Use of atorvastatin in systemic lupus erythematosus in children and adolescents.

OBJECTIVE: Statins reduce atherosclerosis and cardiovascular morbidity in the general population, but their efficacy and safety in children and adolescents with systemic lupus erythematosus (SLE) are unknown. This study was undertaken to determine the 3-year efficacy and safety of atorvastatin in preventing subclinical atherosclerosis progression in pediatric-onset SLE. METHODS: A total of 221 participants with pediatric SLE (ages 10-21 years) from 21 North American sites were enrolled in the Atherosclerosis Prevention in Pediatric Lupus Erythematosus study, a randomized double-blind, placebo-controlled clinical trial, between August 2003 and November 2006 with 36-month followup. Participants were randomized to receive atorvastatin (n=113) or placebo (n=108) at 10 or 20 mg/day depending on weight, in addition to usual care. The primary end point was progression of mean-mean common carotid intima-media thickening (CIMT) measured by ultrasound. Secondary end points included other segment/wall-specific CIMT measures, lipid profile, high-sensitivity C-reactive protein (hsCRP) level, and SLE disease activity and damage outcomes. RESULTS: Progression of mean-mean common CIMT did not differ significantly between treatment groups (0.0010 mm/year for atorvastatin versus 0.0024 mm/year for placebo; P=0.24). The atorvastatin group achieved lower hsCRP (P=0.04), total cholesterol (P<0.001), and low-density lipoprotein (P<0.001) levels compared with placebo. In the placebo group, CIMT progressed significantly across all CIMT outcomes (0.0023-0.0144 mm/year; P<0.05). Serious adverse events and critical safety measures did not differ between groups. CONCLUSION: Our results indicate that routine statin use over 3 years has no significant effect on subclinical atherosclerosis progression in young SLE patients; however, further analyses may suggest subgroups that would benefit from targeted statin therapy. Atorvastatin was well tolerated without safety concerns.

Laboratory markers of cardiovascular risk in pediatric SLE: the APPLE baseline cohort.

As part of the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) Trial, a prospective multicenter cohort of 221 children and adolescents with systemic lupus erythematosus (SLE) (mean age 15.7 years, 83% female) underwent baseline measurement of markers of cardiovascular risk, including fasting levels of high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TG), lipoprotein A (Lpa), homocysteine and high-sensitivity C-reactive protein (hs-CRP). A cross-sectional analysis of the baseline laboratory values and clinical characteristics of this cohort was performed. Univariable relationships between the cardiovascular markers of interest and clinical variables were assessed, followed by multivariable linear regression modeling. Mean levels of LDL, HDL, Lpa, TG, hs-CRP and homocysteine were in the normal or borderline ranges. In multivariable analysis, increased Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), prednisone dose, and hypertension (HTN) were independently associated with higher LDL levels. Higher hs-CRP and creatinine clearance were independently related to lower HDL levels. Higher body mass index (BMI), prednisone dose, and homocysteine levels were independently associated with higher TG levels. Only Hispanic or non-White status predicted higher Lpa levels. Proteinuria, higher TG and lower creatinine clearance were independently associated with higher homocysteine levels, while use of multivitamin with folate predicted lower homocysteine levels. Higher BMI, lower HDL, and longer SLE disease duration, but not SLEDAI, were independently associated with higher hs-CRP levels. The R(2) for these models ranged from 7% to 23%. SLE disease activity as measured by the SLEDAI was associated only with higher LDL levels and not with hs-CRP. Markers of renal injury (HTN, proteinuria, and creatinine clearance) were independently associated with levels of LDL, HDL, and homocysteine, highlighting the importance of renal status in the cardiovascular health of children and adolescents with SLE. Future longitudinal analysis of the APPLE cohort is needed to further examine these relationships.

Usage of intra-articular corticosteroid injections for the treatment of juvenile idiopathic arthritis: a survey of pediatric rheumatologists in the United States and Canada.

OBJECTIVE: To characterize the current usage of intra-articular corticosteroid injections (IACI) by pediatric rheumatologists and the perceived disadvantages of and obstacles to IACI therapy. METHODS: We mailed a 32-item questionnaire to pediatric rheumatologists in the United States and Canada (n=201) to assess treatment strategies for the initial treatment of monoarthritis of the knee in juvenile idiopathic arthritis (JIA). Information regarding the usage of IACI for all patients with JIA and physicians' perceptions of IACI therapy was obtained. Respondents were dichotomized into those who performed frequent pediatric IACI (greater than 50 IACI in the last 12 months) and those who did not. RESULTS: One hundred and twenty-nine (64%) completed questionnaires were returned. IACI were recommended as one therapy for JIA by 99% of respondents, and 90% personally perform IACI. Frequent IACI were performed by 22%, and 15% had performed greater than 10 IACI in a single pediatric patient at one time. Those who did not perform frequent IACI were more likely to report concern about the pain of the procedure, the availability of nursing support, and their own comfort with performing the procedure; they were less likely to have performed greater than 20 pediatric IACI during fellowship training and evaluated fewer clinic patients per week. CONCLUSION: IACI are essentially universally recommended in the treatment regimen for JIA. However, there are differences in the usage of IACI among pediatric rheumatologists. The frequency of IACI use is associated with different perceptions of and training received in IACI therapy.

