Lung involvement in juvenile idiopathic inflammatory myopathy: A systematic review.

OBJECTIVE: Juvenile idiopathic inflammatory myopathies (JIIM) are a group of connective tissue disorders characterized by muscle inflammation and variable systemic involvement, including interstitial lung disease (ILD). Available data on JIIM-associated ILD are very limited. We performed a systematic review of the available clinical, laboratory, and radiological features of JIIM-associated ILD. METHODS: A systematic literature review was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS: A total of 90 patients were identified, of whom 77.8% had JDM, 10% amyopathic JDM, 7.8% anti-synthetase syndrome, 3.3% overlap syndrome, and 1.1% juvenile polymyositis. Anti-melanoma differentiation-associated gene 5 (MDA-5/CADM-140) was the most frequently reported myositis-specific antibody (32.2%). At diagnosis of ILD, 55.5% of patients had respiratory symptoms. Ground glass opacity was the most reported radiological feature (52.9%). Thirty-three % of patients developed rapidly progressive (RP) lung disease; 26.7% were admitted to the intensive care unit (ICU); 28.9% died; all deaths were due to ILD, with a median interval of 2 months (IQR 1.5-4.7) between the onset of respiratory symptoms and death. Patients admitted to the ICU and who died of ILD were more likely to be male, to have a rapidly progressive pattern, progression of radiological features, and a higher level of KL-6. CONCLUSIONS: MDA-5/CADM-14 is associated with RP-ILD. ILD is a rare but severe manifestation among the spectrum of systemic involvement associated with JIIM, with a high rate of ICU admission and mortality. Early recognition and aggressive treatment are needed to prevent a severe outcome.

International Consensus for the Dosing of Corticosteroids in Childhood-Onset Systemic Lupus Erythematosus With Proliferative Lupus Nephritis.

OBJECTIVE: To develop a standardized steroid dosing regimen (SSR) for physicians treating childhood-onset systemic lupus erythematosus (SLE) complicated by lupus nephritis (LN), using consensus formation methodology. METHODS: Parameters influencing corticosteroid (CS) dosing were identified (step 1). Data from children with proliferative LN were used to generate patient profiles (step 2). Physicians rated changes in renal and extrarenal childhood-onset SLE activity between 2 consecutive visits and proposed CS dosing (step 3). The SSR was developed using patient profile ratings (step 4), with refinements achieved in a physician focus group (step 5). A second type of patient profile describing the course of childhood-onset SLE for ≥4 months since kidney biopsy was rated to validate the SSR-recommended oral and intravenous (IV) CS dosages (step 6). Patient profile adjudication was based on majority ratings for both renal and extrarenal disease courses, and consensus level was set at 80%. RESULTS: Degree of proteinuria, estimated glomerular filtration rate, changes in renal and extrarenal disease activity, and time since kidney biopsy influenced CS dosing (steps 1 and 2). Considering these parameters in 5,056 patient profile ratings from 103 raters, and renal and extrarenal course definitions, CS dosing rules of the SSR were developed (steps 3-5). Validation of the SSR for up to 6 months post-kidney biopsy was achieved with 1,838 patient profile ratings from 60 raters who achieved consensus for oral and IV CS dosage in accordance with the SSR (step 6). CONCLUSION: The SSR represents an international consensus on CS dosing for use in patients with childhood-onset SLE and proliferative LN. The SSR is anticipated to be used for clinical care and to standardize CS dosage during clinical trials.

Intravenous administration of anakinra in children with macrophage activation syndrome.

