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Background: Most of the available documentation in the literature on ocular involvement in localised scleroderma (LS) are descriptions of single cases in adult patients. This article reports the frequency and specific features of ocular involvement in a large cohort of children with juvenile LS (JLS)., Methods: Data from a large, multi-centre, multinational study of children with LS were used to collect and analyse specific information on ocular involvement., Results: 24 out of 750 patients (3.2%) revealed a significant ocular involvement. 16 were female and 8 male. 16 patients (66.7%) had scleroderma "en coup de sabre" (ECDS) of the face, 5 (20.8%) had the linear subtype, 2 (8.3%) had generalised morphea (GM) and one (4.2%) had plaque morphea (PM). Of the 24 patients with eye involvement, 10 patients (41.7%) reported adnexa (eyelids and eyelashes) abnormalities, 7 (29.2%) anterior segment inflammation (5 anterior uveitis, 2 episcleritis) and 3 central nervous system-related abnormalities. 4 patients presented single findings such as paralytic strabismus (1), pseudopapilloedema (1) and refractive errors (2). Other extracutaneous manifestations were detected in a significantly higher number of patients with ocular involvement and were mostly neurological., Conclusion: Ocular abnormalities are not unusual in patients with JLS, especially in the ECDS subtype. They are frequently associated with other internal organ involvement, particularly the central nervous system (CNS). Careful ophthalmic monitoring is recommended for every patient with JLS, but is mandatory in those with skin lesions on the face and/or concomitant CNS involvement.

Objective: To develop criteria for the classification of systemic sclerosis (SSc) in children (juvenile SSc)., Methods: The study consisted of 3 phases: 1) collection of data on the signs and symptoms of actual patients with juvenile SSc that are useful for defining involvement of a particular organ; 2) selection of the parameters essential for the classification of juvenile SSc and preparation of a set of provisional classification criteria (PCC) using 2 Delphi surveys; 3) consensus conference consisting of 2 steps: discussion and rating of clinical profiles of 160 patients with definite juvenile SSc, possible juvenile SSc, or other fibrosing diseases as "having or not having juvenile SSc," using nominal group technique, and defining those PCC with the best statistical performance and highest face validity by using the clinical profiles of patients with definite juvenile SSc as the gold standard., Results: In phase 1, 55 centers submitted clinical data on 153 patients with juvenile SSc. A total of 48 signs and symptoms were derived from these patient data and were used to define 9 organ system categories (cutaneous, vascular, gastrointestinal, respiratory, renal, cardiac, neurologic, musculoskeletal, and serologic). During phase 2, these were reduced to 21 criteria (3 major criteria [Raynaud's phenomenon, proximal skin sclerosis/induration of the skin, and sclerodactyly] and 18 minor criteria) and combined to generate 86 different PCC. At the consensus conference, these 86 definitions were tested on the case profiles of 127 patients with juvenile SSc. The PCC with the highest ranking were proximal sclerosis/induration and at least 2 minor criteria., Conclusion: These provisional classification criteria for juvenile SSc will help standardize the conduct of clinical research, epidemiologic and outcome studies, and therapeutic trials.

Objective: To determine the clinical and immunologic features of systemic sclerosis (SSc) in a large group of children and describe the clinical evolution of the disease and compare it with the adult form., Methods: Data on 153 patients with juvenile SSc collected from 55 pediatric rheumatology centers in Europe, Asia, and South and North America were analyzed. Demographic, clinical, and immunologic characteristics of children with juvenile SSc at the onset, at diagnosis, and during the disease course were evaluated., Results: Raynaud's phenomenon was the most frequent symptom, followed by skin induration in approximately 75% of patients. Musculoskeletal symptoms were present in one-third of patients, and the most frequently involved internal organs were respiratory and gastrointestinal, while involvement of renal, cerebral, and cardiovascular systems was extremely rare. Antinuclear antibodies were present in the sera of 81% of patients. Anti-topoisomerase I (Scl-70) and anticentromere antibodies were found to be positive in 34% and 7.1% of patients, respectively. Involvement of the respiratory, gastrointestinal, and cardiovascular systems was more frequent and occurred earlier in patients who died than in those who survived. Compared with the adult form, juvenile SSc appears to be less severe, with the involvement of fewer internal organs, particularly at the time of diagnosis, and has a less characterized immunologic profile., Conclusion: This study provides information on the largest collection of patients with juvenile SSc ever reported. Juvenile SSc appears to be less severe than in adults because children have less internal organ involvement, a less specific autoantibody profile, and a better long-term outcome.

