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Neonatal lupus erythematosus with a high anticardiolipin antibody titer
Nethercott and Holness 7. Veien NK, Hattel T, Justesen O, et al. Causes of eczema in the food industry. Derm Beruf Umwelt 1983;31:84-6. 8. Adams RM. Occupational skin disease. New York: Grune & Stratton, 1983;386-7. 9. Fisher AA. Hand dermatitis: a "baker's dozen." Cutis 1982;29:214-21. 10. Herxheimer H. Skin sensitivityto flour in bakers' apprentices. Lancet 1967;1:83-4. 11. Rydstedt I. Hand eczema in patients with history of atopic manifestations in childhood. Acta Derm Venereol (Stockh) 1985;65:305-12. 12. Pigatto PD, Polenghi MM, Altomare GF. Occupational dermatitis in bakers: a clue for atopic contact dermatitis. Contact Dermatitis 1987;16:263-71. 13. Jarvinen K, Pirila V, Bjorksten F, et al. Unsuitability of bakery work for a person with atopy: a study of 234 bakery workers. Ann Allergy 1979;42:192-5. 14. Schaulow I, Minkow D, Dessew D. Studies on chrome allergy, nickel allergy and cobalt allergy in cement and building trade workers. Berufs-Dermatosen 1965;13:27682.
Journal of the American Academy of Dermatology 15. Wahlberg J. Health screening for occupational skin diseases in building workers. Berufs-Dermatosen 1969; 17:184-92. 16. Hogberg M, Wahlberg J. Health screening for occupational dermatoses in house painters. Contact Dermatitis 1980;6:100-6. 17. Varigos G, Dunt D. Occupational dermatitis: an epidemiological study in the rubber and cement industries. Contact Dermatitis 1981;7:105-10. 18. Hannuksela M. Epicutaneous testing. Allergy 1976;34:510. 19. Fregert S. Manual of contact dermatitis. Chicago: Year Book Medical, 1981:121-3. 20. Pritchard M, Ryan G, Musk A. Wheat flour sensitization and airways disease in urban bakers. Br J Ind Med 1984;41:450-4. 21. Block G, Tse K, Kijek K, et al. Baker's asthma: clinical and immunological studies. Clin Allergy 1983;13:35970. 22. Fregert S. Occupational dermatitis in a 10-year material. Contact Dermatitis 1975;1:96-107.
Neonatal lupus erythematosus with a high anticardiolipin antibody titer Unusual variant of neonatal lupus erythematosus or early-onset systemic lupus erythematosus? Ichiro K a t a y a m a , M D , PhD, Shigeo Kondo, MD, Seiji Kawana, MD, PhD, Kiyoshi Nishioka, M D , PhD, and Shigeo Nishiyama, M D , P h D
Kitasato Sagamihara, Japan A malar rash associated with severe gastrointestinal manifestations developed in a 4-month-old baby 3 months after a normal delivery. Serum complement and IgA levels were low during the active phase of the illness. An increased anticardiolipin antibody titer was demonstrated at the onset of disease and persisted for more than 6 months, at which time the skin and gastrointestinal manifestations subsided. The baby's mother, who had no symptoms, had an elevated Ro (SS-A) antibody titer and a moderately elevated anticardiolipin antibody titer. (J AM ACAD DERMATOL1989;21:490-2.)
Neonatal lupus erythematosus is characterized by a transient annular e r y t h e m a with or without SS-A antibody. Recent clinical studies suggest t h a t From the Departmentof Dermatology,KitasatoUniversitySchoolof Medicine. Accepted for publicationSept. 7, 1988. Reprint requests: Ichiro Katayama,MD, PhD, Department of Dermatology,KitasatoUniversitySchoolof Medicine, l- 15-1, Kitasato Sagamihara, Japan.
490
SS-A antibody from maternal serum is responsible for the disease. In contrast to the frequent association of skin lesions and congenital heart block with neonatal lupus erythematosus, gastrointestinal manifestations and long-standing hypocomplementemia rarely have been described. A case of neonatal lupus erythematosus with severe gastrointestinal hemorrhage and a high anticardiolipin antibody titer is herein reported.