BACKGROUND: Subcutaneous anakinra is an interleukin-1 inhibitor used to treat juvenile idiopathic arthritis. Recent reports suggest anakinra can be a valuable addition to the treatment of COVID-19 associated cytokine storm syndrome and the related multisystem inflammatory syndrome (MIS-C) in children. Herein, we describe our experience with intravenously administered anakinra. FINDINGS: 19 Patients (9 male) received intravenous (IV) anakinra for treatment of macrophage activation syndrome (MAS) secondary to systemic lupus erythematosus (SLE), systemic JIA (SJIA) or secondary hemophagocytic lymphohistiocytosis (sHLH). In most cases the general trend of the fibrinogen, ferritin, AST, and platelet count (Ravelli criteria) improved after initiation of IV anakinra. There were no reports of anaphylaxis or reactions associated with administration of IV anakinra. CONCLUSION: Intravenous administration of anakinra is an important therapeutic option for critically ill patients with MAS/HLH. It is also beneficial for those with thrombocytopenia, subcutaneous edema, neurological dysfunction, or very young, hospitalized patients who need multiple painful subcutaneous injections.

Risk factors associated with Pneumocystis jirovecii pneumonia in juvenile myositis in North America.

OBJECTIVES: Pneumocystis jirovecii pneumonia (PJP) is associated with significant morbidity and mortality in adult myositis patients; however, there are few studies examining PJP in juvenile myositis [juvenile idiopathic inflammatory myopathy (JIIM)]. The purpose of this study was to determine the risk factors and clinical phenotypes associated with PJP in JIIM. METHODS: An research electronic data capture (REDCap) questionnaire regarding myositis features, disease course, medications and PJP infection characteristics was completed by treating physicians for 13 JIIM patients who developed PJP (PJP+) from the USA and Canada. Myositis features and medications were compared with 147 JIIM patients without PJP (PJP-) from similar geographic regions who enrolled in National Institutes of Health natural history studies. RESULTS: PJP+ patients were more often of Asian ancestry than PJP- patients [odds ratio (OR) 8.7; 95% CI 1.3, 57.9]. Anti- melanoma differentiation associated protein 5 (MDA5) autoantibodies (OR 12.5; 95% CI 3.0, 52.4), digital infarcts (OR 43.8; 95% CI 4.2, 460.2), skin ulcerations (OR 12.0; 95% CI 3.5, 41.2) and interstitial lung disease (OR 10.6; 95% CI 2.1, 53.9) were more frequent in PJP+ patients. Before PJP diagnosis, patients more frequently received pulse steroids, rituximab and more immunosuppressive therapy compared with PJP- patients. Seven PJP+ patients were admitted to the intensive care unit and four patients died due to PJP or its complications. CONCLUSIONS: PJP is a severe infection in JIIM that can be associated with mortality. Having PJP was associated with more immunosuppressive therapy, anti-MDA5 autoantibodies, Asian race and certain clinical features, including digital infarcts, cutaneous ulcerations and interstitial lung disease. Prophylaxis for PJP should be considered in juvenile myositis patients with these features.

Simultaneous Presentation of Crohn's Disease and Takayasu Arteritis in a Teenage Patient.

A 14-year-old female with no significant medical history presented with hypertensive urgency, in the setting of 4 to 6 weeks of diarrhea, abdominal pain, headaches, anemia, weight loss, and high blood pressures. Her evaluation revealed signs of a systemic inflammatory process that was most suspicious for inflammatory bowel disease. However, when her hypertension was evaluated with a renal Doppler ultrasound, there were signs of narrowing, stenosis, and hypoplasia that led to a diagnostic angiogram of the abdominal aorta. Full body positron emission tomography scan revealed multiple areas of stenosis and aortic thickening with enhancement compatible with Takayasu arteritis. She received prednisone, methotrexate, and infliximab with marked improvement in her clinical symptoms and inflammatory markers.

Urine biomarkers of chronic kidney damage and renal functional decline in childhood-onset systemic lupus erythematosus.