Objective: Juvenile localized scleroderma (JLS) includes a number of conditions often grouped together. With the long-term goal of developing uniform classification criteria, we studied the epidemiological, clinical and immunological features of children with JLS followed by paediatric rheumatology and dermatology centres., Methods: A large, multicentre, multinational study was conducted by collecting information on the demographics, family history, triggering environmental factors, clinical and laboratory features, and treatment of patients with JLS., Results: Seven hundred and fifty patients with JLS from 70 centres were enrolled into the study. The disease duration at diagnosis was 18 months. Linear scleroderma (LS) was the most frequent subtype (65%), followed by plaque morphea (PM) (26%), generalized morphea (GM) (7%) and deep morphea (DM) (2%). As many as 15% of patients had a mixed subtype. Ninety-one patients (12%) had a positive family history for rheumatic or autoimmune diseases; 100 (13.3%) reported environmental events as possible trigger. ANA was positive in 42.3% of the patients, with a higher prevalence in the LS-DM subtype than in the PM-GM subtype. Scl70 was detected in the sera of 3% of the patients, anticentromere antibody in 2%, anti-double-stranded DNA in 4%, anti-cardiolipin antibody in 13% and rheumatoid factor in 16%. Methotrexate was the drug most frequently used, especially during the last 5 yr., Conclusion: This study represents the largest collection of patients with JLS ever reported. The insidious onset of the disease, the delay in diagnosis, the recognition of mixed subtype and the better definition of the other subtypes should influence our efforts in educating trainees and practitioners and help in developing a comprehensive classification system for this syndrome.

Objective: Juvenile localized scleroderma is usually considered a disease that is confined to the skin and subcutaneous tissue. We studied the prevalence and clinical features of extracutaneous manifestations in a large cohort of children with juvenile localized scleroderma., Methods: Data from a multinational study on juvenile scleroderma was used for this in-depth study. Clinical features of patients with extracutaneous manifestations were compared with those of patients who had exclusively skin involvement., Results: Seven hundred fifty patients entered the study. One hundred sixty-eight patients (22.4%) presented with a total of 193 extracutaneous manifestations, as follows: articular (47.2%), neurologic (17.1%), vascular (9.3%), ocular (8.3%), gastrointestinal (6.2%), respiratory (2.6%), cardiac (1%), and renal (1%). Other autoimmune conditions were present in 7.3% of patients. Neurologic involvement consisted of epilepsy, central nervous system vasculitis, peripheral neuropathy, vascular malformations, headache, and neuroimaging abnormalities. Ocular manifestations were episcleritis, uveitis, xerophthalmia, glaucoma, and papilledema. In more than one-fourth of these children, articular, neurologic, and ocular involvements were unrelated to the site of skin lesions. Raynaud's phenomenon was reported in 16 patients. Respiratory involvement consisted essentially of restrictive lung disease. Gastrointestinal involvement was reported in 12 patients and consisted exclusively of gastroesophageal reflux. Thirty patients (4%) had multiple extracutaneous features, but systemic sclerosis (SSc) developed in only 1 patient. In patients with extracutaneous involvement, the prevalence of antinuclear antibodies and rheumatoid factor was significantly higher than that among patients with only skin involvement. However, Scl-70 and anticentromere, markers of SSc, were not significantly increased., Conclusion: Extracutaneous manifestations of juvenile localized scleroderma developed in almost one-fourth of the children in this study. These extracutaneous manifestations often were unrelated to the site of the skin lesions and sometimes were associated with multiple organ involvement. The risk of developing SSc was very low. This subgroup of patients with juvenile localized scleroderma should be evaluated extensively, treated more aggressively, and monitored carefully.

Scleroderma is a relatively rare disorder in children. Among its subsets, localized scleroderma is more common in children than the systemic variety. No exciting new finding was reported in 2001 specifically applicable to childhood scleroderma. However, many new advances in our understanding of the growth factors, cytokines, and chemokines were reported. These studies should help us to understand the pathogenesis of early lesions of scleroderma, vascular changes, and fibrosis and perhaps lead us toward more rational therapy.

Background: Rice bodies can occur in the joints in many rheumatic conditions, but they are most common in rheumatoid arthritis. They are generally believed to occur rarely in patients with osteoarthritis, but one study reported rice bodies with apatite crystals., Objective: To report on a series of joint fluids with rice bodies containing apatite clumps and examine their clinical pictures., Methods: All synovial fluid analysis reports for 10 years were reviewed for rice bodies and eight patients were reported on. A series of patients with a variety of diseases with synovial fluid rice bodies found to contain calcific material is described. All were examined by compensated polarised light and alizarin red stain, and four were examined by electron microscopy., Results: The eight patients all had alizarin red S chunks embedded throughout the rice body. Transmission electron microscopy disclosed the presence of a matrix of collagen, fibrin, and amorphous materials containing typical apatite crystals. Clinical diagnoses, radiographic findings, and leucocyte counts varied, but six of the eight patients had had previous repeated corticosteroid injections into the joints., Conclusion: Aggregates of apatites may be more common than previously recognised in rice bodies as they are not routinely sought. Whether they are a result of joint damage or depot steroid injections and whether that might contribute to further joint injury now needs to be investigated.

