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.

Rapid effects of insulin on the cycling of the insulin receptor in a human monocyte cell line (U-937).

The insulin receptor and its regulation by insulin was studied in U-937 monocytes, a human cell line with properties similar to those of normal peripheral blood monocytes. Treatment of this cell with insulin for 8-16 h produced an overall loss in the insulin receptor, i.e., a loss of receptors from the cell surface and internal pools. In contrast, short-term insulin treatment (15-30 min) caused a reduction in cell surface receptors but an increase in the internal receptors, as judged by pronase treatment at 4 degrees C to distinguish receptor location. After the removal of insulin and pronase, the internalized receptors were rapidly reinserted back into the cell surface after warming to 37 degrees C. Further studies showed an insulin-mediated increase in fluid-phase pinocytosis as measured by horseradish peroxidase (HRP) uptake. The amount of HRP accumulation and the time course for this stimulation were similar to those for receptor internalization. These features plus other results suggest that the insulin-stimulated internalization of insulin receptors may require an acceleration in the rate of pinocytic vesicle formation.

Cognitive effects of Lyme disease in children.

OBJECTIVE: To measure possible cognitive sequelae of Lyme disease (LD) within a pediatric population. DESIGN: Prospective, blinded, controlled study of cognitive skills in children who had been treated for LD. SETTING: A children's hospital in an area endemic for LD. PATIENTS: Forty-one children with strictly defined LD were compared with 14 control children who had subacute rheumatological diseases, and with 23 healthy sibling controls. OUTCOME MEASURES: Neuropsychologic measures were administered to each child to assess the following cognitive areas: IQ information processing speed, fine-motor dexterity, novel-problem solving and executive functioning, short-term and intermediate memory, and the ability to acquire new learning. Predisease and postdisease academic achievement test scores were also gathered. Impressions from parents concerning the disease's subsequent impact were also obtained. RESULTS: No differences between LD and control groups were found for any of the numerous neuropsychologic measures. Analyses also failed to show differences between LD patients grouped with respect to the presence or absence of known neurologic involvement, disease stage, duration of symptoms before therapy, or type of antibiotic treatment. No predisease versus post-disease difference in academic performance was found. No perceived long-term deterioration in cognitive, social, or personality areas was reported by parents. CONCLUSION: Children appropriately treated for LD have an excellent prognosis for unimpaired cognitive functioning.

Use of western blot and enzyme-linked immunosorbent assays to assist in the diagnosis of Lyme disease.

Without evidence of erythema chronicum migrans, diagnostic confirmation of Lyme disease may be difficult, particularly if there are conflicting laboratory results. Often, for families and physicians, the clinical dilemma is whether fatigue, arthritis/arthralgias, a positive enzyme-linked immunosorbent assay (ELISA), and tick exposure, but no evidence of erythema chronicum migrans, are sufficient to diagnose and treat Lyme disease. Patients with discordant ELISA and Western blot (WB) assay results for Borrelia burgdorferi were studied to determine whether there was sufficient clinical evidence to support a diagnosis of Lyme disease. Of 650 consecutive sera analyzed by ELISA in a laboratory within a 1-year period, 77 were subsequently tested by WB. The clinical data from these patients were then analyzed. The study population was divided into three groups: group 1 (positive ELISA, positive WB), group 2 (positive ELISA, negative WB), and group 3 (negative ELISA, negative WB). Findings included the following: (1) Patients with a strong clinical history of Lyme disease were usually positive by both WB and ELISA (group 1). (2) All patients with erythema chronicum migrans had both positive WB and ELISA tests. (3) Ninety-one percent of group 2 had a rheumatic or inflammatory condition other than Lyme disease. (4) A definite response to antibiotics occurred in 75% of patients wherein both ELISA and WB were positive but in only 11% of cases with a positive ELISA but a negative WB. (5) History of tick exposure and degree of fever were not significantly different among the three serologic groups, and thus they were not diagnostically helpful.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacological management of juvenile rheumatoid arthritis.

The goals of pharmacotherapy in juvenile rheumatoid arthritis (JRA) are to suppress chronic synovitis which causes potential cartilage destruction and deformities, to control the systemic effects of inflammation (including growth retardation and nutritional deficits), relieve pain and limit psychological impact of disease. Currently available methods include nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, salicylates, naproxen, tolmetin, ibuprofen and indomethacin; disease modifying antirheumatic drugs (DMARDs) such as oral and injectable gold salts, hydroxychloroquine, penicillamine, oral and injectable methotrexate, and sulfasalazine; oral (daily or on alternate days), intravenous pulse or intra-articular corticosteroids; immunosuppresants, including cyclophosphamide, chlorambucil, cyclosporin, and azathioprine; and gammaglobulin and other experimental therapies. Over the past 10 years, rheumatologists have adopted more aggressive pharmacological treatment of JRA. As time progresses and the safety of certain drugs such as methotrexate and sulfasalazine becomes clearer, wider and earlier use of these agents can be expected. Still the approach to treatment is a 'step by step' one, starting with the classical NSAIDs and ending with the DMARDs as needed.

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.

Protrusio acetabuli in adult rheumatoid arthritis.

