Search

Background Background: Congenital heart block (CHB) is a transplacentally acquired autoimmune disease associated with anti-Ro/La maternal autoantibodies and is characterized primarily by atrioventricular (AV) block of the fetal heart. Since the Ro/La autoantigens are intracellular proteins, they are not likely the targets of these maternal autoantibodies and likely cross-react with other proteins on the surface of cardiomyocytes. Objectives Objectives: This study aims to investigate whether the α 1G T-type calcium channel is expressed in human fetal hearts, and if maternal serum antibodies from CHB affected pregnancies bind to the α 1G T-type calcium channel subunit in human fetal hearts. Methods Methods: Expression of α 1G was demonstratedin human fetal hearts by RT-PCR, and by Western Blot analysis of human fetal heart lysates. Immunological methods such as Western blot, ELISA, immunofluorescence and flow cytometry were utilized to demonstrate the binding of antibodies in serum from CHB affected pregnancies to the α 1G protein on the surface of human fetal cardiomyocytes. Results Results: We demonstrate differential mRNA expression of CACNA1G (α 1G gene) and CACNA1H (α 1H gene) in the AV junction of human fetal hearts compared to the apex (18-22.6 weeks gestation). Immunoprecipitation and Western blot analysis of α 1G from human fetal hearts (20-22 wks gestation) demonstrates reactivity of maternal serum from CHB affected pregnancies but not from controls. Immunofluorescence (IF) staining and flow cytometry analysis also demonstrates expression of T-type Ca 2+ channel subunits in cardiomyocytes from 20-22 week old human fetal hearts. ELISA was used to assay the reactivity of sera from mothers with pregnancies affected by CHB and from controls to a series of peptides derived from the amino acid sequences of extracellular regions of α 1G . Antibody reactivity to a peptide designated as p305 [corresponding to aa305-319 of the extracellular loop linking transmembrane segments S5-S6 in α 1G repeat I], was significantly higher in the CHB maternal sera compared to controls (p 1H by all CHB sera that were reactive to the α 1G peptide (7/15 amino acids conserved). Conclusions Conclusions: These results taken together indicate that α 1G and possibly α 1H are bound in extracellular regions by autoantibodies found in CHB maternal serum. Autoantibodies involved in CHB may thus cross-react and bind several fetal targets. Disclosure of Interest None Declared

OBJECTIVE: This study was undertaken to investigate the recent finding of a seasonal difference in the onset of systemic-onset juvenile rheumatoid arthritis (SoJRA). We hypothesized that a seasonal onset pattern might implicate an infectious agent as a cause of SoJRA. METHODS: The date of onset was collected from the records of all patients with SoJRA from 1980 to 1992 at presentation to pediatric rheumatology clinics across Canada. The onset pattern of SoJRA was then compared with incidence data on viral infections obtained for the same period. RESULTS: Across Canada the onset of SoJRA was constant across the seasons. However, in the Prairie region there was a statistically significant seasonal pattern, with peaks in autumn and early spring. We could find no evidence that viral incidence correlated with disease incidence either throughout Canada or in the Prairie region. CONCLUSIONS: If a seasonal infectious agent causes SoJRA, then it is likely only one of several causes and may act only in certain regions. Future studies should be carried out in those areas where SoJRA does have a seasonal onset pattern. (J P EDIATR 1996:129:513-8)