Volume 21 Number 3, Part 1 September 1989
Neonatal lupus erythematosus with anticardiolipin antibody 491
CASE REPORT A 4-month-old female baby was brought to us with a transient urticarial erythema on the trunk. Subsequently a distinct annular erythema developed on the malar area and nasal bridge, which was accentuated after sun exposure. One month later, flulike symptoms, with hematemesis and tarry stools, developed. Physical examination revealed a well-defined annular erythema with marginal scaling on the malar area, across the nasal bridge. Peripheral hemorrhage was also noted. A peasized bulla with an urticarial erythematous base was present on the left cheek (Fig. I). An ill-defined, slate-colored erythema was observed in the pubic area. No abnormalities were observed on the scalp or oral mucosa. Hepatosplenomegaly was prominent (liver, 4.5 cm; spleen, 2.5 cm below the costophrenic angle). Heart and pulmonary examinations revealed no significant findings. No lymphadenopathy was demonstrated. The family history was noncontributory. Abnormal laboratory values were as follows: positive ANA test results (titer of 1:40, speclded pattern); anticardiolipin antibody titer, 16.2 U (<4 U); immune complexes (IgM), 12.4 #g/all (<3 izg/dl); decreased serum complement levels: CH50, <5 U; C3, 42 mg/dl (normal 88 to 205 mg/dl); C4, <2.9 mg/dl (normal 14 to 51 mg/dl). Other complement fragments, including C4a, C5a, C2, and Clq, were detected in the serum. Moderate increases in SGQT and SGPT were also observed. Anti--SS-A, anti-SS-B, anti-RNP, and antiSm antibodies were not identified. Partial thromboplastin time was normal. A biopsy specimen obtained from erythematous skin on the buttock showed focal liquefaction degeneration of the basement membrane zone and melanin droplets with moderate mononuclear cell infiltration around blood vessels. No fibrinoid degeneration of blood vessel walls was observed. Deposition of IgG, IgM, C3, C4, and Clq along the basement membrane zone was demonstrated both in the specimen from normal-appearing skin and from the erythematous lesion. After admission, tarry stools and recurrent vomiting persisted. Endoscopic analysis revealed multiple hemorrhagic areas on the mucosal wall of the stomach. Results of repeated examinations for viral antibodies against cytomegalovirus, hepatitis B, and rotavirus were all negative. A possible association with dietary milk allergy was excluded by stopping or changing any suspect milk. The mother's laboratory test results were all within the normal range except for elevated SS-A antibody and anticardiolipin antibody titers. No immunoglobulin or complement deposition was demonstrated in the normalappearing skin of the mother. From these results it was concluded that the skin lesions and gastrointestinal hemorrhage were closely associated with transplacentally transferred SS-A anti-
Fig. 1. Sun-induced malar rash with a blister on left cheek. body as occurs in neonatal lupus erythematosus] although SS-A antibody could not be demonstrated in the child. Without treatment, the child's skin manifestations and gastrointestinal symptoms subsided. Serum complement levels and other abnormal laboratory findings, except for anticardiolipin antibody and ANA, also returned to normal 4 months after onset of the disease. DISCUSSION Neonatal lupus erythematosus is a relatively recently recognized disease with clinical characteristics similar to those of systemic lupus erythematosus. Annular erythema with targetoid features and congenital heart block syndrome are now thought to be specific :manifestations of neonatal lupus erythematosus 1"3 and appear to be closely associated with SS-A antibody derived from maternal serum via transplaeental transfer. 4 Recent reports have suggested that a cross-reactive antigen present in cardiac muscle fiber is the target of SS-A antibody, thereby leading to the development of congenital heart block. The involvement of R N P antibody was suggested by Provost et al? The annular erythema seen in neonatal lupus erythematosus is occasionally found in Sj6gren's syn-
492
Journal of the American Academy of Dermatology
Katayama et aL
