Quinolinic acid in patients with systemic lupus erythematosus and neuropsychiatric manifestations.

OBJECTIVE: To evaluate the relationship between quinolinic acid, a neuroactive metabolite of L-tryptophan, and neuropsychiatric manifestations of systemic lupus erythematosus (SLE). METHODS: Forty specimens of cerebrospinal fluid (CSF) were obtained from 39 patients with SLE who were evaluated for 40 episodes of neuropsychiatric dysfunction. The diagnosis of the neuropsychiatric dysfunction was determined clinically. CSF and serum specimens were analyzed for levels of quinolinic acid without knowledge of the clinical diagnosis. RESULTS: Neuropsychiatric dysfunction attributed to SLE (NPSLE) was confirmed in 30 patient-episodes (Group 1), whereas in the other 10 (Group 2) other etiologies were felt to explain their CNS dysfunction. The median levels of CSF quinolinic acid for Group 1 (232.5 nmol/l) were significantly higher than those for Group 2 (median 38.2 nmol/l) (p < 0.014). CSF and serum quinolinic acid levels correlated significantly (p < 0.003) but there was not correlation between CSF quinolinic acid and CSF protein concentrations or white blood cell counts. CONCLUSION: We conclude that elevated quinolinic acid levels in the CSF and serum may be associated with NPSLE and could possibly play a role in its pathogenesis.

Leukocyte adhesion deficiency: report of a case and review of the literature.

Leukocyte adhesion deficiency (LAD) is a rare inherited immunodeficiency that is characterized by deficiency of the beta 2 integrin leukocyte adhesion molecules Mac-1, LFA-1, and p150,95. We describe a case of the severe form of LAD in an infant with recurrent infections and with a complete deficiency of beta 2 integrin molecules, and review the clinical aspects of the syndrome.

Characterization of in vivo mutated T cell clones from patients with systemic lupus erythematosus.

Patients with systemic lupus erythematosus (SLE) have increased percentages of activated T cells and increased numbers of cells with mutations in their hypoxanthineguanine phosphoribosyltransferase (hprt) gene, as judged by growth in the presence of 6-thioguanine. To study the relevance of these mutant T cells to disease pathogenesis, we have assessed the phenotype and functional capabilities of such cells from 21 patients with SLE who never had received cytotoxic drugs. The frequency of T cells with mutations in hprt in the blood of these patients ranged from normal to 25 times normal (mean +/- SEM [21.1 +/- 6.1] x 10(-6) versus [4.8 +/- 0.8] x 10(-6), in 15 age-matched normal individuals, P < 0.001) and correlated significantly with disease duration. CD4+ and CD8+ phenotypes were comparable among mutated and nonmutated clones from both patients and normals. Although the frequency of CD3+CD4-CD8- cells was low, it was increased among SLE-derived T cells (mutated and wild-type) compared with clones derived from normals (5% for SLE vs 1% for normals). A substantial percentage of all clones were able to help autologous B cells to produce anti-ssDNA, 11 of 68 (16%) selected clones and 3 of 28 (11%) nonselected clones. Help for autoantibody production was confined to CD4+ SLE-derived T cell clones. It could be blocked using an anti-HLA-DR mAb, suggesting that classical cognate help was operative. This represents the first estimate of the frequency of T cells able to drive autoantibody production in SLE.

Neurosarcoidosis presenting as secondary amenorrhea in a teenager.

Sarcoidosis is a systemic inflammatory disease of unknown etiology characterized by non-caseating epithelioid cell granulomata. The lungs and reticulo-endothelial system are typically involved, and virtually any organ system may be affected. Sarcoidosis involving the central nervous system is relatively uncommon, estimated to occur in approximately 5% of patients with sarcoidosis in the United States, while the incidence throughout the world may be as high as 15%. Hypothalamic dysfunction is the most common manifestation of central nervous system parenchymatous disease in neurosarcoidosis. Polyuria and polydipsia are the most frequently occurring symptoms in patients with sarcoidosis who have dysfunction of the pituitary and hypothalamus. We describe a patient with secondary amenorrhea resulting from neurosarcoidosis involving the pituitary and hypothalamus.

Elevated soluble CD8 antigen and soluble interleukin-2 receptors in the sera of patients with juvenile rheumatoid arthritis.