Objectives To determine the health of mothers of offspring with complete congenital heart block (CHB) both at the time of delivery of the affected child and in the long-term, and the percentage of mothers of children with CHB who had antiSSA/Ro and/or SSB/La antibodies. Patients and methods Sixty-four mothers of 64 children with CHB (seen between 1964 and 1993) were identified through the Cardiology database of The Hospital for Sick Children, Toronto, Canada. Medical information from these of children with CHB was evaluated. Data were obtained from the mothers by mailed questionnaire, telephone interview, and/or from the attending physicians. The presence of anti-Ro antibodies and anti-La antibodies were evaluated by ELISA assay. Results The mean age at the time of delivery of the first child with CHB was 28 ± 6 years. At the time of delivery 42 (66%) mothers were healthy, 2 (3%) had systemic lupus erythematosus (SLE), 2 (3%) had linear scleroderma, 2 (3%) had rheumatoid arthritis; 3 (5%) had a history of rheumatic fever (but were otherwise well), 1 (2%) had Sjogren's syndrome (SS), and 12 (19%) had an undifferentiated autoimmune syndrome (UAS) (arthralgia, myalgia, photosensitivity, skin vasculitis, Raynaud's phenomenon). The mean time to follow-up from delivery to study was 121 ± 88 months. The mean maternal age at study was 38 ± 9 years. Three of 12 mothers who initially had a UAS progressed to SLE (average follow-up time of 80 months, median 96), and 2 developed SS (with average follow-up time 140 months, median 132) and 1 went into remission. The mean follow-up time for the other mothers who did not develop an autoimmune disease was 150 ± 102 months. Thirty-six of the 42 initially healthy mothers remained well. One mother developed SLE; 1 developed hyperthyroidism; 1 developed ankylosing spondylitis; and 3 developed an UAS. The mean follow-up time of the 36 mothers who remained healthy was similar (123 ± 97 months) to the 6 initially healthy mothers who developed an autoimmune disease (121 ± 36 months). Anti-Ro and/or anti-La antibodies were positive in 32 of 53 (60%) mothers tested. Fourteen of the 53 mothers were symptomatic at the time of delivery and 39 were asymptomatic. Anti-Ro and/or anti-La antibodies were positive in 12 of 13 mothers tested at the time of delivery. Conclusions The long-term maternal outcome in our cohort was very good as most of the initially healthy mothers remained well at follow-up. Twenty-five percent of the mothers with a UAS and only 2% of the initially healthy mothers developed SLE. The development of an autoimmune disease in an asymptomatic mother identified by the birth of a child with CHB was less common in our study than in previous studies. However, close follow-up of mothers with UAS is warranted.

We describe three cases of cerebral vein thrombosis (CVT) in girls with systemic lupus erythematosus. Severe, persistent, unremitting headache was a common manifestation. In the first patient, although the clinical features were suggestive of CVT, the diagnosis was delayed and she had a significant cerebral infarct. In the other two patients the diagnosis was made earlier and led to more rapid treatment; the institution of early therapy may have prevented further sequelae. The CVT was diagnosed in all patients with a combination of computed tomography and magnetic resonance imaging studies without the need for angiography. All patients were treated for their underlying systemic lupus erythematosus and with anticoagulation. All are receiving long-term low doses of warfarin and have not had any recurrences.

Three children with systemic lupus erythematosus who developed hemorrhagic tendencies as a consequence of a clotting factor II (prothrombin) deficiency are described. All three responded rapidly to treatment with corticosteroids. A literature review added 25 case reports, with the following findings. First, factor II deficiency occurs in the presence of the lupus anticoagulant, although the interrelationship between the two is not understood. Second, the deficiency is presumed to be secondary to rapid clearing of the antigen/antibody factor II complex in the liver. Finally, most cases respond to corticosteroid therapy with or without the coadministration of vitamin K or fresh frozen plasma. In corticosteroid-dependent patients, the addition of antimetabolites such as azathioprine has enabled reduction in steroid doses.

Localized scleroderma (LS), a rare disease that occurs primarily in the pediatric age group, differs from systemic sclerosis (SSc) in that it is usually limited to the skin and subcutaneous tissue and is only rarely associated with systemic manifestations. The authors' experience with pediatric LS seen in 30 patients at a tertiary care center was reviewed: 26 had linear scleroderma, 19 on an extremity and 7 on the face; 3 had morphea; and 1 had generalized morphea. Antinuclear antibodies were present in 76% and rheumatoid factor in 39%. Five of 19 patients with linear scleroderma that involved an extremity had growth failure in that limb, and 1 required surgery. Sclerodermatous involvement over a joint resulted in limited range of movement in 6 patients, and 1 required surgery. One of the 30 patients developed SSc and polymyositis. There was difficulty in evaluating disease activity and hence in evaluating treatment. This experience with a large patient population suggests that LS, although usually a self-limiting disease, can result in significant morbidity.

Background Neonatal Lupus Erythematodus (NLE) is a rare disease occurring in offspring from mothers with anti-Ro with or without anti-La antibodies. Much is known about the individual manifestations (congenital heart block (CHB), cutaneous rash, hematologic and hepatic laboratory abnormalities and macrocephaly) but it is unclear how these and other autoantibodies (anti-dsDNA, anti-RNP and anti-Sm antibodies) influence disease phenotype.

