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Unlabelled: Juvenile primary fibromyalgia syndrome (JPFS) is a chronic pain condition associated with significant impairment in physical functioning, but no studies have used newer technologies such as actigraphy to document objective physical activity levels in JPFS. This is the first study to objectively describe physical activity in JPFS patients and examine the relationship of pain, perceived functional impairment, and depressive symptoms on physical activity. One hundred four clinically referred adolescents with JPFS (ages 11 to 18 years) wore a hip-mounted actigraph for 1 week. Data on pain intensity, functional disability, depressive symptoms, and psychiatric diagnoses were obtained using self- and parent-report measures and a standardized psychiatric interview. Results showed that younger patients were more active. Pain intensity was not significantly associated with physical activity levels overall, but the most highly active group of adolescents reported lower levels of pain and disability than the least active. Parent report of adolescents' physical functioning and depressive symptoms were significantly correlated with adolescents' physical activity levels. Actigraphy provides a unique source of information about physical functioning which is distinct from adolescents' self-report of physical functioning in JPFS. Preliminary findings suggest that further study of factors that predict perceived and actual physical functioning in JPFS is warranted., Perspective: This study presents the results of physical activity monitoring in adolescents with JPFS using actigraphy. Results indicate that actigraphy provides a unique source of objective information that can advance our understanding of physical disability in JPFS and the factors associated with physical impairment., (Copyright © 2010 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the clinical use patterns, clinical effect and safety of cyclosporine A (CSA) in juvenile idiopathic arthritis (JIA) in the setting of routine clinical care., Methods: An open-ended, phase IV post marketing surveillance study was conducted among members of the Pediatric Rheumatology Collaborative Study Group (PRCSG) and of the Paediatric Rheumatology International Trials Organisation (PRINTO) to identify patients with polyarticular course JIA who had received CSA during the course of their disease., Results: A total of 329 patients, half of whom had systemic JIA, were collected in 21 countries. Data were collected during 1240 routine clinic visits. CSA was started at a mean of 5.8 years after disease onset and was given at a mean dose of 3.4 mg/kg/day. The drug was administered in combination with MTX in 61% and along with prednisone in 65% of the patients who were still receiving CSA. Among patients who were still receiving CSA therapy at the last reported visit, remission was documented in 9% of the patients, whereas in 61% of the patients the disease activity was rated as moderate or severe. The most frequent reason for discontinuation of CSA was insufficient therapeutic effect (61% of the patients); only 10% of the patients stopped CSA because of remission. In 17% of the patients, side effects of therapy was given as the primary reason for discontinuation., Conclusion: This survey suggests that CSA may have a less favourable efficacy profile than MTX and etanercept, whereas the frequency of side effects may be similar. The exact place of CSA in the treatment of JIA can only be established via controlled clinical trial.

Objective: To examine the effects of daily supplementation with calcium (Ca) in combination with vitamin D on total body and lumbar spine bone mineral density (BMD) in patients with juvenile rheumatoid arthritis (JRA) who had not taken corticosteroids for at least 3 months prior to the beginning of the study., Methods: One hundred ninety-eight children and adolescents (141 girls and 57 boys) with JRA, ages 6 to 18 years, with a mean +/- SD age of 11.7 +/- 3.3 years and a mean +/- SD disease duration of 5.6 +/- 3.8 years at the beginning of the study, were enrolled in this randomized double-blind, placebo-controlled trial to receive either daily oral supplements of 1,000 mg of Ca and 400 IU of vitamin D (n = 103) or matched placebo tablets and 400 IU of vitamin D (n = 95) for 24 months. Total body BMD (TBBMD) was measured by dual x-ray absorptiometry at baseline and every 6 months for 24 months., Results: At baseline, the mean +/- SD TBBMD was 0.89 +/- 0.14 gm/cm2 among patients randomized to the Ca group and 0.87 +/- 0.14 gm/cm2 among those randomized to placebo (P = 0.445). At 24 months, the mean +/- SD TBBMD among those receiving Ca was 0.95 +/- 0.13 gm/cm2, compared with 0.92 +/- 0.14 gm/cm2 among those receiving placebo. A longitudinal random-effects mixed model analysis that controlled for differences in the subject's initial BMD, sex, Tanner stage, adherence to the study medication regimen, and body composition revealed significantly higher TBBMD among patients who received Ca compared with patients who received placebo during the study period (P = 0.03)., Conclusion: Ca supplementation resulted in a small, but statistically significant, increase in TBBMD compared with placebo in children with JRA.

Objective: To correlate disease course and complications in children with juvenile dermatomyositis (JDM) and polymyositis (JPM) with specific features of muscle pathology on biopsy., Methods: This is a retrospective cohort analysis of 59 children diagnosed with JDM or JPM between 1965 and 1998 and followed at the Cincinnati Children's Hospital Medical Center (CCHMC) for a mean duration of 7.3 years (range 1.1-24.5 years). Disease course was characterized as limited, chronic non-ulcerative or chronic ulcerative, similar to previously defined disease course subtypes reported by Crowe et al.(1). All subjects had diagnostic muscle biopsies performed at CCHMC and had disease for at least two years' duration in order to classify their disease course as either limited or chronic. Features of muscle histopathology that were evaluated included loss of the intramuscular capillary bed, infarct, perifascicular myopathy, direct immunofluorescence (DIF) staining of the intramuscular vasculature and specifically, the locale of DIF staining, i.e., small arteries or capillaries. Disease complications that were assessed included calcinosis, contractures, muscle atrophy, lipodystrophy, gastrointestinal ulceration, cutaneous ulceration and death. Data analysis was completed using Chi-square or Fisher's exact tests and logistic regression modeling., Results: Twenty-two children (37%) had limited disease, 24 (41%) had chronic non-ulcerative disease and 13 (22%) had chronic ulcerative disease. Neither loss of the intramuscular capillary bed nor perifascicular myopathy on muscle biopsy significantly correlated with disease course or the various complications evaluated in this study. DIF staining of intramuscular vessels overall was not significantly associated with clinical disease course, but the localization of DIF staining to intramuscular arteries (rather than to capillaries) was significantly associated with the outcome of chronic ulcerative disease. Nine of the 13 children with chronic ulcerative disease had DIF-arterial staining on muscle biopsy (69%), significantly greater than DIF-arterial staining in children with limited disease (32% had DIF-arterial staining) (p = 0.04), chronic non-ulcerative disease (8% had DIF-arterial staining) (p = 0.0002), and non-ulcerative disease overall (limited + chronic non-ulcerative disease groups combined) (20% had DIF-arterial staining), with p = 0.001. Additionally, lack of DIF-arterial staining on biopsy was significantly correlated with patients not having gastrointestinal ulceration (p = 0.002), cutaneous ulceration (p = 0.004) and/or death (p = 0.02) as disease-related complications. Infarct on muscle biopsy was significantly associated with the development of chronic ulcerative disease (p = 0.02), being present on biopsy in 23% of children with chronic ulcerative disease compared with none of the patients with chronic non-ulcerative disease and 4% of those with limited disease. Infarct on muscle biopsy correlated with the outcomes of death (p = 0.01) and gastrointestinal ulceration (p = 0.03), but not with the development of cutaneous ulceration (p = 0.18)., Conclusion: DIF-arterial staining and infarct on muscle biopsy are significantly associated with the development of chronic ulcerative disease in JDM and JPM, while perifascicular myopathy and loss of the intramuscular capillary network are not associated with disease course. The presence of DIF-arterial staining and infarct on biopsy should suggest early use of second-line therapeutic agents to more quickly bring disease activity under control.

