Predicting duration of beneficial effect of joint injection among children with chronic arthritis by measuring biomarkers concentration in synovial fluid at the time of injection.

OBJECTIVES: Intra-articular corticosteroids injection (IAC) is a mainstay for the treatment of children with chronic arthritis; nonetheless its efficacy showed variability among published studies and it is still not possible to predict the outcome in a single patient. Our objective was to study the profile of biomarkers in the synovial fluid (SF) obtained at the time of injection and establish if such profile predicts duration of effect. METHODS: SF obtained from patients who underwent knee arthrocentesis and injection was procured and stored for cytokine analysis. Records of those patients who had at least 6 months of follow-up from the injection were reviewed. Time to flare was recorded. Levels of IL-6, IL-1alpha, TNF-alpha, IL-2sR, MMP-3, IL-10 and TGF-Beta1 were measured by ELISA. For primary analysis each patient was utilized once. For secondary analysis each injected knee was considered a single event. RESULTS: 60 samples from 33 patients were obtained. In the primary analysis we found a correlation between MMP-3 synovial fluid levels and outcome at 6 months (p=0,02; p=0,03 for different quartiles). In the secondary analysis we found that IL-6 and IL-10 levels predicted outcome at six and at 12 months (IL-6: p=0.01; p=0.02 respectively) (IL-10: p=0.017; p=0.01 respectively), with higher levels of IL-6 predicting shorter time to relapse and higher levels of IL-10 longer duration of corticosteroids effect. CONCLUSIONS: Our study identified MMP-3 and possibly IL-6 and IL-10 as candidates for the development of a set of biomarkers to predict response to IAC among children with chronic arthritis at the time of injection.

Arthritis following recombinant outer surface protein A vaccination for Lyme disease.

As more individuals receive outer surface protein A (OspA) vaccination, adverse effects not detected during phase III clinical trials may become apparent. Although arthritis has been described following other human vaccines, we found no reports of human cases after Lyme disease vaccination. We describe 4 males (2 children, 2 adults) who developed arthritis following recombinant OspA vaccination. The potential arthritogenic effect of OspA suggested by in vitro and animal studies finds a clinical correlate in these 4 cases.

Successful treatment of retroperitoneal fibrosis with tamoxifen in a child.

We describe our experience with tamoxifen in a prepubertal girl with retroperitoneal fibrosis who had failed treatment with high dose corticosteroid therapy. Her response was excellent.

Effect of immunization with recombinant OspA on serologic tests for Lyme borreliosis.

This study evaluated the effects of vaccination with OspA on the use of serologic tests as aids in the diagnosis of Lyme borreliosis. Sera from control and OspA-immunized mice and from OspA-immunized human volunteers were tested for serologic reactivity to Borrelia burgdorferi. Testing was performed with samples obtained prior to administration of vaccine and at 30 days following administration of an initial and a second dose of OspA vaccine. The assays used to assess serologic reactivity included an in-house-developed enzyme-linked immunosorbent assay (ELISA), an in-house-developed Western blot assay, two commercial Western blot tests, and a commercially available dot blot assay. Data obtained from this study demonstrate that immunization with the OspA vaccine will cause ELISA to yield positive results (as reported previously) for the majority of vaccine recipients. Results obtained from Western blot analysis indicate that vaccination with recombinant OspA induces production of antibodies which bind to several different borrelial proteins. The degree of reactivity detected by Western blotting varied greatly between the three assays used. The in-house assay showed the least reactivity, while one commercial Western blot test actually yielded positive test results for infection with B. burgdorferi. The usefulness of all three Western blot assays for the diagnosis of potential infection in a vaccine recipient is severely limited by the extensive reactivity caused by vaccination alone. Antibodies produced in response to OspA vaccination did not significantly affect the performance of the dot blot test; thus, it could provide a reliable means to test for infection with B. burgdorferi in OspA vaccine recipients.

Lipophagic granulomatous panniculitis with lipoatrophy mimicking arthritis with pitting edema.

We describe a preadolescent girl with intense ankle synovitis and pitting edema that obscured the subcutaneous origin of the inflammation. Typical nodular disease emerged after corticosteroid tapering when regional atrophy developed.

Long-term cognitive effects of Lyme disease in children.