Neonatal lupus erythematosus (NLE) is associated with the transplacental passage of maternal anti-Ro and anti-La antibodies. In order to better determine the risk of delivery of a child with NLE, we examined the frequency of anti-Ro and anti-La antibody secreting cells in mothers of children with NLE and in mothers at risk to deliver a child with NLE. We established limiting dilution experiments, using EBV-infected peripheral blood mononuclear cells, from 10 mothers following delivery of a child with NLE and from six mothers with anti-Ro and anti-La antibodies who delivered an unaffected child. Supernatants were assessed, by Poisson analysis, to determine the frequency of IgG and IgM anti-Ro and anti-La antibody-secreting B cells. We found that the frequency of anti-Ro and anti-La IgM antibody secreting B cells was greater than the frequency of IgG antibody secreting B cells of the same autoantibody specificity. We found no correlation between serum IgM and IgG anti-Ro or anti-La antibody titres and their respective precursor cell frequencies. We found that the mothers of children with NLE who later developed SLE tended to have higher anti-Ro and anti-La antibody-committed B cells than did the mothers who remained well. Although anti-Ro and anti-La antibody precursor frequencies were similar within a patient, they varied significantly from patient to patient. We found that most of the experiments with a precursor frequency of < 1 per million were from mothers of children with NLE rather than the mother with SLE who delivered normal children. Overall, we found that, in anti-Ro and anti-La antibody-positive women, a low anti-Ro or anti-La antibody B cell precursor frequency tended to be associated with the birth of a child with NLE.

Two unrelated patients with a family history of rheumatic fever had isolated, acquired chorea. Both index cases, as well as affected family members, had increased expression of the rheumatic B-cell alloantigen D8/17. This test may help differentiate Sydenham chorea from lupus chorea.

Temporomandibular joint (TMJ) disease is uncommon in children but frequently occurs in juvenile rheumatoid arthritis (JRA). Involvement is often asymptomatic; however, it can lead to growth disturbances and facial deformity. Thirty TMJs in 15 children (11 girls and 4 boys aged 3.5-18 years) with JRA were evaluated clinically and by MRI. Plain films were reviewed when available. Magnetic resonance imaging parameters included T1-weighted and in some cases T2-weighted or gradient recall echo sequences. We assessed condylar configuration, glenoid fossa changes, presence of erosions, disk abnormality, range of motion, and presence of joint effusions or pannus. Abnormalities included cortical erosions (n = 19), disk thinning (n = 18), and perforation (n = 2). Reduction of joint movement (n = 20), joint locking (n = 3), and pannus/effusions (n = 5) were also found. Magnetic resonance imaging is a useful technique for the detection of TMJ involvement in JRA. Early detection and therapeutic intervention may lessen or prevent subsequent deformities.

Systemic lupus erythematosus (SLE) is an autoimmune disorder resulting in inflammation of multiple organ systems. Although SLE is not common in children, it must be considered in the differential diagnosis of any child who has multisystem disease. The onset of SLE in children may be acute, with severe disease affecting one or more major organ systems, or it may be insidious, with intermittent symptoms of fever, malaise, rashes, arthritis, or pleuritis. SLE also must be considered if a child is found to have a positive antinuclear antibody (ANA) test result. Although almost all children who have SLE have a positive result, this laboratory test alone does not establish the diagnosis of SLE. Classification Criteria Eleven disease manifestations are included in the revised classification criteria for SLE established by the American College of Rheumatology (Table 1). These criteria were established as a classification tool to guide in selecting patients for clinical and laboratory studies rather than as a diagnostic system. Nevertheless, they have proven useful in the assessment of both pediatric and adult patients who may or may not have SLE. Epidemiology Childhood onset of SLE accounts for approximately 20% of all cases. The annual incidence in the United States is approximately 0.6 cases per 100 000 total population, with higher rates found in the African-American, Oriental, and Hispanic populations.