Objective: Anti-cyclic citrullinated peptide (anti-CCP) antibodies have been detected in patients with juvenile rheumatoid arthritis (JRA), particularly in those with polyarticular, rheumatoid factor (RF)-positive JRA. Our objectives were to determine whether anti-CCP antibodies are associated with HLA-DR4 in children with polyarticular JRA, whether anti-CCP antibodies are associated with clinical features of disease, and whether affected sibling pairs (ASPs) with JRA are concordant for this antibody., Methods: Stored serum samples obtained from 230 HLA-typed patients with JRA (77 with polyarticular-onset disease and 153 with pauciarticular- or systemic-onset disease), 100 JRA ASPs, and 688 healthy children were tested for anti-CCP antibodies and RF., Results: Thirteen percent of the patients with polyarticular-onset JRA and 2% of the other JRA patients exhibited anti-CCP antibodies, compared with only 0.6% of the controls. Fifty-seven percent of RF-positive patients with polyarticular-onset JRA had anti-CCP antibodies. HLA-DR4-positive patients with polyarticular-onset JRA were more likely to have anti-CCP antibodies than were those without HLA-DR4 alleles (odds ratio [OR] 5.20, 95% confidence interval [95% CI] 1.30-20.9). Anti-CCP antibodies were associated with polyarticular onset (OR 7.46, 95% CI 1.99-28.0), a polyarticular disease course (OR 9.78, 95% CI 1.25-76.7), and erosive disease (OR 14.3, 95% CI 3.01-67.9). Concordance rates for anti-CCP antibodies among ASPs were statistically significant., Conclusion: These data demonstrate increased anti-CCP antibody formation in HLA-DR4-positive patients with polyarticular-onset JRA. The overall prevalence of anti-CCP antibodies in JRA is low, but a substantial proportion of RF-positive patients with polyarticular-onset JRA have these antibodies. Anti-CCP antibodies in JRA are associated with polyarticular onset, a polyarticular course, and erosive disease.

Possible correlations have been proposed between autoimmune diseases, such as systemic lupus erythematosus (SLE), and infection with human cytomegalovirus (CMV). The recent observation that an adenovirus expressing the immunodominant envelope glycoprotein of CMV, glycoprotein B (gB), may be capable of inducing autoantibodies in certain mouse strains has prompted interest in exploring potential relationships between gB immunization and autoimmune disease. We examined whether a recombinant CMV gB vaccine, or a gB canarypox vectored vaccine (ALVAC-CMVgB), administered to a total of 76 CMV-seronegative subjects, was capable of inducing cross-reactive antibodies to Smith antigen (Sm), ribonucleoprotein complex (RNP), and the U1-70 kDa component of the RNP complex. Using immunofluorescence, EIA and immunoblot analyses, we failed to identify induction of autoantibodies following vaccination with gB, whether administered alone as a purified protein subunit with adjuvant, or in combination with expression in a vectored approach using a recombinant canarypox. These data reinforce the favorable safety profile of CMV gB vaccines.

We describe 2 adolescent boys with facial swelling and/or subcutaneous nodules and fever. Extensive evaluation, including several biopsy specimens, led to a diagnosis of subcutaneous panniculitic T-cell lymphoma, an entity rarely seen in children. Both patients were treated with oral cyclosporine in an effort to suppress the cytokine release from T-cells that has been thought to induce the hemophagocytic syndrome. The patients responded dramatically to cyclosporine treatment with defervescence of the fever and reduction in number and size of the subcutaneous nodules. Subsequent therapy with multidrug chemotherapy achieved complete remission in the first patient. This report suggests the value of cyclosporine as a first-line agent coupled with chemotherapy in the treatment of patients with subcutaneous panniculitic T-cell lymphoma. A clinicopathologic review of 8 described pediatric cases of subcutaneous panniculitic T-cell lymphoma is also presented.

Objective: To describe the health and functional status of children with juvenile rheumatoid arthritis (JRA) diagnosed in the early 1990s., Methods: Patients were obtained from the Pediatric Rheumatology Disease Registry, a database of patients seen in pediatric rheumatology centers across the United States. Questionnaires designed to be filled out after retrospective chart review were sent to pediatric rheumatologists caring for children diagnosed with JRA between 1992 and 1997., Results: We studied 703 patients -- 376 with pauciarticular onset (pauci), 232 with polyarticular onset (poly), and 95 with systemic onset JRA (systemic). At 1 year after diagnosis, half of the pauci and systemic patients no longer required medication, compared to 78% of the poly patients; 98% of the patients functioned in Steinbrocker classes I and II. Six percent of pauci, 27% of poly, and 11% of systemic patients had limitations in school function. Nearly 1/3 of poly patients already had joint space narrowing on radiograph. By 5 years after diagnosis, all pauci, 88% of poly, and 70% of systemic patients were in Steinbrocker classes I and II; but 6% of pauci, 28% of poly, and 44% of systemic patients had limitations in school function. Nearly 2/3 of poly and systemic patients had joint space narrowing., Conclusion: In these children treated prior to the era of biologic therapy, at 5 years after onset, > 25% of poly and nearly half of systemic patients had functional limitations that required modifications in their school schedule. Radiographically evident joint space damage was seen within a year of onset in poly patients, and by 5 years 2/3 of poly and systemic patients had damage.