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

Objective: To determine the point prevalence and pattern of silent cardiac abnormalities and associations with suspected risk factors in a sample of children with systemic lupus erythematosus (SLE)., Methods: Cross-sectional analysis of 19 children with SLE from a referral-based rheumatology clinic at an urban children's hospital. Patients were eligible if they were 20 years of age or younger and classified with SLE using the revised criteria of the American College of Rheumatology. Each patient completed a survey, physical examination, standard 12-lead electrocardiogram (ECG), echocardiogram, and had laboratory determinations of complement, triglyceride, and cholesterol levels., Results: Six patients (32%) had cardiac abnormalities on ECG or echocardiogram. In 3, the abnormalities were mild and considered within the normal range. In 5, the abnormalities were considered silent. These abnormalities included ischemic changes (3 patients), valvular insufficiency (3 patients), ventricular repolarization defects (2 patients), cardiac enlargement (1 patient), and ventricular dysfunction (1 patient). Only a recent history of palpitations was significantly associated with the presence of cardiac abnormalities (p = 0.04)., Conclusions: Silent cardiac abnormalities can occur in children with SLE. A recent history of palpitations may be associated with cardiac abnormalities. Routine evaluation of children with SLE using ECG and echocardiogram may help screen for these abnormalities. However, future studies comprising larger sample sizes and longitudinal followup will be required to determine the natural history of cardiac abnormalities in children with SLE and to identify risk factors.

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

Objective: AI/RHEUM is a multimedia expert system developed originally to assist in the diagnosis of rheumatic diseases in adults. In the present study we evaluated the usefulness of a modified version of this diagnostic decision support system in diagnosing childhood rheumatic diseases., Methodology: AI/RHEUM was modified by the addition of 5 new diseases to the knowledge base of the system. Criteria tables for each of the diseases included in the knowledge base were modified to suit the needs of children. The modified system was tested on 94 consecutive children seen in a pediatric rheumatology clinic., Results: AI/RHEUM made the correct diagnosis in 92% of the cases when the diagnosis was available in the knowledge base of the system. It was also shown to be effective in the education of pediatric trainees through its multimedia features., Conclusions: AI/RHEUM is an expert system that may be helpful to the nonspecialist as a diagnostic decision support system and as an educational tool.

Objective: Turner's syndrome (TS) is a disorder associated with characteristic defects in the X chromosome. Autoimmune conditions such as thyroiditis, inflammatory bowel diseases and diabetes have been described in association with TS., Methods: We have studied the association between TS and juvenile arthritis (JA) by using a survey in which 28 pediatric rheumatology centers (15 in the USA, 10 in Europe, and 3 in Canada) participated., Results: Eighteen cases of TS in a population of approximately 15,000 JRA patients have been found. Two different patterns of arthritis were present: polyarticular (7) and oligoarticular (11). Children with polyarticular disease had early onset, seronegative, progressively deforming arthritis and growth retardation. Those with oligoarticular arthritis had a benign course and were ANA+ (8/11). The oligoarticular children had varying karyotypes whereas almost all of the polyarthritic patients shared the same 45X0 karyotype (6/7). The light and electron microscopic studies of synovium performed in two patients showed chronic inflammation and hyperplasia of the synovial lining cells, vascular proliferation and infiltration with lymphocytes, plasma cells and mononuclear phagocytes., Conclusion: Juvenile arthritis is a new autoimmune condition association with Turner's syndrome. The prevalence seems to be at least six times greater than would be expected if the two conditions were only randomly associated. This is the first description of the synovium in Turner's syndrome; no differences from other forms of juvenile rheumatoid arthritis were found.

This article discusses the effects of sex steroids and anterior pituitary hormones on the immune system. Data from clinical and experimental studies on the effects of CRH, FSH, LH, and prolactin are reviewed. This is followed by a summary of results from our studies on the effects of FSH, LH, and prolactin on PBMC, CD4+ cells, and CD8+ cells in vitro.

