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We reviewed 53 patients referred to a pediatric rheumatology clinic in Asuncion, Paraguay. In 6 patients, a diagnosis of rheumatic fever was confirmed and in 47 patients other clinically significant diagnoses were made. Eighteen children had nonspecific findings and did not develop a rheumatologic condition on follow-up. Overdiagnosis of rheumatic fever can falsely inflate incidence and prevalence statistics and clinically significant diagnoses may be overlooked.

The care and study of children with rheumatic diseases began slowly in the 19th century, with the most attention centered on rheumatic fever. Other rheumatic diseases of children received little attention until the 1940s. Rheumatic diseases taken together remain a significant cause of chronic illness in children throughout the world. A number of other conditions that masquerade as rheumatic diseases in children also demand recognition and management. Although ultimate causes and cures of childhood rheumatic diseases remain elusive, advances in therapy have improved the outlook for affected children, and advances in biomedical research are adding to our basic understanding of the disease process involved. Pediatric rheumatology has become a well-organized, although underpopulated, specialty that enhances recognition and care of affected children and contributes to basic research knowledge in infectious disease, immunology, and genetics. This review focuses most prominently on the early history of pediatric rheumatology and its development as a specialty. The recent burgeoning of new biomedical science and new means of treatment will be better told in the historical perspective of years to come.

The purpose of this study was to present the clinical courses and histologic findings of 4 children with cutaneous vasculitis characterized by tender cutaneous nodules and fever in the absence of major organ involvement. We conducted a retrospective chart review of 4 patients with cutaneous vasculitis followed up for a mean of 68 months (range, 12-114 months). The patients included 3 boys and 1 girl (ages at onset, 2-10 years). Clinical and laboratory manifestations included tender erythematous cutaneous nodules (n = 4/4), fever 39 degrees C or higher (4/4), nondeforming arthritis (3/4), leukocytosis and elevated erythrocyte sedimentation rate (4/4), positive antinuclear antibodies (1/4), and elevated streptococcal enzymes (3/4). Skin biopsy results showed inflammation of medium-sized cutaneous arteries with a mixed inflammatory cell infiltrate consistent with cutaneous polyarteritis nodosa (4/4). Patients were treated with prednisone with good initial response, but exacerbation occurred once prednisone was tapered. Additional medications given were methotrexate (2/4), dapsone (2/4), colchicine (1/4), and cyclophosphamide (1/4). One patient is in clinical remission after 48 months of disease; the others have continuing disease that requires treatment. Patients with evidence of streptococcal infection received oral penicillin prophylaxis; two of the three patients had recurrent attacks of vasculitis despite penicillin. No patients have developed major organ system involvement after 12 to 114 months of follow-up. Cutaneous polyarteritis nodosa in children is a recognizable entity characterized by painful nodules, fever, absence of major organ involvement, and chronic or recurrent course. Patients should be screened for streptococcal infection and treated with antibiotics when needed.

E-selectin and intercellular adhesion molecule (ICAM)-1 are crucial to the inflammatory response in chronic inflammatory arthritis. Soluble (s) levels of these molecules in sera and synovial fluid (SF) correlate with some clinical parameters and synovial tissue expression of the same molecules in rheumatoid arthritis. Studies of sera from children with chronic inflammatory arthritis corroborate this information; corresponding SF data are relatively lacking. We thus studied SF sE-selectin and sICAM-1 in 28 children with active juvenile rheumatoid arthritis or a spondyloarthropathy. Levels were correlated with erythrocyte sedimentation rate (ESR), SF leukocyte counts, duration of disease, and duration of response to concomitant intra-articular corticosteroid injection. Levels were compared according to use of methotrexate and/or sulfasalazine. Synovial fluid sE-selectin correlated with ESR and SF leukocyte counts. There was a trend toward lower sICAM-1 in patients treated with sulfasalazine and/or methotrexate. We conclude that SF levels of sE-selectin accurately reflect intra-synovial inflammation. Soluble ICAM-1 levels may reflect the effects of disease-modifying agents.