SUMMARY The perpetuation of chronic synovitis in juvenile arthritis (JA) is a complex interaction of local and systemic regulatory mechanism. We examined the cell surface phenotypc of synovial fluid cells and peripheral blood lymphocytes from 15 patients with J A to better understand the mechanism of local inflammation. Synovial fluid and peripheral blood mononuclcar cells were analysed for cell surface expression of CD2, CD3, CD4, CD8, CD19, CD25, CD29, CD45R and Ia using flow cytometry. We found a very low percentage of B cells with a concomitant increase of T cells in synovial fluid as compared with peripheral blood. A large percentage of the synovial fluid T cells were HLA-DR+.or activated T cells, and there was a relative decrease in CD4+ cells in synovial fluid as compared with peripheral blood. There was only a minimal increase in CD25+ synovial fluid cells. The synovial fluid CD4+ cells were mainly of the CD2high. CD29+, CD45RO phenotype. This CD4 phenotype found on synovial fluid cells from patients with JA and in particular the CD29 cell surface marker, which recognizes a common β-chain of adhesion molecules, is associated with binding to extracellular matrix proteins and is also associated with “primed” T cells. Our results demonstrated the presence of T cells which either selectively migrate to synovium and synovial fluid or are activated in situ in the joint.

Eosinophilic synovitis occurred in a 7-year-old boy. Synovial fluid leukocytes were mostly eosinophils; the peripheral blood showed only mild eosinophilia. The level of eosinophil-derived neurotoxin in the synovial fluid was higher than that in the serum, suggesting intraarticular eosinophil degranulation. The IgE level was also elevated in the synovial fluid (3854 ng/ml) but normal in the serum (408 ng/ml), suggesting a localized immediate hypersensitivity immune response.

We retrospectively reviewed the charts and radiographs of 38 patients with systemic-onset juvenile rheumatoid arthritis, attempting to identify early in the disease course the clinical and laboratory observations most predictive of the later development of destructive arthritis. In 12 of the patients, destructive arthritis developed within 2 years of disease onset. When first examined, these patients could not readily be differentiated from those in whom joint destruction did not develop, but they more commonly had hepatosplenomegaly (p less than 0.04), serositis (p less than 0.01), and a lower mean serum albumin concentration (26.7 vs 31.3 gm/L; p less than 0.02). However, by 6 months after onset, patients with destructive arthritis more frequently had persistent systemic symptoms (92% vs 12%; p less than 0.0001), polyarthritis (67% vs 19%; p less than 0.0005), a lower mean hemoglobin level (95 vs 114 gm/L; p less than 0.001), a higher mean leukocyte count (21.2 vs 10 x 10(9)/L; p less than 0.0003), a higher mean platelet count (794 vs 400 x 10(9)/L; p less than 0.0001), and a higher mean erythrocyte sedimentation rate (43 vs 24 mm/hr; p less than 0.05). Multivariate analysis of the results at 6 months revealed that persistent systemic symptoms and a platelet count greater than or equal to 600 x 10(9)/L were the variables most highly predictive of the later development of joint destruction. We conclude that patients at high risk for the development of destructive arthritis may be identified within 6 months of disease onset, thereby indicating the need for more aggressive early therapy.

Objective Barriers to medical care may influence health status. It is unclear whether problems with access can predict clinical outcomes in lupus. This study aimed to determine whether care barriers are associated with increased disease activity and damage in a multi-center, multiethnic SLE cohort. We also compared concordance between care barriers as reported by the patient and lupus specialist. Methods Data from SLE patients in 12 Canadian centers collected at annual visits, including demographics, treatment, disease activity and damage were analyzed. Results 654 patients were enrolled with ethnic groups being Caucasian [CC] (64%), Aboriginal [ABO] (9%), Asian [AS] (21%), and Black [BLK] (6%). 50.8% had at least one barrier to care including travel to a rheumatologist (32.0%), waiting to see a rheumatologist and cost of medications. Access to medication and costs were significantly associated with co-morbidity (p < 0.001, p = 0.04). There were significant associations between ethnicity and any physician perceived care barrier < p < 0.001), mostly in Aboriginal. Doctors identified half of patients who had access to medication problems (p = 0.003) and the relationship between doctors and patients identifying similar care barriers was weak (r = 0.09). A lower total household income significantly predicted the presence of any care barrier (p < 0.001). Conclusions Despite access to a lupus specialist many care barriers were identified, although we found few associations between care barriers and patient outcomes. The cost of medication was related to SLE disease activity; however, we cannot determine if this was cause or effect. Care barriers identified by lupus patients are significantly underestimated by physicians.