drome,6, 7 suggesting the involvement of SS-A antibody in SjSgren's syndrome as well as neonatal lupus erythematosus, s-l° Other clinical complications associated with neonatal lupus erythematosus include thrombocytopenia, leukocytopenia, and transient liver dysfunction) Our patient showed severe gastrointestinal manifestations, including vomiting and tarry stools along with hepatosplenomegaly and abnormal liver function. Long-standing hypocomplementemia was also observed during the active phase of the disease. These gastrointestinal complications might have been induced by immune complex-mediated vascular injury in the gut system, as is occasionally seen in systemic lupus erythematosus. 1~ Recently, anticardiolipin antibody has been reported to play a role in endothelial injury and recurrent thrombosis. 12,1~Thus in our patient anticardiolipin antibody might have played a role in the development of the gastrointestinal hemorrhage, although the possibility of involvement of other undefined antibodies cannot be excluded. A lupuslike syndrome is occasionally reported with complement deficiency. TM In this patient all complement fragments were detected in the serum in the active phase and they returned to normal levels thereafter; this excluded the possibility that the clinical manifestations were induced by complement deficiency. Finally, our patient had neonatal lupus erythematosus at the age of 3 months, which is relatively late when compared with the ages of previously described patients? Provost et al. 5 stated that immunoglobulin transferred from maternal serum can be detected until 6 months after delivery. Therefore in our patient neonatal lupus erythematosus could have been induced by SS-A antibody derived from maternal serum, although the possibility cannot be excluded that systemic lupus erythematosus developed when the child was 3 months of age. The absence of SS-A antibody in the patient and the presence of antic~rdiolipin antibody at the age of 4 months are difficult to explain. Watson et al? reported that they could not detect any anticardiolipin activity in 10 patients with neonatal lupus erythematosus. In contrast, our
patient had an increased anticardiolipin antibody titer at the age of 4 months, which persisted even at age 6 months when other symptoms had subsided. The I g M deposition along the basement membrane zone suggested that the patient had the ability to produce antibodies against foreign substances at age 4 months. Thus in this patient anticardiolipin antibody rather than SS-A antibody might have played an essential role in the development of the disease. REFERENCES
1. Watson RM, Lane AT, Barnet NK, et al. Neonatal lupus erythematosus: a clinical, serologicaland immunogenetic study with reviewof the literature. Medicine 1984;63:36278. 2. Reed BR, Lee LA, Harmon C, et al. Autoantibodies to SS-A/Ro in infants with congenitalheart block. J Pediatr 1983;103:889-91. 3. VonderheidEC, Koblenzer PJ, Ming PM, et al. Neonatal lupus erythematosus.Arch Dermatol 1976;112:698-705. 4. Miyagawa S, Kitamura W, Yoshioka J, et al. Placental transfer of anticytoplasmicantibodies in annular erythema of newborns. Arch Dermatol 1981;117:569-72. 5. ProvostTT, Watson R, Gammon WR, et al. The neonatal lupus syndrome associated with U1RNP (nRNP) antibodies. N Engl J Med 1987;316:1135-8. 6. Kamo K, Nagashima S. Sj6gren syndrome with special reference to a case complaining of erythematous lesion. (In Japanese.) Rinsho Dermatol 1976;30:761-71. 7. Teramoto N, Katayama I, Arai H, et al. Annular erythema: a possibleassociationwith Sj6gren's syndrome. J AM ACADDERMATOL1989;20:596-601. 8. Weston WL, Harmon C, Peebles C, et al. A serological marker for neonatal lupus erythematosus. Br J Dermatol 1982;107:377-82. 9. Kephart DC, Hood AF, Provost TY. Neonatal lupus erythematosus:new serologicalfindings. J Invest Dermatol 1981;77:331-3. 10. Franco HL, Weston WL, Peebles C, et al. Autoantibodies directed against sicca syndrome antigens in the neonatal lupus syndrome. J AM Ac~a~DERMATOL1981;4:67-77. 1i. Mayer LF. Gastrointestinal manifestations of systemic lupus erythematosus. In; Lahita RG, ed. Systemic lupus erythematosus. New York: John Wiley & Sons, 1987:709-20. 12. Harris EN, Gharavi AE, Boey ML, et al. Anticardiolipin antibodies: detection by radioimmunoassay and association with thrombosis in systemic lupus erythematosus. Lancet 1983;2:1211-4. 13. Sontheimer RD. The anti-cardiolipin syndrome. Arch Dermatol 1987;123:590-5. 14. Agnello V. Complement deficiency and systemic lupus erythematosus.In: Lahita RG, ed. Systemic lupus erythematosus. New York: John Wiley & Sons, 1987:56589.