OBJECTIVES: To delineate urine biomarkers that reflect kidney structural damage and predict renal functional decline in pediatric lupus nephritis (LN). METHODS: In this prospective study, we evaluated kidney biopsies and urine samples of 89 patients with pediatric LN. Urinary levels of 10 biomarkers [adiponectin, ceruloplasmin, kidney injury molecule-1, monocyte chemotactic protein-1, neutrophil gelatinase-associated lipocalin, osteopontin, transforming growth factor-ß (TGFß), vitamin-D binding protein, liver fatty acid binding protein (LFABP), and transferrin] were measured. Regression analysis was used to identify individual and combinations of biomarkers that determine LN damage status [NIH-chronicity index (NIH-CI) score ≤ 1 vs. ≥ 2] both individually and in combination, and biomarker levels were compared for patients with vs. without renal functional decline, i.e., a 20% reduction of the glomerular filtration rate (GFR) within 12 months of a kidney biopsy. RESULTS: Adiponectin, LFABP, and osteopontin levels differed significantly with select histological damage features considered in the NIH-CI. The GFR was associated with NIH-CI scores [Pearson correlation coefficient (r) = - 0.49; p < 0.0001] but not proteinuria (r = 0.20; p > 0.05). Similar to the GFR [area under the ROC curve (AUC) = 0.72; p < 0.01], combinations of osteopontin and adiponectin levels showed moderate accuracy [AUC = 0.75; p = 0.003] in discriminating patients by LN damage status. Renal functional decline occurred more commonly with continuously higher levels of the biomarkers, especially of TGFß, transferrin, and LFABP. CONCLUSION: In combination, urinary levels of adiponectin and osteopontin predict chronic LN damage with similar accuracy as the GFR. Ongoing LN activity as reflected by high levels of LN activity biomarkers heralds renal functional decline. KEY MESSAGES: • Levels of osteopontin and adiponectin measured at the time of kidney biopsy are good predictors of histological damage with lupus nephritis. • Only about 20% of children with substantial kidney damage from lupus nephritis will have an abnormally low urine creatinine clearance. • Continuously high levels of biomarkers reflecting lupus nephritis activity are risk factors of declining renal function.

Timing of infliximab and adalimumab initiation despite methotrexate in children with chronic non-infectious anterior uveitis.

AIMS: Methotrexate (MTX) is standard treatment in pediatric chronic anterior uveitis (CAU). Addition of tumor necrosis factor-α inhibitors (TNFi) is often needed. We describe the timing and risk factors for TNFi use in children with CAU on MTX. METHODS: In this retrospective study, we reviewed 51 records, and 46 met inclusion criteria. Primary outcome was the addition of TNFi due to active CAU per Standardization of Uveitis Nomenclature criteria. Time to TNFi and factors associated with their addition were assessed using survival analysis models. RESULTS: Of 46 children treated with MTX for uveitis (36 juvenile idiopathic arthritis-associated uveitis, 10 idiopathic CAU), 72% had ocular complications. MTX was started a median of 5.0 months, and TNFi 43 months from uveitis diagnosis. Kaplan-Meier estimates suggest that cumulatively, 12% (95% CI: 4-23%) start TNFi within 6 months of MTX, 21% (12-37%) within 1 year, and 39% (24-54%) within 2 years. On Cox Proportional Hazard regression analysis, children with idiopathic CAU required TNFi earlier in their uveitis course (at 3 months (Hazard Ratio 6.06; 95% confidence interval (1.25-29.41))). Females appeared less likely to require TNFi early. Children treated in 2012 and later were more likely to receive TNFi earlier than those treated before 2012. CONCLUSION: Little is known about optimal time to initiate treatment or factors associated with the need to add TNFi in children on MTX. Children with idiopathic CAU and males required TNFi earlier in their course. Factors associated with these potential risk factors for TNFi warrant further investigation.

Serum S100A8/A9 and S100A12 Levels in Children With Polyarticular Forms of Juvenile Idiopathic Arthritis: Relationship to Maintenance of Clinically Inactive Disease During Anti-Tumor Necrosis Factor Therapy and Occurrence of Disease Flare After Discontinuation of Therapy.