The documentation of treatments used for Juvenile Rheumatoid Arthritis (JRA) is important to allow for the evaluation of practice patterns for future outcome studies. A survey of nine pediatric rheumatologists was performed between September 1999 and February 2000. Each of the physicians prospectively recorded demographic and treatment information on consecutively sampled JRA patients (n=395). Pauciarticular onset JRA was present in 46%, polyarticular onset JRA in 35%, and systemic onset JRA in 19% of the children. Naproxen was the most frequently prescribed medication (55% of the patients), followed by methotrexate (MTX), which was used in 39% of the patients. Folic acid supplementation (1 mg/day) was provided to 69% of the patients treated with MTX. Etanercept was used in 11% of the children. Eleven percent of the patients received corticosteroids, and 13% of children on corticosteroids took calcium supplements. Uveitis was present in 8% and had a chronic course in 79% of those cases. Although systemic medications were used in 50% of the children with uveitis to control eye inflammation, severe damage to the eyes developed in 30% of them. Fourteen percent of the patients required gastroprotective medications. Compared with findings of a similar survey performed in 1993, there was no significant change in the frequency of use of naproxen, but nabumetone is now more often prescribed, and COX-2 inhibitors have been introduced in the therapy of JRA. Changes among second-line agents used for JRA have also occurred, although there was no change in the frequency of use of MTX or corticosteroids. JRA continues to be a treatment challenge for the practicing pediatric rheumatologist. Patients often show incomplete response to the currently available medications. Therefore, new therapeutic agents need to be evaluated for their use in JRA, and the treatment of JRA associated uveitis especially needs to be improved.

Purpose: To determine the magnetic resonance (MR) imaging findings in the knee in early juvenile rheumatoid arthritis., Materials and Methods: MR imaging (1.5 T) was performed in the more symptomatic knee in 30 children with juvenile rheumatoid arthritis with a symptom duration 1 year or less. Conventional, fast spin-echo, three-dimensional gradient-echo, and gadolinium-enhanced T1-weighted images were assessed. Two radiologists independently read the images, and a third resolved disagreements. These images were compared with knee radiographs in 27 children., Results: Mean maximal synovial thickness was 4.8 mm +/- 2.4 (SD). Mean synovial volume was 15.4 mL +/- 10.8. Suprapatellar joint effusions were seen in 26 (87%) of 30 knees, meniscal hypoplasia in 11 (37%) of 30 knees, and abnormal epiphyseal marrow in eight (27%) of 30 knees. Three knees had articular cartilage contour irregularity, fissures, and/or thinning. One knee had a bone erosion. Knee radiographs showed suprapatellar fullness in 78% of the knees, joint space narrowing in one knee, and no bone abnormalities., Conclusion: Synovial hypertrophy and joint effusions are the most frequent MR imaging findings of knees in early juvenile rheumatoid arthritis. Early in the disease, radiographically occult cartilage and bone erosions are uncommonly seen at MR imaging. The potential relationship of synovitis to cartilage abnormalities deserves further study.

To understand the mechanisms that promote recruitment and survival of T cells within the pediatric inflamed joint, we have studied the expression of CCR4 and CCR5 on synovial fluid T cells and matched peripheral blood samples from juvenile rheumatoid arthritis (JRA) patients using three-color flow cytometric analysis. Thymus- and activation-regulated chemokine and macrophage-derived chemokine, ligands for CCR4, were measured by ELISA in JRA synovial fluid, JRA plasma, adult rheumatoid arthritis synovial fluid, and normal plasma. IL-4 and IFN-gamma mRNA production was assessed in CD4+/CCR4+ and CD4+/CCR4(-) cell subsets. We found accumulations of both CCR4+ and CCR5+ T cells in JRA synovial fluids and a correlation for increased numbers of CCR4+ T cells in samples collected early in the disease process. Thymus- and activation-regulated chemokine was detected in JRA synovial fluid and plasma samples, but not in adult rheumatoid arthritis synovial fluid or control plasma. Macrophage-derived chemokine was present in all samples. CD4+/CCR4+ synovial lymphocytes produced more IL-4 and less IFN-gamma than CD4+/CCR4(-) cells. These findings suggest that CCR4+ T cells in the JRA joint may function early in disease in an anti-inflammatory capacity through the production of type 2 cytokines and may play a role in determining disease phenotype.

Objectives: To design, implement, and assess the impact of an office-based intervention designed to improve rheumatologists' identification of risk behaviors, especially alcohol use and sexual activity, among adolescents and young adults with chronic rheumatologic conditions., Designs: Prospective intervention study., Setting: Midwestern academic pediatric rheumatology practice., Participants: Ten attending rheumatologists and fellows and 178 patients (mean age, 18.1 years; 67% female; 88% white; 69% with juvenile rheumatoid arthritis) seen in the practice during the baseline and intervention years., Main Outcome Measures: Change in the rate of screening for alcohol use and sexual activity from the baseline to the intervention year, and physician perceptions of the intervention., Results: Screening for alcohol use increased from 4.2% (9/208) at baseline to 31.6% (56/177) after the intervention (P<.001). Of those patients undergoing screening at follow-up, 20 (36%) of 56 patients reported any alcohol use and 11 (20%) reported current alcohol use. Of those reporting current use, 7 (64%) were counseled or referred. Methotrexate use increased the likelihood of alcohol screening (43% [33/76] vs 26% 123/871; P = .02). Screening for sexual activity increased from 12.4% (27/ 218) to 36.2% (64/177) (P<.001) from baseline to follow-up. Of 52 females undergoing screening at follow-up, 31 (60%) were sexually active. Eleven (41%) of 27 sexually active females were not using contraception other than condoms (4 were not asked about contraception); 7 (82%) of these were referred for contraceptive counseling. Seven rheumatologists completed in-depth semistructured interviews after the intervention. All reported time as a main barrier to screening. Other barriers included logistical problems, discomfort with the subject area, ambivalence about whether risk behavior screening is the province of pediatric rheumatologists, and perceived lack of applicability to their patients., Conclusions: Despite knowledge and concern about the interaction of immunosuppressive therapy and risk behaviors, few rheumatologists adequately screen the behavior of their adolescent and young adult patients. Time constraints, organizational issues, and physician beliefs remain barriers to widespread screening.