Most studies of adults infected with Lyme disease (LD) have found adverse cognitive effects from the disease. In contrast, the only controlled study investigating cognitive effects of LD in a pediatric population found no effects after a 2-year follow-up. However, it was questioned whether the negative effects might take longer than 2 years to emerge. Therefore, this investigation reports a 4-year follow-up of the original sample. Twenty-five children with strictly defined LD were compared with 17 sibling control children. A neuropsychological battery was utilized, including assessment of the cognitive areas of IQ, information processing speed, fine-motor dexterity, novel problem solving and executive functioning, short-term and intermediate memory, and acquisition of new learning. In addition, parents' subjective ratings were obtained on the disease's impact on their child's participation in everyday activities. No between-group differences were found for 17 of the 18 neuropsychological test measures, nor were there differences in parents' subjective ratings. Therefore, in contrast with studies of adults with LD, the results of long-term follow-up of the pediatric population continue to strongly support the finding that children treated appropriately for LD have an excellent prognosis for normal cognitive functioning.

Intrafamilial occurrence of tubulointerstitial nephritis with uveitis and Vogt-Koyanagi-Harada syndrome.

We describe a child with acute tubular dysfunction, reversible renal failure, and uveitis, whose father has Vogt-Koyanagi-Harada syndrome. This is the first reported familial association of these 2 syndromes with distinctively overlapping clinical characteristics. A pathogenic association is proposed.

Use of ELISA to measure antinuclear antibodies in children with juvenile rheumatoid arthritis.

OBJECTIVE: To compare a series of commercial ELISA tests with an indirect immunofluorescent antibody (IFA) test for the detection of antinuclear antibodies (ANA) in children with juvenile rheumatoid arthritis (JRA). METHODS: Sera from 178 patients with JRA (88 pauciarticular, 68 polyarticular, 22 systemic) were compared with 26 healthy pediatric subjects. Twenty-one samples from patients with systemic lupus erythematosus (SLE) were also tested. All samples were analyzed by IFA and by 3 commercial ELISA methods. Concordance of ELISA results with IFA results (selected standard) were used as a measure of performance. Sensitivity and specificity were calculated for each test and likelihood ratios (LR) were established for IFA and ELISA in pauciarticular and polyarticular JRA sera. The increment in pretest probability was then obtained for each test as an additional measure of test performance. RESULTS: IFA rendered positive results on 18-77% of the JRA sera depending upon the subset, 100% of SLE sera, and 15% of normal patient sera. Using IFA as the standard, correspondence with positive results among patients with JRA ranged from 0 to 74% for the 3 ELISA tests, while it ranged from 5 to 73% in IFA negative sera. IFA tests showed intermediate range likelihood ratios (0.3, 0.5, 3.5, and 5) and increments in pretest probability ranging from 25 to 45%. While one of the ELISA tests attained 50% of increment in pretest probability for the positive test, it showed 0% increment as a negative test. The other 2 ELISA tests incremented the pretest probability from 0 to 25%. CONCLUSION: Our findings indicate that in JRA, the lack of correspondence with the historic standard IFA precludes the use of ELISA tests for detection of ANA. In addition, IFA out-performs ELISA by a substantial degree when "clinical utility" analysis of test performance is utilized. Detection of ANA in children with JRA should either continue to rely on IFA or be based on a different set of antigens if an ELISA format is chosen.

Cognitive effects of Lyme disease in children: a 4 year followup study.

OBJECTIVE: To measure cognitive effects of Lyme disease (LD) in a pediatric population 4 years after disease onset. METHODS: Prospective, blinded, multivariable controlled study of cognitive skills in children who have been treated for LD. The setting was a children's hospital in an area endemic for LD. Twenty-five children with strictly defined LD were compared with 17 control children (6 disease-control and 11 sibling-control). OUTCOME MEASURES: An extensive set of neuropsychological measures was administered. These included assessment of the cognitive areas of IQ, information processing speed, fine-motor dexterity, novel problem solving and executive functioning, short term and intermediate memory, and acquisition of new learning. Parents' ratings were also obtained concerning disease impact upon everyday activities. RESULTS: Seventeen of the 18 neuropsychological test measures showed the LD and control groups similar at time of 4 year followup. There were no differences between the groups regarding parents' impressions of disease impact. CONCLUSION: In contrast to studies of adults with LD, the results of longterm followup of the pediatric population continue to strongly support the finding that children treated appropriately for LD have an excellent prognosis for normal cognitive functioning.

Peer cluster theory and adolescent alcohol use: an explanation of alcohol use and a comparative analysis between two causal models.

