the keratinocyte. Although ultravioletradiation can induce or exacerbate the skin lesions, it isnot required for their development. Because of limitedopportunity for solar exposure in neonates and younginfants, photosensitivity is more commonly seen afterphototherapy for neonatal hyperbilirubinemia.11Prof Ariyanto Harsono MD PhD SpA(K)

12. photosensitivity is more commonly seen after phototherapy for neonatalhyperbilirubinemia12Prof Ariyanto Harsono MD PhD SpA(K)

13. EpidemiologyNLE is a rare acquired autoimmune disease that occurs in 1 of every20,000 live births in the USA . Elsewhere, epidemiology is usuallydescribed in small case series. The presence of certain majorhistocompatibility complexes such as human leukocyte antigen B8and human leukocyte antigen DR3 in the mother predisposes theinfant to NLE and congenital heart block. Although there is noapparent racial predilection, disparity in outcomes betweenminorities and whites has been observed. Like many autoimmunediseases, reports from the Research Registry for Neonatal Lupus/USindicate that the female-to-male ratio is approximately 2:1 withcutaneous NLE, but the gender distribution for cardiac disease isapproximately equal . The risk of NLE or congenital heart blockdeveloping in a woman who tests positive for Ro/SSA who has neverhad a child with NLE or congenital heart block is less than 1%.13Prof Ariyanto Harsono MD PhD SpA(K)

14. Many seropositive mothers with anti-Ro/SSA and anti-La/SSB antibodies give birth to infants who do not showsigns and symptoms of NLE. However, in those whohave had an infant with NLE, the risk of cardiac and/orskin disease for a future pregnancy is high. Theincidence of congenital heart block is 1530% in infantswith NLE. Heart block usually develops in uterobetween the 18th and 24th weeks of pregnancy. Infantsborn to mothers with hypothyroidism due to thyroidautoantibodies and anti-Ro/SSA positivity are at ninetimes higher risk of developing congenital completeheart block than infants born to mothers with only anti-Ro/SSA positivity.14Prof Ariyanto Harsono MD PhD SpA(K)

15. Approximately 4060% of mothers are asymptomaticwhen the infants are diagnosed to have NLE. Theremaining mothers may have SLE, Sjgrensyndrome, rheumatoid arthritis, or undifferentiatedautoimmune disorder. Mothers with primarySjgren syndrome or undifferentiated autoimmunesyndrome have a greater risk of delivering an infantwith congenital complete heart block than thosewith SLE. There is no association with paternalautoimmune diseases.15Prof Ariyanto Harsono MD PhD SpA(K)

16. Clinical ManifestationsThe most common clinical manifestations of NLE are, indecreasing order offrequency, dermatologic, cardiac, and hepaticabnormalities. Some infants may also havehematologic, neurologic, or splenic abnormalities. Oneor more systems may be involved. Wisuthsarewong etal. performed a retrospective study to review clinicalmanifestations on 17 patients (10 girls and 7 boys) withNLE seen at the Department of Pediatrics, SirirajHospital from 1993 to 2008.Cutaneous, cardiac, hepatobiliary, and hematologicalinvolvement was found in 70.6%, 64.7%, 52.9%, and35.3% of infants, respectively.16Prof Ariyanto Harsono MD PhD SpA(K)

17. Cutaneous lesions may be present at birth but often appearwithin the first few weeks of life. Annular erythematous orpolycystic plaques with or without fine scales characterizeNLE and appear predominately on the scalp, neck, or face(typically periorbital in distribution), but similar plaques mayappear on the trunk or extremities. The dermatitis resemblesthe rash of subacute cutaneous lupus erythematosus ratherthan the malar rash of SLE. Periorbital erythema, referred toas raccoon eye or owl eye, is a very commoncharacteristic. At times, the lesions may be urticarial,desquamative, ulcerative, or crusted. Bullous lesions may beseen with a particular predilection for the soles of the feet.17Prof Ariyanto Harsono MD PhD SpA(K)

18. 18Prof Ariyanto Harsono MD PhD SpA(K)The dermatitis resembles the rash of subacute cutaneous lupus erythematosus rather than the malar rash ofSLE

19. Periorbital erythema, referred to as raccoon eye or owl eye, is a verycommon characteristic19Prof Ariyanto Harsono MD PhD SpA(K)

20. Bullous lesions may be seen with a particular predilection for the soles of thefeet.20Prof Ariyanto Harsono MD PhD SpA(K)

