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1.  Increased VCAM-1 Expression in Short Duration, Untreated Juvenile Dermatomyositis Muscle Biopsies is Regulated by miR-126 
Arthritis and rheumatism  2012;64(11):3809-3817.
To evaluate Juvenile Dermatomyositis (JDM) for duration of untreated disease (DUD) impact on: vascular cell adhesion molecule-1 (VCAM-1) and microRNA (miRNA) expression in muscle biopsy (MBx); soluble VCAM-1 (sVCAM-1) and TNF-α in sera.
Pediatric controls (n=8) and untreated JDM (n=28) enrolled. Short DUD (n=11, symptoms ≤2 months before MBx); long DUD (n=17, >2 months symptoms). Vascular structures, characterized by immunoflorescence using antibodies against von Willebrand factor (vWF), VCAM-1, and α-smooth muscle actin (SMA), were measured for total area (microns2) and intensity (pixels) (SlideBook 4.2). Circulating sVCAM-1 and TNF-α levels (Mesoscale) were determined (JDM [6 short, 8 long DUD], 5 controls). MiR-126 differential expression in JDM MBx ([3 long, 3 short DUD], 2 controls) was detected by Exiqon’s miRCURY microRNA Array, and confirmed (qRT-PCR) in JDM ([5 short, 5 long], 5 controls).
Short DUD JDM had higher total positive area (p=0.043) and intensity/high power field, (p=0.015) of VCAM-1 expression than long DUD JDM or controls (p=0.004, p=0.001 respectively). vWF:Ag+ vasculature displayed greater VCAM-1 intensity in short DUD compared to long DUD (p=0.001). Circulating sVCAM-1 and TNF-α were higher in JDM short DUD than controls (p=0.013, p=0.048 respectively). MiR-126, a negative regulator of VCAM-1 expression, was decreased by 3.39 fold, p=0.006 in controls vs. short DUD; for controls vs. long DUD, no significant difference (0.145 fold, p=0.548).
In short DUD, miR-126 downregulation is associated with increased VCAM-1 in both muscle and blood, suggesting that VCAM-1 plays a critical role early in JDM disease pathophysiology, augmented by TNF-α.
PMCID: PMC3469762  PMID: 22740338
2.  Methylation Alterations of WT1 and Homeobox Genes in Inflamed Muscle Biopsies from Untreated Juvenile Dermatomyositis Suggests Self-renewal Capacity 
Arthritis and rheumatism  2012;64(10):3478-3485.
To determine the impact of methylation alteration in inflamed muscles from children with Juvenile Dermatomyositis (JDM) and other Idiopathic Inflammatory Myopathies (IIM).
MRI-directed diagnostic muscle biopsies (MBx) from 20 JDM children and 4 healthy controls were used for genome-wide DNA methylation profiling (IRB# 200813457). Bisulfite pyrosequencing confirmed methylation status in JDM and other IIM. Immunohistochemistry defined localization and expression levels of WT1.
Comparison of genome-wide DNA methylation profiling between JDM and normal controls revealed 27 genes with significant methylation difference, enriched with transcription factors and cell cycle regulators, unrelated to duration of untreated disease. Six homeobox genes were among them: ALX4, HOXC11, HOXD3 and HOXD4 were hypomethylated; EMX2 and HOXB1 were hypermethylated. WT1 was significantly hypomethylated in JDM (Δβ = −0.41, p < 0.001). Bisulfite pyrosequencing verification in 56 JDM samples confirmed the methylation alterations of these genes. Similar methylation alterations were observed in Juvenile Polymyositis (JPM, n = 5) and other IIM (n = 9). Concordantly, WT1 protein was increased in JDM muscle, with average positive staining of 11.6%, but was undetectable in normal muscles (p < 0.05).
These results suggest that affected muscles of children with JDM and IIM have the capacity to repair, and that homeobox and WT1 genes are epigenetically marked to facilitate this repair process, potentially suggesting new avenues of therapeutic intervention.
PMCID: PMC3462248  PMID: 22674142
3.  Clinical Status and Cardiovascular Risk Profile of Adults with a History of Juvenile Dermatomyositis 
The Journal of pediatrics  2011;159(5):795-801.
A pilot study of adults who had onset of juvenile dermatomyositis (JDM) in childhood, before current therapeutic approaches, to characterize JDM symptoms and subclinical cardiovascular disease.
Study design
Eight adults who had JDM assessed for disease activity and 8 healthy adults (cardiovascular disease controls) were tested for carotid intima media thickness and brachial arterial reactivity. Adults who had JDM and 16 age-, sex-, and body mass index-matched healthy metabolic controls were evaluated for body composition, blood pressure, fasting glucose, lipids, insulin resistance, leptin, adiponectin, proinflammatory oxidized high-density lipoprotein (HDL), and nail-fold capillary end row loops.
Adults with a history of JDM, median age 38 years (24–44 years) enrolled a median 29 years (9–38 years) after disease onset, had elevated disease activity scores, skin (7/8), muscle (4/8), and creatine phosphokinase (2/8). Compared with cardiovascular disease controls, adults who had JDM were younger, had lower body mass index and HDL cholesterol (P = .002), and increased intima media thickness (P = .015) and their brachial arterial reactivity suggested impairment of endothelial cell function. Compared with metabolic controls, adults who had JDM had higher systolic and diastolic blood pressure, P = .048, P = .002, respectively; lower adiponectin (P = .03); less upper arm fat (P = .008); HDL associated with end row loops loss (r = −0.838, P = .009); and increased proinflammatory oxidized HDL (P = .0037).