Journal of the American Academy of Dermatology 15. Wahlberg J. Health screening for occupational skin diseases in building workers. Berufs-Dermatosen 1969; 17:184-92. 16. Hogberg M, Wahlberg J. Health screening for occupational dermatoses in house painters. Contact Dermatitis 1980;6:100-6. 17. Varigos G, Dunt D. Occupational dermatitis: an epidemiological study in the rubber and cement industries. Contact Dermatitis 1981;7:105-10. 18. Hannuksela M. Epicutaneous testing. Allergy 1976;34:510. 19. Fregert S. Manual of contact dermatitis. Chicago: Year Book Medical, 1981:121-3. 20. Pritchard M, Ryan G, Musk A. Wheat flour sensitization and airways disease in urban bakers. Br J Ind Med 1984;41:450-4. 21. Block G, Tse K, Kijek K, et al. Baker's asthma: clinical and immunological studies. Clin Allergy 1983;13:35970. 22. Fregert S. Occupational dermatitis in a 10-year material. Contact Dermatitis 1975;1:96-107.
Neonatal lupus erythematosus with a high anticardiolipin antibody titer Unusual variant of neonatal lupus erythematosus or early-onset systemic lupus erythematosus? Ichiro K a t a y a m a , M D , PhD, Shigeo Kondo, MD, Seiji Kawana, MD, PhD, Kiyoshi Nishioka, M D , PhD, and Shigeo Nishiyama, M D , P h D
Kitasato Sagamihara, Japan A malar rash associated with severe gastrointestinal manifestations developed in a 4-month-old baby 3 months after a normal delivery. Serum complement and IgA levels were low during the active phase of the illness. An increased anticardiolipin antibody titer was demonstrated at the onset of disease and persisted for more than 6 months, at which time the skin and gastrointestinal manifestations subsided. The baby's mother, who had no symptoms, had an elevated Ro (SS-A) antibody titer and a moderately elevated anticardiolipin antibody titer. (J AM ACAD DERMATOL1989;21:490-2.)
Neonatal lupus erythematosus is characterized by a transient annular e r y t h e m a with or without SS-A antibody. Recent clinical studies suggest t h a t From the Departmentof Dermatology,KitasatoUniversitySchoolof Medicine. Accepted for publicationSept. 7, 1988. Reprint requests: Ichiro Katayama,MD, PhD, Department of Dermatology,KitasatoUniversitySchoolof Medicine, l- 15-1, Kitasato Sagamihara, Japan.
490
SS-A antibody from maternal serum is responsible for the disease. In contrast to the frequent association of skin lesions and congenital heart block with neonatal lupus erythematosus, gastrointestinal manifestations and long-standing hypocomplementemia rarely have been described. A case of neonatal lupus erythematosus with severe gastrointestinal hemorrhage and a high anticardiolipin antibody titer is herein reported.