21. Cutaneous involvement was characterized as erythematouspatches (91.7%), subacute cutaneous lupus erythematosuslesions (50%), petechiae (41.7%), persistent cutis marmorata(16.7%), and discoidal lesions (8.3%). In some infants, solarexposure seems to precipitate the eruption. These lesionstypically last for weeks or months and then resolvespontaneously consequent to the disappearance of maternalantibodies in the neonatal circulation. Active erythematouslesions after the first year of life should be suspect.Dyspigmentation is frequent but usually resolvesspontaneously. Atrophic lesions and, rarely, atrophic scars maydevelop. The atrophic telangiectatic changes are mostevident near the temples and scalp and do not necessarilyoccur in the same sites as the erythematous lesions. Thelatter site may occasionally be associated with a permanentalopecia. Telangiectasia, scarring, and atrophic changes areexpected to persist. 21Prof Ariyanto Harsono MD PhD SpA(K)

22. Cutaneous involvement was characterized as erythematous patches (91.7%)22Prof Ariyanto Harsono MD PhD SpA(K)

23. The cardiac manifestations include conduction abnormalities(first-, second-, and third-degree heart block) andcardiomyopathy. Third-degree heart block, onceestablished, is usually irreversible. Congenital heart blockmay present as bradycardia noted in utero or duringphysical examination at birth. Conduction disturbances mayalso present as irregular heartbeat and prolongation of theQT interval. Congenital heart block may be associated withendocardial fibroelastosis and cardiomyopathy. In somecases, myocarditis and pericarditis can develop which maylead to bradycardia. Heart failure is a well-recognizedcomplication during the neonatal period.23Prof Ariyanto Harsono MD PhD SpA(K)

24. The clinical pictures of hepatobiliary involvement maytake the forms of elevation of liver enzymes (suchas aspartate aminotransferase and alanineaminotransferase) and/or conjugatedhyperbilirubinemia occurring a few weeks ormonths after birth and resolving thereafter. Someinfants may have mild hepatomegaly and, lesscommonly, splenomegaly. The hepatomegaly andsplenomegaly are usually transient. Cholestatichepatitis and hepatic failure may also occur.24Prof Ariyanto Harsono MD PhD SpA(K)

25. Hematologic disturbances (e.g., hemolyticanemia, thrombocytopenia, and neutropenia) mayoccur in the first 2 weeks of life. Infants withhematological involvement are usually asymptomatic.Autoantibodies, mainly anti-Ro, bind directly to theneutrophil and cause neutropenia. Thrombocytopeniamay manifest as petechiae. Hematologic symptomsusually appear at around the second week of life anddisappear by the end of the second month.Lymphopenia is a relatively common finding in adultswith SLE but is not a characteristic hematologicabnormality of NLE. 25Prof Ariyanto Harsono MD PhD SpA(K)

26. Other abnormalities such as hydrocephalus andmacrocephaly may occur. Aseptic meningitis andmyelopathy have rarely been reported. Pneumonitismay manifest as tachypnea and/or tachycardia.26Prof Ariyanto Harsono MD PhD SpA(K)

27. Diagnosis and Differential DiagnosisThe diagnosis is usually established based on theclinical features and the demonstration of NLE-associated antibodies in the serum of the mother orthe affected infant. NLE can mimic many conditions.Differential diagnosis of NLE includes seborrheicdermatitis, atopic dermatitis, neonatal acne, tineacorporis, psoriasis, granuloma annulare, erythemamultiforme, Langerhans cellhistiocytosis, congenital rubella, congenitalsyphilis, Bloom syndrome, and Rothmund-Thomsonsyndrome.27Prof Ariyanto Harsono MD PhD SpA(K)

28. Laboratory InvestigationsNLE is associated with the anti-Ro/SSA antibody in more than 90% of patients.Occasionally, patients only have anti-La/SSB or anti-U1RNP antibodies. Screening ofinfants with NLE for the presence of these antibodies is strongly recommended.Many asymptomatic mothers have positive putative antibodies during pregnancy.As such, these mothers of patients suspected of having neonatal lupuserythematosus should be screened for antinuclear, anti-double-stranded DNA, anti-Ro/SSA, anti-La/SSB, and anti-U1-RNP antibodies, irrespective of their symptoms orclinical status. As anti-Ro/SSA antibodies can be detected in one in 200 pregnantwomen, the risk for an anti-Ro/SSA-positive woman to have an infant with NLE isrelatively low. On the other hand, high anti-Ro/SSA levels correlate with the risk ofcardiac complications. Serial prenatal ultrasonography/electrocardiography shouldtherefore be performed on pregnant women with high anti-Ro titers (50U/mL).Prenatal ultrasonography may help identify NLE that affects the heart.28Prof Ariyanto Harsono MD PhD SpA(K)

29. 29

30. Echocardiography may reveal various types ofstructural deformities in the heart; combinedelectrocardiography and 24-hour Holter monitoringmay reveal various cardiac conduction disorders ordifferent types of heart blocks.Laboratory investigations may revealpancytopenia, thrombocytopenia, leukopenia, orelevated transaminase level.31Prof Ariyanto Harsono MD PhD SpA(K)