OBJECTIVE: To determine the relationship between serum levels of S100A8/A9 and S100A12 and the maintenance of clinically inactive disease during anti-tumor necrosis factor (anti-TNF) therapy and the occurrence of disease flare following withdrawal of anti-TNF therapy in patients with polyarticular forms of juvenile idiopathic arthritis (JIA). METHODS: In this prospective, multicenter study, 137 patients with polyarticular-course JIA whose disease was clinically inactive while receiving anti-TNF therapy were enrolled. Patients were observed for an initial 6-month phase during which anti-TNF treatment was continued. For those patients who maintained clinically inactive disease over the 6 months, anti-TNF was withdrawn and they were followed up for 8 months to assess for the occurrence of flare. Serum S100 levels were measured at baseline and at the time of anti-TNF withdrawal. Spearman's rank correlation test, Mann-Whitney U test, Kruskal-Wallis test, receiver operating characteristic (ROC) curve, and Kaplan-Meier survival analyses were used to assess the relationship between serum S100 levels and maintenance of clinically inactive disease and occurrence of disease flare after anti-TNF withdrawal. RESULTS: Over the 6-month initial phase with anti-TNF therapy, the disease state reverted from clinically inactive to clinically active in 24 (18%) of the 130 evaluable patients with polyarticular-course JIA; following anti-TNF withdrawal, 39 (37%) of the 106 evaluable patients experienced a flare. Serum levels of S100A8/A9 and S100A12 were elevated in up to 45% of patients. Results of the ROC analysis revealed that serum S100 levels did not predict maintenance of clinically inactive disease during anti-TNF therapy nor did they predict disease flare after treatment withdrawal. Elevated levels of S100A8/A9 were not predictive of the occurrence of a disease flare within 30 days, 60 days, 90 days, or 8 months following anti-TNF withdrawal, and elevated S100A12 levels had a modest predictive ability for determining the risk of flare within 30, 60, and 90 days after treatment withdrawal. Serum S100A12 levels at the time of anti-TNF withdrawal were inversely correlated with the time to disease flare (r = -0.36). CONCLUSION: Serum S100 levels did not predict maintenance of clinically inactive disease or occurrence of disease flare in patients with polyarticular-course JIA, and S100A12 levels were only moderately, and inversely, correlated with the time to disease flare.

Pilot study comparing the childhood arthritis and rheumatology research alliance consensus treatment plans for induction therapy of juvenile proliferative lupus nephritis.

BACKGROUND: To reduce treatment variability and facilitate comparative effectiveness studies, the Childhood Arthritis and Rheumatology Research Alliance (CARRA) published consensus treatment plans (CTPs) including one for juvenile proliferative lupus nephritis (LN). Induction immunosuppression CTPs outline treatment with either monthly intravenous (IV) cyclophosphamide (CYC) or mycophenolate mofetil (MMF) in conjunction with one of three corticosteroid (steroid) CTPs: primarily oral, primarily IV or mixed oral/IV. The acceptability and in-practice use of these CTPs are unknown. Therefore, the primary aims of the pilot study were to demonstrate feasibility of adhering to the LN CTPs and delineate barriers to implementation in clinical care in the US. Further, we aimed to explore the safety and effectiveness of the treatments for induction therapy. METHODS: Forty-one patients were enrolled from 10 CARRA sites. Patients had new-onset biopsy proven ISN/RPS class III or IV proliferative LN, were starting induction therapy with MMF or IV CYC and high-dose steroids and were followed for up to 24 months. Routine clinical data were collected at each visit. Provider reasons for CTP selection were assessed at baseline. Adherence to the CTPs was evaluated by provider survey and medication logs. Complete and partial renal responses were reported at 6 months. RESULTS: The majority of patients were female (83%) with a mean age of 14.7 years, SD 2.8. CYC was used more commonly than MMF for patients with ISN/RPS class IV LN (vs. class III), those who had hematuria, and those with adherence concerns. Overall adherence to the immunosuppression induction CTPs was acceptable with a majority of patients receiving the target MMF (86%) or CYC (63%) dose. However, adherence to the steroid CTPs was poor (37%) with large variability in dosing. Renal response endpoints were exploratory and did not show a significant difference between CYC and MMF. CONCLUSIONS: Overall, the immunosuppression CTPs were followed as intended in the majority of patients however, adherence to the steroid CTPs was poor indicating revision is necessary. In addition, our pilot study revealed several sources of treatment selection bias that will need to be addressed in for future comparative effectiveness research.