Polyarthritis in a child with Rosai-Dorfman disease.

A 5-year-old boy presented with fever, rash, lymphadenopathy and polyarthritis. Systemic onset juvenile idiopathic arthritis was initially considered in the differential diagnosis, but lymph node biopsy established the diagnosis of Rosai-Dorfman disease (RDD). The arthritis recurred twice. Both times it correlated with the severity of the other clinical and laboratory abnormalities of RDD and responded to treatment with dexamethasone and vinblastine. This report adds inflammatory arthritis to the extranodal manifestations of RDD in children and suggests that this disorder should be considered as a rare cause of fever with rash, lymphadenopathy and arthritis.

Pain syndromes in children.

The pediatric rheumatologist cares for children who may have a wide variety of causes of musculoskeletal pain. These include such diverse conditions as arthritis, low-back pain, hypermobility, metabolic bone pain, and amplified pain syndromes such as complex regional pain syndrome and fibromyalgia. This review examines the recent literature on these and other conditions causing musculoskeletal pain in children and adolescents. Overall, headway is being made, but differentiating soma from psyche remains a problem. This is perhaps due to the marked and unique effect pain brings to each of us. Children are different from adults in causes, presentations, and outcome. Vigilance in history, physical examination, and judicious use of laboratory investigations are usually sufficient in establishing a diagnosis, as well as an appreciation for the variety of presentations each condition can manifest.

Family reinforcement of illness behavior: a comparison of adolescents with chronic fatigue syndrome, juvenile arthritis, and healthy controls.

Parental encouragement of illness behavior is hypothesized to correlate with psychosocial dysfunction in adolescents with chronic illness. To explore this hypothesis, adolescents aged 11 to 17 years with chronic fatigue syndrome (CFS) (n = 10), juvenile rheumatoid arthritis (JRA) (n = 16), and healthy adolescents (n = 14) were recruited for the study. Measures included the Achenbach parent and youth self report forms, the Family Adaptability and Cohesion Evaluation Scale-II (FACES II), the Children's Depression Rating Scale, and number of days absent from school. The Illness Behavior Encouragement Scale (IBES) generated measures of parental reinforcement of illness behavior. As predicted, the teens with CFS scored statistically higher on measures of depression, total competence, and number of days of school missed in the previous 6 months (mean = 40). Children with JRA scored significantly lower than the CFS group on the measure of parental reinforcement of illness behavior. The healthy group produced intermediate scores. Results and implications for future clinical and research activity are discussed.

Initial intravenous gammaglobulin treatment failure in Kawasaki disease.

OBJECTIVES: To determine initial intravenous gammaglobulin (IVIG) treatment failures in Kawasaki disease (KD) and to report the outcome of retreatment and our use of pulse intravenous (IV) methylprednisolone and cyclophosphamide in patients with persistent KD. STUDY DESIGN: Retrospective analysis of the treatment and response of children with KD over 3 years. RESULTS: Fifty (77%) of 65 patients completely responded to a single treatment with IVIG (2 g/kg). Fifteen patients (23%) required retreatment; 10 patients fully responded but 5 had persistent disease (3 developed coronary aneurysms and 4 developed coronary artery thrombosis). Four of these 5 patients with persistent disease were treated with pulse IV methylprednisolone and 2 were also treated with IV cyclophosphamide. There was no progression of coronary aneurysms and no deaths. No initial patient characteristics predicted IVIG treatment failure or the development of coronary aneurysms. CONCLUSION: Nearly 23% of patients with KD may require retreatment and 8% may develop coronary aneurysm. Additional antiinflammatory therapy, such as IV methylprednisolone and IV cyclophosphamide, may be helpful in treating persistent KD.

An overview of amplified musculoskeletal pain syndromes.