Adults who had JDM, 29 years after disease onset, had progressive disease and increased cardiovascular risk factors.
PMCID: PMC3193560  PMID: 21784434
4.  Ovarian Teratoma Mimicking Features of Juvenile Dermatomyositis in a Child 
Pediatrics  2011;128(5):e1293-e1296.
An 8-year-old girl complained for 4 months of right arm pain, weakness in both legs, difficulty in arising from a seated or squatting position, and 1 month of pain in her hips, ankles, and knees. On physical examination, she had weak neck flexors, weak proximal and abdominal muscles, and an assisted Gower maneuver; both knees and ankles were painful. Erythematous macules on her elbows, knees, and medial ankles were present without heliotrope rash or dilated eyelid capillaries. She had nail-fold erythema and decreased numbers of nail-fold capillary end-row loops (ERLs) (5.42 ERLs per mm [normal: ≥6.8 ERLs per mm]) without digital ulcers or tight skin. Laboratory testing revealed slightly elevated creatine phosphokinase (440 IU/L [normal: ≤199 IU/L]) and aldolase (11.7 U/L [normal: ≤8.6 U/L]) levels. Her eosinophilia (7.2%) was not characteristic of juvenile dermatomyositis. Rheumatologic evaluation included a positive antinuclear antibody test result (1:5120 titer), speckled pattern (normal: <80 titer), myositis-associated and -specific antibodies that showed indeterminate Mi-2, with the others negative, including p155/140, elevated immunoglobulin G (IgG) (1440 mg/dL [normal range: 608–1229]) and IgE (409 kU/L [normal: <160 kU/L]) levels, and normal levels of IgM and IgA. She had an increased neopterin level (20 nm/L [normal: <10 nm/L]) and decreased absolute count of CD3-CD56/16+ natural killer cells (89 [lower normal limit: 138]). MRI of her thigh muscles revealed serpiginous increased T-2 signals consistent with inflammation and a complex round mass in the left pelvis. A muscle biopsy did not indicate juvenile dermatomyositis. Pelvic ultrasound confirmed a solid mass of the left ovary consistent with a mature teratoma. After surgical removal of the teratoma, the myositis, synovitis, and cutaneous findings resolved over 4 months without further therapy.
PMCID: PMC3208967  PMID: 21969283
myositis; teratoma; immune modulation; paraneoplastic syndrome
5.  Detection of anti-Ro, La, Smith and RNP autoantibodies by autoantigen microarray analysis and interferon-alpha induction in juvenile dermatomyositis 
Arthritis and rheumatism  2013;65(9):2424-2429.
To evaluate serum interferon-α (IFNα) activity in the context of autoantibody profiles in patients with juvenile dermatomyositis (JDM).
Sera from 36 JDM patients were analyzed. Autoantibody profiles were determined by probing microarrays, fabricated with ~80 distinct autoantigens, with serum and a Cy3-conjugated secondary antibody. Arrays were scanned and analyzed to determine antigen reactivity. Serum IFNα activity was measured using a functional reporter cell assay. Sera were assayed alone or in combination with cellular material released from necrotic U937 cells to stimulate peripheral blood mononuclear cells from healthy donors in vitro, and IFNα production in culture was measured by a dissociation-enhanced lanthanide fluorescent immunoassay (DELFIA).
Reactivity against at least 1 of 41 autoantigens on the microarray, including Ro 52, Ro 60, La, Sm, and RNP, was observed in 75% of the serum samples from patients with JDM. IFNα activity was detected in 7 samples by reporter cell assay. The reporter cell assay showed a significant association of reactivity against Ro, La, Sm, and proliferating cell nuclear antigen with serum IFNα activity (P = 0.005). Significance Analysis of Microarrays (SAM) identified increased reactivity against Sm, RNP, Ro 52, U1-C, and Mi-2 in these sera. Sixteen samples induced IFNα production as measured by DELFIA, and there was a significant association of reactivity against Ro, La, Sm, and RNP with the induction of IFNα by serum and necrotic cell material (P = 0.034). SAM identified increased reactivity against Ro 60 in these sera.
These data support the hypothesis that nucleic acid–associated autoantibodies, including the Ro/La and Sm/RNP complexes, may stimulate the production of active IFNα in children with JDM.
PMCID: PMC4169271  PMID: 23740815
6.  Familial Aggregation of Autoimmune Disease in Juvenile Dermatomyositis 
Pediatrics  2011;127(5):e1239-e1246.
Familial aggregation of autoimmune diseases likely reflects shared pathogenic factors between different diseases. Familial aggregation of autoimmunity has not been examined in juvenile dermatomyositis. Interferon-α is thought to be a pathogenic factor in both systemic lupus erythematosus and juvenile dermatomyositis, and we have previously demonstrated familial aggregation of serum interferon-α.
Family histories were obtained from 304 families of children with juvenile dermatomyositis via 3-generation structured interviews performed by the same person. Rates of autoimmune disease in families of children with juvenile dermatomyositis were compared with published population rates. Serum interferon-α, tumor necrosis factor-α, and neopterin were measured using standard techniques.