Risk, Timing, and Predictors of Disease Flare After Discontinuation of Anti-Tumor Necrosis Factor Therapy in Children With Polyarticular Forms of Juvenile Idiopathic Arthritis With Clinically Inactive Disease.

OBJECTIVE: To determine the frequency, time to flare, and predictors of disease flare upon withdrawal of anti-tumor necrosis factor (anti-TNF) therapy in children with polyarticular forms of juvenile idiopathic arthritis (JIA) who demonstrated ≥6 months of continuous clinically inactive disease. METHODS: In 16 centers 137 patients with clinically inactive JIA who were receiving anti-TNF therapy (42% of whom were also receiving methotrexate [MTX]) were prospectively followed up. If the disease remained clinically inactive for the initial 6 months of the study, anti-TNF was stopped and patients were assessed for flare at 1, 2, 3, 4, 6, and 8 months. Life-table analysis, t-tests, chi-square test, and Cox regression analysis were used to identify independent variables that could significantly predict flare by 8 months or time to flare. RESULTS: Of 137 patients, 106 (77%) maintained clinically inactive disease while receiving anti-TNF therapy for the initial 6 months and were included in the phase of the study in which anti-TNF therapy was stopped. Stopping anti-TNF resulted in disease flare in 39 (37%) of 106 patients by 8 months. The mean/median ± SEM time to flare was 212/250 ± 9.77 days. Patients with shorter disease duration at enrollment, older age at onset and diagnosis, shorter disease duration prior to experiencing clinically inactive disease, and shorter time from onset of clinically inactive disease to enrollment were found to have significantly lower hazard ratios for likelihood of flare by 8 months (P < 0.05). CONCLUSION: Over one-third of patients with polyarticular JIA with sustained clinically inactive disease will experience a flare by 8 months after discontinuation of anti-TNF therapy. Several predictors of lower likelihood of flare were identified.

Consensus Treatment Plans for Chronic Nonbacterial Osteomyelitis Refractory to Nonsteroidal Antiinflammatory Drugs and/or With Active Spinal Lesions.

OBJECTIVE: To develop standardized treatment regimens for chronic nonbacterial osteomyelitis (CNO), also known as chronic recurrent multifocal osteomyelitis (CRMO), to enable comparative effectiveness treatment studies. METHODS: Virtual and face-to-face discussions and meetings were held within the CNO/CRMO subgroup of the Childhood Arthritis and Rheumatology Research Alliance (CARRA). A literature search was conducted, and CARRA membership was surveyed to evaluate available treatment data and identify current treatment practices. Nominal group technique was used to achieve consensus on treatment plans for CNO refractory to nonsteroidal antiinflammatory drug (NSAID) monotherapy and/or with active spinal lesions. RESULTS: Three consensus treatment plans (CTPs) were developed for the first 12 months of therapy for CNO patients refractory to NSAID monotherapy and/or with active spinal lesions. The 3 CTPs are methotrexate or sulfasalazine, tumor necrosis factor inhibitors with optional methotrexate, and bisphosphonates. Short courses of glucocorticoids and continuation of NSAIDs are permitted for all regimens. Consensus was achieved on these CTPs among CARRA members. Consensus was also reached on subject eligibility criteria, initial evaluations that should be conducted prior to the initiation of CTPs, and data items to collect to assess treatment response. CONCLUSION: Three consensus treatment plans were developed for pediatric patients with CNO refractory to NSAIDs and/or with active spinal lesions. Use of these CTPs will provide additional information on efficacy and will generate meaningful data for comparative effectiveness research in CNO.

Urine Biomarkers to Predict Response to Lupus Nephritis Therapy in Children and Young Adults.