Objective: To determine, in a case-control study, if patients with new-onset juvenile dermatomyositis (juvenile DM) have increased symptoms prior to onset, exposure to certain environmental conditions, frequency of familial autoimmune diseases, or antibody titers, compared with 2 control groups., Methods: A structured interview with the families of 80 children with juvenile DM, 40 children with juvenile rheumatoid arthritis (JRA), or 23 healthy children, from the same geographic area as the children with juvenile DM, was conducted. All children's sera were tested for antibody to Toxoplasma gondii, herpes simplex virus (HSV), or coxsackievirus B (CVB)., Results: A high proportion of children with juvenile DM had constitutional symptoms 3 months before the disease-onset date (P = 0.013 versus control children). Children with JRA had more relatives with rheumatoid arthritis (P = 0.0001) and pernicious anemia (P = 0.003) than did children with juvenile DM or healthy children. Among children < or =7 years of age, elevated enteroviral titers were more frequent in those with juvenile DM (81%) and in healthy controls (90%) than in those with JRA (64%), suggesting a common environmental exposure. Titers to T gondii, HSV, or CVB 1-6 were normal., Conclusion: Frequencies of familial autoimmune disease, exposure to environmental factors, or elevated antibody titers to T gondii, HSV, or CVB are not increased in juvenile DM. Children with juvenile DM do have symptoms of illness 3 months before the disease-onset date, and young patients have elevated enteroviral titers, as do young geographic controls.

There are many questions and no clear answers raised by these children. These syndromes, however, seem to be biologic experiments of nature and present unique opportunities to study the various elements involved in the pathogenesis of arthritis. Pediatric rheumatologists are in a unique position to study these syndromes.

Objective: To investigate the association of polyarthritis and chromosome 22q11.2 deletions., Methods: Eighty patients with chromosome 22q11.2 deletion syndrome followed up at The Children's Hospital of Philadelphia were examined for evidence of arthropathy or arthritis. Patients with chromosome 22q11.2 deletion syndrome and polyarthritis underwent laboratory evaluations of immunologic function to determine the relationship of their immunodeficiency to the polyarthritis., Results: The prevalence of polyarthritis in patients with chromosome 22q11.2 deletion syndrome was markedly increased over the prevalence of polyarticular juvenile rheumatoid arthritis (JRA) in the general population. All 3 patients with polyarthritis had evidence of impaired T cell function. Two of the patients with polyarthritis also had IgA deficiency., Conclusion: The chromosome 22q11.2 deletion syndrome represents a primary T cell disorder which can be associated with a JRA-like polyarthritis. All 3 patients with polyarthritis had evidence of more extensive immunoregulatory derangements than those typically seen in patients with chromosome 22q11.2 deletion, and these derangements may have predisposed to the development of polyarthritis.

Our understanding of the pathogenesis of vasculitis has improved significantly in recent years. The study of cytokines, endothelium, and adhesion molecules in the initiation of inflammatory responses has opened new avenues of investigation and treatment of these disorders. The recognition of newer antibodies such as antineutrophil cytoplasmic antibody has given us newer classification of some of the vasculitides. In this paper, articles published in 1995 on childhood vasculitis with both clinical and research importance are reviewed.

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

Cytophagic histiocytic panniculitis (CHP) can be a severe variant of Weber-Christian disease characterized by the histopathologic appearance of lobular panniculitis infiltrated by histiocytes containing blood cell fragments and by a clinical course with marked systemic features including multiorgan failure, hypertriglyceridemia, and coagulopathy, which may lead to death. Therapy of CHP includes standard treatment for panniculitis, such as antimalarials, plus immunosuppressives for more severe cases. The response to treatment, however, is unpredictable. In several recent reports, cyclosporine A has been successfully used to treat panniculitis. We report a patient and review the literature on CHP and the use of cyclosporine A as therapy. Published reports reveal that in instances of severe CHP when cyclosporine A was not given, 19 of 27 patients died (70% mortality). When severe CHP was treated with cyclosporine A, rapid remission was achieved in our patient and all five previously published cases (0% mortality). We believe cyclosporine A is the drug of choice in severe CHP and should be considered in all such patients.

Rheumatic diseases are one of the common groups of chronic diseases of childhood. They are multifactorial in origin and tend to involve multiple organ systems. Consequently management of these diseases requires the expertise of many health and allied health professionals. This review article focuses on the medical management of three of the relatively common diseases: juvenile rheumatoid arthritis (JRA), systemic lupus erythematozus (SLE) and dermatomyositis (DM).

Common vasculitic disorders in children include those associated with infections (e.g., Rickettsiae, subacute bacterial endocarditis), Schonlein-Henoch purpura, and Kawasaki disease. Recent advances have occurred in understanding the pathogenesis of vasculitides. In this review, the reader will be exposed to some of the developments in adhesion molecules, antineutrophil cytoplasmic antibodies, antiendothelial antibodies, and antiphospholipid antibodies. Classification criteria and diagnostic strategies are also summarized.