A total of 51% of families of children with juvenile dermatomyositis reported at least 1 additional member affected by an autoimmune disease. In particular, both type 1 diabetes and systemic lupus erythematosus were significantly more common than would be expected (odds ratio >5, P ≤ 1 × 10−7 for both). Pedigree analysis showed particularly strong familial clustering of systemic lupus erythematosus with little decrease in incidence across generations, suggesting the possibility of rare causal genes with large effect. Untreated subjects with juvenile dermatomyositis with a family history of systemic lupus erythematosus had higher serum interferon-α than those who did not (P = .047).
We find strong familial aggregation of specific autoimmune diseases in families of children with juvenile dermatomyositis, suggesting that these conditions share pathogenic factors. Higher serum interferon-α in juvenile dermatomyositis patients with a family history of systemic lupus erythematosus suggesting that interferon-α is one such shared factor.
PMCID: PMC3081190  PMID: 21502224
juvenile dermatomyositis; systemic lupus erythematosus; diabetes mellitus type I; psoriasis; celiac disease; interferons
7.  Lesional and Nonlesional Skin From Patients With Untreated Juvenile Dermatomyositis Displays Increased Numbers of Mast Cells and Mature Plasmacytoid Dendritic Cells 
Arthritis and Rheumatism  2010;62(9):2813-2822.
To investigate the distribution of mast cells and dendritic cell (DC) subsets in paired muscle and skin (lesional/nonlesional) from untreated children with juvenile dermatomyositis (DM).
Muscle and skin biopsy samples (4 skin biopsy samples with active rash) from 7 patients with probable/definite juvenile DM were compared with muscle and skin samples from 10 healthy pediatric controls. Mast cell distribution and number were assessed by toluidine blue staining and analyzed by Student’s t-test. Immunohistochemical analysis was performed to identify mature DCs, myeloid DCs (MDCs), and plasmacytoid DCs (PDCs) by using antibodies against DC-LAMP, blood dendritic cell antigen 1 (BDCA-1), and BDCA-2, respectively. Myxovirus resistance protein A (MxA) staining indicated active type I interferon (IFN) signaling; positive staining was scored semiquantitatively and analyzed using the Mann-Whitney U test.
Both inflamed and nonlesional skin from patients with juvenile DM contained more mast cells than did skin from pediatric controls (P = 0.029), and comparable numbers of mast cells were present in lesional and nonlesional skin. Interestingly, mast cell numbers were greater in skin than in paired muscle tissue from patients with juvenile DM (P = 0.014) and were not increased in muscle from patients with juvenile DM compared with control muscle. Both muscle and skin from patients with juvenile DM showed more mature PDCs and MxA staining than did their corresponding control tissues (P < 0.05). In both muscle and skin from patients with juvenile DM and in pediatric control muscle, there were fewer MDCs than PDCs, and the distributions of MDCs and PDCs were similar in pediatric control skin samples.
The identification of mast cells in skin (irrespective of rash) from patients with juvenile DM, but not in paired muscle tissue, suggests that they have a specific role in juvenile DM skin pathophysiology. In skin from patients with juvenile DM, increased numbers of PDCs and increased expression of type I IFN–induced protein suggest a selective influence on T cell differentiation and subsequent effector function.
PMCID: PMC3312790  PMID: 20506305
8.  Normal Nailfold End Row Loops are Associated with a Shorter Duration of Untreated Disease in Children with Juvenile Dermatomyositis 
Arthritis and Rheumatism  2010;62(5):1533-1538.
To determine the association of normal end row loops (ERL) at diagnosis of juvenile dermatomyositis (JDM) with clinical findings in untreated children and identify predictors of the development of decreased ERL.
Clinical and laboratory data of 80 untreated children with JDM were collected. ERL scores were recorded at time of diagnosis, and at 24 months and 36 months thereafter. Twelve children with normal ERL at diagnosis were compared with the remaining 68 children. Outcomes included: duration of untreated disease, time on immunosuppresive medications, family medical history, disease activity score (DAS), and levels of creatine phosphokinase (CPK), aldolase, absolute CD3−CD56+/16+ NK cells, and von Willebrand factor antigen (vWF:Ag). Cross-sectional and longitudinal analyses were performed.
At diagnosis, children with normal ERL had a shorter duration of untreated disease (p=0.03) and a lower skin DAS (p=0.045). Over time, an increased likelihood for having abnormal ERL was associated with a longer duration of untreated disease and with higher skin DAS.
The presence of a normal number of ERL in JDM appears to be associated with a shorter duration of symptoms and may be a useful indicator of disease chronicity in the newly diagnosed child. Normal ERL is also associated with lower skin DAS. The lack of association between normal ERL and other variables indicates that normal NFC should not be used as a justification to delay immunosuppressive therapy in children with typical JDM symptoms.
PMCID: PMC3304541  PMID: 20213809
Arthritis care & research  2010;62(11):1533-1541.
To develop a provisional definition for the evaluation of response to therapy in juvenile dermatomyositis (JDM) based on the PRINTO JDM core set of variables.