In a retrospective study of 100 patients with adult rheumatoid arthritis, 23/100 (23%) were found presenting protrusio acetabuli (PA). PA of the hips was present in 28/193 (14.5%). This complication was more frequent in females, with 19/23 cases (82%), and its presence and severity were associated with longer duration of disease. On analysing the probable relationship between PA and glucocorticoid intake, no statistically significant differences were found between patients who had received such drugs and those who had not. With the method employed and in a selected rheumatoid arthritis population, PA was found in high prevalence.

The overdiagnosis of Lyme disease in children residing in an endemic area.

The medical records of 227 children ages 1 to 19 years referred to the Lyme disease pediatric clinic over a 32-month period since May 1990 were reviewed. Clinico-serologic criteria for a positive diagnosis were applied. One hundred thirty-eight of 227 referred children did not fulfill those criteria and became the study population. Four subsets of patients emerged: (1) 54 patients with predominantly subjective symptoms; (2) 52 patients with objective evidence for an alternative diagnosis; (3) eight patients who had documented infection in the past and continued with symptoms after antibiotic treatment; and (4) 24 patients with a history of tick attachment or prenatal/family history of Lyme disease. Serologic testing data from commercial laboratories were available for the 54 children from the "predominantly subjective" group; 50% were negative, and 50% were borderline or positive. Ninety-two percent of these patients were negative at retesting by our enzyme-linked immunosorbent assay (ELISA) and 100% were negative by Western blot. Fifty-seven percent of these patients had received treatment prior to our evaluation. Children residing in an endemic area who present with vague symptoms are being diagnosed with and treated for Lyme disease without clinical or serologic documentation. In addition, fear in the lay community may be inducing doctors to diagnose Lyme disease in patients with symptoms that may be suggestive of an alternative diagnosis.

Physician beliefs, attitudes, and approaches toward Lyme disease in an endemic area.

To assess the beliefs and practice habits regarding Lyme disease among practitioners, questionnaires were sent to physicians in a seven-county Lyme-endemic region. One hundred twenty-four evaluable responses were returned from 53 family physicians, 39 pediatricians, 27 internists, and five subspecialists who diagnosed three to four cases of Lyme disease per year, on average. The majority presented with erythema migrans (EM) or other early symptoms, although arthritis was the presenting sign in 16%. The enzyme-linked immunosorbent assay (ELISA) was the most frequently ordered diagnostic test, but 45% of respondents did not specify which test when ordering Lyme serology. The majority would use amoxicillin or doxycycline to treat EM in children or adults, respectively. Nearly all would use ceftriaxone for meningitis, and half would use it to treat Lyme arthritis or Bell's palsy. Physicians differed markedly in the duration of therapy they would prescribe. Eighty-three percent would treat a patient for possible Lyme disease with antibiotics (many intravenously), even in the absence of EM or positive serology. Thirty-five percent of practitioners prescribed antibiotics for deer-tick bites. Our survey documents significant variation in approaches to Lyme disease among primary-care physicians and suggests the need for well-designed clinical trials, continuing basic research, and physician education.

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.

Liver involvement in familial granulomatous arthritis (Blau syndrome).

We describe hepatic granulomata in a patient with familial granulomatous synovitis (Blau syndrome). While visceral involvement is a previously unrecognized manifestation of Blau syndrome, its occurrence has been well documented in a similar disease, childhood sarcoidosis. Our findings suggest that the 2 conditions (Blau syndrome and childhood sarcoidosis) are more closely related than thought.

Comparative evaluation of adsorption with E. coli on ELISA tests for Lyme borreliosis.

OBJECTIVE: To evaluate prospectively in a clinical setting the use of a soluble fraction of E. coli to adsorb nonspecific antibodies which can cause false positive ELISA tests for Lyme borreliosis. METHODS: The patient population tested was obtained from individuals referred to or initially presenting at a pediatric Lyme disease clinic in Wilmington, DE. Patients were followed for a minimum of 6 months subsequent to primary presentation at the clinic. RESULTS: A total of 209 met criteria for study inclusion, 93 of whom were diagnosed as having Lyme borreliosis and 116 of whom had other diagnoses. Results of ELISA tests were compared with different diagnoses and, when available, ELISA results from commercial laboratories. Findings indicate that some commercial laboratories have excessively high rates of false positive results (> 90% of positives were found to be false positives). CONCLUSION: Adsorption with E. coli antigens effectively removed antibodies causing false positive results including those occurring at commercial laboratories and did not cause any significant reduction in assay sensitivity.

Pseudothrombophlebitis complicating childhood lyme arthritis.

Calf pseudothrombophlebitis is defined as the acute onset of nontraumatic, nonthrombotic painful swelling of the calf after knee synovitis. The name underscores the clinical similarities between this condition and "true" femoral/popliteal thrombophlebitis pointed out by Baker more than a century ago. A variety of arthritic conditions of the knee, primarily chronic, can be complicated by calf pseudothrombophlebitis. Pseudothrombophlebitis as a complication of Lyme arthritis has been mentioned in clinical reviews of the disease, but to our knowledge, no documented cases of such association were published. Furthermore, pseudothrombophlebitis in the setting of Lyme disease is particularly challenging, both from the diagnostic and therapeutic points of view.Herein, we describe three children who developed pseudothrombophlebitis as a presenting feature of Lyme disease. One of the patients is described in detail, and the clinical findings on the whole group are summarized.

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.

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.