Objective: To develop, validate, and determine the measurement characteristics of a quantitative tool for assessing the severity of muscle involvement in children with idiopathic inflammatory myopathies., Methods: The Childhood Myositis Assessment Scale (CMAS) was developed from 2 existing observational functional assessment tools to assess muscle function in the areas of strength and endurance across a wide range of ability and ages. The 14 ordinal items included were chosen to assess primarily axial and proximal muscle groups and are ranked with standard performance and scoring methods. Following the development of the CMAS, a training video and written instructions were developed and reviewed by the physicians participating in this study. Subsequently, utilizing a randomized block design, 12 physicians independently scored 10 children (9 with dermatomyositis, 1 with polymyositis; ages 4-15 years) twice in one day (morning and afternoon) on the CMAS. A pediatric physical therapist performed quantitative manual muscle strength testing (MMT) twice on each child (morning and afternoon), including the neck, trunk, and proximal and distal extremity muscle groups., Results: The CMAS has a potential range of 0-51, with higher scores indicating greater muscle strength and endurance. The observed mean for the 10 patients was 36.4 (median 44, SD 14.1, observed range 5-51). The total score for the CMAS correlated with the physician's global assessment (by visual analog scale) of disease activity, the MMT score, serum creatine kinase level, and the Juvenile Arthritis Functional Assessment Report score. The score on the CMAS was not correlated with patient age. Interrater reliability (Kendall's coefficient of concordance) ranged from 0.77 to 1.0 for individual items (all P < 0.001), and overall, it was 0.95 (P < 0.001). Intrarater reliability for the individual physicians was measured by correlation of the CMAS scores for each patient on 2 separate evaluations and ranged from 0.97 to 0.99, with an overall correlation for all physicians of 0.98 (all P < 0.001)., Conclusion: The CMAS demonstrated an acceptable range of observed scores, excellent convergent validity, and excellent inter- and intrarater reliability. The CMAS is validated to quantitatively assess muscle function in the areas of strength and endurance in children with idiopathic inflammatory myopathies. It can be used in routine clinical care as well as therapeutic trials.

Objective: To define the onset and duration of effect of the HLA alleles that are associated with disease susceptibility and protection in juvenile rheumatoid arthritis (JRA) and 2 of its subtypes., Methods: We typed 680 patients with JRA and 254 ethnically matched unrelated controls for HLA class I and II genes. The frequency of each allele was calculated for each of the age-at-onset, onset type, and sex categories and plotted against the allele frequency in the control population. Survival analysis (with onset of disease as the terminating event) was used to calculate the age by which 50% (St0.5) and 80% (St0.2) of the children with particular alleles and combinations of alleles develop disease. This allele-specific survival analysis also allowed for the comparison of the overall survival functions for the various JRA subtype and sex categories., Results: Certain alleles are strongly associated with early susceptibility to pauciarticular JRA, including HLA-A2, DR8, DR5, and DPB1*0201. Fifty percent of the children carrying at least 1 of these alleles had disease onset prior to their third birthday. Among children who carried HLA-A2 and any 2 HLA-DR alleles (DR3, DR5, DR6, or DR8), the median age at the onset of pauciarticular disease was 2.7 years. Combinations of A2 and DPB1*0201 and one DR allele narrowed the window further to a median age at onset of 2.4 years. B27 and DR4 were associated with protection early in life but with increased risk later in childhood, with St0.5 values of 7.3 and 6.6 years, respectively, for pauciarticular JRA and St0.5 values of 10.2 and 10.7 years, respectively, for polyarticular JRA. Sex strongly influenced the age at which many of the alleles have their effect., Conclusion: These data define at what age and for how long various HLA alleles influence susceptibility and protection (window-of-effect) in patients with JRA. In addition, these data establish more clearly the boundaries of ages-at-onset for 2 of the subtypes of the disease.

Objective: To examine the relationship between hepatotoxic risk factors and liver histopathology in patients with juvenile rheumatoid arthritis (JRA) treated with methotrexate (MTX)., Study Design: We graded the histology of 33 percutaneous liver biopsy specimens from 25 patients with JRA treated at Children's Hospital Medical Center, Cincinnati, Ohio, using the Roenigk Classification Scale. Stepwise linear and logistic regression analyses were performed to examine the relationship of the Roenigk grade and presence of liver fibrosis of biopsy specimens with potential risk factors., Results: Twenty-seven biopsy specimens (82%) were classified as grade I, 4 (12%) as grade II, and 2 (6%) as grade IIIA; none demonstrated significant fibrosis. The frequency of biochemical abnormalities (P <.001) and body mass index (P =.05) were the only risk factors found to significantly relate to the Roenigk grade. The following factors were not significantly associated with the Roenigk grade: age, gender, disease duration, JRA subtype and course, duration of MTX administration, weekly MTX dose, cumulative dose of MTX, route of MTX administration, use of folic acid supplementation, concurrent use of other medications, and potential hepatotoxic comorbidities., Conclusions: Serial biochemical abnormalities are significantly associated with Roenigk grade and the presence of liver fibrosis. These findings concur with studies of patients with rheumatoid arthritis, suggesting that guidelines for monitoring MTX hepatotoxicity in rheumatoid arthritis may be applicable to patients with JRA.

Objective: To determine the prevalence of substance use among adolescents with juvenile rheumatoid arthritis and to assess available opportunities for rheumatologists to identify high risk teens., Methods: Fifty-two teens (mean age 13.9 years, 86% female) completed questionnaires regarding substance use (alcohol, tobacco, marijuana, and other illicit substances), functional disability, and frequency of health care contacts., Results: Alcohol use was reported by 30.7% of teens, including 23.5% of those for whom methotrexate was prescribed; 15.4% reported tobacco use in the last year, and 13.4% reported other illicit substance use in their lifetime, although most use was experimental. No teen reported marijuana use. The majority reported regular contact with their rheumatologist but only 26.9% were ever interviewed alone., Conclusion: Many teens with juvenile rheumatoid arthritis, including those prescribed methotrexate, used substances, especially alcohol. When rheumatologists see adolescents, particularly in situations where methotrexate may be prescribed, a clinical setting conductive to confidentially, physician comfort in asking about sensitive topics such as substance abuse, and referral relationships with skilled adolescent health and substance abuse counseling providers are essential.

Methotrexate continues to be the safest and most efficacious second-line drug for the treatment of JRA. In addition, it is useful in other inflammatory conditions in children. Careful education is necessary, particularly with regard to the importance of laboratory tests and the avoidance of comorbidity such as pregnancy and alcohol-induced liver injury. Health care providers should be comfortable discussing these issues with children and adolescents.

Objective: To determine the pattern of expression of Type 1 and Type 2 cytokines in synovial tissues and fluids (SF) of patients with different forms of juvenile rheumatoid arthritis (JRA) and juvenile spondyloarthropathy (JSpA), and to contrast these with findings in adult patients with RA., Methods: Sixty-three SF mononuclear cell preparations and synovial tissue samples from 50 patients with JRA or JSpA and 7 synovial tissues from patients with adult onset RA were analyzed by reverse transcription polymerase chain reaction for the presence or absence of interleukin 2 (IL-2), tumor necrosis factor-beta (TNF-beta), interferon-gamma (IFN-gamma), and IL-10 and IL-4 mRNA., Results: IL-4 mRNA was identified significantly more often in the synovial compartment of patients with pauciarticular onset disease (JRA or JSpA) compared with polyarticular onset JRA (58 vs 14%; p < 0.01) or RA (29%). Similarly, IL-4 mRNA was detected more often in those with a persistently pauciarticular disease course compared to those with a polyarticular course (68 vs 30%; p < 0.01). Furthermore, the combination of IL-4 and IL-10 mRNA was found more frequently in nonerosive compared with erosive disease (38 vs 15%; p < 0.05). IL-2 and TNF-beta mRNA were found in all groups. IFN-gamma mRNA was detected in 33% of those with systemic onset JRA compared with 85% of other types of JRA (p < 0.01)., Conclusion: This study provides further evidence of immunopathological differences between chronic forms of arthritis with childhood onset, and highlights similarities with and differences from adult RA. Our findings suggest that IL-4, possibly in combination with IL-10, has an antiinflammatory or disease restricting role.