Thirty-seven experienced pediatric rheumatologists from 27 countries, achieved consensus on 128 difficult patient profiles as clinically improved or not improved using a stepwise approach (patients rating, statistical analysis, definition selection). Using the physicians’ consensus ratings as the “gold-standard measure”, chi-square, sensitivity, specificity, false positive and negative rate, area under the ROC, and kappa agreement for candidate definitions of improvement were calculated. Definitions with kappa >0.8 were multiplied with the face validity score to select the top definitions.
The top definition of improvement was: at least 20% improvement from baseline in 3/6 core set variables with no more than 1 of the remaining worsening by more than 30%, which cannot be muscle strength. The second highest scoring definition was at least 20% improvement from baseline in 3/6 core set variables with no more than 2 of the remaining worsening by more than 25%, which cannot be muscle strength which is definition P1 selected by the IMACS group. The third is similar to the second with the maximum amount of worsening set to 30%. This indicates convergent validity of the process.
we proposes a provisional data driven definition of improvement that reflects well the consensus rating of experienced clinicians, which incorporates clinically meaningful change in core set variables in a composite endpoint for the evaluation of global response to therapy in JDM.
PMCID: PMC2964396  PMID: 20583105
juvenile dermatomyositis; core set; response to therapy; disease activity; consensus
10.  Mycophenolate Mofetil, a Possible Therapeutic Agent for Children with Juvenile Dermatomyositis 
Arthritis care & research  2010;62(10):1446-1451.
To determine if mycophenolate mofetil (MMF) diminished skin and muscle disease activity in children with juvenile dermatomyositis (JDM) permitting decrease in corticosteroid dosage.
Retrospective data review for 50 JDM children identified the following: 38 (76%) girls, 39 (78%) white, 10 (20%) Hispanic, 1 (2%) black, mean age 12.2 ± 5.0 years who had been given MMF for 12 months. MMF dose and frequency, type of infection, white blood cell count (WBC), corticosteroid dose and validated disease activity score (DAS), (sub scores for skin [DAS-S], muscle [DAS-M]), were obtained.
Twelve months after start of MMF, mean DAS-S decreased from 5.24 ± 0.29 to 3.72 ± 0.29 (p=0.001) and DAS-M dropped from 2.44 ± 0.39 to 1.17 ± 0.28 (p=0.002). Prednisone dose decreased from 0.39 mg/kg/day ± 0.06 mg to 0.23mg/kg/day ± 0.02 mg (p=0.0001), with resumption of linear growth (p=0.008). The WBC/lymphocyte count was unchanged over 12 months on MMF. Infection rate was assessed in a subset of 26 children with JDM followed for 12 months before start of MMF and compared with ensuing 12 months on MMF. There was no significant difference between pretreatment and first 6 months of MMF (p=0.44), but infection rate dropped in months 7–12 (p=0.001).
MMF appears to be worthy of consideration as an additional therapeutic modality for treatment of children with JDM. These data suggest that use of MMF decreases skin and muscle disease activity and is steroid sparing. MMF appears to be well tolerated, but patients should be monitored for infection.
PMCID: PMC2952049  PMID: 20521307
11.  Protocols for the Initial Treatment of Moderately Severe Juvenile Dermatomyositis: Results of a Children's Arthritis and Rheumatology Research Alliance Consensus Conference 
Arthritis care & research  2010;62(2):219-225.
To use juvenile dermatomyositis (JDM) survey data and expert opinion to develop a small number of consensus treatment protocols which reflect current initial treatment of moderately severe JDM.
A consensus meeting was held in Toronto, Ontario, Canada on December 1-2, 2007. Nominal group technique was used to achieve consensus on treatment protocols which represented typical management of moderately severe JDM. Consensus was also reached on which patients these protocols would be applicable to (inclusion and exclusion criteria), initial investigations which should be done prior to initiating one of these protocols, data which should be collected to evaluate these protocols, concomitant interventions that would be required or recommended.
Three protocols were developed which described the first 2 months of treatment. All protocols included corticosteroids and methotrexate. One protocol also included intravenous gammaglobulin. Consensus was achieved for all issues that were addressed by conference participants, although there were some areas of controversy
This study shows that it is possible to achieve consensus on the initial treatment of JDM, despite considerable variation in clinical practice. Once these protocols are extended beyond 2 months, these protocols will be available for clinical use. By using methods which account for differences between patients (confounding by indication), the comparative effectiveness of the protocols will be evaluated. In the future, the goal will be to identify the optimal treatment of moderately severe JDM.
PMCID: PMC2909837  PMID: 20191521
12.  Juvenile Dermatomyositis (JDM) Calcifications Selectively Display Markers of Bone Formation 
Arthritis and rheumatism  2009;61(4):501-508.
To determine the presence of SIBLING and bone components in Juvenile Dermatomyositis (JDM) pathologic calcifications.
Calcifications, removed from 4 girls with JDM symptoms for 36.9 ± 48.3 months, were stained for SIBLING proteins: osteopontin OPN (full length), bone sialoprotein (BSP), dentin matrix protein 1 (DMP1), dentin phosphoprotein (DPP), matrix extracellular phosphoglycoprotein (MEPE); bone markers: osteocalcin (OC), core binding factor alpha 1 (Cbfa1), and alkaline phosphatase (ALP) for osteoblasts; tartrate resistant acid phosphatase (TRAP) for osteoclasts, as well as the mineral regulators osteonectin (ON) and matrix Gla protein (MGP). The deposit center, periphery, adjacent connective tissue, and vascular endothelial cells were examined.