OBJECTIVE: To delineate urine biomarkers that forecast response to therapy of lupus nephritis (LN). METHODS: Starting from the time of kidney biopsy, patients with childhood-onset systemic lupus erythematosus who were diagnosed with LN were studied serially. Levels of 15 biomarkers were measured in random spot urine samples, including adiponectin, α-1-acid glycoprotein (AGP), ceruloplasmin, hemopexin, hepcidin, kidney injury molecule 1, monocyte chemotactic protein-1, lipocalin-like prostaglandin D synthase (LPGDS), transforming growth factor-ß (TGF-ß), transferrin, and vitamin D binding protein (VDBP). RESULTS: Among 87 patients (mean age 15.6 yrs) with LN, there were 37 treatment responders and 50 nonresponders based on the American College of Rheumatology criteria. At the time of kidney biopsy, levels of TGF-ß (p < 0.0001) and ceruloplasmin (p = 0.006) were significantly lower among responders than nonresponders; less pronounced differences were present for AGP, hepcidin, LPGDS, transferrin, and VDBP (all p < 0.05). By Month 3, responders experienced marked decreases of adiponectin, AGP, transferrin, and VDBP (all p < 0.01) and mean levels of these biomarkers were all outstanding (area under the receiver-operating characteristic curve ≥ 0.9) for discriminating responders from nonresponders. Patient demographics and extrarenal disease did not influence differences in biomarker levels between response groups. CONCLUSION: Low urine levels of TGF-ß and ceruloplasmin at baseline and marked reduction of AGP, LPGDS, transferrin, or VDBP and combinations of other select biomarkers by Month 3 are outstanding predictors for achieving remission of LN. If confirmed, these results can be used to help personalize LN therapy.

Validation of the Lupus Nephritis Clinical Indices in Childhood-Onset Systemic Lupus Erythematosus.

OBJECTIVE: To validate clinical indices of lupus nephritis activity and damage when used in children against the criterion standard of kidney biopsy findings. METHODS: In 83 children requiring kidney biopsy, the Systemic Lupus Erythematosus Disease Activity Index renal domain (SLEDAI-R), British Isles Lupus Assessment Group index renal domain (BILAG-R), Systemic Lupus International Collaborating Clinics (SLICC) renal activity score (SLICC-RAS), and SLICC Damage Index renal domain (SDI-R) were measured. Fixed effects and logistic models were calculated to predict International Society of Nephrology/Renal Pathology Society (ISN/RPS) class; low-to-moderate versus high lupus nephritis activity (National Institutes of Health [NIH] activity index [AI]) score: ≤10 versus >10; tubulointerstitial activity index (TIAI) score: ≤5 versus >5; or the absence versus presence of lupus nephritis chronicity (NIH chronicity index) score: 0 versus ≥1. RESULTS: There were 10, 50, and 23 patients with ISN/RPS class I/II, III/IV, and V, respectively. Scores of the clinical indices did not differentiate among patients by ISN/RPS class. The SLEDAI-R and SLICC-RAS but not the BILAG-R differed with lupus nephritis activity status defined by NIH-AI scores, while only the SLEDAI-R scores differed between lupus nephritis activity status based on TIAI scores. The sensitivity and specificity of the SDI-R to capture lupus nephritis chronicity was 23.5% and 91.7%, respectively. Despite being designed to measure lupus nephritis activity, SLICC-RAS and SLEDAI-R scores significantly differed with lupus nephritis chronicity status. CONCLUSION: Current clinical indices of lupus nephritis fail to discriminate ISN/RPS class in children. Despite its shortcomings, the SLEDAI-R appears best for measuring lupus nephritis activity in a clinical setting. The SDI-R is a poor correlate of lupus nephritis chronicity.

Development of a Novel Renal Activity Index of Lupus Nephritis in Children and Young Adults.