Volume 21 Number 3, Part 1 September 1989
Neonatal lupus erythematosus with anticardiolipin antibody 491
CASE REPORT A 4-month-old female baby was brought to us with a transient urticarial erythema on the trunk. Subsequently a distinct annular erythema developed on the malar area and nasal bridge, which was accentuated after sun exposure. One month later, flulike symptoms, with hematemesis and tarry stools, developed. Physical examination revealed a well-defined annular erythema with marginal scaling on the malar area, across the nasal bridge. Peripheral hemorrhage was also noted. A peasized bulla with an urticarial erythematous base was present on the left cheek (Fig. I). An ill-defined, slate-colored erythema was observed in the pubic area. No abnormalities were observed on the scalp or oral mucosa. Hepatosplenomegaly was prominent (liver, 4.5 cm; spleen, 2.5 cm below the costophrenic angle). Heart and pulmonary examinations revealed no significant findings. No lymphadenopathy was demonstrated. The family history was noncontributory. Abnormal laboratory values were as follows: positive ANA test results (titer of 1:40, speclded pattern); anticardiolipin antibody titer, 16.2 U (<4 U); immune complexes (IgM), 12.4 #g/all (<3 izg/dl); decreased serum complement levels: CH50, <5 U; C3, 42 mg/dl (normal 88 to 205 mg/dl); C4, <2.9 mg/dl (normal 14 to 51 mg/dl). Other complement fragments, including C4a, C5a, C2, and Clq, were detected in the serum. Moderate increases in SGQT and SGPT were also observed. Anti--SS-A, anti-SS-B, anti-RNP, and antiSm antibodies were not identified. Partial thromboplastin time was normal. A biopsy specimen obtained from erythematous skin on the buttock showed focal liquefaction degeneration of the basement membrane zone and melanin droplets with moderate mononuclear cell infiltration around blood vessels. No fibrinoid degeneration of blood vessel walls was observed. Deposition of IgG, IgM, C3, C4, and Clq along the basement membrane zone was demonstrated both in the specimen from normal-appearing skin and from the erythematous lesion. After admission, tarry stools and recurrent vomiting persisted. Endoscopic analysis revealed multiple hemorrhagic areas on the mucosal wall of the stomach. Results of repeated examinations for viral antibodies against cytomegalovirus, hepatitis B, and rotavirus were all negative. A possible association with dietary milk allergy was excluded by stopping or changing any suspect milk. The mother's laboratory test results were all within the normal range except for elevated SS-A antibody and anticardiolipin antibody titers. No immunoglobulin or complement deposition was demonstrated in the normalappearing skin of the mother. From these results it was concluded that the skin lesions and gastrointestinal hemorrhage were closely associated with transplacentally transferred SS-A anti-
Fig. 1. Sun-induced malar rash with a blister on left cheek. body as occurs in neonatal lupus erythematosus] although SS-A antibody could not be demonstrated in the child. Without treatment, the child's skin manifestations and gastrointestinal symptoms subsided. Serum complement levels and other abnormal laboratory findings, except for anticardiolipin antibody and ANA, also returned to normal 4 months after onset of the disease. DISCUSSION Neonatal lupus erythematosus is a relatively recently recognized disease with clinical characteristics similar to those of systemic lupus erythematosus. Annular erythema with targetoid features and congenital heart block syndrome are now thought to be specific :manifestations of neonatal lupus erythematosus 1"3 and appear to be closely associated with SS-A antibody derived from maternal serum via transplaeental transfer. 4 Recent reports have suggested that a cross-reactive antigen present in cardiac muscle fiber is the target of SS-A antibody, thereby leading to the development of congenital heart block. The involvement of R N P antibody was suggested by Provost et al? The annular erythema seen in neonatal lupus erythematosus is occasionally found in Sj6gren's syn-
492
Journal of the American Academy of Dermatology
Katayama et aL