Activated T lymphocytes release various molecules including soluble CD8 (sCD8) antigen and soluble interleukin-2 receptor (sIL-2R). Elevated serum sCD8 antigen levels have been found in patients with viral infections, certain hematologic malignancies, and rheumatoid arthritis. On the other hand, elevated serum levels of sIL-2R have been found in various diseases including juvenile rheumatoid arthritis (JRA). We measured sCD8 antigen and sIL-2R levels using enzyme-linked immunosorbent assays in the sera of 49 afebrile patients with JRA (systemic 15, polyarticular 16, and pauciarticular 18) and 16 normal children. Disease activity was classified as mild, moderate, and severe. Sera from patients with severe JRA expressed statistically significant higher levels of both sCD8 and sIL-2R, whereas patients with mild disease had the lowest levels. There were no differences in the serum sCD8 and sIL-2R levels between the groups of patients with pauciarticular-, systemic-, and polyarticular-onset disease. Patients who were treated with prednisone had statistically nonsignificant higher serum levels of sCD8 and sIL-2R. A statistically significant positive correlation was found between sCD8 and sIL-2R levels, sCD8 levels and erythrocyte sedimentation rate (ESR), and sIL-2R levels and ESR. Our findings further suggest the presence of activated lymphocytes in patients with JRA and show that sCD8 antigen serum levels correlate with both serum levels of sIL-2R and ESR and thus may represent alternative indicators of disease activity.

Calcium absorption and metabolism in children with juvenile rheumatoid arthritis assessed using stable isotopes.

OBJECTIVE: To assess calcium intake, absorption, urinary excretion and the fraction of urinary calcium originating from bone and diet in patients with juvenile rheumatoid arthritis (JRA). METHODS: A dual tracer stable isotope technique was used to study 6 girls and 3 boys with JRA. RESULTS: Fractional absorption in the 6 girls, ages 4-9, with JRA was significantly lower than that in 10 similar, healthy girls (22.6 +/- 4.7% vs 30.4 +/- 8.4%, p = 0.033). Urinary calcium excretion tended to be higher in the girls with JRA than in controls, (2.9 +/- 1.5 vs 1.6 +/- 1.7, p = 0.15). The urinary calcium in patients with JRA was derived principally from bone, and there was no increase in diet derived urinary calcium. One of the boys with new onset JRA was markedly hypercalciuric and in negative calcium balance (-222 mg/day). CONCLUSION: Our data show that hypercalciuria in patients with JRA results from bone resorption, not hyperabsorption of dietary calcium and suggest that increases in calcium intake may benefit children with JRA.

Development of a radioreceptor assay to measure glucocorticoids.

We have developed a radioreceptor assay to measure glucocorticoids. The assay employs the partially purified 95-kDa receptor isolated from human liver and purified by size fractionation on high-performance liquid chromatography (HPLC). In the assay [3H]prednisolone competes with steroids (endogenous and exogenous) for binding to the receptor. Bound and free are separated by treatment with charcoal. The between-day precision [% coefficient of variation (CV)] at concentrations of 9.4, 18.7, and 69.9 micrograms/L prednisolone is 16.6, 9.3 and 4.5%, respectively. Specificity studies revealed that hydrocortisone, deoxycorticosterone, 4-pregnene-17 alpha,21-diol-3,20-dione, 17 alpha-hydroxyprogesterone, corticosterone and beta-hydroxyprogesterone all compete with [3H]prednisolone for binding to the receptor. Prednisone and 6 alpha-methyl prednisolone displace [3H]prednisolone to only a minor degree. The assay has been used to assess "glucocorticoid activity" in children with rheumatic diseases treated with prednisolone.

Use of a radioreceptor assay in the assessment of cushingoid features in patients with juvenile rheumatic diseases.

A marked variation has been observed in severity of cushingoid appearance in patients with rheumatic diseases (RD) following steroid administration. We studied ten children with RD to determine if a relationship exists between cushingoid features and an individual's steroid activity as measured by prednisolone equivalents using a radioreceptor assay. Cushingoid features were clinically assessed by a "cushing score" according to the method of Bergrem. Patients were assigned to either the cushingoid (C) or noncushingoid (NC) group at study entry according to their cushing score. Blood was drawn prior to prednisone ingestion and then at 30, 60, 90, 120, 240, and 360 minutes and each sample was assessed for prednisolone equivalents and also for free and total cortisol. Group comparisons of dose-adjusted area under curve (AUC) and peak response are reported. Cushingoid patients had higher plasma prednisolone equivalents (PE) than noncushingoid patients as measured by peak PE and AUC. The PE.6 h/L average AUC for C patients was 248 micrograms PE.6 h/L versus 134 micrograms PE.6 h/L for NC patients. This nearly twofold difference was also noted between mean peak values (C 82 micrograms/L vs. NC 44 micrograms/L). Spearman correlations of Cushing scores with these two parameters indicated significant (p less than 0.05) relationships. A patient's Cushing score correlated best with peak response (rs = 0.78) and also with AUC (rs = 0.72). Measurement of plasma peak PE or AUC could be valuable for individualizing steroid dosing in children with RD.