This study tests the premise of peer cluster theory as it applies to individual alcohol use, and makes a comparative analysis between its ability to explain alcohol use and marijuana use. Using the results of a 1996 drug and alcohol survey of 1312 Western Kentucky University students, path analysis was used to measure the influence of six of peer cluster theory's psychosocial characteristics on the percentage of the respondent's college friends who use alcohol. All of these variables were then regressed on the respondent's alcohol use. The results of the causal models did show some support for peer cluster theory. The direct effect of the student's association with alcohol-using peers on individual alcohol use was shown to have the strongest direct influence on this outcome variable. However, a few limitations of this theoretical perspective were identified. The causal model for alcohol use showed that the indirect influence of two of these psychosocial characteristics (parental attitudes on alcohol use and success in school) was weaker than their direct influence on individual alcohol use. And, the comparative analysis showed that peer cluster theory is better suited to explain the use of marijuana than the use of alcohol.

Comparison of immunodot and western blot assays for diagnosing Lyme borreliosis.

Two commercially available serologic tests for use in diagnosing Lyme borreliosis were evaluated by using a test panel comprised of sera from patients diagnosed with Lyme borreliosis, non-Lyme disease controls, and healthy subjects. The test methods examined were a Western blot assay and an immunodot assay. The study was initiated to determine how the immunodot assay, which contains purified and recombinant proteins to those borrelial antigens recommended for immunoglobulin M (IgM) detection in the Dearborn criteria, would compare with the Western blot assay as a confirmatory method for serologic diagnosis of Lyme borreliosis. Results obtained showed that the two test methods performed comparably for detecting IgG antibodies. For IgM antibody detection, the immunodot and Western blot assays had similar sensitivities; however, the immunodot assay was more specific and had greater positive predictive value than the Western blot assay. The results obtained indicate that the immunodot assay performs as well as or better than the Western blot assay for diagnosing Lyme borreliosis. Furthermore, because it uses a limited panel (n = 5) of antigens, the immunodot is easier to read and interpret than standard Western blots.

Prevalence and outcome of uveitis in a regional cohort of patients with juvenile rheumatoid arthritis.

OBJECTIVE: To determine the prevalence and outcome of chronic uveitis in patients with juvenile rheumatoid arthritis (JRA). METHODS: A retrospective analysis of 760 patients with JRA followed in 4 pediatric rheumatology centers. Patients with chronic uveitis were identified and their medical and ophthalmologic records were reviewed. RESULTS: Seventy-four patients with uveitis were identified. The prevalence of uveitis was 9.3%. The mean interval from the onset of JRA to the onset of uveitis was 21 months, and 90% of the patients who developed uveitis did so within the first 4 years of their disease. Visual complications (synechiae, band keratopathy, cataract, or glaucoma) developed in 31% of the patients with uveitis. Complications were more common in patients who presented with uveitis early in the course of their JRA. Complications were also more common in antinuclear antibody (ANA) negative than in ANA positive patients. Visual loss to 20/50 or worse occurred in only 11% of patients with uveitis, and no patient became blind. CONCLUSION: In a very large cohort of patients with JRA, uveitis was uncommon and poor visual outcome was rare. Visual complications did not necessarily result in a poor outcome.

Lyme disease and seventh nerve paralysis in children.

PURPOSE: This study was undertaken to determine the frequency of Lyme disease (LD) as a cause of transient facial nerve palsy (FNP) in children. Acute onset FNP in children has been primarily associated with acute otitis media (AOM). Recently, LD has emerged in regions where the deer-tick vector is present and has been associated with multiple cranial neuropathies. PATIENTS AND METHODS: Fifty children with transient FNP were evaluated and treated at our institution over a 5.5-year period. RESULTS: The rank of etiologies confirmed LD to now be the most common (50%), followed by AOM (12%), varicella (6%), Herpes zoster (4%), and coxsackievirus (2%). Thirteen children (26%) had idiopathic FNP consistent with Bell's palsy. CONCLUSION: We conclude that transient FNP in children is most commonly caused by LD for regions with endemic infections caused by Borrelia burgdorferi.

Infection-related arthritis.

Postinfection arthritis represents a significant portion of the referrals to pediatric rheumatology centers, particularly in the United States. Many viral and common bacterial infections can be associated with arthritis, and their recognition can sometimes be difficult on a clinical basis. In patients with acute onset of arthritis, the clinician should actively seek epidemiologic, clinical, or laboratory evidence of infection. Diagnostic tests should be used rationally and results interpreted carefully. Some infections, once recognized, require antibiotic treatment, but in most cases anti-inflammatory therapy is successful in treating articular symptoms.

Correlation of seroreactivity with response to antibiotics in pediatric Lyme borreliosis.