Juvenile rheumatoid arthritis (JRA) is a chronic inflammatory disease primarily affecting the joints but also extra articular tissue. The long-term outcome of JRA has different aspects, which include disease outcome, mortality, iridocyclitis and stature. Several studies, which have addressed these issues, are reviewed in this article. In addition, functional, educational and employment status of patients with JRA are also reviewed. To facilitate better understanding of these various studies, a description of the terminology used in defining disease is provided. Several of the instruments that are available for assessing outcome among patients are described. The role of laboratory and radiological evaluation in predicting outcome is also addressed.

Objective: To identify features of the T cell receptors (TCRs) present on clonally expanded T cells in the joints of patients with similar types of childhood rheumatic disease. Vbeta8 and Vbeta20 TCRs were selected as prototypic for polyarticular juvenile rheumatoid arthritis (JRA) and pauciarticular/juvenile spondylarthropathy (SpA), respectively., Methods: The portion of the TCR beta chain involved in antigen recognition in the synovial tissue, synovial fluid, and peripheral blood from patients with JRA and juvenile SpA was cloned and sequenced. The frequency of expanded clonotypes, size of expansions, the Jbeta region, and sequence motifs were determined for >2,000 sequences., Results: The majority of Vbeta20 and Vbeta8 clonal expansions were found in the joint rather than the peripheral blood. While instances of both Vbeta8 and Vbeta20 clonal expansion were detected in all disease types, the features of these expanded clonotypes were specific for disease type and Vbeta family. For example, Vbeta20 clonal expansion was characterized by many small expanded clonotypes in samples from patients with pauciarticular JRA and juvenile SpA while single large Vbeta8-specific expansions were found only in patients with polyarticular disease. Motifs specific to individual patients were identified, and for Vbeta20 clonotypes, a motif was found in synovial tissue samples., Conclusion: Identification of common TCR features in oligoclonal expansions within individual patients and between patients with the same type of JRA suggests the recognition of a common or limited group of antigens in these diseases.

Objectives: This study was undertaken to examine the role of magnetic resonance imaging (MRI) in the management of patients with juvenile rheumatoid arthritis (JRA)., Methods: A Medline search was performed to identify all publications pertaining to MRI in JRA. Further searches and identification of articles from bibliographies identified articles pertaining to plain radiograph imaging in JRA and MRI in adult rheumatoid arthritis., Results: Studies in both children and adults have shown superiority of MRI to plain radiography in detecting synovial hypertrophy and articular cartilage abnormalities. Several studies in adults have shown a good correlation of MR images with gross anatomic as well as histological findings at arthroscopy. Biochemical changes that occur before structural changes within the joint may even be detectable with magnetic resonance spectroscopy., Conclusions: MRI holds promise for the assessment of disease progression in JRA and may be useful in serial evaluation, as in clinical trials.

Objective: To determine if the long-term use of methotrexate (MTX) in juvenile rheumatoid arthritis (JRA) is associated with the development of significant liver fibrosis, and to describe the presence of risk factors for liver fibrosis in patients with JRA., Methods: Needle biopsies of the liver were performed on a cross-section cohort of 14 patients with JRA who had received a total cumulative dose of MTX that was either > 3,000 mg or > 4,000 mg/1.73 m2 of body surface area. Biopsy samples were independently graded according to the Roenigk Classification Scale by 2 pathologists. The presence of risk factors for MTX hepatotoxicity, especially biochemical abnormalities reflective of liver injury and alcohol consumption, were assessed., Results: Thirteen biopsy samples (93%) were classified as grade I, and 1 (7%) as grade II; none demonstrated significant fibrosis. However, histologic abnormalities were found in 13 biopsy samples (93%). Only 2 patients (14%) consumed more than 1 alcoholic drink per month. Thirteen patients (93%) had biochemical abnormalities while being treated with MTX, but only 5 patients (36%) had at least 1 determination in which the aspartate or alanine aminotransferase elevation was > 3 times the upper limit of normal., Conclusion: Long-term use of MTX for JRA does not appear to be associated with the development of significant liver fibrosis. Although nearly all patients had minor histologic changes, no significant clinical consequences were apparent. A prospective study of a larger population will more accurately define the incidence of MTX-related liver fibrosis and appropriate monitoring guidelines in JRA.

Objective: To determine the reliability, content validity, and responsiveness of physician global assessments of disease activity and damage in the juvenile idiopathic inflammatory myopathies (IIM), and to investigate concordance among physician, parent, and patient global ratings., Methods: Sixteen pediatric rheumatologists rated 10 juvenile IIM paper patient cases for global disease activity and damage, and assessed the importance of 51 clinical and laboratory parameters in formulating their global assessments. Then, 117 juvenile IIM patients were enrolled in a protocol to examine the relationship between Likert and visual analog scale global assessments, their sensitivity to change, and the comparability of physician, parent, and patient global ratings., Results: Pediatric rheumatologists demonstrated excellent interrater reliability in their global assessments of juvenile IIM disease activity and damage (97.7% and 94.7% agreement among raters, respectively), and agreed on a core set of clinical parameters in formulating their judgments. Likert scale ratings correlated with those on a visual analog scale, and both were comparable in responsiveness (standardized response means -0.56 for disease activity, 0.02 [Likert] and 0.14 [visual analog] for damage, measured over 8 months). Parent global ratings of disease activity correlated with physician assessments, but were not colinear (Spearman's correlation [r] = 0.41-0.45). Patient global disease activity assessments correlated with those done by parents (r = 0.57-0.84) and physicians (r = 0.37-0.63), but demonstrated less responsiveness (standardized response means -0.21 and -0.12, respectively, over 8 months)., Conclusion: Physician global assessments of juvenile IIM disease activity and damage demonstrated high interrater reliability and were shown to be comprehensive measures. Both physician and parent disease activity assessments should be considered valuable as quantitative measures for evaluating therapeutic responses in juvenile IIM patients.