Bone changes associated with cystic fibrosis.

Musculoskeletal symptoms are known to occur frequently in patients with cystic fibrosis. Radiographs of the hands and wrists, and of the tibia and fibula of 56 patients with cystic fibrosis were reviewed. No radiographic joint abnormalities were detected. However, it was noted that the fourth metacarpal was shortened in 5 of 56 patients (9%), a finding that has not been previously documented. Hypertrophic pulmonary osteoarthropathy was present in 3 patients (5.5%).

Immune abnormalities in the pathogenesis of juvenile rheumatoid arthritis.

Juvenile rheumatoid arthritis (JRA) is the most common rheumatic disease of childhood. Although the etiology remains unknown, immunoregulatory imbalances are thought to be important in the pathogenesis of JRA. Numerous immunologic abnormalities have been described in these patients, but it remains unclear which are fundamental to the pathogenesis of the disease and which are secondary. In this article, the authors review lymphocyte and lymphokine abnormalities in children with JRA with emphasis on the possible role of these immune abnormalities in the pathogenesis of JRA.

Acute airway obstruction in relapsing polychondritis: treatment with pulse methylprednisolone.

We describe 2 adolescents with relapsing polychondritis who developed acute airway obstruction. Both were successfully treated with intravenous steroids for this complication following failure with oral steroids. Early respiratory tract involvement in younger patients seems predictive of a poor outcome and aggressive therapy with intravenous high dose steroids and/or immunosuppressive drugs appears to be indicated.

Nutritional status and growth in juvenile rheumatoid arthritis.

The specific cause of short stature in juvenile rheumatoid arthritis (JRA) is unknown. One hypothesis links altered growth to inadequate dietary intake. In this study, nutritional status was assessed in 34 children with JRA (8 with systemic JRA, 14 with polyarticular JRA, and 12 with pauciarticular JRA) and 9 healthy controls using 3-day diet records, anthropometrics, and biochemical analyses. Differences in growth were found among the three types of JRA. One third of all subjects were at or below the 10th percentile in height for age (these being predominantly among the systemic and polyarticular groups). With few exceptions, the mean dietary intake for calories and essential nutrients was found to be adequate for each of the three groups. However, more than half of those with systemic JRA reportedly consumed less than the recommended caloric intake for their age and weight. No significant correlations were found linking dietary intake to growth percentiles in any of the groups studied. Biochemical abnormalities were found among the systemic and polyarticular groups. These abnormalities included low plasma levels of vitamins A and C, proteins (albumin, prealbumin, and retinol binding protein) and zinc; and increased levels of copper and glutathione peroxidase activity. Plasma selenium and vitamin E levels were unchanged. The discrepancy between intake and certain circulating nutrient levels may reflect alterations in the requirements, absorption, or use of these nutrients in the presence of chronic inflammation.

Neuropsychologic deficits and antineuronal antibodies in pediatric systemic lupus erythematosus.

Pediatric research has been limited regarding the neuropsychologic status in systemic lupus erythematosus (SLE) despite frequent involvement of the central nervous system early in the disease process. SLE is a multisystem autoimmune disorder which often presents with significant neuropsychiatric manifestations including objective neurologic findings and severe psychiatric symptoms. Neuropsychological evaluation provides an objective method for delineating changes in higher cortical functions. We studied 21 pediatric patients who met SLE criteria (12 moderate, 9 mild disease activity) and had no history of CNS damage unrelated to lupus. Mean age was 15.8 years; mean SLE duration at the time of the neuropsychological examination was 2.4 years. Comparison of these SLE patients to a contrast group of 11 patients with juvenile rheumatoid arthritis (JRA) revealed decreased complex problem solving ability for the SLE group. Individual, IQ-adjusted neuropsychological profile analysis yielded a significant difference in the number of specific neuropsychologic deficits for the 2 groups, with impairment rates of 43% for SLE and 18% for JRA. Longer duration of lupus was associated with lower cognitive status. Neuron-reactive antibody studies for IgG and IgM were negative. Results suggest that the prevalence of higher cortical impairment may be as great for younger individuals with lupus as has been documented for older populations.

Autoimmune thrombocytopenia in pediatric systemic lupus erythematosus: alternative therapeutic modalities.

