Juvenile Fibromyalgia: A Primary Pain, or Pain Processing, Disorder.

Juvenile fibromyalgia (JFM), a chronic disorder of widespread musculoskeletal pain in combination with autonomic, sensory, and cognitive dysfunction, is responsible for considerable morbidity and impaired quality of life in affected patients and their families. Historically, fibromyalgia has been incorrectly characterized as a psychosomatic or psychogenic disorder, but new understanding of the science of pain has demonstrated unambiguously that it is an organic disorder of the pain processing system itself. This new science provides a framework for understanding the pathophysiology of fibromyalgia and for developing rational therapeutic interventions. Advances in JFM include the verification of adult criteria for diagnosis in pediatric patients and the publication of effective therapies based on cognitive and physical neuromuscular intervention. Although primarily nonpharmacologic therapy can include adjunctive medications as well. Finally, the recognition that JFM is a disorder of the central and peripheral nervous systems suggests that neurologists can be important in the care of these patients.

Novel method to collect medication adverse events in juvenile arthritis: results from the childhood arthritis and rheumatology research alliance enhanced drug safety surveillance project.

OBJECTIVE: Few data are available regarding the rates of serious adverse events (SAEs) and important medical events (IMEs) outside of product-based registries and clinical trials for juvenile idiopathic arthritis (JIA). The Enhanced Drug Safety Surveillance Project (EDSSP) was developed to pilot a novel system to collect SAEs/IMEs in children with JIA. This analysis reports the results from this 4-year (2008-2012) EDSSP. METHODS: Participating physicians were surveyed monthly to ascertain whether their JIA patients experienced an SAE or IME. Sites were surveyed every 6 months to determine the number of unique JIA patients seen at each site during that 6-month period. Reporting rates were calculated per 100 person-years and 95% confidence intervals (95% CIs) were calculated based on a Poisson distribution. RESULTS: Thirty-seven Childhood Arthritis and Rheumatology Research Alliance sites with 115 physicians participated. The mean response rate to the monthly surveys was 65%. There were 147 total SAEs and 145 total IMEs. The largest proportion of SAEs and IMEs occurred in children with polyarticular JIA (39% and 37%, respectively). The majority of SAEs and IMEs were reported for patients receiving therapy with biologic agents (76% and 69%, respectively). The total event rate for SAEs and IMEs combined was 1.07 events per 100 person-years (95% CI 0.95-1.19). The rates for SAEs and IMEs were 0.54 per 100 person-years (95% CI 0.45-0.63) and 0.53 per 100 person-years (95% CI 0.49-0.62), respectively. CONCLUSION: The EDSSP provided a simple tool for SAE/IME reporting within an established research network and resulted in a similar range of reported events as captured by a traditional product-based registry.

Pulmonary hypertension and other potentially fatal pulmonary complications in systemic juvenile idiopathic arthritis.

OBJECTIVE: Systemic juvenile idiopathic arthritis (JIA) is characterized by fevers, rash, and arthritis, for which interleukin-1 (IL-1) and IL-6 inhibitors appear to be effective treatments. Pulmonary arterial hypertension (PAH), interstitial lung disease (ILD), and alveolar proteinosis (AP) have recently been reported with increased frequency in systemic JIA patients. Our aim was to characterize and compare systemic JIA patients with these complications to a larger cohort of systemic JIA patients. METHODS: Systemic JIA patients who developed PAH, ILD, and/or AP were identified through an electronic Listserv and their demographic, systemic JIA, and pulmonary disease characteristics as well as their medication exposure information were collected. Patients with these features were compared to a cohort of systemic JIA patients enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) registry. RESULTS: The patients (n = 25) were significantly (P < 0.05) more likely than the CARRA registry cohort (n = 389) to be female; have more systemic features; and have been exposed to an IL-1 inhibitor, tocilizumab, corticosteroids, intravenous immunoglobulin, cyclosporine, and cyclophosphamide. Twenty patients (80%) were diagnosed with pulmonary disease after 2004. Twenty patients (80%) had macrophage activation syndrome (MAS) during their disease course and 15 patients (60%) had MAS at pulmonary diagnosis. Sixteen patients had PAH, 5 had AP, and 7 had ILD. Seventeen patients (68%) were taking or recently discontinued (<1 month) a biologic agent at pulmonary symptom onset; 12 patients (48%) were taking anti-IL-1 therapy (primarily anakinra). Seventeen patients (68%) died at a mean of 10.2 months from the diagnosis of pulmonary complications. CONCLUSION: PAH, AP, and ILD are underrecognized complications of systemic JIA that are frequently fatal. These complications may be the result of severe uncontrolled systemic disease activity and may be influenced by medication exposure.

