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.

Psychologic aspects of childhood reflex neurovascular dystrophy.

Psychosocial factors in 21 families with children affected by reflex neurovascular dystrophy were studied. Each family was interviewed and given a battery of standardized psychologic tests. Two distinct types of families were identified. Fifteen families showed high internal cohesion, expressiveness, and organization and low levels of conflict. Six families showed high overt conflict with low levels of family cohesion, expressiveness, and organization. In all families parental enmeshment with the patient was present. Marital discord was present in 12 families. Thirteen patients had significant school problems (ten had learning disabilities). Although most of the children were described as especially bright, only four had above average intelligence test scores. Four had a history of sexual abuse. The patients and their mothers perceived the health problem as significantly worse than did children with arthritis from whom similar scores had been obtained. Possible role models with similar symptoms were reported by ten patients. These data support the concept that childhood reflex neurovascular dystrophy is frequently a stress-related disease; the therapeutic approach to treating these children and their families must take these psychosocial factors into account.

Transient thrombocytopenia in systemic onset juvenile rheumatoid arthritis.

Three children have been presented who have had long-standing, typical systemic juvenile rheumatoid arthritis. They also had a transient illness with thrombocytopenia, antiplatelet antibodies, and the simultaneous appearance of anti-DNA antibodies and hypocomplementemia. Other single abnormalities included the development of a positive ANA, Coombs, and lupus bands test. All responded to high-dose steroid therapy. Their similar clinical and serologic findings are noteworthy and represent one of the numerous complications seen in patients with systemic juvenile rheumatoid arthritis.

Psychosomatic musculoskeletal pain in childhood: clinical and psychological analyses of 100 children.

The clinical and psychological findings on 100 children with psychosomatic musculoskeletal pain seen at a major pediatric rheumatology referral center are reported. Most (76%) were female, median age was 13 years, and median duration of symptoms was 1 year. Multiple painful sites were common (66%). The pain was constant (63%) or intermittent (37%); 45% had hyperesthesia, and almost all maintained a cheerful affect when complaining of severe pain. Two predominant abnormal family milieu were seen. One was cohesive, stable, and organized, but intolerant of separation and individuation. The other was chaotic, emotionally unsupportive, with high levels of conflict. Members of the cohesive family type reported significantly less distress than members of chaotic families. Enmeshment between mother and child was common in both family types. Although frequently viewed as bright, most of these children had normal intelligence, and some had unrecognized academic difficulty. These children, compared with those with arthritis, had a significantly lower global well-being score. Clinical depression was unusual (11%). Most (97%) responded favorably to intensive physical and occupational therapy along with individual or family psychotherapy; 78% become symptom free or fully functional. Children with these signs and symptoms should have full psychological evaluations and respond well to treatment directed toward decreasing pain and restoring function.

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.

Autoantibody production in Kawasaki syndrome.

Although a variety of autoantibodies are produced in patients with Kawasaki syndrome (KS), their specificities in many instances are controversial and their role in disease pathogenesis is undetermined. Autoantibody production was studied in 14 patients with Kawasaki syndrome (KS). Antibodies to myeloperoxidase (MPO), the dominant antigen responsible for perinuclear antineutrophil cytoplasmic antibody (pANCA) reactivity, were detected by ELISA in 73% of acute phase and 89% of convalescent phase KS specimens, in contrast to 4% of normal adult control subjects (p < 0.002 and p < 0.001, respectively). MPO and cytoplasmic antineutrophil antibody (cANCA) levels measured by ELISA were significantly elevated above levels for adult normal control subjects (p < 0.005 and p < 0.01, respectively), but not above recently ill childhood controls. Among patients who developed a positive ANCA, antibody titers tended to rise in serial specimens despite clinical improvement. Antibodies to myocardial muscle, cardiac perimysial connective tissue, nuclear antigens (ANA), and smooth muscle were also detected in some KS patients, but titers did not differ significantly from control patients. Autoantibody results were not predictive of patients with echocardiographic abnormalities.

Stroke and mixed connective tissue disease.

We describe the clinical presentation and course of two girls with cerebrovascular disease and mixed connective tissue disease. One developed rapid onset hemiparesis and aphasia secondary to left internal carotid artery occlusion. She experienced a complete recovery after treatment with prednisone and cyclophosphamide. The other patient was diagnosed as having mixed connective tissue disease but had acute neurologic deterioration. She died due to an intracerebral hemorrhage. Autopsy demonstrated small-vessel fibrinoid necrosis. Although cerebrovascular disease secondary to central nervous system vasculitis is a manifestation of systemic lupus erythematosus, this is the first description of cerebrovascular disease as a primary sign in mixed connective tissue disease. These cases demonstrate the range of cerebrovascular disease observed in children with mixed connective tissue disease.

Childhood polymyositis as a paraneoplastic phenomenon.

Childhood polymyositis and dermatomyositis are rare conditions that are not generally associated with malignancy even though an association between adult-onset and malignancy has been reported. A child is presented with typical polymyositis in whom an immunoblastic sarcoma subsequently became manifest; the literature also is reviewed concerning the association between malignancy and these childhood conditions.

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.

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.

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.

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.

Preliminary report of higher dose methotrexate treatment in juvenile rheumatoid arthritis.

Methotrexate (MTX) is widely used to treat juvenile rheumatoid arthritis (JRA). Although most patients respond to lower doses (0.15-0.5 mg/kg/wk), some patients have required higher doses of MTX to control their arthritis. Thirteen children were treated with MTX 0.82-1.1 mg/kg/wk for 2-26 months. Although all children initially responded (> 50% improvement in joint index, erythrocyte sedimentation rate, morning stiffness and global evaluation), 4 patients discontinued treatment because of side effects or lack of prolonged efficacy. Five patients have continued taking higher dose MTX for 4-26 months, while 4 other patients have been able to decrease their MTX dose and maintain improvement. Twenty-four hour MTX levels were done on all patients at initiation of higher dose MTX and all cleared MTX well. Our report suggests that MTX in doses of 0.82-1.1 mg/kg/wk can successfully treat active synovitis in some children with severe JRA with few short term toxicities. Longterm use at these doses has not been studied and thus its safety is not known.

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.