Three patients with pediatric systemic lupus erythematosus (PSLE) and autoimmune thrombocytopenia (AT), who developed unacceptable side effects (pseudotumor cerebri, hypertension, excessive weight gain) from treatment with steroids, were treated successfully with vincristine (2 patients) or intravenous immunoglobulin (1 patient). All patients remained off steroids without any complications for 11 to 23 months.

Immune abnormalities in the pathogenesis of juvenile rheumatoid arthritis.

This article reviews the immune abnormalities involved in the pathogenesis of juvenile rheumatoid arthritis (JRA). We review both the humoral and cellular immune systems of children with JRA with emphasis on the possible role of these immune abnormalities in the pathogenesis of JRA.

Relapsing polychondritis in an adolescent.

Relapsing polychondritis (RP) is an uncommon systemic disorder with a highly variable course. A 17-year-old woman recently presented with a 1-month history of depression, weight loss, chest wall tenderness, hoarseness, and dysphagia. Physical examination revealed cachexia, low-grade fever, pharyngeal erythema, and tenderness of the right auricle, anterior chest, cricothyroid cartilage, and both knees. Laboratory studies included a hematocrit of 34% and a sedimentation rate of 50 mm/hr. Initial improvement on oral corticosteroids was followed by respiratory distress. At that time calcified tracheal cartilage, subglottic stricture, and a saddle nose deformity were present. Despite therapy with steroids, dapsone, and pulse cyclophosphamide, the respiratory distress reoccurred, eventually necessitating tracheostomy. Tracheal cartilage biopsy confirmed the presumptive diagnosis of RP. Bilateral auricular chondritis developed after initial presentation, as did acute vertigo. Although seen in all age groups, less than 10% of cases of RP are seen in children and adolescents. Auricular chondritis (89% of all cases), inflammatory asymetric arthritis (81% of all cases), nasal chondritis (72% of all cases), respiratory tract chondritis (56% of all cases), and audiovestibular abnormalities (46% of all cases) were present in our patient. Relapsing polychondritis may follow a slowly evolving or rapidly progressive course. Appropriate diagnosis and aggressive therapy are recommended to lessen the morbidity and mortality.

Pneumococcal immunization in patients with systemic lupus erythematosus treated with immunosuppressives.

Immunogenicity of 14 valent pneumococcal vaccine was evaluated in a placebo controlled, double blind, randomized study involving 77 patients with systemic lupus erythematosus (SLE). Antibodies to 12 type specific capsular antigens were measured prior to and one and 6 months post injection. In 17 patients treated with prednisone plus cyclophosphamide and/or azathioprine, mean body concentrations (ng antibody nitrogen/ml serum) increased from 528 to 1328 and 852, respectively, in vaccinated patients compared to 307, 308 and 344 following placebo. In 60 patients not receiving immunosuppressives, mean antibody concentrations were 355, 1361 and 920 post vaccine and 401, 473 and 377 post placebo. Our study demonstrates that antibody responses to pneumococcal vaccine in SLE patients is unaffected by these immunosuppressive agents.

Interleukin-2 restores the depressed allogeneic cell-mediated lympholysis and natural killer cell activity in patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is characterized by a variety of profound T-cell abnormalities among which are decreased cytotoxic capacity measured by allogeneic cell-mediated lympholysis (CML), natural killer cell (NK) activity, and decreased lymphokine production. In a group of 13 patients with active SLE, allogeneic CML, tested by a 4-hr 51Cr-release assay, was 18.2 +/- 2.7% while in the group of normal individuals CML was 41.2 +/- 2.7%. If optimal doses of affinity-purified interleukin-2 (IL-2) were present during the mixed lymphocyte culture, the CML of SLE patients was increased to normal levels (40.4 +/- 4.0%). In contrast, interferon-alpha (IFN-alpha) increased (but not significantly) the levels of CML. Mixed lymphocyte reaction, tested by tritiated thymidine incorporation, was also decreased in the group of patients (14,820 +/- 815 cpm vs 28,972 +/- 5880 cpm in normals) and it was increased to normal levels if IL-2, but not IFN-alpha was added to the cultures. NK activity was decreased in the group of patients tested by 51Cr-release assay, harvested at 6 and 18 hr. IL-2 increased the NK activity up to normal levels, while IFN-alpha was only partially efficacious. These results demonstrate that IL-2, but not IFN-alpha, can potentiate or even fully restore the deficient cytotoxic effector function of peripheral mononuclear cells in patients with SLE.