Objective: To determine serum levels of soluble (s) adhesion molecules in patients with juvenile rheumatoid arthritis (JRA), and to determine whether differences exist in these levels among the 3 subtypes of JRA, and whether levels of these molecules correlate with other measures of disease activity., Methods: Serum levels of soluble forms of intercellular adhesion molecule-1 (ICAM-1), ICAM-3, vascular (V) CAM-1, L-selectin, and E-selectin were determined by sandwich ELISA in 16 patients with JRA (6 systemic, 6 polyarticular, 4 pauciarticular). Differences in levels among JRA subtypes were determined by ANOVA, and correlations between levels and the following clinical variables were assessed by linear regression analysis: erythrocyte sedimentation rate (ESR), total white blood cell count (WBC), hematocrit (HCT), platelet count (PLT), and total swollen joint count (JC)., Results: sE-selectin levels were significantly higher in patients with systemic disease compared to other subtypes (p<0.04). Furthermore, there was a trend toward higher levels of sICAM-1 in systemic disease, which did not reach statistical significance. Significant correlations were found between sE-selectin and ESR (r = 0.68, p<0.006), WBC (r = 0.70, p<0.003), and PLT (r = 0.54, p<0.05) and between sL-selectin and WBC (r = 0.55, p<0.03)., Conclusion: Because of the small number of patients studied, and the lack of age matched control data, our results must be interpreted with caution. Nonetheless, levels of sE-selectin, and possibly ICAM-1 appear to be relatively elevated in systemic JRA, and may indicate cytokine induction and endothelial cell activation in that subtype. Several molecules, especially sE-selectin, correlate with hematologic variables in JRA. These results suggest that serum levels of these molecules may provide a useful additional marker for disease activity in certain patients.

Objective: To study the prevalence of coagulation abnormalities in children with systemic juvenile rheumatoid arthritis (JRA) using a sensitive marker of fibrin degradation, and to determine whether serial levels of this variable parallel disease activity or predict response to medications in this disease., Methods: Levels of d-dimer were determined in 24 consecutive patients with systemic JRA in conjunction with complete blood counts, erythrocyte sedimentation rate, maximum fever, duration of morning stiffness, and swollen joint count. Serial levels were then obtained in 11 patients. Linear regression analyses were done to determine any correlations between d-dimer and the other variables; and paired t test was used to compare levels before and after treatment interventions. Levels of d-dimer were also compared against concurrent clinical events such as pericarditis., Results: Elevated levels of d-dimer were found in 23/24 of the patients (96%). When serial levels were analyzed, there were correlations between levels of d-dimer and fever (p = 0.03) and total leukocyte count (p = 0.04), but not with other variables. There was a significant reduction in levels before and after treatment in patients deemed to be clinical responders to immunomodulatory agents (p = 0.02). Elevated levels were also indicative of severe disease over the remainder of followup; lack of d-dimer indicated a benign disease course., Conclusion: With the use of a sensitive and specific marker of fibrinolysis known as d-dimer, coagulation abnormalities were more prevalent in children with systemic JRA than previously reported, and are frequently found during periods of active disease. Furthermore, serial levels of d-dimer appear to parallel response to disease modifying agents, and may predict outcome over a short followup period. Fibrin d-dimer may represent a novel marker that, when used in combination with known variables, could enhance that assessment of disease activity and response to medications in children with systemic onset JRA.

The rheumatic diseases constitute a significant group of chronic illnesses affecting children of all ages, including adolescents. This chapter provides an overview of rheumatic diseases and medical treatment options. Issues of sexuality and self-image that may influence treatment course and outcome are explored. The author emphasizes the importance of cooperation and communication between patient and physician, which enable adolescents to participate in the design and maintenance of their regimens.