Children may have a wide variety of amplified musculoskeletal pain syndromes that may or may not be associated with overt autonomic signs and may be diffuse or localized to one body part. It is most common in pre- to adolescent girls. Hallmarks of the diagnosis include increasing pain over time, allodynia, an incongruent affect, disproportional dysfunction, and the absence of other causes. Psychological distress within the child or family is apparent in most, but not all, since it also is associated with injury or illness. Once the diagnosis is established, all medicines and testing are stopped. A sympathetically driven pain model is used to explain the pain to make it understandable. Treatment is an intense exercise program; ours is 5 hours daily. We focus on functional aerobic training specifically using the involved body part such as sports related drills, running, play activities, and swimming. Allodynia is treated with desensitization such as towel rubbing. A psychological evaluation is done and specific psychotherapy is recommended if indicated. The average duration of the daily program is 2 weeks with a 1 hour home program being done for another 2 to 8 weeks. After one month roughly 80% of the children have no pain and are fully functional, another 15% are fully functional with mild or recurrent pain; 5% are not better. Significant relapses are infrequent; 15% require retreatment. Five to 10% of the children will develop a different symptom of psychological distress. At 5 years, 90% are doing well.

Episcleritis in childhood.

OBJECTIVE: To describe the characteristics and systemic disease associations of episcleritis in childhood. DESIGN: Retrospective, observational case series. PARTICIPANTS: Twelve children diagnosed with episcleritis between July 1981 and June 1998. METHODS/TESTING: Complete eye and systemic evaluations. MAIN OUTCOME MEASURES: Characteristics of episcleritis and presence and nature of concurrent systemic disease. RESULTS: The 12 children (10 boys and 2 girls) ranged in age from 13 months to 16 years. Five children had bilateral simple episcleritis, one had bilateral nodular episcleritis, and six had unilateral simple episcleritis. The eye examination was otherwise normal and recovery was uneventful in all cases. Six of the nine children older than 5 years of age had one of the following rheumatologic diseases: systemic lupus erythematosus, juvenile rheumatoid arthritis, spondyloarthropathy, inflammatory bowel disease, rheumatic fever, or polyarteritis nodosa. All three children younger than 5 years of age had simple episcleritis, an antecedent viral illness, and presented within 2 months of each other. CONCLUSIONS: Episcleritis is a rare occurrence in childhood, especially in children younger than 5 years of age. In older children, it is frequently associated with rheumatologic disease.

Prevention of leg length discrepancy in young children with pauciarticular juvenile rheumatoid arthritis by treatment with intraarticular steroids.

OBJECTIVE: To determine if intraarticular (i.a.) injection of triamcinolone hexacetonide (steroids) used early in the course of pauciarticular juvenile rheumatoid arthritis (pauci JRA) is associated with less leg length discrepancy (LLD) or thigh circumference discrepancy (TCD). METHODS: Children with pauci JRA who had asymmetric lower-extremity arthritis diagnosed before age 7 years in Seattle, Washington (WA; n = 16) and in Chapel Hill and Durham, North Carolina (NC; n = 14) were retrospectively identified. WA children were given i.a. steroids within 2 months of diagnosis; the injections were repeated if synovitis recurred in the same joint or in a different joint. These children were compared with NC children who were not treated with i.a. steroids. Thigh circumference was measured at 10 cm above the patella, and leg length was measured from the anterior superior iliac spine to the mid-medial malleolus, by a single observer. LLD and TCD are reported as the percentage of difference between leg measurements in each subject. RESULTS: The WA and NC subjects had comparable disease severity and duration of followup (in months). Twelve WA children had subsequent i.a. steroid injections (mean 3.25 injections per child over mean +/- SD 42 +/- 11 months). The WA subjects had significantly less LLD (P = 0.005, by Student's 2-sided t-test) and prescriptions for shoe lifts (P = 0.002, by Fisher's 2-sided exact test). There was not a significant difference in TCD between the 2 groups (P = 0.139, by Student's 2-sided t-test). Similar findings were obtained when the analysis was limited to children with monarticular knee arthritis. CONCLUSION: Early and continued use of i.a. steroids may be associated with less LLD in young children with pauci JRA. This may indicate decreased duration of synovitis.

Short- and long-term outcomes of children with complex regional pain syndrome type I treated with exercise therapy.

OBJECTIVE: To report the initial and long-term outcome after an intensive exercise therapy program for childhood complex regional pain syndrome, type I (CRPS). DESIGN: Prospective follow-up. SETTING: A children's hospital. SUBJECTS: We followed 103 children (87 girls; mean age = 13.0 years) with CRPS. Forty-nine subjects were followed for more than 2 years (mean = 5 years 3 months). INTERVENTIONS: An intensive exercise program (most received a daily program of 4 hours of aerobic, functionally directed exercises, 1-2 hours of hydrotherapy, and desensitization). No medications or modalities were used. All had a screening psychological evaluation, and 79 (77%) were referred for psychological counseling. MAIN OUTCOME MEASURES: Outcomes included pain, presence of physical dysfunction, or recurrent episodes of CRPS or other disproportional musculoskeletal pain. RESULTS: The mean duration of exercise therapy was 14 days, but over the past 2 years has decreased to 6 days. Ninety-five children (92%) initially became symptom free. Of those followed for more than 2 years, 43 (88%) were symptom free (15, or 31 %, of these patients had had a reoccurrence), 5 (10%) were fully functional but had some continued pain, and 1 (2%) had functional limitations. The median time to recurrence was 2 months; 79% of the recurrences were during the first 6 months after treatment. CONCLUSION: Intense exercise therapy is effective in initially treating childhood CRPS and is associated with low rate of long-term symptoms or dysfunction.