Response to treatment with antibiotics was compared with serologic reactivity and clinical symptoms in a pediatric population with presumptive diagnoses of Lyme borreliosis. The population analyzed for this study consisted of a subset of a larger Lyme clinic population being monitored as part of a prospective study on pediatric Lyme borreliosis. All patients resided in an area in which Ixodes scapularis and Borrelia burgdorferi are considered endemic. Serum from patients was tested by enzyme-linked immunosorbent assay and Western blotting. Response to antibiotics was evaluated by members of a pediatric Lyme clinic. Results showed that positive serologic test results correlate with a favorable response to antibiotics, as does the presence of erythema migrans (EM), regardless of serologic status. Seronegative patients without EM had chronic fatigue and arthralgia and/or myalgia as primary symptoms and did not respond to antibiotics, even when multiple courses of treatment were given. These results indicate that serologic tests designed to have high specificity can reliably rule out Lyme borreliosis in patients with chronic symptoms, thus preventing unnecessary treatment with antibiotics.

The effects of daily intake of folic acid on the efficacy of methotrexate therapy in children with juvenile rheumatoid arthritis. A controlled study.

OBJECTIVE: To determine the effect of 1 mg/day of folic acid on the efficacy of methotrexate (MTX) to control disease activity in children with juvenile rheumatoid arthritis (JRA). METHODS: Randomized, double blind, placebo controlled, crossover trial of 13 weeks' duration. Nineteen children with the diagnosis of JRA, fulfilling the American College of Rheumatology diagnostic criteria, who had been receiving MTX for at least 6 months and whose disease status had remained stable for at least one month before entry were enrolled in the study. Subjects were randomly assigned to receive 1 mg/day of liquid folic acid or a liquid placebo for 6 weeks, followed by a one week washout period, and subsequent crossover to the alternate form for another 6 weeks. Disease activity indicators, including swollen joint count, duration of morning stiffness, physician and patient global assessment, and C-reactive protein, were assessed at study entry and at 6 and 13 weeks. RESULTS: One patient flared during the first 2 weeks while taking placebo, requiring study withdrawal and exclusion from outcome analysis. For the remaining 18 patients, there was no statistical difference in disease activity indicators with folic acid treatment compared to placebo. CONCLUSION: Supplementation with 1 mg/day of folic acid may not affect the clinical efficacy of oral weekly MTX in children with JRA.

Clinical characteristics of antiphospholipid antibody syndrome in children.

OBJECTIVE: To evaluate the clinical features and outcome of antiphospholipid syndrome (APS) in children. STUDY DESIGN: Retrospective chart review of patients seen at the Children's Hospital of Philadelphia and Children's Seashore House Pediatric Rheumatology Center between 1988 and 1993. RESULTS: Nine patients with ages ranging from 8 months to 17 years are presented. Clinical features of five patients with primary APS, described in detail, were digital ischemia, stroke, chorea, Addison disease, and pulmonary vaso-occlusive disease. The four children with secondary APS had systemic lupus erythematosus. Clinical features of these patients include livedo reticularis, deep venous thrombosis, and pulmonary hypertension. Antiphospholipid titers, results of coagulation studies, and serologic findings did not predict outcome. CONCLUSION: APS in children has diverse clinical features similar to those in adults and should be considered in cases of unexplained vaso-occlusive disease.

Residual serologic reactivity in children with resolved Lyme arthritis.

OBJECTIVE: To define the pattern of persistent antibody response in children with resolved Lyme arthritis. METHODS: From a cohort of 67 children with Lyme arthritis followed in our department since 1989, 19 were selected using these criteria: All patients (1) were asymptomatic; (2) had an ELISA titer < or = 1:160; (3) had been in treatment a minimum of 6 months. Their initial and late samples were assessed by Western blot and the pattern of reactivity was analyzed. RESULTS: The mean interval between treatment and last sample was 9.6 months (6-23). Analysis of the last sample showed that only 5/19 were negative by ELISA and 4/19 were at the cutoff limit (1:80). Only 6 patients had fewer than 4 reactive bands, 4 had 4 bands, and 9 had 5-11 bands on Western blot. The 41, 39, and 60 kDa were the most commonly observed reactive bands at last evaluation. 31 and 34 kDa bands, while relatively common in initial samples (36%), became uncommon (5%) on late samples. A significant finding was the absence of IgM reactivity in 18/19: 1/19 had 41 kDa reactivity. Only 4 patients had both ELISA (< 1:80) and Western blot tests negative (< 5 reactive bands). CONCLUSION: All patients with resolved Lyme arthritis continue to show serologic reactivity beyond 6 months of therapy. 68% of the patients satisfy Western blot criteria for positivity in our laboratory. IgM reactivity to any antigen was minimal and IgG reactivity against the 41 kDa antigen, considered diagnostic of infection in initial samples by some laboratories, is very common (16/19).