Background: Although the numbers of women in training and in entry-level academic positions in medicine have increased substantially in recent years, the proportion of women in senior faculty positions has not changed. We conducted a study to determine the contributions of background and training, academic productivity, distribution of work time, institutional support, career attitudes, and family responsibilities to sex differences in academic rank and salary among faculty members of academic pediatric departments., Methods: We conducted a cross-sectional survey of all salaried physicians in 126 academic departments of pediatrics in the United States in January 1992. Of the 6441 questionnaires distributed, 4285 (67 percent) were returned. The sample was representative of U.S. pediatric faculty members. Multivariate models were used to relate academic rank and salary to 16 independent variables., Results: Significantly fewer women than men achieved the rank of associate professor or higher. For both men and women, higher salaries and ranks were related to greater academic productivity (more publications and grants), more hours worked, more institutional support of research, greater overall career satisfaction, and fewer career problems. Less time spent in teaching and patient care was related to greater academic productivity for both sexes. Women in the low ranks were less academically productive and spent significantly more time in teaching and patient care than men in those ranks. Adjustment for all independent variables eliminated sex differences in academic rank but not in salary., Conclusions: Lower rates of academic productivity, more time spent in teaching and patient care and less time spent in research, less institutional support for research, and lower rates of specialization in highly paid subspecialties contributed to the lower ranks and salaries of female faculty members.

Objective: To review the presentation, clinical characteristics, and outcome of children with prolonged fevers of unknown origin who are referred for pediatric rheumatologic evaluation., Methods: We used a retrospective review of the charts of the 40 children (23 boys and 17 girls, aged 9 months to 14.6 years) with fevers persisting longer than 1 month who were referred to the Pediatric Rheumatology Clinic between 1984 and 1994, in whom evaluation did not result in diagnosis. Follow-up with children's families, pediatricians, or both was done by telephone., Results: Of the 40 children, 29 had periodic fevers, and 11 had daily fevers without pattern. Patients with periodic fever were younger at onset, had longer duration of symptoms before referral, and higher maximum temperatures. The two groups did not differ in frequency of associated symptoms or signs. At follow-up (mean 60.5 +/- 5 months, n = 37), 10 children with daily fevers (within 24 months) and 23 children with periodic fevers (within 48 months) had completely recovered; three patients continue to have periodic fevers. In patients with daily fevers one had Crohn disease (7 months after initial evaluation) and another had uveitis (4 years after evaluation). One patient with periodic fevers had inflammatory bowel disease 3.5 years after the onset of fevers. Petit mal seizures developed in one patient with periodic fever, and another had mitochondrial encephalopathy. Four children with periodic fevers have attention-deficit hyperactivity disorder, and two have developmental delays., Conclusions: Fevers without an obvious source usually have a benign outcome, although patients should be monitored for changes in symptoms. Of the children with periodic fevers, 29% were later found to have neurologic problems; the relation to the previous fevers is uncertain.

Objective: To describe the presentation and clinical course of bicipital synovial cysts in 6 patients with juvenile rheumatoid arthritis (JRA) and to elucidate their anatomy using ultrasonography., Methods: A clinical description of the cyst, JRA subtype, activity of concurrent arthritis, systemic disease features, and erythrocyte sedimentation rate was recorded for each patient. Ultrasonographic examination of the cyst was performed for each patient., Results: Bicipital cysts generally presented as a sudden painless swelling on the flexor aspect of the upper arm, but on was in the forearm. Five of 6 patients had systemic disease. All patients had active arthritis when the cysts developed. Five of 6 cysts resolved spontaneously in less than 12 weeks. Ultrasonography confirmed a cystic structure in all patients, and in all cases was associated with thickening of the biceps tendon. Fluid was found within or adjacent to the biceps tendon in all cases., Conclusion: Bicipital synovial cysts should be considered a cause of acute arm swelling in patients with JRA, especially those with systemic disease. Ultrasonography is a useful diagnostic adjunct in this condition. This condition is generally self-resolving.