Objective: To estimate the frequency of documented clinically significant gastrointestinal (GI) side effects secondary to nonsteroidal antiinflammatory drugs (NSAID) therapy and to describe the adverse events., Methods: Computerized medical records of 702 patients with juvenile rheumatoid arthritis (JRA) administered NSAID were searched for the occurrence of clinically significant gastropathy (esophagitis, gastritis, peptic ulcer disease)., Results: Five children were identified who had a total of 10 events of gastropathy documented by either barium swallow or endoscopy, and thought to be attributable to NSAID therapy. Each child had at least 2 separate events of clinically significant gastropathy., Conclusion: Although mild GI disturbances are frequent side effects associated with NSAID therapy, the number of children with JRA who experience clinically significant gastropathy appears to be low.

Objective: To develop and validate a self- or parent-administered instrument for measuring functional status in children with juvenile rheumatoid arthritis (JRA)., Methods: We adapted the Stanford Health Assessment Questionnaire (HAQ) for use in children ages 1-19 years, by adding several new questions, such that for each functional area, there was at least 1 question relevant to children of all ages. The face validity of the instrument was evaluated by a group of 20 health professionals and parents of 22 healthy children. The questionnaire was then administered to parents of 72 JRA patients (mean age 9.1 years, onset type systemic in 16, polyarticular in 21, pauciarticular in 35)., Results: The instrument showed excellent internal reliability (Cronbach's alpha = 0.94), with a mean inter-item correlation of 0.6. The convergent validity was demonstrated by strong correlations of the Disability Index (average of scores on all functional areas) with Steinbrocker functional class (Kendall's tau b = 0.77, P < 0.0001), number of involved joints (Kendall's tau b = 0.67, P < 0.0001), and morning stiffness (Kendall's tau b = 0.54, P < 0.0001). Spearman's correlation coefficient between Disability Index scores from questionnaires administered to parents and those from questionnaires administered to older children (> 8 years) was 0.84 (n = 29; P < 0.001), showing that parents can accurately report for their children. The test-retest reliability, studied at a 2-week interval, revealed virtually identical Disability Index scores measured on the 2 occasions (0.96 versus 0.96; P > 0.9 by paired t-test; Spearman's correlation coefficient = 0.8, P < 0.002)., Conclusion: The Childhood HAQ, which takes less than 10 minutes to complete, is a valid, reliable, and sensitive instrument for measuring functional status in children with JRA.

A number of conditions can cause color and temperature changes in the extremities. These include physical and chemical insults (eg, frost-bite; ergot), vasculitis (eg, systemic lupus erythematosus), or conditions associated with vascular tone. This article reviews two conditions that are commonly seen in children (Raynaud syndrome and reflex sympathetic dystrophy) and a recently recognized condition associated with antiphospholipid antibody. The emphasis is on differences between the adult and childhood forms of these disorders.

We describe five children with varied rheumatic manifestations, including fibromyalgia and arthralgias, ultimately proved to be associated with hypothyroidism. All musculoskeletal symptoms improved after thyroid replacement therapy. We conclude that rheumatic manifestations of hypothyroidism can be as varied in children as in adults.

Studies in adults with systemic lupus erythematosus (SLE) have shown normal estrogen and lowered androgen levels in serum and abnormal metabolism of estrogen. In our prospective study we tested the hypothesis that one or more of the following factors account for the increased incidence of SLE and pauciarticular juvenile rheumatoid arthritis (JRA) in females: (a) increased estrogen; (b) decreased androgen and (c) increased estrogen receptor in the peripheral blood mononuclear cells (PBMC). Serum and PBMC were collected from 51 healthy children (36 M: 20 F), 17 with JRA (all female) and 37 with SLE (11 M: 26 F). Estrogen receptor was measured in cytosol from PBMC using monoclonal antibody to estrogen receptor and solid phase enzyme immune assay. Serum levels of estrogen, androgen, prolactin, follicle stimulating hormone (FSH) and luteinizing hormone (LH) were measured using standard radioimmunoassay. There were no significant differences in serum levels of estrogen and prolactin between healthy children and patients. Free androgen was lower in postpubertal boys and girls with SLE compared to healthy children. FSH and LH levels were higher in postpubertal boys and girls with SLE compared to healthy individuals. This trend, while not reaching statistical significance, was supported by a higher percentage of female patients with SLE and abnormal serum levels of FSH (p = 0.001), LH (p = 0.004) and prolactin (p = 0.001). The results of these preliminary studies suggest that the role of prolactin, FSH and LH in rheumatic diseases deserves further study.