31. Skin biopsy is useful in patients with NLE when the diagnosis isin doubt. Histologic examination shows interfacedermatitis, keratinocyte damage, moderatehyperkeratosis, follicular plugging, and vacuolar degenerationin the basal cell layer. Epidermal atrophy may be found.Inflammatory infiltrate may be intense with bulla formationhistologically. An immunofluorescent examination reveals agranular deposition of immunoglobulin G (IgG) at thedermoepidermal junction; IgM and C3 deposition may also beevident.Skin biopsy is not pathognomonic. Various inflammatory andinfectious conditions may show similar histological features.In typical cases of NLE and positive autoantibodies, skinbiopsy is not mandatory to confirm the diagnosis.32Prof Ariyanto Harsono MD PhD SpA(K)

32. Skin Biopsy33Prof DR Dr Ariyanto Harsono SpA(K)Histologic examination shows interfacedermatitis, keratinocyte damage, moderatehyperkeratosis, follicular plugging, and vacuolardegeneration in the basal cell layer. Epidermalatrophy may be found. Inflammatory infiltratemay be intense with bulla formationhistologically.

33. Treatment and Follow upNeonates with NLE should be managed at a tertiarycare center. Multidisciplinary team involvementmay also be indicated. Patients with NLE withcardiac involvement require regular monitoring toassess cardiac function and the need for apacemaker. A pacemaker is often necessary forthose who are unable to compensate for a slowheart rate. Serial echocardiography to monitor for aprolonged PR interval should also be arranged. Ifthe cardiac involvement is severe, activity may haveto be restricted in the young child.34Prof Ariyanto Harsono MD PhD SpA(K)

34. Sunscreens may be useful in the treatment of cutaneous lupuserythematosus, but a neonate is less likely to be exposed tosunlight excessively. Nevertheless, solar exposure should beavoided if possible. Parents should be advised to apply sunscreenwell before solar exposure and to use a sunscreen with a high SPFthat provides a broad-spectrum (UV-A) coverage which is waterresistant. Behavior modification to include solar avoidance shouldbe encouraged. Protective clothing is highly desirable. Strategiesaimed at preventing disease before irrevocable scarring ensues area high priority. Skin lesions of NLE can be treated with mild topicalcorticosteroids. Anti malarial agents have potential toxicity and aslow onset of action that their use in the treatment of thistransient condition is probably not indicated. Laser therapy may beconsidered for residual teleangiectasia.35Prof Ariyanto Harsono MD PhD SpA(K)

35. Systemic corticosteroids and immunosuppressive agentsare generally not indicated in the treatment of NLE.Children with NLE need continued follow up, especiallybefore adolescence and if the mother herself has anautoimmune disease. Although the child may not be atincreased risk of developing SLE, the development ofsome form of autoimmune disease in early childhoodmay be of concern.Infants with severe hepatic and hematologicalinvolvement may require treatment with systemiccorticosteroids, intravenous immunoglobulin, and/orimmunosuppressive agents .Prof Ariyanto Harsono MD PhD SpA(K) 36

36. PrognosisThe morbidity and mortality of SLE of childhood depend on the organsystems affected. Children with NLE have an excellent long-termoutcome when only skin lesions are present. The cutaneous lesionsusually disappear by 6 months of age coincident with the clearance ofmaternal antibodies from the childs circulation. Involvement of theskin may, rarely, lead to scar formation. Although children withcutaneous disease may be more prone to develop SLE orautoimmunity later in life, this is mainly due to their geneticpredisposition, not that they had NLE. Their non affected siblings arealso at risk for development of SLE or autoimmunity. While thecutaneous lesions of NLE are themselves benign, cutaneous NLE isassociated with a 610-fold risk for a subsequent child with cardiacNLE.37Prof Ariyanto Harsono MD PhD SpA(K)

37. NLE with cardiac involvement is associated with a 2030% mortalityrate in the neonatal period. Mortality is particularly high in casesof congenital heart block with concurrent cardio-myopathy.Death most often results from congestive heart failure caused bycongenital heart block. Approximately 57 to 66% of patients withcongenital heart block eventually require a pacemaker. Thosewith pacemakers are at risk of developing dilated cardio-myopathy in their lives. Deaths may also occur later in life as aresult of the failure of the pacemaker. However, many childrenwith congenital heart block may be relatively asymptomatic untiladolescence, when they begin to exercise. At that time, they maydevelop syncope and require a pacemaker implantation.38Prof Ariyanto Harsono MD PhD SpA(K)