Current treatment by United States and Canadian pediatric rheumatologists.

OBJECTIVE: To determine current treatment practices for 11 selected pediatric rheumatic diseases. METHODS: A questionnaire was mailed to 224 US and Canadian physicians who were listed in membership directories that included pediatric rheumatologists. RESULTS: One hundred seventy-four questionnaires (78%) were returned. Board certified pediatricians accounted for 86% of respondents. Nonsteroidal antiinflammatory drugs were the most commonly used medicines for all forms of juvenile rheumatoid arthritis (JRA), seronegative enthesopathy and arthropathy syndrome (SEA), and Henoch-Schönlein purpura, whereas oral corticosteroids were most frequently used for systemic lupus erythematosus (SLE), juvenile dermatomyositis, polyarteritis nodosa, and sarcoidosis. Intraarticular corticosteroid injection was the second most common therapy for pauciarticular JRA, but methotrexate (MTX) was second for polyarticular and systemic onset forms of JRA, and sulfasalazine was second for SEA. For all diseases, MTX was administered orally roughly twice as often as subcutaneously. In treating SLE, cyclophosphamide was used more frequently than azathioprine, cyclosporin A, or intravenous immunoglobulin. CONCLUSION: The results from this survey should allow individual practitioners to compare their treatment patterns to pediatric rheumatologists in the US and Canada as a whole.

Joint distribution at presentation in children with pauciarticular arthritis.

The most frequently affected joints in 215 children with pauciarticular arthritis (fewer than 5 joints involved) were knees, ankles, fingers, toes, wrists, elbows, and hips, respectively. Antinuclear antibodies were present in 68% and uveitis in 16%. Small joint arthritis should alert the physician to the possibilities of pauciarticular arthritis.

Methotrexate for resistant chronic uveitis in children with juvenile rheumatoid arthritis.

We used low-dose methotrexate to treat seven children with juvenile rheumatoid arthritis-associated uveitis complicated by cataract and glaucoma or resistant to topical corticosteroid. The use of methotrexate decreased the severity of uveitis in six of seven patients and allowed for the discontinuation or reduction of corticosteroid drops.

Methotrexate-induced hypersensitivity pneumonitis in a child with juvenile rheumatoid arthritis.

Low-dose methotrexate, widely used for juvenile rheumatoid arthritis, has been reported to cause pneumonitis in adults. We report on methotrexate-induced hypersensitivity pneumonitis in a child with juvenile rheumatoid arthritis. Physicians should be aware of this rare complication.

Trial of intravenous pulse cyclophosphamide and methylprednisolone in the treatment of severe systemic-onset juvenile rheumatoid arthritis.

OBJECTIVE: Not uncommonly, some children with systemic-onset juvenile rheumatoid arthritis (JRA) have persistently active disease with joint destruction and profound growth delay despite maximum treatment with known medications. Based on previous observations of improvement in synovitis following intravenous (I.V.) cyclophosphamide (CYC) and methylprednisolone (MP) treatments, a group of children with severe systemic-onset JRA was treated in an attempt to control active synovitis and to allow tapering of corticosteroids. METHODS: Four patients with systemic-onset JRA were continued on a daily regimen of nonsteroidal antiinflammatory agents and prednisone, with a weekly subcutaneous dose of methotrexate (1 mg/kg). In addition, 1 patient continued receiving sulfasalazine and 1 patient remained on a regimen of sulfasalazine and hydroxychloroquine. Patients received 6-10 monthly treatments of I.V. CYC (500-1,000 mg/m2) and MP (30 mg/kg; 1 gm maximum) accompanied by I.V. mesna and large amounts of I.V. fluids. Subsequent treatments were given once every 2-3 months. RESULTS: After 12-20 I.V. pulses of CYC, all patients showed improvement, and 3 achieved remission of disease. All were able to discontinue corticosteroid use and all had an increase in linear growth. CONCLUSION: Monthly I.V. pulse CYC treatments can be useful to control disease in selected children with severe, destructive JRA.

Musculoskeletal pain in children.

Musculoskeletal pain in childhood due either to underlying known rheumatic diseases or to primary pain syndromes remains a subject infrequently studied in the past year. Fibromyalgia has received the most attention albeit mostly in adult populations. This review examines the recent literature regarding a variety of causes of childhood musculoskeletal pain.