The 10-year survival rate of patients with systemic lupus erythematosus (SLE) currently is more than 85|X%; the greater longevity permits late complications to emerge. Recent studies have shown an increased incidence of coronary artery disease (CAD), frequently in young adults. CAD currently is among the most common causes of death in patients with SLE who survive longer than 5 years. Multiple risk factors, some specific to SLE, are implicated in premature development of CAD. These include coronary artery vasculitis, hypertension and hyperlipidemia, corticosteroid therapy, and antiphospholipid antibodies, which may result in coronary thrombotic events. Therefore, risk factors for CAD should be actively sought as part of routine care of patients with SLE, and appropriate modification strategies, including medications if necessary, should be employed. Noninvasive cardiac tests should be used early in the evaluation of any symptoms consistent with myocardial ischemia, heart failure, or cardiac arrhythmias.

Objective: To characterize synovial T cell infiltrate, in terms of CD4/CD8 ratio and level of activation of T cells, in juvenile rheumatoid arthritis (JRA) and juvenile spondyloarthropathy(JSpA), to correlate these findings with clinical outcomes of the different forms of disease, and to compare them with findings in adult RA synovium., Methods: We studied synovial tissue specimens from 22 individuals with childhood onset of chronic arthritis (12 polyarticular JRA, 5 pauciarticular JRA, 5 JSpA) and 4 with adult RA. Specimens were selected from an initial bank from 40 patients on the basis of significant inflammation on hematoxylin and eosin and CD3 and CD68 monoclonal antibody staining (T cells and macrophages, respectively). Indirect immunohistochemistry was used with monoclonal antibodies to CD3, CD4, CD8, and interleukin 2 receptor alpha to determine CD4/CD8 ratios and the levels of activation within the T cell subsets. The distribution of gamma delta T cells was also studied., Results: Two patterns of T cell infiltration were seen. The majority of patients had lymphocytic aggregates associated with diffuse infiltrates; a few tissue specimens had diffuse infiltrates without aggregates. The CD4/CD8 ratio was significantly lower in pauciarticular course JRA than polyarticular JRA (p < 0.01) and RA (p < 0.05). Similarly patients with JSpA had a significantly lower CD4/CD8 ratio than patients with polyarticular JRA (P < 0.05). The level of T cell activation (CD3+IL-2R+) was significantly higher in pauciarticular compared with both polyarticular JRA (P < 0.01) and RA (p < 0.05). In general, higher levels of activation of CD8 cells than CD4 cells were seen, particularly in the pauciarticular JRA and JSpA groups. gamma delta T cells were prominent in 2 patients., Conclusion: Demonstrated differences in T cell subset distribution between types of childhood chronic arthritis at a histopathological level may reflect different pathogenic mechanisms.

Objective: To assess the expression of tumor necrosis factor alpha (TNF alpha), TNF beta, and their receptors in synovia of patients with juvenile rheumatoid arthritis (JRA) and juvenile spondylarthropathy (JSpA), and to determine similarities with and differences from adult RA., Methods: Twenty-eight synovial tissue samples from patients with JRA, 6 from patients with JSpA, and 6 from patients with RA, selected for the presence of inflammatory infiltrates, were analyzed for the expression of TNF alpha, TNF beta, and their receptors (p55 and p75 TNFR), utilizing the dual approach of reverse transcriptase-polymerase chain reaction and immunohistochemistry analysis., Results: The presence of both TNF alpha and TNF beta expression was demonstrated in most JRA and JSpA tissues, although samples from patients with pauciarticular JRA had somewhat lesser amounts of these cytokines. TNF beta expression correlated significantly with the occurrence of lymphocytic aggregates in tissues. Staining with monoclonal antibodies specific for the p55 and p75 receptors revealed that a diverse range of cell types expressed the receptors, with the most intense p55 staining on vascular endothelial cells. In the vast majority of synovial tissues, far greater numbers of cells expressed the p55 form of the receptor than the p75 form., Conclusion: JRA and JSpA synovia are characterized by the presence of TNF alpha, TNF beta, and cells expressing TNFR. These findings provide further evidence that TNF, through autocrine/paracrine mechanisms, may amplify local inflammation, leading to joint destruction. The prominence of TNF beta in the synovium in particular subgroups of JRA patients and in JSpA patients may be a distinguishing feature of these diseases.

This survey was performed to review medication usage by pediatric rheumatologists in the care of patients with juvenile rheumatoid arthritis (JRA). Prospective data from 50 patients per physician with JRA were recorded by six pediatric rheumatologists in the Fall of 1993. Naproxen was used most frequently-in 48% of all patients. Next in order of frequency were methotrexate (39%), prednisone (15%), tolmetin (12%), indomethacin (11%) and folic acid (10%). Salicylates (acetylsalicylic acid, trisalicylate and salsalate) were used in 7%, and myochrysine was used in 2% of patients. Overall, nonsteroidal anti-inflammatory drugs were used in 93% of all patients, slower-acting antirheumatic drugs (SAARDs) were used in 54% and prednisone in 15%.Medication usage varied by disease type in predictable ways but also varied by physician in ways that could not be accounted for by population differences. Methotrexate was the most-often used of all SAARDs and supplanted myochrysine in JRA. Naproxen was the most often used NSAID in the treatment of JRA and had largely supplanted salicylates. With the arrival of practice guidelines, reasons for and impact of these changes (as well as the interesting variations between physicians) will need to be examined.

Objective: To determine the potential contribution of the MHC class II region proteasome subunit gene, LMP2, to disease susceptibility, severity, and phenotype in patients with juvenile rheumatoid arthritis (JRA)., Methods: A CfoI restriction site polymorphism in the coding region of the LMP2 gene was evaluated in 279 patients with JRA and 107 healthy controls of similar ethnicity. Patients were divided into 5 groups on the basis of clinical presentation; 46% had early onset pauciarticular disease, 10% early onset polyarticular, 10% late onset pauciarticular, 20% late onset polyarticular, and 11% systemic onset arthritis. The influence of this LMP2 polymorphism on susceptibility to disease, clinical subtype of disease at onset (age and number of joints involved), progression and severity of joint disease (pauci to polyarticular course and radiographic changes), and occurrence of inflammatory eye disease was evaluated., Results: Comparison of genotypes revealed a significantly increased prevalence of homozygosity for the LMP2 B allele (LMP2 BB genotype) in patients who were older (> or = 6 years) at onset of disease (65%, p < 0.05), particularly in those with pauciarticular (71%) involvement at presentation (p < 0.05), compared to controls (51%). The BB genotype was also more prevalent in patients with a polyarticular course, either from onset (63%) or those who progressed from pauciarticular disease (69%), compared with controls, (p = 0.05 and < 0.05, respectively). Stratification for HLA-B27 and DR4, the HLA alleles most frequently associated with late onset pauciarticular and late onset polyarticular JRA, respectively, revealed a persistent effect of LMP2 BB homozygosity on disease susceptibility and phenotype that remained statistically significant in HLA-B27 positive children, and was not due to linkage disequilibrium., Conclusion: We show that homozygosity of the B allele of the proteasome subunit LMP2 increases susceptibility to certain subgroups of JRA, and influences the phenotype of disease, predisposing to more progressive and severe articular disease.