Many children with acute leukemia have musculoskeletal complaints and non-specific hematologic abnormalities. A total of 10 children with acute leukemia and 10 with systemic juvenile rheumatoid arthritis were compared to delineate which early features could differentiate these diagnoses. Attention to evolving hematologic abnormalities and musculoskeletal findings may expedite diagnosis of these diseases.

Clinical observations on patients with systemic lupus erythematosus and rheumatoid arthritis and studies in murine models of autoimmune diseases suggest an important role for the sex and pituitary hormones in immune function. Estrogen and testosterone have been shown to modulate B cell functions in vitro. Prolactin (PRL) has been shown to have immunomodulatory functions. Follicle stimulating hormone (FSH) and luteinizing hormone (LH) have homology to thioredoxin, a potentiator of T-cell growth. We therefore studied the proliferative response of peripheral blood mononuclear cells (PBMC) from normal adult males to various stimuli in the presence or absence of estradiol (E2), testosterone (Te), PRL, FSH, and LH and the effect of these hormones on T-cell subsets by flow cytometry. Unfractionated PBMC were stimulated with 1% phytohemagglutinin (PHA) (polyclonal activation), anti-CD3 (T-cell receptor stimulation), or recombinant interleukin 2 (IL-2) (late stages of activation). We assessed the effects of E2 (0.3-30 ng/ml), Te (3-300 ng/ml), PRL (2-200 ng/ml), FSH (1-100 mIU/ml), and LH (1-100 mIU/ml). E2 and Te had no consistent effect on PBMC proliferation in response to any of the stimuli. E2 significantly decreased the percentage of CD4+ cells following PHA stimulation (P = 0.022), while significantly enhancing the percentage of CD8+ cells following IL-2 stimulation (P = 0.007). Te significantly increased the percentage of CD4+ cells following IL-2 stimulation (P = 0.03). PRL enhanced proliferation in response to IL-2 and PHA without subset-specific effects. FSH and LH both enhanced IL-2-induced proliferation, particularly in physiological doses (10 mIU/ml). FSH at 100 mIU/ml significantly decreased the percentage of CD4+ cells in unstimulated cultures (P = 0.003), while it enhanced the percentage of CD8+ cells following PHA stimulation (P = 0.004). The enhancement in CD8+ cells appeared the most marked in the CD8+CD28+ subset. LH at 10 mIU/ml significantly enhanced the percentage of CD4+ cells following IL-2 stimulation (P = 0.009) and at higher doses (100 mIU/ml) enhanced the percentage of CD4+ cells following PHA stimulation (P = 0.011). Thus, sex steroids and adenohypophyseal hormones (PRL, FSH, and LH) have subset-specific effects on T-cell activation which may influence sex-related differences in immune response.

A young black man with sickle cell disease with recurrent painful vasoocclusive crises developed at 16 years of age a rapid disabling polyarticular chondrolysis leading to a bilateral hip arthroplasty in 1 year. Light microscopy showed erosion and chondrocyte loss with deep clones in the cartilage and congested vessels with extravasation of red blood cells and mononuclear cells in the synovium. Electron microscopy of the synovium disclosed partially occluded blood vessels and phagocytic cells containing red blood cell debris and crystalline hemoglobin-like material. These observations suggest a role for the phagocytic cells in the joint destruction.

Older adolescents are in the midst of many life changes related to physical and emotional development, education and career choices, family and peer relationships. The presence of a chronic disease adds an additional burden. At this stage of development, transfer of care to an adult facility becomes a major challenge for the adolescent, parents, and pediatric and adult care providers. This article describes an interdisciplinary transition program from pediatric to adult health care for older adolescents with rheumatic diseases. Care is transferred to an internist-rheumatologist who collaborates closely with the pediatric team. Scope of the program includes pretransitional assessments and interventions, including education, counseling, and referral around career, postsecondary education, sexuality, and other transitional issues. Benefits of and barriers to a structured transition program are discussed.

The patterns of pulmonary involvement in 13 children with progressive systemic sclerosis were investigated. Eight patients (61%) had respiratory symptoms or signs and 7 patients (55%) had abnormalities on chest roentgenogram. Twelve patients (92%) had abnormal pulmonary function tests: 7 had restrictive disease, 2 had obstructive disease, 2 had small airway disease, and 1 had an isolated reduction in the diffusing capacity of carbon monoxide. Nine patients had the test performed during the first year of illness, 3 during the second year, and 1 at 5 years. All patients had abnormal pulmonary function tests when first studied. Subsequent pulmonary function tests over a period of 3 to 10 years (mean 6.2 years) showed substantial changes in only 2 patients (1 patient had initial worsening of diffusing capacity of carbon monoxide followed by normalization and another patient showed improvement of obstructive disease). Two patients died during follow-up, 1 of pulmonary hypertension, the other of severe restrictive lung disease and myocardial fibrosis. The major findings of this study were (1) high frequency of pulmonary disease in children with progressive systemic sclerosis, (2) early involvement of the lungs, (3) relatively indolent progression of lung disease, and (4) the prognostic importance of the severity of pulmonary disease. Pulmonary manifestations of progressive systemic sclerosis in children appear to be similar to those of affected adults.