Alizarin red stained calcified deposits, which did not localize with collagen, like bone, under polarized light. H+E stain revealed a paucity of connective tissue and absence of bone-like structures. The deposits, connective tissue, and vascular endothelial cells were positive for BSP, DPP, DMP1, and ALP; MEPE was not detected. OC, ON and MGP were present in the deposits and vascular endothelial cells; OPN and Cbfa1 were present in deposits and connective tissue. TRAP positive osteoclasts were localized to the calcification periphery.
The disorganized JDM calcifications differ in structure, composition and protein content from bone, suggesting that they may not form through an osteogenic pathway. Osteoclasts at the deposit surface represent an attempt to initiate its resolution.
PMCID: PMC2741135  PMID: 19333978
13.  The Role of Aggressive Corticosteroid Therapy in Patients With Juvenile Dermatomyositis: A Propensity Score Analysis 
Arthritis and rheumatism  2008;59(7):989-995.
To compare outcomes at 36 months in patients newly diagnosed with juvenile dermatomyositis (DM) treated with aggressive versus standard therapy.
At diagnosis, 139 untreated juvenile DM patients were given aggressive therapy (intravenous methylprednisolone or oral prednisone 5–30 mg/kg/day; n = 76) or standard therapy (1–2 mg/kg/day; n = 63) by the treating physician. Aggressive therapy patients were more ill at diagnosis. Matching was based on the propensity for aggressive therapy because propensity scoring can reduce confounding by indication. Logistic regression of the matched data determined predictors of outcomes, controlling for clinical confounders and propensity score. Outcomes comprised Disease Activity Score (DAS) for skin and muscle, range of motion (ROM), and calcification.
Sex, race, and age were similar between groups, and initial DAS weakness and ROM significantly predicted the therapy chosen. Based on propensity scores, 42 patients from each group were well matched. In the matched pairs, there were no significant differences in outcomes. Methotrexate use (odds ratio [OR] 3.6, 95% confidence interval [95% CI] 1.15–11.5) and duration of untreated disease (OR 1.2, 95% CI 1–1.38) were associated with ROM loss, hydroxychloroquine use (OR 11.2, 95% CI 3.7–33) and calcification (OR 6.8, 95% CI 1.8–25.4) with persistent rash, abnormal baseline lactate dehydrogenase (OR 11.2, 95% CI 1.4–92) and age at onset (OR 1.3, 95% CI 1–1.4) with weakness, and duration of untreated disease (OR 1.2, 95% CI 1–1.39) with calcification.
Using a retrospective, nonrandomized design with propensity score matching, there was little difference in efficacy outcomes between aggressive and standard therapy; however, the sickest patients were treated with aggressive therapy and were not included in the matched analysis. Comprehensive clinical studies are needed to determine therapeutic pathways to the best outcome.
PMCID: PMC2830150  PMID: 18576304
14.  Persistent Association of Nailfold Capillaroscopy Changes and Skin Involvement Over Thirty-Six Months With Duration of Untreated Disease in Patients With Juvenile Dermatomyositis 
Arthritis and rheumatism  2008;58(2):571-576.
To determine the association of changes on nailfold capillaroscopy with clinical findings and genotype in children with juvenile dermatomyositis (DM), in order to identify potential differences in disease course over 36 months.
At diagnosis of juvenile DM in 61 children prior to the initiation of treatment, tumor necrosis factor α (TNFα) −308 allele and DQA1*0501 status was determined, juvenile DM Disease Activity Scores (DAS) were obtained, and nailfold capillaroscopy was performed. The disease course was monitored for 36 months. Variations within and between patients were assessed by regression analysis.
At diagnosis, shorter duration of untreated disease (P = 0.05) and a lower juvenile DM skin DAS (P = 0.035) were associated with a unicyclic disease course. Over 36 months, end-row loop (ERL) regeneration was associated with lower skin DAS (P < 0.001) but not muscle DAS (P = 0.98); ERL regeneration and decreased bushy loops were associated with a shorter duration of untreated disease (P = 0.04 for both). At 36 months, increased ERL regeneration (P = 0.007) and improvement of skin DAS (P < 0.001) and muscle DAS (P = 0.025) were associated with a unicyclic disease course.
Early treatment of juvenile DM may lead to a unicyclic disease course. The non-unicyclic disease course usually involves continuing skin manifestations with persistent nailfold capillaroscopy changes. The correlation of nailfold capillaroscopy results with cutaneous but not with musculoskeletal signs of juvenile DM over a 36-month period suggests that the cutaneous and muscle vasculopathies have different pathophysiologic mechanisms. These findings indicate that efforts to identify the optimal treatment of cutaneous features in juvenile DM require greater attention.
PMCID: PMC2830145  PMID: 18240225
15.  Apoptosis in the Skeletal Muscle of Untreated Children with Juvenile Dermatomyositis: Impact of Duration of Untreated Disease* 
Clinical immunology (Orlando, Fla.)  2007;125(2):165-172.