38. The recurrence rate of congenital heart block is low, about 15%, butthis is nearly three times higher than the risk for congenital heartblock in a primigravida with the putative antibodies. Prospectiveclinical trials on use of antenatal fluorinated steroids in womenwith anti-SSA/Ro and/or anti-SSB/La antibodies and fetuses withheart block identified in utero are required before definitiverecommendations can be made. A number of anecdotal casessupport the use of dexamethasone for treatment of hydrops andpossibly incomplete block.Most patients with NLE affecting liver or blood have transient diseasethat spontaneously resolves within 46 months. In somecases, cholestatic hepatitis and liver failure may occur which isassociated with a poor prognosis. Anemia, thrombocytopenia, andneutropenia are self-limited. However, if severe thrombocytopeniais present, internal bleeding can lead to a poor prognosis.39Prof Ariyanto Harsono MD PhD SpA(K)

39. Future PregnanciesAlthough the fetal disease is called neonatal lupuserythematosus, this is considered a misnomer since only about25% of mothers actually fulfill criteria for the diagnosis of SLE.Furthermore, asymptomatic mothers do not invariably become ill.Mothers of infants with NLE, particularly infants with congenitalheart block, have a 2-fold to 3-fold increased risk of having anaffected infant in a subsequent pregnancy. On the other hand, therisk for an unselected anti-Ro/SSA-positive woman has beenestimated at 1-2%. A prospective controlled study of pregnancyoutcome in 100 women with autoimmune diseases and anti-Ro/SSA antibodies showed that the prevalence of congenital heartblock in newborns of prospectively followed up women alreadyknown to be anti-Ro/SSA positive and with known connectivetissue disorders was 2%.40Prof Ariyanto Harsono MD PhD SpA(K)

40. In mothers with anti-Ro/SSA and/or anti-La/SSBantibodies and infants with congenital heart block, therisk of recurrence in subsequent offspring is 1725%.Therefore, carefully monitoring of subsequentpregnancies with serial ultrasonography andechocardiography, particularly at 1824 weeksgestation, is essential. Intravenous immunoglobulinmerits evaluation as a potential prophylactic approachin mothers who have previously had an affected child.However, two studies failed to demonstrate benefit inoutcome from intravenous immunoglobulin. On theother hand, the use of hydroxychloroquine forpatients with SLE has been associated with a lowerrate of NLE during pregnancy.41Prof Ariyanto Harsono MD PhD SpA(K)

41. Shinohara et al. assessed the possibility of preventing cardiac orcutaneous manifestations of NLE or treating the fetus withcongenital heart block by administering corticosteroid therapy tothe mother. Eighty seven offspring of 40 anti-Ro/SSA-positivemothers, followed up from 1979 to 1996, were evaluated. None of26 neonates whose mothers received corticosteroid maintenancetherapy initiated before 16 weeks gestation demonstratedcongenital heart block, whereas 15 of 61 neonates whose mothersreceived no corticosteroids during pregnancy or began receivingsteroid therapy after 16 weeks gestation had congenital heartblock. Complete congenital heart block, once developed, did notrespond to corticosteroid treatment in utero. Four infants whosemothers received corticosteroid treatment before 16 weeksgestation had skin lesions of NLE.42Prof Ariyanto Harsono MD PhD SpA(K)

42. Once established, complete congenital heart blockwas irreversible, and maternal corticosteroidtherapy did not effectively prevent cutaneous LE.However, prenatal maintenance therapy withprednisolone or betamethasone given to themother starting early in pregnancy (before 16weeks gestation) might reduce the risk ofdeveloping antibody-mediated congenital heartblock in the offspring.Prof Ariyanto Harsono MD PhD SpA(K) 43

43. Mothers with SLE should be treated with drugs that are effective andsafe for the fetus. Such an approach may diminish or reduce theprevalence of complete heart block associated with NLE. Tincani etal. recently reported increased occurrence of learning disabilities inchildren born to mothers with SLE. Corticosteroids and someimmunosuppressive drugs can be used in pregnancy to controlmaternal disease. Some data suggest that prolonged fetal exposureto dexamethasone may impair cerebral development. On the otherhand, Tincani et al. followed 6 children (age range, 1465months), born to patients treated with dexamethasone because ofcongenital heart block. These children were found to have a normalintelligence quotient . However, the authors remarked thatinformation about long-term outcome of children exposed toimmunosuppressive drugs in utero are still lacking, and moreefforts are needed in this research area.44Prof Ariyanto Harsono MD PhD SpA(K)

44. SummaryNeonatal lupus erythematosus (NLE) refers to aclinical spectrum of cutaneous, cardiac, andsystemic abnormalities observed in newborn infantswhose mothers have autoantibodies against Ro/SSAand La/SSB. The condition may be associated withserious sequelae. Neonates with NLE should bemanaged at a tertiary care center, andmultidisciplinary team involvement may beindicated.45Prof Ariyanto Harsono MD PhD SpA(K)

45. 46Prof Ariyanto Harsono MD PhD SpA(K)