The measurement of function in children with rheumatic diseases is an intimate part of not only the initial diagnostic work-up, but also of every clinic visit during the course of these chronic diseases. This article focuses on the development of specific and general instruments used to systematically measure function and thus, outcome of the rheumatic diseases and their treatments. Reference is made to instruments developed for use in the general pediatric and adult rheumatology population as a basis for the discussion of the instruments in use in pediatric rheumatology. Specifically, the dimensions of physical function, psychosocial impact, economic impact and quality of life are addressed.

Objective: The presence of clonally expanded T lymphocytes appears to be a characteristic feature of autoimmune diseases, including juvenile rheumatoid arthritis (JRA), although the relevance of such clones to immunopathogenesis is not clear. Identification of clones specific for a disease and/or particular MHC haplotypes should help differentiate those of pathogenic importance., Methods: A reverse transcriptase polymerase chain reaction assay for T cell receptor (TCR) complementarity determining region 3 (CDR3) length heterogeneity and cDNA sequencing were used to identify clonal expansion in synovial fluid (SF) samples obtained from 36 patients with JRA., Results: The majority of patients had multiple synovial T cell clones using different TCR V beta families. Fifty-eight percent of these clonally expanded T cell populations used one of six TCR V beta families (V beta 2, V beta 8, V beta 14, V beta 16, V beta 17, and V beta 20). Patients with polyarticular, as opposed to pauciarticular, JRA had higher numbers of clones in joints. TCR V beta 8, V beta 14, V beta 16, and V beta 17 families were most frequently found in these clones. Overall, the most frequently used V beta family was V beta 20, which was observed in 18 of 36 SF samples. Of 18 patients exhibiting TCR V beta 20 clonal expansion, 14 (78%) had pauciarticular onset JRA. The V beta 20 association was especially strong in patients who possessed HLA-DR8+ haplotypes (p = 0.01, Fisher's exact test). SF from the patients who had other types of JRA (and other MHC haplotypes) did not show this association., Conclusion: The distinct clinical subtypes of JRA are characterized by different patterns of synovial T cell clonality. These findings imply that different molecular pathways underlie the development of arthritis in each subtype of JRA.

Objective: To assess the efficacy and safety of intravenous immunoglobulin (IVIG) in juvenile rheumatoid arthritis (JRA)., Methods: Thirty-one children with active, refractory, systemic JRA were randomized into a multicentered, double blinded, placebo controlled trial. Patients received infusions of 1.5 g/kg of IVIG or placebo (0.1% albumin) every 2 weeks for 2 months, then monthly for 4 months (total: up to 9 infusions over 6 months). Twenty-nine of the 31 patients were included in the efficacy subset., Results: Fourteen patients discontinued prematurely from study, 7 in each treatment group. A higher proportion of patients in the IVIG group improved (50 vs 27%) as assessed by the physician's global assessment. However, the sample size was small and this difference was not statistically significant. IVIG was not more effective than placebo in reducing the number of days with fever or other systemic manifestations. Changes from baseline in the joint count, hemoglobin, albumin, platelet count, and erythrocyte sedimentation rate did not differ between treatment groups., Conclusion: Our results suggest that high dose IVIG has limited clinical utility in systemic JRA. However, this trial failed to enroll adequate numbers of patients to permit valid statistical intergroup comparisons, and the results must be considered nondefinitive.

Objective: To evaluate the efficacy of 0.5% brimonidine tartrate, an alpha 2-adrenergic agonist, in preventing intraocular pressure (IOP) elevation following argon laser trabeculoplasty., Design: In a multicenter, double-masked, randomized study, 248 patients (248 eyes) who underwent argon laser trabeculoplasty were allocated to four treatment groups: (1) brimonidine administered before and after the procedure; (2) brimonidine administered before the procedure; (3) brimonidine administered after the procedure; and (4) a vehicle administered before and after the procedure., Results: In the first 3 hours after argon laser trabeculoplasty, only one (0.54%) of the 183 brimonidine-treated patients had a postlaser IOP increase of 10 mm Hg or more, while increases of this magnitude occurred in 13 (23%) of the 56 patients who received only the vehicle (P < .001). The three brimonidine-treatment groups demonstrated significant mean reductions in IOP from the pretrabeculoplasty level (-4 to -8 mm Hg), whereas the vehicle-treated group showed an increase in mean IOP (4 mm Hg). Side effects associated with brimonidine treatment included conjunctival blanching (40.9%), lid retraction (7.6%), and a slight lowering of the systolic blood pressure., Conclusions: One drop of 0.5% brimonidine administered either before or after surgery was found to be efficacious and safe in preventing posttrabeculoplasty elevations in IOP.

To determine whether genetic markers for chronic iridocyclitis could be identified, we used both serologic and oligonucleotide dot blot techniques to characterize immunogenetically 164 children with early-onset pauciarticular juvenile rheumatoid arthritis. Seventy-eight children (47.6%) had chronic iridocyclitis and 86 (52.4%) had not had evidence of eye disease during a mean follow-up period after the onset of arthritis of 15.8 years (minimum of 5.5 years). Control subjects were 218 healthy, unrelated individuals. The analysis was limited to alleles known to be associated with an increased or decreased risk of early-onset pauciarticular juvenile rheumatoid arthritis or of chronic iridocyclitis in this form of juvenile rheumatoid arthritis. Only one split of human leukocyte antigen (HLA)-DR5, HLA-DRB1* 1104, showed a statistically significant association with a risk of chronic iridocyclitis (chi-square value = 7.52; p = 0.036 adjusted; odds ratio 3.45); HLA-DQA1* 0501 and HLA-DQB1* 0301, both in linkage disequilibrium with HLA-DRB1* 1104, also were significantly associated with eye disease. Patients with both the DRB1* 1104 and DPB1* 0201 genes had a 7.7-fold increased risk for chronic iridocyclitis compared with that for other patients. The presence of HLA-DRB1* 1104 was about four times as specific, but only about one third as sensitive, as antinuclear antibodies in identifying patients at risk for eye disease. Although all children with early-onset pauciarticular juvenile rheumatoid arthritis should undergo periodic slit-lamp examinations, those with the HLA class II gene DRB1* 1104 are at particularly high risk for eye disease, and we recommend that they be monitored carefully for its evolution.