Juvenile Dermatomyositis (JDM) is the most common myopathy in children with characteristic skin rash and muscle weakness, in which longer duration of untreated disease was associated with less muscle weakness. The duration of untreated inflammation may alter the apoptotic pathways involved in skeletal muscle damage. Diagnostic muscle biopsies from 14 untreated patients were stained for apoptosis markers. TUNEL-positive nuclei and caspase 3 were detected within the laminin layer, indicating apoptosis of skeletal muscle nuclei. Untreated JDM disease duration greater than 2 months (“long”), was associated with higher Fas positive cell counts in the perivascular region compared with the “short” disease duration group, 2 months or less. Within the “long” duration group, higher Fas positive cell counts were positively associated with increased TUNEL-positive nuclei and caspase 3. We conclude that the duration of untreated disease (chronic inflammation) influences the mode of continuing cell damage and death in children with JDM.
PMCID: PMC2219965  PMID: 17704000
apoptosis; Juvenile Dermatomyositis (JDM); disease duration; skeletal muscle
16.  A Mouse Model of Human Primitive Neuroectodermal Tumors Resulting from Microenvironmentally-Driven Malignant Transformation of Orthotopically Transplanted Radial Glial Cells 
PLoS ONE  2015;10(3):e0121707.
There is growing evidence and a consensus in the field that most pediatric brain tumors originate from stem cells, of which radial glial cells constitute a subtype. Here we show that orthotopic transplantation of human radial glial (RG) cells to the subventricular zone of the 3rd ventricle - but not to other transplantation sites - of the brain in immunocompromised NOD-SCID mice, gives rise to tumors that have the hallmarks of CNS primitive neuroectodermal tumors (PNETs). The resulting mouse model strikingly recapitulates the phenotype of PNETs. Importantly, the observed tumorigenic transformation was accompanied by aspects of an epithelial to mesenchymal transition (EMT)-like process. It is also noteworthy that the tumors are highly invasive, and that they effectively recruit mouse endothelial cells for angiogenesis. These results are significant for several reasons. First, they show that malignant transformation of radial glial cells can occur in the absence of specific mutations or inherited genomic alterations. Second, they demonstrate that the same radial glial cells may either give rise to brain tumors or differentiate normally depending upon the microenvironment of the specific region of the brain to which the cells are transplanted. In addition to providing a prospect for drug screening and development of new therapeutic strategies, the resulting mouse model of PNETs offers an unprecedented opportunity to identify the cancer driving molecular alterations and the microenvironmental factors that are responsible for committing otherwise normal radial glial cells to a malignant phenotype.
PMCID: PMC4380339  PMID: 25826270
17.  Genome-wide Association Study of Dermatomyositis Reveals Genetic Overlap with other Autoimmune Disorders 
Arthritis and rheumatism  2013;65(12):3239-3247.
To identify new genetic associations with juvenile and adult dermatomyositis (DM).
We performed a genome-wide association study (GWAS) of adult and juvenile DM patients of European ancestry (n = 1178) and controls (n = 4724). To assess genetic overlap with other autoimmune disorders, we examined whether 141 single nucleotide polymorphisms (SNPs) outside the major histocompatibility complex (MHC) locus, and previously associated with autoimmune diseases, predispose to DM.
Compared to controls, patients with DM had a strong signal in the MHC region consisting of GWAS-level significance (P < 5x10−8) at 80 genotyped SNPs. An analysis of 141 non-MHC SNPs previously associated with autoimmune diseases showed that three SNPs linked with three genes were associated with DM, with a false discovery rate (FDR) < 0.05. These genes were phospholipase C like 1 (PLCL1, rs6738825, FDR=0.00089), B lymphoid tyrosine kinase (BLK, rs2736340, FDR=0.00031), and chemokine (C-C motif) ligand 21 (CCL21, rs951005, FDR=0.0076). None of these genes was previously reported to be associated with DM.
Our findings confirm the MHC as the major genetic region associated with DM and indicate that DM shares non-MHC genetic features with other autoimmune diseases, suggesting the presence of additional novel risk loci. This first identification of autoimmune disease genetic predispositions shared with DM may lead to enhanced understanding of pathogenesis and novel diagnostic and therapeutic approaches.
PMCID: PMC3934004  PMID: 23983088
dermatomyositis; adult; juvenile; shared autoimmunity genes
19.  Gene-Gene-Sex Interaction between Cytokine Gene Polymorphisms Revealed by Serum Interferon Alpha Phenotype in Juvenile Dermatomyositis 
The Journal of pediatrics  2010;157(4):653-657.
To detect genetic polymorphisms associated with high serum interferon alpha (IFN-α) in juvenile dermatomyositis (JDM) and explore interactions between associated polymorphisms.
Study design
Eighty-five children of European ancestry with definite/probable JDM were studied. Selected genetic polymorphisms which were associated with high IFN-α in twelve untreated patients newly diagnosed with JDM were genotyped in a validation cohort of 73 children with JDM, and analyzed for gene-gene and gene-sex interactions.
Newly diagnosed untreated children with JDM carrying both the osteopontin (OPN) rs28357094G and tumor necrosis factor alpha (TNF-α) -308 A alleles had significantly increased serum IFN-α. These two polymorphisms were genotyped in the validation cohort, and the OPN rs28357094G allele was more common in female subjects with JDM (OR=3.97, p=0.012). This OPN allele was most strongly enriched in female carriers of TNF-α -308A as compared with male carriers of TNF-α -308A (OR>9.0, p=7.2×10−3).