OBJECTIVE: Noninvasive estimation of the degree of inflammation seen on kidney biopsy with lupus nephritis (LN) remains difficult. The objective of this study was to develop a Renal Activity Index for Lupus (RAIL) that, based solely on laboratory measures, accurately reflects histologic LN activity. METHODS: We assayed traditional LN laboratory tests and 16 urine biomarkers (UBMs) in children (n = 47) at the time of kidney biopsy. Histologic LN activity was measured by the National Institutes of Health activity index (NIH-AI) and the tubulointerstitial activity index (TIAI). High LN-activity status (versus moderate/low) was defined as NIH-AI scores >10 (versus ≤10) or TIAI scores >5 (versus ≤5). RAIL algorithms that predicted LN-activity status for both NIH-AI and TIAI were derived by stepwise multivariate logistic regression, considering traditional biomarkers and UBMs as candidate components. The accuracy of the RAIL for discriminating by LN-activity status was determined. RESULTS: The differential excretion of 6 UBMs (neutrophil gelatinase-associated lipocalin, monocyte chemotactic protein 1, ceruloplasmin, adiponectin, hemopexin, and kidney injury molecule 1) standardized by urine creatinine was considered in the RAIL. These UBMs predicted LN-activity (NIH-AI) status with >92% accuracy and LN-activity (TIAI) status with >80% accuracy. RAIL accuracy was minimally influenced by concomitant LN damage. Accuracies between 71% and 85% were achieved without standardization of the UBMs. The strength of these UBMs to reflect LN-activity status was confirmed by principal component and linear discriminant analyses. CONCLUSION: The RAIL is a robust and highly accurate noninvasive measure of LN activity. The measurement properties of the RAIL, which reflect the degree of inflammatory changes as seen on kidney biopsy, will require independent validation.

Pilot study of etanercept in patients with refractory juvenile dermatomyositis.

OBJECTIVE: To evaluate the efficacy of etanercept in patients with juvenile dermatomyositis (DM) refractory to standard treatment. METHODS: Nine patients with juvenile DM prospectively received etanercept 0.4 mg/kg subcutaneous twice weekly concurrently with baseline medications for 12 weeks. Patients were reevaluated 12 weeks (week 24) after stopping etanercept. Outcome measures included a validated Disease Activity Score (DAS), serum muscle enzymes, Childhood Myositis Assessment Scale (CMAS), and nailfold capillaroscopy (NFC). RESULTS: Six patients completed all visits; 2 patients completed through week 12 and 1 patient stopped after the fifth etanercept dose due to marked worsening of a rash. At week 12, 7 patients had a mild decrease in DAS and 1 patient noted worsening of the DAS. At week 24, 1 patient remained stable, 2 patients had worsening of the DAS, and 3 patients had improvement of the DAS (1 patient with inactive disease), including the patient who worsened while receiving etanercept. This patient and the patient who stopped (worsening rash) both had the tumor necrosis factor α (TNFα) 308A allele. There was a trend of worsening NFC at week 12, while at week 24 improvement of NFC was noted. There was no appreciable change in serum muscle enzymes or CMAS throughout the study. CONCLUSION: In this trial of patients with refractory juvenile DM, etanercept did not demonstrate appreciable improvement and some patients noted worsening of disease. Caution should be taken when recommending TNF receptor inhibitors to patients with active symptoms of juvenile DM, and close followup is warranted. Further investigation of the interaction of the TNFα-308A polymorphism and type I interferon is needed to define the mechanism of TNF blockade in juvenile DM.

La crosse virus encephalitis preceding neurosarcoidosis diagnosed by brain biopsy.

Childhood neurosarcoidosis is rare, and its etiology is unknown. La Crosse virus is one of the most common causes of encephalitis in North America. We report the case of a 12-year-old boy who had La Crosse virus encephalitis and subsequently developed imaging and pathologic findings suggestive of neurosarcoidosis. He presented with acute onset of transient aphasia 4 months after an episode of encephalitis; serology results at the time of aphasia were positive for La Crosse virus. Brain MRI revealed diffuse subcortical nodular lesions. His serum angiotensin-converting enzyme level was elevated, and brain biopsy revealed noncaseating granuloma. It is interesting to note that he has had no recurrence of aphasia; repeat MRI showed significant improvement of nodular lesions without therapy. To our knowledge, this is the first case of La Crosse virus encephalitis associated with neurosarcoid findings.

RANKL:osteoprotegerin ratio and bone mineral density in children with untreated juvenile dermatomyositis.