We describe a 16-year-old girl with systemic-onset juvenile arthritis who presented with pulmonary hypertension, without evidence of pleural or parenchymal involvement of the lung, pulmonary vasculitis, or immune deposition in the pulmonary vasculature. Pleuropulmonary involvement occurs occasionally in juvenile arthritis, but primary pulmonary hypertension has not, to our knowledge, been previously reported. Histocompatibility typing showed positivity for HLA-DR3 and DRw52, both of which are associated with idiopathic pulmonary hypertension in children, and with pulmonary hypertension among patients with systemic sclerosis. Treatment with cyclosporine and corticosteroids resulted in a marked improvement in the clinical findings and pulmonary function in our patient.

Because patients with Kawasaki disease have low serum concentrations of salicylates despite high doses, and because the free (unbound) drug is responsible for the pharmacologic effects of salicylates, we assessed salicylate protein binding in patients with Kawasaki disease. During the acute phase of the disease, protein binding of salicylate in 36 children with Kawasaki disease was 73 +/- 12%, significantly lower than during the subacute phase (90.4 +/- 8.7%; p less than 0.0005). Mean serum albumin concentration was 29.2 +/- 6.4 gm/L during the acute phase and 36.7 +/- 7.8 gm/L during the subsequent subacute phase (p less than 0.005). Salicylate protein binding was affected independently by both serum albumin and total salicylate levels. During the acute phase of Kawasaki disease, children had an average twofold increase in free salicylate compared with normoalbuminemic control subjects. A nomogram has been devised to derive free salicylate levels from the known total salicylate and serum albumin concentrations.

Intravenous (IV) gamma globulin has been successfully used as replacement therapy for antibody-deficient patients and, more recently, in the treatment of autoimmune diseases such as idiopathic thrombocytopenic purpura, myasthenia gravis, and Kawasaki disease. In view of the successful treatment of these diseases, we initiated a pilot study of the effect of IV gamma globulin in systemic juvenile rheumatoid arthritis (JRA). Eight patients with active systemic JRA that was unresponsive to first-line agents, second-line agents, and/or corticosteroids received this therapy monthly for 6 months. Outcome measures included changes in articular and extraarticular features, steroid dosage, and laboratory parameters. Following IV gamma globulin therapy, there was significant improvement in arthritis and/or morning stiffness in 5 of 8 patients, while extraarticular features significantly improved in 7 of 8 patients. At study entry, 6 of 8 patients were receiving prednisone; at study end, prednisone was discontinued in 3 patients and decreased by more than 50% in the other 3. Overall, there was an 80% reduction in the prednisone dosage. Initially, all patients had anemia, low levels of serum albumin, and an elevated erythrocyte sedimentation rate, while a thrombocytosis was seen in 7 of 8 patients. Serum IgG was initially elevated in 6 patients. IV gamma globulin therapy resulted in a significant increase in hemoglobin and albumin levels and a significant decrease in the mean serum IgG level, platelet count, and erythrocyte sedimentation rate. In only 1 patient did IV gamma globulin fail to significantly improve the clinical or laboratory features of the disease. We suggest that this therapy may be beneficial in the treatment of systemic JRA.