Dystrophic calcification is seen in more than 50% of children with juvenile dermatomyositis and tends to resolve spontaneously in some patients. Calcinosis universalis is the least common type of calcification seen and rarely regresses. We describe a boy with juvenile dermatomyositis and calcinosis universalis who developed hypercalcemia during spontaneous regression of dystrophic calcification. The treatment and possible mechanisms of this complication are discussed.

Based on clinical experience and the aforementioned studies, a number of opinions can be entertained concerning the historically traditional conservative management of children with JRA. 1. Because the inflammatory changes of JRA on the bones and joints once established are irreversible in most children, there are ample theoretical reasons to start more effective therapy (if available) early. 2. Most of the currently available drugs control inflammation only partially or temporarily. 3. Most children stop taking the various SAARDS after approximately 2 years of disease because of lack of efficacy or the development of toxicity. 4. Whereas corticosteroids are the most potent and effective anti-inflammatory agents, long-term use in children, even in low dosage, is severely limited, especially by their effect on growth. 5. Methotrexate appears to be the most effective of the alternative agents and much safer than expected when used in the currently recommended protocol. 6. More effective therapy must await a better understanding of the pathogenesis of JRA, although currently available medications might be used more rationally by taking into consideration available pharmacologic studies.

LB is a multisystem illness caused by the spirochete B. burgdorferi. As with other spirochetal diseases, LB evolves in stages. Some manifestations are the result of persistent infection, whereas other symptoms are a consequence of immunologic changes secondary to the infection. Most disease manifestations are not specific to this illness. In addition, in endemic areas, almost 100% of the tick vector, the Ixodes species, are infected and the incidence rate of LB is as high as 1%. Because of these factors, the illness is overdiagnosed and overtreated. We have reviewed the current state of diagnosis and treatment of LB as well as questions that arise during the management of this illness.

Twenty-nine children with juvenile rheumatoid arthritis were studied to determine the safety and efficacy of methotrexate therapy. The initial dose of methotrexate averaged 7.1 mg/m2/wk and was given as a single, oral weekly dose or as three divided doses, each separated by 12 hours. Current antiinflammatory medications were continued; 25 of 29 children had had lack of efficacy, and 8 of 29 had toxic effects, with one or more prior drugs such as intramuscularly or orally administered gold, hydroxychloroquine, or D-penicillamine. Intolerable corticosteroid dependency or toxic effects were present in 18 of 29 cases. Methotrexate-treated patients were examined monthly; minimum treatment duration required to assess efficacy and toxicity was 6 months. The range of treatment duration was 8 to 39 months (mean 18.5 months). Efficacy was assessed by comparing pretreatment versus posttreatment fever and rash, swollen-joint counts, articular indexes, duration of morning stiffness, functional class, hemoglobin levels, and platelet counts. Treatment with methotrexate effectively controlled fever and rash in 83% of children with systemic juvenile rheumatoid arthritis, reduced morning stiffness by 63%, eliminated recalcitrant joint restriction in 48%, and reduced numbers of swollen joints and swelling indexes by 46% and 52%, respectively. No significant toxic effects were observed. Juvenile rheumatoid arthritis of long duration, or with major erosions, was more likely to be refractory to methotrexate therapy. We recommend earlier consideration of methotrexate in place of other slow-acting antirheumatic drugs for juvenile rheumatoid arthritis not responding well to usual therapy. Future studies should address potential methotrexate toxic effects in the lungs and reproductive system, as well as outcome after discontinuation of methotrexate treatment.

A syndrome of granulomatous arthritis-uveitis-rash has been described in children. Since the clinical features of arthritis in this syndrome closely resemble those seen in early onset sarcoidosis, and since large vessel vasculitis has been seen in children with sarcoidosis, it is possible that early onset sarcoidosis and granulomatous arthritis-uveitis-rash syndrome are part of the same clinical spectrum. Clinical features of a child with sarcoidosis and Takayasu arteritis described in this report support this hypothesis.