This study examines the differences which may distinguish systemic lupus erythematosus (SLE) presenting in adult life or childhood. A common database was established, with analysis of clinical, serological and outcome features of a cohort of patients with SLE, with disease diagnosed before the age of 16 (n = 39) or after the age of 16 (n = 165). Disease onset was generally more severe in the childhood-onset patients. Cardiopulmonary disease was more common in the older-onset group, but major haematological manifestations were more frequent in the childhood-onset group. Serologically, anti-DNA, anti-Sm and anti-RNP antibodies and a low C3 were all found more frequently in the younger patients. Twice as many adult-onset cases had died at the time of the last follow-up (10 vs 5%), but this group had been followed for a longer period (average 7.5 yr, S.D. 3.9 for adults vs average 4.8 yr, S.D. 3.2 for children). However, the younger patients were twice as likely (82 vs 40%) to require high-dose prednisone, although the requirement for immunosuppressive agents was similar in the two groups. Clinicians should anticipate that children with SLE have a more severe disease onset than adults in general.

Objective: A parent consultant program was established to promote active family involvement in the health care process and to provide parent-to-parent support, education, and training., Methods: Parents of children with rheumatic disease were hired by 7 pediatric rheumatology centers to serve as role models and advocates for other parents whose children attended the clinics. In the clinic, the parent consultants provided support, advocacy, and education regarding specific nonmedical issues. At the local level, they assisted parents in obtaining community-based services, such as individual educational plans at school, local physical therapy, or access to recreational resources., Results: Program impact was evaluated by an anonymous, mail-response questionnaire sent to parents who met with a parent consultant during a clinic visit for their child. Surveys were sent within 6 months of the initial parent consultant meeting; 257 questionnaires were mailed, 33% were returned. The majority of respondents (87%) felt their interaction with the parent consultant was helpful. The general support received and the specific information and/or assistance received were found to be equally useful by respondents. The majority of respondents (98%) stated they would recommend that other parents meet with the parent consultant., Conclusion: Parents of children with rheumatic disease are effective peer counselors, providing general support and specific assistance to enhance family involvement in care.

Neuropsychological assessments of adults with SLE have shown cognitive impairment, sequential processing deficits, memory loss, increased incidence of left handedness, learning disabilities and emotional distress compared with healthy individuals or subjects with other medical conditions. Neuropsychological testing regarding these variables in children and adolescents with SLE has been infrequently reported. For this study, eight children with SLE (age 9-17 years at diagnosis) were assessed with neuropsychological testing at a median of 10.5 months (range 1 week to 30 months) after diagnosis. Tests included Wechsler Intelligence Scale for Children-Revised or Wechsler Adult Intelligence Scale-Revised, Wide Range Achievement Test-Revised, Standard Binet Intelligence Scale Fourth Edition Memory Subtests or Wechsler Memory Scale (all mean = 100 +/- 15) and Gates MacInitie Reading Comprehension Test, Achenbach Child Behavior Checklist and Achenbach Youth Self Report. Mean intellectual scores were in the low average range (Wechsler Full Scale mean = 85.0 +/- 11.9, Verbal Scale mean 85.2 +/- 13.9, Performance Scale mean = 88.0 +/- 13.9). Academic achievement was globally depressed (reading recognition mean = 79.5 +/- 22.0, spelling mean = 78.9 +/- 23.5), especially in arithmetic (mean = 70.5 +/- 14.9). Children with SLE averaged 5 years behind grade placement in reading comprehension. Visual memory was also depressed in patients with SLE. Behavior ratings failed to demonstrate any significant aberrations in the test subjects.

Objective: To evaluate whether plasma von Willebrand factor (vWF) levels are a useful indicator of disease activity in juvenile dermatomyositis (DM)., Methods: Serum vWF levels were prospectively measured in 15 patients with juvenile DM and were compared to serum muscle enzyme levels, muscle strength, and presence of extramuscular manifestations., Results: 6/15 active disease periods were accompanied by an increase in vWF; 9 were not. Elevated vWF levels did not relate to the presence of active skin disease or calcinosis. vWF was not consistently related to muscle strength, CPK, or aldolase in the study group. Two patients had elevations of vWF in association with viral infections while their DM was quiescent., Conclusion: An elevated vWF level is often indicative of a disease exacerbation in DM, and thus may be helpful in managing difficult cases. However, it is not consistently elevated in, nor specific for active disease in DM. It therefore cannot be recommended as a routine test in patients with DM. When used, results should be interpreted with caution.