rhagic colitis in a nursing home. N Engl J Med 1987;317:1496500. 2. Karmali MA, Petrie M, Lira C, et al. The association between idiopathic hemolytic-uremic syndrome and infection by vetotoxin-producing Escherichia coli. J Infect Dis 1985;151:77582. 3. Butler T, Islam MR, Azad MAK, et al. Risk factors for development of hemolytic-uremic syndrome during shigellosis. J PEDIATR 1987;110:894-7. 4. Cimolai N, Carter JE, Morrison B J, Anderson JD. The progression of Escheriehia eoli O157:H7 enteritis to hemolyticuremic syndrome: anti-diarrheal agent use and age as risk factors? Clin Invest Med 1988;ll(suppl):C71. 5. Gransden WR, Damm MAS, Anderson JD, et al. Further evidence associating hemolytic-uremic syndrome with infection by verotoxin-producing Eseherichia cob O 157:H7. J Infect Dis 1986;154:522-4. 6. Ryan CA, Tauxe RV, Hosek GW, et al. Eseherichia coli O 157:H7 diarrhea in a nursing home: clinical, epidemiological, and pathological findings. J Infect Dis 1986;154:631-8. 7. Dupont HL, Hornick RB. Adverse effect of LomotiI therapy in shigellosis. JAMA 1973;226:1525-8. 8. Pittman FE. Adverse effect of Lomotil. Gastroenterology 1974;67:408-10. 9. Novak E, Lee JG, Seckman CE, et al. Unfavourable effect of atropine-diphenoxylate (Lomotil) therapy in lincomycin. caused diarrhea. JAMA 1976;235:1451-4. 10. Sprinz H. Pathogenesis of intestinal infections. Arch Pathol 1969;87:556-62. 11. Smith FW, Law DH, Nickel WF, et al. Fulminant ulcerative colitis with toxic dilation of the colon: medical and surgical management of eleven cases with observations regarding etiology. Gastroenterology 1962;421:233-43. 12. Johnson PC, Ericsson CD, Dupont HL, et al. Comparison of loperamide with bismuth subsalicylate for the treatment of acute travelers' diarrhea. JAMA 1986;255:757-60. 13. Kent TH, Formal SB, Labrec EH. Acute enteritis due to Salmonella typhimurium in opium-treated guinea pigs. Arch Pathol 1966;81:501-8. 14. Formal SB, Abrams GD, Schneider H, et al. Experimental Shigella infections VI: role of the small intestine in an experimental infection in guinea pigs. J Bacteriol 1963;85:119-25. 15. Cimolai N, Anderson JD, Morrison BJ. Antibiotics for Escherichia coti O157:H7 enteritis? J Antimicrob Chemother 1989;23:807-8. 16. Spika JS, Parsons JE, Nordenberg D, et al. Hemolytic-uremic syndrome and diarrhea associated with Escherichia coli O157:H7 in a daycare center. J PEDIATR 1986;109:287-91.

We report a case of Behcet's syndrome with myositis in a pediatric patient, emphasizing the importance of muscle involvement in the differential diagnosis of calf pain and swelling in Behcet's syndrome. A review of the English-language literature from 1965 to the present suggests that the clinical picture of Behcet's syndrome in children differs from that in adults, in that there is a lower frequency of ocular disease, and unusual manifestations appear to be more common.

A Superantigen in Lactobacillus casei Cell Wall Extract Induces Coronary Arteritis: An Animal Model for Kawasaki Diseasee

Background: Severe myocarditis leading to heart failure is a specific entity complicating the acute phase of Kawasaki disease (KD) in children. Clinical course and response to therapy appear to differ in those children with myocarditis requiring inotropic treatment. Objective: To characterize specific clinical, laboratory and imaging findings in patients with severe myocarditis and delineate their response to therapeutic intervention. Methods: A 3 year retrospective chart review of all patients seen at the HSC (1998-2001) with the diagnosis of KD plus severe myocarditis was performed. The demographic features, clinical, lab and imaging findings and response to treatment were analyzed. Results: 5 patients (3female/ 2male) with a mean age at onset of 3.4years (range 1.5 to 4.4yrs) met diagnostic criteria for KD. In addition all children had significant fatigue, severe tachycardia (mean HR161/min) and hypotension (5/5

Fetal and Neonatal Manifestations in a Murine Model of Congenital Heart Block, Including Fetal Echocardiographic Assessment

Pathologic reports and animal models of congenital complete AV block(CCAVB) suggest that the sinus node may be affected in this disease. Assessment of chronotropic competence of the sinus node has not been performed in large numbers of patients with CCAVB. Demonstration of chronotropic competence of the sinus node in these patients would influence the choice of pacing device, application and mode (VDD vs DDDR). METHODS: To assess the chronotropic competence of the sinus node, we evaluated the intrinsic atrial rate at peak exercise during Bruce treadmill exercise tests in 27 CCAVB patients (59% female) age 12.2±3.3 years and compared them to published normal data. RESULTS: The data summarised below indicate that normal atrial rate response to exercise testing was present in 24/27 patients (89%), but 3/27 (11%) demonstrated atrial chronotropic incompetence. CONCLUSION: Although the majority of patients with CCAVB show an appropriate atrial rate response to exercise, it remains important to evaluate the chronotropic competence of the sinus node prior to deciding on the specific pacemaker therapy they require. In the majority a VDD system would suffice. Figure