Although routinely used in health surveys, the factors affecting maternal perceptions of health in children, especially those with health problems, have received little examination. This question has been addressed using a telephone interview of families of 483 children followed in one of three clinics at Children's Hospital of Philadelphia: the Neonatal Follow-up Program, the Pediatric Rheumatology Center and the Spina Bifida Program. Limitations in activities of daily living due to the health of the child, medical care use and variables indicative of socio-economic disadvantage were associated with a maternal rating of child health as fair/poor in all groups. The relationship was strongest in the rheumatologic group and less strong in the other two, suggesting that mothers may distinguish between a chronic active disease in a previously healthy child and the disability following a neonatal event in conceptualizing health. The results add to our information about maternal perceptions in assessing child health and suggest ways in which such ratings may prove useful in assessing health and health services for children with health problems.

Six patients with reflex sympathetic dystrophy were investigated during the period between 1973 and 1978. Children do not develop the severe, disabling pain nor the patchy osteoporosis (Sudeck's atrophy) which are considered essential features of reflex sympathetic dystrophy in adults. In contrast to the adult variety, reflex sympathetic dystrophy in children is a self-limiting condition which usually responds well to mild analgesics and physical therapy. Frequently it may be necessary to administer the physical therapy in an intensive, inpatient program, both to break the pain-disability cycle and to remove the patient from a stressful family environment that may have initiated or prolonged the syndrome. The use of steroids (dexamethasone) had no appreciable effect on the clinical course in these children.

Three patients with cystic fibrosis were noted to have swelling of knee and ankle joints during exacerbation of their lung disease. Synovial fluid was analyzed in one patient and the synovium underwent biopsy in another. These studies excluded other causes of arthritis but did not contribute any new information on the nature of secondary hypertrophic osteoarthropathy. Radiological examination of long bones confirmed the diagnosis of hypertrophic osteoarthropathy in all three patients. Since many patients with cystic fibrosis survive longer, more instances of hypertrophic osteoarthropathy are expected in the future.

Pseudotumor cerebri is a clinical syndrome characterized by elevated intracranial pressure with normal biochemical and cellular characteristics of the cerebrospinal fluid and normal radiologic studies of the skull. This syndrome has been reported infrequently as a primary feature of central nervous system involvement by systemic lupus erythematosus (SLE). We report clinical features in 3 adolescent black females with pseudotumor cerebri as a presenting manifestation of SLE.

Standard scales were used to measure the reaction of the parent and family to long-term disability in a child in terms of family stress, both emotional and financial. The most significant factors that bear upon family impact were the level of education of the respondent, parenteral perception of the health of the child, and the number of limitations of activities of daily living that were experienced by that child.

Rheumatoid factor is commonly used by clinicians to assess children with possible juvenile rheumatoid arthritis. To assess its usefulness, we reviewed the case histories of patients in whom latex agglutinating rheumatoid factor was determined during 1981 to 1982 at our institution. A total of 437 charts were available for review. There were 11 patients with positive tests for rheumatoid factor, of whom five had juvenile rheumatoid arthritis, all polyarticular. A total of 426 children had negative results, of whom 100 had juvenile rheumatoid arthritis. This yields a sensitivity of 4.8% and a specificity of 98%. We then estimated the prevalence of juvenile rheumatoid arthritis in three clinical settings: a primary practitioner's office, a tertiary children's hospital walk-in clinic, and a pediatric rheumatology center. The predictive values and marginal benefits for rheumatoid factor were then calculated in those settings using Bayes' theorem. In the two general outpatient settings, the primary practitioner's office and tertiary walk-in clinic, the positive predictive values were 0.7% and 0.5%, respectively; marginal benefits were 0.4% and 0.3%, respectively. Rheumatoid factor testing appeared to be of some benefit in the pediatric rheumatology center with a positive predictive value of 72.5% and marginal benefit of 22.5%. In no case was rheumatoid factor testing helpful in establishing a diagnosis of juvenile rheumatoid arthritis or in ruling it out. Testing for rheumatoid factor is a poor screening procedure for juvenile rheumatoid arthritis in the general situations in which it is more likely to be requested and of supportive diagnostic value only in the highly restricted population of older children with polyarticular arthritis.

Three siblings with a recently recognized form of familial arthropathy were studied clinically and by light and electron microscopy of the synovium. On light microscopy, the synovium from all 3 children showed synovial hyperplasia, necrotic villi, deposition of eosinophilic and PAS-positive material, and large numbers of multinucleated giant cells. Electron microscopy of the synovium in one patient revealed giant cells with profuse rough and smooth endoplasmic reticulum. Some phagocytic cells contained degenerated collagen in vacuoles or invaginations. There was granular and fibrinlike material on the synovial surface, but no amyloid. This symmetrical arthropathy now reported in three families appears to have characteristic histological appearance of synovium that allows its identification as distinct from other known joint diseases.