OBJECTIVE: To determine bone mineral density (BMD) in patients at the time of diagnosis of juvenile dermatomyositis (DM), to compare the RANKL:osteoprotegerin (OPG) ratio in patients with juvenile DM with that in healthy control subjects, and to evaluate whether BMD is associated with the RANKL:OPG ratio and the duration of untreated disease. METHODS: Thirty-seven children with juvenile DM were enrolled. Dual x-ray absorptiometry (DXA) was performed before treatment, and Z scores for the lumbar spine (L1-L4) were determined. The duration of untreated disease was defined as the period of time from the onset of rash or weakness to the time at which DXA was performed. Serum specimens obtained at the time of DXA were analyzed for concentrations of RANKL and OPG, using enzyme-linked immunosorbent assay. The RANKL:OPG ratio was also determined in 44 age-matched healthy control subjects. RESULTS: At the time of diagnosis of juvenile DM, patients had a significantly increased RANKL:OPG ratio compared with that in healthy children (mean +/- SD 2.19 +/- 3.03 and 0.13 +/- 0.17, respectively; P < 0.0001). In patients with a lumbar spine BMD Z score of -1.5 or lower, the RANKL:OPG ratio was significantly higher than that in patients with a lumbar spine BMD Z score higher than -1.5 (P = 0.038). Lumbar spine BMD Z scores (mean +/- SD -0.13 +/- 1.19 [range -2.10 to 2.85]) were inversely associated with the duration of untreated disease (R = -0.50, P = 0.003). CONCLUSION: Children with juvenile DM have an elevated RANKL:OPG ratio at the time of diagnosis, resulting in expansion of the number of osteoclasts and activation of the bone resorptive function. This may lead to a lack of normal bone mineral accretion and a subsequent reduction in the lumbar spine BMD Z score. Patients with a longer duration of untreated juvenile DM have reduced lumbar spine BMD Z scores. These data suggest that early diagnosis could reduce the likelihood of reduced lumbar spine BMD in these patients by prompting intervention strategies at an early stage.

Catheter-related bacteremia due to Roseomonas species in pediatric hematology/oncology patients.

Roseomonas is a newly described genus of pink-pigmented, gram-negative bacteria. Human infections caused by Roseomonas species are very rare. We report two cases of central venous catheter-related bacteremia associated with Roseomonas species (one case with R. gilardii and one with R. fauriae), and review the clinical spectrum of previously reported cases in the literature. Clinicals should be aware that Roseomonas species may cause serious infections in children.

Bone health in pediatric rheumatic disease.

PURPOSE OF REVIEW: Children with chronic rheumatic disease have decreased bone mass. In adults, lowered bone mineral density is associated with increased fracture risk. This morbidity is undetermined in pediatric rheumatic disease as osteoporosis has not been well-defined in children. This review compares methods for determining bone mass in children, examines insights into molecular mechanisms of bone metabolism, and discusses the prevention and treatment of decreased bone mass in children. RECENT FINDINGS: Peak bone mass, attained during adolescence and early adulthood, is critical in determining fracture risk. Studies of children with chronic rheumatic disease demonstrate decreased bone mineral density, and potentially lowered peak bone mass. Dual energy x-ray absorptiometry is the most commonly used technique for monitoring bone mineral density and should be interpreted utilizing age-appropriate Z-scores. Recent studies suggest quantitative ultrasound may be as reliable as dual energy x-ray absorptiometry and lacks radiation exposure. The molecular mechanisms by which inflammation alters bone mineral density involve receptor activator of nuclear factor kappaB ligand (RANKL)/osteoprotegerin, tumor necrosis factor-alpha, and interleukin-1. Limited data on the use of bisphosphonates and calcitonin in children suggest they are safe and effective, but should be used cautiously. SUMMARY: Children with chronic rheumatic disease should have bone mass monitored by dual energy x-ray absorptiometry Z-scores. Targeting the RANKL/osteoprotegerin pathway may lead to therapies that improve bone health in this population. More studies on the role of bisphosphonates and calcitonin must be pursued to establish guidelines for use in pediatric patients with chronic rheumatic disease. For now, supplemental calcium and vitamin D should be implemented in these children.