ARE PATIENTS AT EXTREMES OF AGE AT INCREASED RISK FOR CORONARY ARTERY INVOLVEMENT IN KAWASAKI DISEASE? † 805

Little is known about any possible association of Class II MHC antigens with Kawasaki syndrome. Recent refinements in molecular genetic techniques have allowed precise determination of the extensive polymorphism now known to reside in the HLA-D region. Accordingly, 22 Caucasians, 8 Asians, and 3 American Blacks were typed for DRBI, DRB3, DRB4, DQAI, DQBI, and DPBI alleles by oligonucleotide probe hybridization of polymerase chain reaction-amplified genomic DNA and/or RFLP analysis. Among 15 DRBI, 3 DRB3, 9 DQAI, 15 DQBI, and 19 DPBI alleles examined, none were found to be slgnlflcantly associated with Kawasaki !syndrome, although DRw52a (DRB3*OIOI) was slightly decreased in frequency in Caucasians compared to race matched ~controls (P=O.03 uncorr, RR=0.24). These data, therefore, do not support a role for Class II MHC alleles in the : pathogenesis of Kawasaki syndrome. P28

ANCA have been described in a number of vasculitic conditions, such as Wegener's Granulomatosis, Polyarteritis Nodosa, ChurgStrauss vasculitis and crescentic glomerulonephritis, and may be a marker of disease activity. We have studied 55 children with Kawasaki Disease (KD) aged 3 months to 8 years for the presence of ANCA by indirect immunofluorescence (IF) of ethanol-fixed neutrophils and by using a commercially available ELISA kit (Biocarb Diagnostics). Forty-nine patients fuEilled 5 or 6 criteria for the diagnosis of KD, and 6 had 4 criteria. All patients were ueated with high dose ASA and intravenous gammaglobulin (IVGG) followed by low dose ASA as per standard protocol. Thirty-seven samples were tested in the acute (0-2wks), 54 in the subacute (2-10 wks) and 22 in the recovery phase (>!0 wks). A positive ANCA was found in 39/55 patients (70%) by IF or ELISA. All IF positive scra were cytoplasmic in pattern. The majority of samples were positive in the subacute phase (33/54). Sixteen of 19 patients (84%) with coronary artery lesions (CAL = dilatation/ectasia/ ancurysm) were ANCA positive, compared to 23/36 (64%) of patients without CAL. Six of 8 patients with coronary aneurysms and all 5 patients with persistent aneurysms were ANCA positive in the acute or suhacute phase. Three of 4 patients with ventriculomegaly on echocardiogram but no CAL and 4/8 patients with isolated pericardial effusion were ANCA positive. All 5 patients who were retreated with IVGG for failure to respond or recurrence of KD were ANCA positive, and 3/5 had CAL (2 with persistent aneurysms). ANCA was detected in 2/33 or 6% of control patients. The high incidence of positive ANCA in this series of patients with KD likely reflects the presence of systemic vasculitis. The majority of samples were positive in the subacute phase, suggesting that ANCA occurs as part of a primary immune response. ANCA appears to be sensitive for CAL in KD but is not specific. As every patient with KD is treated with IVGG, the natural history of the disease is altered and may influence the development of anti-nuclear cytoplasmic antibodies. P24

Quantitative assays for C3 and C4 activation were carried out simultaneously on blood from children with varied types of juvenile arthritis. Factor VIII-related antigen was also measured as an indicator of vascular damage. In active systemic juvenile arthritis, the C4d/C4 ratio was frequently elevated and was usually associated with elevated C3d/C3 ratios and elevated concentrations of factor VIII-related antigen. Children with chronic polyarticular arthritis, no matter which forms of onset they had had, also had increased levels of the C4d/C4 ratio, C3d/C3 ratio, and factor VIII-related antigen, but these were less consistent and were not associated with each other. In contrast, in pauciarticular arthritis there was a uniquely isolated increase in the C3d/C3 ratio. This work implies that there are different mechanisms responsible for complement activation in the different types and at different stages of juvenile arthritis.