Much remains to be learned about the optimal therapy for children with rheumatic diseases. Current therapies remain inexact and are aimed at either the inflammatory or the immune responses of patients. There have been a few advances, for example in the treatment of children with dermatomyositis, lupus and, in particular, Kawasaki disease. Progress in the treatment of juvenile rheumatoid arthritis (JRA) and the spondylarthropathies has lagged behind, however, although methotrexate does appear to be promising in the short-term treatment of JRA. Another urgent problem which remains to be resolved is the identification of those children who will have poor outcomes and who warrant early, aggressive treatment. A number of interesting alternative therapies for adults have been proposed, but their applicability to children remains an open question. Further investigation of combined therapies with various drugs also warrants exploration.

Objective: To examine the descriptive epidemiology of a regional cohort of children with rheumatic disease, and to document the variety and frequency of diseases encountered among pediatric rheumatology centers., Methods: Pediatric rheumatology centers in southern New England participated in a prospective multicenter patient registry. All outpatients attending clinics at 8 pediatric rheumatology centers were enrolled as subjects during the 8-year period of study (n = 4585). Diagnostic criteria defined the rheumatic disease cases which were determined by clinical examination by a pediatric rheumatologist, and record linkage was achieved to avoid duplication of subjects., Results: Rheumatic conditions were diagnosed in 1742 subjects. Juvenile rheumatoid arthritis (JRA) was the most frequently encountered rheumatic condition (53%), followed by spondyloarthropathy syndromes (13%), vasculitis (10%), systemic lupus erythematosus (SLE) (6%), isolated Raynaud's phenomenon (5%), dermatomyositis/polymyositis (DM/PM) (5%), and scleroderma (2%). The mean annual incidence of JRA, spondyloarthropathy syndromes, SLE and DM/PM among children referred to pediatric rheumatology centers in Massachusetts was 4.0, 2.0, 0.4 and 0.4 per 100,000 children at risk, respectively. Nonrheumatic conditions were diagnosed in 2843 subjects, among which musculoskeletal conditions were most frequent (56%) followed by infectious disorders (18%), psychogenic disorders (3%), fever of unknown origin (2%), and abnormal immune serology without a specific diagnosis (2%)., Conclusion: The use of a multicenter patient registry was successful in allowing the collection of descriptive epidemiologic data on a large and well defined sample of children with rare disorders.

Objective: Although the more than 6 million Afghan refugees represent the largest single group of refugees worldwide, little information is available about their health status., Research Design: Case series assessing the health and socioeconomic status of female Afghan refugees and their families and the nutritional and developmental status of their children., Setting and Patients: Fifty-one female Afghan refugees and their children accompanying them at a maternal child health clinic in Quetta, Pakistan., Results: All families had suffered serious losses from the war. Thirty-three women (65%) had lost at least one liveborn child, most commonly to gastroenteritis, "hunger," or neonatal tetanus. Thirteen children had been killed by bombardment, mine injuries, or gunshot wounds. The nutritional status of the children was markedly poor: z scores were less than -2 for weight in 67% of children and also less than -2 for head circumference in 50% of children. Serial z scores for weight in 23 children showed marked decline in 15 children (65%). Sixty-nine percent of children were overdue for vaccinations. Developmental milestones were significantly delayed., Conclusion: Afghan refugee children and their mothers are extremely needy and vulnerable and may be considered among the hidden casualties of war.

