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1.  Biologic predictors of clinical improvement in rituximab-treated refractory myositis 
To examine the longitudinal utility of a biomarker signature in conjunction with myositis autoantibodies (autoAbs) as predictors of disease improvement in refractory myositis patients treated with rituximab.
In the RIM Trial, all subjects received rituximab on 2 consecutive weeks. Using start of treatment as baseline, serum samples (n = 177) were analyzed at baseline and after rituximab with multiplexed sandwich immunoassays to quantify type-1 IFN-regulated and other pro-inflammatory chemokines and cytokines. Biomarker scores were generated for the following pathways: type-1 IFN-inducible (IFNCK), innate, Th1, Th2, Th17 and regulatory cytokines. Myositis autoAbs (anti-synthetase n = 28, TIF-γ n = 19, Mi-2 n = 25, SRP n = 21, MJ n = 18, non-MAA n = 24, unidentified autoantibody n = 9, and no autoantibodies n = 33) determined by immunoprecipitation at baseline, were correlated with outcome measures. Kruskal-Wallis rank sum tests were used for comparisons.
The mean (SD) values for muscle disease and physician global disease activity VAS scores (0–100 mm) were 46 (22) and 49 (19). IFNCK scores (median values) were higher at baseline in subjects with anti-synthetase (43), TIF1-γ (31) and Mi-2 (30) compared with other autoAb groups (p < 0.001). At 16 weeks after rituximab, anti-synthetase and Mi-2 autoAb positive subjects and non-MAA had a greater improvement in IFNCK scores (− 6.7, − 6.1 and −7.2, p < .001). Both IFNCK high scores (>30) and autoAb group (Mi-2, non-MAA, and undefined autoantibody) demonstrated the greatest clinical improvement based on muscle VAS (muscle-interaction p = 0.075).
Biomarker signatures in conjunction with autoAbs help predict response to rituximab in refractory myositis. Biomarker and clinical responses are greatest at 16 weeks after rituximab.
PMCID: PMC4574570  PMID: 26382217
2.  Mineral Oil Aspiration Related Juvenile Idiopathic Arthritis 
Case Reports in Pulmonology  2015;2015:403109.
We describe the development of rheumatoid factor-positive migratory polyarthritis in a 5-year-old male who had been administered bidaily oral mineral oil as a laxative since birth. Minor respiratory symptoms, radiographic and bronchoscopic findings were consistent with chronic lipoid pneumonia. We speculate that immune sensitization to mineral oil promoted the clinical syndrome of juvenile idiopathic arthritis.
PMCID: PMC4478361  PMID: 26171269
3.  Adipokine gene expression in peripheral blood of adult and juvenile dermatomyositis patients and their relation to clinical parameters and disease activity measures 
Recently adipokines have been implicated in the regulation of immune and inflammatory responses in autoimmune disease. To investigate the role of adipokines in adult and pediatric patients with newly diagnosed dermatomyositis (DM), we analyzed peripheral blood and skeletal muscle gene expression of four adipokines: visfatin, leptin, adiponectin and resistin.
Peripheral blood mononuclear cells (PBMCs) were collected for 21 adult DM, 26 juvenile DM, 5 non-disease adult controls, and 6 non-disease pediatric controls at two time points: baseline and 6 months. Muscle biopsies from 5 adult DM patients and 5 non-disease adult controls were collected at baseline. Similarly, muscle biopsies from 7 juvenile DM patients and 5 non-disease pediatric controls were collected at baseline. The gene expression levels of leptin, adiponectin, resistin, visfatin and related inflammatory cytokines, IL-6, TNF- α, and housekeeping genes GAPDH, B2M, and ACTB were generated using a custom RT2 Profiler PCR Array.
Visfatin gene expression levels in peripheral blood were significantly higher in newly diagnosed adult DM cases compared to non-disease controls (P = 0.004) and these levels correlated with baseline clinical parameters such as age (r = 0.34, P = 0.020), male sex (r = −0.35, P = 0.017), prednisone use (r = −0.42, P = 0.006), and DMARD use (r = 0.35, P = 0.025). No significant association was found between change in visfatin gene expression levels and change in disease activity measures. While visfatin gene expression was significantly up-regulated in muscle tissue of juvenile DM patients (P = 0.028), in adult DM patients only a trend towards significance was observed (P = 0.08). Also, muscle gene expression levels of resistin were significantly elevated in both adult and juvenile DM patients compared respectively to non-disease adult and pediatric controls. Furthermore, an association between peripheral blood resistin gene expression and DM disease activity, including global, muscle, and extra-skeletal disease activity was also observed.