The mechanisms leading to the previously reported difficulties in achieving therapeutic serum concentrations of salicylates in Kawasaki disease were studied in eight children, once during the acute (febrile) phase and again during the nonfebrile (subacute) phase of the disease. Salicylate bioavailability was impaired during the acute phase of the disease (47.7% +/- 6.6%), and increased significantly thereafter to 75.1% +/- 9.3%. During the febrile phase there was a significant correlation between salicylate bioavailability and steady-state serum concentrations. Salicylate renal clearance was significantly higher during the febrile phase (14.45 +/- 2.5 mL/kg.h), compared with the nonfebrile phase (7 +/- 1.6 mL/kg.h, P less than 0.05). The change in salicylate clearance could be explained by decreased protein binding in the acute phase (82.5% +/- 1.9%) with substantially more free salicylates caused by significantly lower serum albumin concentrations. Changes in urine metabolites during the acute and subacute phases were consistent with the changes in dose administered (100 mg/kg in the acute phase vs 10 mg/kg in the subacute phase). The pattern of metabolites excreted in the urine of children with Kawasaki disease receiving 100 mg/kg was similar to that in children with juvenile rheumatoid arthritis receiving the same dose.

A coagulopathy resembling disseminated intravascular coagulation may occur in systemic juvenile rheumatoid arthritis. We have seen this in seven patients with three different circumstances of disease activity or drug treatment. In one patient, a coagulopathy was not associated with drug therapy, and required corticosteroid therapy for control. A second group of patients was receiving orally nonsteroidal anti-inflammatory drugs during an acute flare-up of disease associated with low serum albumin concentrations. Coagulopathy in these patients may be a result of reduced vascular endothelial cell cyclooxygenase activity secondary to increased levels of unbound nonsteroidal anti-inflammatory drug. In these children, corticosteroid therapy was required for control. A third form of coagulopathy was seen in patients receiving a second injection of aurothiomalate. This form appears to be idiosyncratic, self-limiting, and relatively benign.

Epidermolysis bullosa (EB), a heterogeneous group of hereditary diseases, varies in mode of inheritance, extent, severity, and presence or absence of scarring and dystrophy. Fourteen cases (13 in infants and 1 in a young adult) were studied. Subtyping by ultrastructural findings in normal and blistered skin biopsies was as follows: EB simplex (2), EB letalis (3), EBD dominant (2), and EBD recessive (7). One case diagnosed as recessive dystrophic by electron microscopy (EM) followed a benign course with little scaring and was re-classified clinically and after reviewing the EM as dominant dystrophic. Defining the level of bulla formation by EM allowed accurate diagnosis of subtypes. In 6 patients with EBD recessive, normal and bullous skin showed collagenolysis and no anchoring fibrils. In patients with EBD dominant, rudimentary fibrils were noted in normal skin. Whether absence of anchoring fibrils is primary or secondary in these two types and the role of collagenolysis remain unresolved.

Using the radioligand beta-adrenergic blocker [125I]cyanopindolol (ICYP), we have characterized the beta-adrenergic receptors on Leu 3+ (T helper [TH]), Leu 2+, 9.3- (T suppressor [Ts]) and Leu 2+, 9.3+ (T cytolytic [Tc]) subsets of human lymphocytes. Peripheral blood T cells were isolated by rosetting, and then subsets were purified by their affinities to monoclonal antibodies against their Leu 3 and 9.3 markers. ICYP binding to the subsets was saturable with time and with concentration; the binding was stereoselective and reversible by beta-adrenergic antagonists. A biological response produced by beta agonists increased intracellular concentrations of cAMP and corresponded to the number of binding sites. Each subset of cells had a number of binding sites, which was characteristic for the given subset. The data indicate that the density of distribution of beta-adrenergic receptors was not homogeneous on the precursors of phenotypically and functionally distinct T cells (Ts approximately 2900, Tc approximately 1800 and TH approximately 750 binding sites). The displacement studies using beta-adrenergic agonists were performed on the cytolytic and suppressor T cell subsets, suggesting that the receptors were mainly of the beta-2 type. The immunobiological significance of such selective distribution of numbers and subtypes of beta-adrenergic receptors on distinct T cell subsets is under investigation.