These data support a complex gene-gene-sex interaction between the OPN and TNF-α promoter regions in JDM, defining a high serum IFN-α subgroup within JDM. This suggests pathogenic synergy between the OPN and TNF-α loci in females with JDM, which may underlie some of the increased incidence of this condition in females.
PMCID: PMC2936662  PMID: 20605164
Idiopathic Inflammatory Myopathies; Genetics; Systemic Lupus Erythematosus; Osteopontin; Tumor Necrosis Factor Alpha
20.  Serum Neopterin Levels as a Diagnostic Marker of Hemophagocytic Lymphohistiocytosis Syndrome ▿ 
The objective of this study was to retrospectively evaluate the utility of serum neopterin as a diagnostic marker of hemophagocytic lymphohistiocytosis (HLH). The medical records of patients diagnosed with HLH (familial and secondary) between January 2000 and May 2009 were reviewed retrospectively, and clinical and laboratory information related to HLH criteria, in addition to neopterin levels, was recorded. A group of 50 patients with active juvenile dermatomyositis (JDM) (who routinely have neopterin levels assessed) served as controls for the assessment of the accuracy, sensitivity, and specificity of neopterin as a diagnostic test for HLH. The Pearson correlation was used to measure the association between serum neopterin levels and established HLH-related laboratory data. Serum neopterin levels were measured using a competitive enzyme immunoassay. During the time frame of the study, 3 patients with familial HLH and 18 patients with secondary HLH were identified as having had serum neopterin measured (all HLH patients were grouped together). The mean neopterin levels were 84.9 nmol/liter (standard deviation [SD], 83.4 nmol/liter) for patients with HLH and 21.5 nmol/liter (SD, 10.13 nmol/liter) for patients with JDM. A cutoff value of 38.9 nmol/liter was 70% sensitive and 95% specific for HLH. For HLH patients, neopterin levels correlated significantly with ferritin levels (r = 0.76, P = 0.0007). In comparison to the level in a control group of JDM patients, elevated serum neopterin was a sensitive and specific marker for HLH. Serum neopterin has value as a diagnostic marker of HLH, and prospective studies are under way to further evaluate its role as a marker for early diagnosis and management of patients.
PMCID: PMC3122569  PMID: 21270283
21.  MxA gene expression in juvenile dermatomyositis peripheral blood mononuclear cells: Association with muscle involvement 
Clinical immunology (Orlando, Fla.)  2006;120(3):319-325.
Juvenile dermatomyositis (JDM), a systemic vasculopathy, is characterized by inflammation of skin and muscle. Muscle biopsies from untreated JDM patients show upregulation of type I interferon (IFN)-inducible genes, including myxovirus resistance protein A (MxA). The present study examines whether MxA mRNA expression in peripheral blood mononuclear cells (PBMC) from JDM patients: (1) is elevated compared to healthy controls, (2) reflects disease activity, and (3) changes with the onset of clinically effective treatment. MxA mRNA expression in JDM PBMC obtained at the initial clinic visit was elevated compared to controls and was positively correlated with Disease Activity Score (DAS) for muscle, but not with DAS for skin, suggesting that damage to skin and muscle in JDM may each have a discrete pathophysiology. During the course of clinically effective treatment, decrease in muscle symptoms was associated with a decrease in PBMC MxA mRNA expression.
PMCID: PMC3163162  PMID: 16859997
Juvenile dermatomyositis; Interferon; MxA; PBMC; Muscle
22.  Validation of Manual Muscle Testing and a Subset of Eight Muscles (MMT8) for Adult and Juvenile Idiopathic Inflammatory Myopathies 
Arthritis care & research  2010;62(4):465-472.
To validate manual muscle testing (MMT) for strength assessment in juvenile and adult dermatomyositis (DM) and polymyositis (PM).
Seventy-three children and 45 adult DM/PM patients were assessed at baseline and reevaluated 6–9 months later. We compared Total MMT (a group of 24 proximal, distal, and axial muscles) and Proximal MMT (7 proximal muscle groups) tested bilaterally on a 0–10 scale with 144 subsets of six and 96 subsets of eight muscle groups tested unilaterally. Expert consensus was used to rank the best abbreviated MMT subsets for face validity and ease of assessment.
The Total, Proximal and best MMT subsets had excellent internal reliability (rs:Total MMT 0.91–0.98), and consistency (Cronbach’s α 0.78–0.97). Inter- and intra-rater reliability were acceptable (Kendall’s W 0.68–0.76; rs 0.84–0.95). MMT subset scores correlated highly with Total and Proximal MMT scores and with the Childhood Myositis Assessment Scale, and correlated moderately with physician global activity, functional disability, magnetic resonance imaging, axial and distal MMT scores and, in adults, with creatine kinase. The standardized response mean for Total MMT was 0.56 in juveniles and 0.75 in adults. Consensus was reached to use a subset of eight muscles (neck flexors, deltoids, biceps, wrist extensors, gluteus maximus and medius, quadriceps and ankle dorsiflexors) that performed as well as the Total and Proximal MMT, and had good face validity and ease of assessment.
These findings aid in standardizing the use of MMT for assessing strength as an outcome measure for myositis.