drome,6, 7 suggesting the involvement of SS-A antibody in SjSgren's syndrome as well as neonatal lupus erythematosus, s-l° Other clinical complications associated with neonatal lupus erythematosus include thrombocytopenia, leukocytopenia, and transient liver dysfunction) Our patient showed severe gastrointestinal manifestations, including vomiting and tarry stools along with hepatosplenomegaly and abnormal liver function. Long-standing hypocomplementemia was also observed during the active phase of the disease. These gastrointestinal complications might have been induced by immune complex-mediated vascular injury in the gut system, as is occasionally seen in systemic lupus erythematosus. 1~ Recently, anticardiolipin antibody has been reported to play a role in endothelial injury and recurrent thrombosis. 12,1~Thus in our patient anticardiolipin antibody might have played a role in the development of the gastrointestinal hemorrhage, although the possibility of involvement of other undefined antibodies cannot be excluded. A lupuslike syndrome is occasionally reported with complement deficiency. TM In this patient all complement fragments were detected in the serum in the active phase and they returned to normal levels thereafter; this excluded the possibility that the clinical manifestations were induced by complement deficiency. Finally, our patient had neonatal lupus erythematosus at the age of 3 months, which is relatively late when compared with the ages of previously described patients? Provost et al. 5 stated that immunoglobulin transferred from maternal serum can be detected until 6 months after delivery. Therefore in our patient neonatal lupus erythematosus could have been induced by SS-A antibody derived from maternal serum, although the possibility cannot be excluded that systemic lupus erythematosus developed when the child was 3 months of age. The absence of SS-A antibody in the patient and the presence of antic~rdiolipin antibody at the age of 4 months are difficult to explain. Watson et al? reported that they could not detect any anticardiolipin activity in 10 patients with neonatal lupus erythematosus. In contrast, our
patient had an increased anticardiolipin antibody titer at the age of 4 months, which persisted even at age 6 months when other symptoms had subsided. The I g M deposition along the basement membrane zone suggested that the patient had the ability to produce antibodies against foreign substances at age 4 months. Thus in this patient anticardiolipin antibody rather than SS-A antibody might have played an essential role in the development of the disease. REFERENCES
1. Watson RM, Lane AT, Barnet NK, et al. Neonatal lupus erythematosus: a clinical, serologicaland immunogenetic study with reviewof the literature. Medicine 1984;63:36278. 2. Reed BR, Lee LA, Harmon C, et al. Autoantibodies to SS-A/Ro in infants with congenitalheart block. J Pediatr 1983;103:889-91. 3. VonderheidEC, Koblenzer PJ, Ming PM, et al. Neonatal lupus erythematosus.Arch Dermatol 1976;112:698-705. 4. Miyagawa S, Kitamura W, Yoshioka J, et al. Placental transfer of anticytoplasmicantibodies in annular erythema of newborns. Arch Dermatol 1981;117:569-72. 5. ProvostTT, Watson R, Gammon WR, et al. The neonatal lupus syndrome associated with U1RNP (nRNP) antibodies. N Engl J Med 1987;316:1135-8. 6. Kamo K, Nagashima S. Sj6gren syndrome with special reference to a case complaining of erythematous lesion. (In Japanese.) Rinsho Dermatol 1976;30:761-71. 7. Teramoto N, Katayama I, Arai H, et al. Annular erythema: a possibleassociationwith Sj6gren's syndrome. J AM ACADDERMATOL1989;20:596-601. 8. Weston WL, Harmon C, Peebles C, et al. A serological marker for neonatal lupus erythematosus. Br J Dermatol 1982;107:377-82. 9. Kephart DC, Hood AF, Provost TY. Neonatal lupus erythematosus:new serologicalfindings. J Invest Dermatol 1981;77:331-3. 10. Franco HL, Weston WL, Peebles C, et al. Autoantibodies directed against sicca syndrome antigens in the neonatal lupus syndrome. J AM Ac~a~DERMATOL1981;4:67-77. 1i. Mayer LF. Gastrointestinal manifestations of systemic lupus erythematosus. In; Lahita RG, ed. Systemic lupus erythematosus. New York: John Wiley & Sons, 1987:709-20. 12. Harris EN, Gharavi AE, Boey ML, et al. Anticardiolipin antibodies: detection by radioimmunoassay and association with thrombosis in systemic lupus erythematosus. Lancet 1983;2:1211-4. 13. Sontheimer RD. The anti-cardiolipin syndrome. Arch Dermatol 1987;123:590-5. 14. Agnello V. Complement deficiency and systemic lupus erythematosus.In: Lahita RG, ed. Systemic lupus erythematosus. New York: John Wiley & Sons, 1987:56589.