Human parvovirus B19 (HPV B19) infection has been associated with chronic joint complaints in adult patients. We now report 22 children with joint complaints associated with recent HPV B19 infection. These children had either erythema infectiosum or serologic evidence of recent infection. Twenty children had arthritis; two had arthralgias. Eleven children had associated constitutional symptoms. Laboratory findings were generally normal. The duration of joint symptoms was less than 4 months in 14 children; however, six children have had persistent arthritis for 2 to 13 months, which would fulfill criteria for the diagnosis of juvenile rheumatoid arthritis. Although HPV B19 is usually associated with acute arthritis of brief duration, in some children infection with HPV B19 may be associated with the development of chronic arthritis.

Objective: To review the clinical course of 16 children with recalcitrant dermatomyositis (DM), who were treated with oral methotrexate (MTX) in addition to prednisone., Methods: Sixteen patients with recalcitrant DM who were treated with MTX in addition to prednisone were followed between 1984 and 1990. The patients' clinical responses to treatment, including alterations in muscle strength and muscle enzyme levels, changes in prednisone dosage, and development of toxicity or complications were reviewed retrospectively., Results: All 12 patients who received MTX for at least 8 months regained normal muscle strength. In 11 of the 12, the prednisone dosage could eventually be tapered to < or = 5 mg/day. Complications during MTX treatment required discontinuation of MTX in 5 patients, and were unrelated to the cumulative dose of the drug. Active disease recurred in 5 patients in whom MTX had been discontinued after apparent clinical remission had been achieved., Conclusion: MTX, in combination with prednisone, is a useful adjunct in the treatment of recalcitrant childhood DM. However, recurrence of disease after withdrawal of MTX suggests that the drug may have a suppressive, rather than a remittive, effect.

Our study documents the direct costs, family costs and community (extra school) costs. One hundred and twenty families with children who had juvenile rheumatoid arthritis (JRA) diagnosed by established criteria and who lived in New England were asked to participate. All data except inpatient charged were collected via questionnaire. The questionnaire return rate was 59% (N = 70). The mean annualized direct cost/child was 7,905 (inpatient, $1,717; outpatient, $5,700; and nonmedical, $488). Family costs averaged $1,524/year (out of pocket medical and nonmedical, $1,196; lost salary, $328), which represented 5% of mean family income. The mean extra school cost was $1,449/9 months. The economic impacts of JRA appear to be substantial.

The immunogenetic basis of pauciarticular-onset juvenile rheumatoid arthritis is unclear. We therefore analyzed the HLA and T cell receptor genes present in a clinically well-defined group of patients. We found that the DR8 haplotype contributes most of the HLA-associated risk, although alleles at other loci contribute independently. A candidate disease-associated T cell receptor polymorphism, in contrast, was not identified in this population. Mechanistic implications of these findings are discussed.

In a prospective study, levels of interleukin-1 beta (IL-1 beta), interleukin-6) (IL-6), and tumor necrosis factor (TNF) were measured in a blind fashion in cord blood plasma from 92 neonates by specific immunoassays, and were correlated with the clinical courses of the infants, including type of delivery and perinatal complications. Plasma IL-1 beta concentration was undetectable in infants born by normal vaginal delivery or elective cesarean section but was significantly increased in infants born after induced vaginal deliveries (142 +/- 68 pg/ml) or urgent cesarean section (290 +/- 21 pg/ml; both p less than 0.05 compared with normal deliveries). The IL-1 beta levels were elevated in infants with severe perinatal complications (282 +/- 116 pg/ml; p less than 0.001), whereas TNF and IL-6 levels were not related to these complications. Infants with isolated perinatal infectious complications had elevated levels of plasma IL-6 compared with those of sick neonates without infection (p less than 0.001). In contrast, TNF plasma levels and IL-1 beta production by cord blood leukocytes were decreased in infants with infectious complications alone (both p less than 0.05). These studies suggest that the levels of IL-1 beta, IL-6, and TNF in the cord plasma relate differentially to clinical complications in the perinatal period.

The three principal syndromes of juvenile rheumatoid arthritis have distinctive features that aid in early diagnosis and can contribute to specificity of treatment. Guidelines are given for differentiating JRA from other disorders producing joint pain.