PMCID: PMC2924143  PMID: 20391500
23.  Damage Extent and Predictors in Adult and Juvenile Dermatomyositis and Polymyositis Using the Myositis Damage Index 
Arthritis and rheumatism  2009;60(11):3425-3435.
We validated the Myositis Damage Index (MDI) in juvenile and adult myositis, to describe the degree and types of damage and to develop predictors of damage.
Retrospective MDI evaluations and prospective assessment of disease activity and illness features were conducted. Juvenile-onset patients (n = 143) were evaluated a median of 18 months after diagnosis; 135 patients were assessed 7–9 months later, and 121 were last assessed 82 months after diagnosis. Adult-onset patients (n = 96) with dermatomyositis (DM) or polymyositis (PM) had a baseline assessment a median of 30 months after diagnosis; 77 had a 6-month follow-up evaluation, and 55 had a final assessment 60 months after diagnosis.
Damage was present in 79% of juvenile and 97% of adult patients. In juveniles, scar, contractures, persistent weakness, muscle dysfunction and calcinosis (23–30%) were most frequent on last evaluation. In adults, muscle atrophy, muscle dysfunction and weakness were most frequent (74–84%). MDI severity correlated with physician global damage, functional disability, weakness and muscle atrophy on MRI. MDI damage scores and frequency were highest in patients with a chronic illness course and in adult patients who died. Predictors of damage included functional disability, active disease duration, onset severity, global activity, and illness features, including ulcerations in children and pericarditis in adults.
Damage is common in myositis patients after a median of 5 years duration in adult-onset and 6.8 years in juvenile-onset patients. The MDI has good content, construct and predictive validity in juvenile and adult myositis.
PMCID: PMC2793533  PMID: 19877055
24.  Elevated Serum Interferon Alpha Activity in Juvenile Dermatomyositis: Associations with Disease Activity at Diagnosis and After 36 Months of Therapy 
Arthritis and rheumatism  2009;60(6):1815-1824.
Interferon alpha (IFN-α) has been implicated in the pathogenesis of juvenile dermatomyositis (JDM). We examined serum IFN-α activity in a cohort of children with JDM to determine relationships between IFN-α and indicators of disease activity and severity.
39 children with definite/probable JDM were included in the study. Samples were studied from 18 newly diagnosed untreated children, and 11 of these children had a second sample taken at 24 months while they were receiving treatment. 7 of these children also had a third sample available at 36 months, and 21 additional children were studied 36 months after their initial diagnosis. Serum IFN-α was measured using a functional reporter cell assay.
JDM patients had higher serum IFN-α activity than both pediatric and adult healthy controls. In untreated patients, serum IFN-α activity was positively correlated with serum muscle enzymes (p<0.05 for CPK, AST, and aldolase) and inversely correlated with duration of untreated disease (p=0.017). The TNF-α-308A allele was associated with higher serum IFN-α only in untreated patients (p=0.038). At 36 months, serum IFN-α was inversely correlated with muscle enzymes in those patients still requiring therapy, and inversely correlated with skin DAS in those who had completed therapy (p=0.002).
Serum IFN-α activity was associated with higher serum levels of muscle derived enzymes and shorter duration of untreated disease in newly diagnosed patients, and inversely correlated with measures of chronic disease activity at 36 months post-diagnosis. These data suggest that IFN-α could play a role in disease initiation in JDM.
PMCID: PMC2697261  PMID: 19479879
25.  Pharmacokinetic Study of Oral Prednisolone Compared With Intravenous Methylprednisolone in Patients With Juvenile Dermatomyositis 
Arthritis and rheumatism  2008;59(2):222-226.
To determine areas under the curve (AUCs) of oral prednisolone (OP) and intravenous methylprednisolone (IVMP) in patients with juvenile dermatomyositis (DM) and assess the association with nailfold end-row loops (ERLs). Patients with active disease have fewer ERLs that possibly occur in the gastrointestinal tract, impairing absorption of oral medications.
Six patients with juvenile DM received 50 mg/m2 of OP (day 1) and IVMP (day 2). Blood was drawn at baseline and at 5, 15, 30, 45, 60, and 90 minutes, and hourly (hours 2–8) after each dose. Samples were analyzed by reverse-phase high-performance liquid chromatography for levels of prednisolone and methylprednisolone. AUCs of OP and IVMP were determined by the trapezoid method; pharmacokinetic parameters were obtained using noncompartmental and compartmental analysis. ERLs were determined from freeze-frame video microscopy and nailfold capillaroscopy.
There was a trend toward significance in difference in mean AUC of IVMP (116.72 µg × ml/hour) compared with OP (65.16 µg × ml/hour; P = 0.059). Mean peak concentration was higher for IVMP (34.49 µg/ml) than OP (7.08 µg/ml); mean half-life was shorter for IVMP (1.90 hours) than OP (2.36 hours). There was an inverse association between ΔAUCs (IVMP AUC − OP AUC) and ERLs (R = −0.68, P = 0.044).
Patients with juvenile DM and ERL loss may have decreased bioavailability of OP compared with IVMP. This can provide the rationale for greater efficacy of IVMP in patients with active vasculopathy of juvenile DM. Further studies investigating the pharmacokinetics and pharmacodynamics of high-dose IVMP need to be performed in patients with juvenile DM.
PMCID: PMC2852143  PMID: 18240180

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