Concomitant thrombotic thrombocytopenic purpura and ANCA-associated vasculitis in an adolescent.

Thrombotic thrombocytopenic purpura (TTP) rarely occurs with systemic vasculitis. A 17-year-old girl presented with non-bloody diarrhea, menorrhagia, and syncope. She had severe anemia (hemoglobin = 3.8 g/dl), thrombocytopenia (platelet = 7,000/mm(3)), and acute kidney injury (serum creatinine, Cr = 2.3 mg%). Peripheral smear examination confirmed the presence of microangiopathic hemolytic anemia. Additionally, she had a positive anti-nuclear antibody (1:1600) and normal complement levels. We considered the diagnosis of TTP, possibly associated with systemic lupus erythematosus, and promptly initiated pulse methylprednisolone and daily 3-4 l of plasma exchange therapy. Following resolution of her thrombocytopenia in 48 h, we performed a kidney biopsy that revealed diffuse proliferative, focal crescentic, and necrotizing glomerulonephritis with mild IgG immunofluorescence staining. Concomitantly, autoimmune work-up was significant for positive perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA = 1:640) and decreased von Willebrand factor cleaving protease activity (<5%). A final diagnosis of TTP with microscopic polyangiitis (p-ANCA-mediated) was made and treatment with daily oral cyclophosphamide and prednisone resolved her renal injury over 2 months (follow-up Cr = 1.0 mg%). Our case highlights the importance of identifying systemic disorders such as ANCA-associated vasculitis with TTP.

Soluble adhesion molecules in pediatric rheumatic diseases.

OBJECTIVE: To determine serum levels of adhesion molecules ICAM-1, ICAM-3, VCAM-1, L-selectin, and E-selectin in children with a variety of pediatric rheumatic diseases and investigate their relationship to clinical disease activity. METHODS: Retrospective review of records of 18 children with rheumatic diseases who had banked sera available for study. Eight children had systemic lupus erythematosus (SLE), 2 mixed connective tissue disease, 4 dermatomyositis (DM), and 4 various forms of vasculitis. Levels of the soluble adhesion molecules were determined by sandwich ELISA. Levels were compared among patients with the various diagnoses and between patients with active vs inactive disease. Levels were also correlated with erythrocyte sedimentation rate in all patients; C3, C4, and total hemolytic complements and anti-dsDNA antibodies in SLE; and creatine phosphokinase, aldolase, and von Willebrand factor (vWF) antigen levels in DM. Levels also correlated with disease activity scores, which varied by diagnosis. RESULTS: A trend toward higher levels of sE-selectin was found in vasculitis vs other diagnoses (p = 0.08). sICAM-1 was higher in patients with active vs inactive disease (p = 0.05) across all diagnoses. L-selectin levels correlated with C4 complement levels in SLE patients (r = 0.76, p = 0.03), and there was a trend toward an inverse correlation between levels of sE-selectin and vWF (r = -0.93, p = 0.08). There was no direct correlation of the adhesion molecule levels with any of the disease activity scores. CONCLUSION: The small number of patients and retrospective design of this study mean that any results must be interpreted with caution. We conclude: (1) Elevated E-selectin levels in vasculitis likely reflect the high degree of endothelial activation and possibly overt vascular damage in those conditions. (2) The correlation of sL-selectin with C4 in SLE may indicate that downregulation of shedding of cell surface L-selectin is involved in continued adherence of leukocytes to endothelium, possibly causing further damage and immune complex deposition in this condition. (3) The trend toward inverse correlation between sE-selectin and vWF:Ag in DM is curious, but may show that the role of endothelium in the pathophysiology of this disease is different from those such as vasculitis. (4) Levels of sICAM- I may be a useful marker of active vs quiescent disease in general in the pediatric rheumatic diseases, although lack of correlation with disease activity indices may indicate that it is too insensitive to smaller differences in disease activity to be recommended for routine clinical use.