In a cohort of 72 patients with iridocyclitis (iritis) and early onset pauciarticular juvenile rheumatoid arthritis (EOPA-JRA) the course of the eye disease was matched with ocular outcome. Chronicity of inflammation (greater than 6 months/episode) was correlated with complications of eye disease that caused impairment of vision. HLA antigens in these patients were compared with the HLA antigens in a cohort of 77 patients with EOPA-JRA in whom iridocyclitis had failed to develop over a followup of 5 years or longer. HLA-DR5 (11) was correlated with the presence of eye disease, and HLA-DR1 with its absence; HLA-DRw8, which strongly predisposes to EOPA-JRA, was neutral with respect to eye disease.

The risk of iridocyclitis in children with early onset pauciarticular juvenile rheumatoid arthritis (EOPA-JRA) has been shown to be associated with certain HLA haplotypes. Our report contains an actuarial analysis, using one-year intervals, of 161 subjects and estimates haplotype specific risks. Individuals who possess the major susceptibility haplotype HLA-DR5 (11) developed eye disease earlier and with a greater frequency than did those with the protective HLA-DR1 haplotype. Highly significant differences were found between the resulting life-table curves for HLA-DR5 and HLA-DR1 positive subjects (p = 0.00003). These time oriented risk estimates may aid clinicians in determining more precisely the probability of iridocyclitis throughout the course of the disease in children with EOPA-JRA.

The effect of exercise conditioning on elevated intraocular pressure has not been previously described among sedentary individuals. We prospectively observed intraocular pressure for nine sedentary subjects suspected of having glaucoma before and after 3 months of aerobic exercise training. Mean (+/- SEM) aerobic capacity, as assessed by maximal oxygen uptake, increased 6.3 +/- 1.6 mL.kg-1.min-1 (30%) (P less than .02). Mean intraocular pressure decreased 4.6 +/- 0.4 mmHg (20%) (P less than .001) at the end of the conditioning period. With cessation of exercise and subsequent detraining, intraocular pressure returned to elevated preconditioning levels by 3 weeks. Regular aerobic exercise is associated with a reduction in elevated intraocular pressure and may represent an effective nonpharmacologic intervention for patients suspected of having glaucoma.

Ninety-two children with juvenile rheumatoid arthritis were randomly assigned to treatment in a multicenter, double-blind, 12-week trial designed to compare the efficacy and safety of a liquid formulation of ibuprofen at a dosage of 30 to 40 mg/kg/day versus those of aspirin at a dosage of 60 to 80 mg/kg/day. No significant intergroup differences in response rates or in the amount of improvement in articular indexes of disease activity were observed. More children treated with aspirin discontinued treatment early because of adverse reactions. After this trial, 84 additional patients with juvenile rheumatoid arthritis entered a 24-week, multidose (30, 40, and 50 mg/kg/day), open trial of ibuprofen suspension. Favorable response rates for the three groups were similar, and continued improvement was observed throughout the 24-week period. A dose-response relationship was observed with respect to adverse reactions of the upper gastrointestinal tract. We conclude that ibuprofen suspension is an effective nonsteroidal antiinflammatory drug and that its tolerability in children is acceptable.

A patient with acquired esotropia underwent apparently successful strabismus surgery. Subsequent recurrence of esotropia, associated with square-wave jerks and downbeat nystagmus led to further investigation. Although standard CT scan was normal, rescanning after instillation of metrizamide demonstrated a Chiari I malformation. Posterior fossa decompression alleviated the esotropia. Acquired esotropia has not been recognized as a manifestation of Chiari I malformation. Our case illustrates that a high degree of suspicion is required to make the diagnosis of Chiari I malformation. Specialized techniques, such as metrizamide cisternography, or magnetic resonance imaging may be necessary if routine diagnostic measures are unrevealing.

Plasma timolol levels were measured in our timolol-treated glaucoma patients employing three protocols: (1) measurements in ten patients over age 60 on chronic timolol therapy before, one hour, and three hours after receiving one drop of 0.5% timolol, (2) measurements in nine adult patients, with and without punctal occlusion, and (3) random measurement of plasma timolol in children on chronic timolol therapy while under general anesthesia. In the ten patients over age 60 years, baseline mean plasma timolol was 0.34 ng/ml, increasing to a mean of 1.34 ng/ml one hour after receiving drops. When punctal occlusion was applied, the mean one-hour plasma timolol diminished to 0.9 ng/ml, approximately 40% less than that observed without punctal occlusion. The plasma timolol levels examined in nine determinations in five children ranged from a low 3.5 ng/ml in a five-year-old child to 34 ng/ml in a three-week-old infant.

We diagnosed ocular syphilis in three homosexual men infected with human immunodeficiency virus (HIV). Ocular inflammation included uveitis, optic neuritis, and retinitis. Dermatologic and central nervous system manifestations of secondary syphilis were also present. The history of homosexuality was difficult to obtain. Concomitant infection with HIV may alter the course of syphilis, obscure the diagnosis, and impair the response to therapy.

We studied the intraocular pressure response to short-term maximal aerobic exertion before and after exercise conditioning in ten healthy sedentary volunteers. Before exercise conditioning, mean intraocular pressure +/- S.E.M. decreased by 5.9 +/- 0.6 mm Hg after short-term maximal aerobic exercise, returning to baseline in a mean of 37 +/- 4 minutes. After four months of exercise conditioning, this ocular hypotensive response was significantly dampened, with a mean intraocular pressure reduction of only 1.6 +/- 0.4 mm Hg after short-term maximal aerobic exercise (P less than .01). Additionally, a significant reduction in baseline intraocular pressure occurred, with a mean intraocular pressure of 14.3 +/- 0.7 mm Hg before exercise conditioning, declining to a mean intraocular pressure of 13 +/- 0.9 mm Hg (P less than .02) after four months of physical training. Exercise conditioning may significantly reduce baseline intraocular pressure and attenuate the hypotensive response to short-term maximal aerobic exercise.

Raynaud's phenomenon occurred in a 2-year-old girl 17 months after starting multiagent chemotherapy for an endodermal sinus tumor of the vagina. Symptoms began 2 months after receiving her final dose of bleomycin, and gradually resolved over a 6-month period despite continuing vinblastine. Chemotherapy-associated Raynaud's phenomenon appears to be unusual in young children, although mild episodes of vasospasm may not be reported by children or their parents. Specific questions regarding symptoms of Raynaud's phenomenon should be asked of all children receiving vinblastine and bleomycin therapy.