Peripheral blood visfatin gene expression and muscle resistin gene expression are significantly increased in newly diagnosed adult DM patients. Further longitudinal studies should explore the possibility of using gene expression levels of adipokines such as visfatin and resistin as novel clinical diagnostic biomarkers in DM.
PMCID: PMC4410479  PMID: 25918482
Dermatomyositis; Adipokines; Biomarkers; Visfatin; Resistin; Leptin; Adiponectin
4.  Changes in Novel Biomarkers of Disease Activity in Juvenile and Adult Dermatomyositis are Sensitive Biomarkers of Disease Course 
Arthritis and rheumatism  2012;64(12):4078-4086.
Muscle enzyme levels are insensitive markers of disease activity in juvenile and adult dermatomyositis (DM), especially during the active treatment phase. To improve our ability to monitor DM disease activity longitudinally, especially in the presence of immune modulating agents, we prospectively evaluated whether IFN-dependent peripheral blood gene and chemokine signatures could serve as sensitive and responsive biomarkers for change in disease activity in adult and juvenile DM.
Peripheral blood and clinical data were collected from 51 juvenile and adult DM subjects prospectively over 2 study visits. Disease activity measures, whole-blood type I IFN gene and chemokine score were collected. We also measured serum levels of other pro-inflammatory cytokines, including IL-6.
Changes in juvenile and adult DM global disease activity correlated positively and significantly with changes in the type I IFN gene score before (r=0.33, p=0.023) and IFN chemokine score before and after adjustment for medication use (r=0.53, p<0.001 and r=0.50, p=<0.001). Changes in muscle and extramuscular VAS subscales positively correlated with change in IFN gene and chemokine score (p=0.002). Serum levels of IL-6, IL-8 and TNFα were positively correlated with changes in global, muscle and extra-muscular VAS before and after adjustment for medications (p<0.05).
Our findings suggest that changes in type I IFN gene and chemokine scores as well as levels of IL-6, IL-8 and TNFα may serve as sensitive and responsive longitudinal biomarkers of change in disease activity in juvenile and adult DM, even in the presence of immunosuppressant use.
PMCID: PMC3510329  PMID: 22886447
5.  Updates on Morphea: Role of Vascular Injury and Advances in Treatment 
Autoimmune Diseases  2013;2013:467808.
Morphea and systemic sclerosis are fibrosing disorders of the skin that share common inflammatory and immunologic pathways that are responsible for the vascular changes, increased collagen production, and extracellular matrix proliferation seen in both conditions. Recent advances in molecular biology techniques have furthered our knowledge of the potential underlying pathogenic mechanisms and offer new and provocative areas of research for novel diagnostic and therapeutic interventions. This review focuses on the role of vascular injury in the development of morphea, the use of ultrasonography as a diagnostic modality, and well-established and newly proposed treatments.
PMCID: PMC3844232  PMID: 24319593
6.  Predictors of Clinical Improvement in Rituximab-Treated Refractory Adult and Juvenile Dermatomyositis and Adult Polymyositis 
The aim was to identify the clinical and laboratory predictors of clinical improvement in a cohort of myositis patients treated with rituximab.
We analyzed data for 195 myositis patients [75 adult polymyositis/72 adult dermatomyositis/48 juvenile dermatomyositis (JDM)] in the Rituximab in Myositis trial. Clinical improvement was defined as 20% improvement in at least 3 of 6 core set measures (CSM) of disease activity: physician and patient/parent global disease activity, manual muscle testing, physical function, muscle enzymes, and extramuscular disease activity. We analyzed the association of the following baseline variables with improvement: myositis clinical subgroup, demographics, myositis damage, clinical and laboratory parameters, CSM, rituximab treatment, and myositis autoantibodies (anti-synthetase, -Mi-2, -SRP, -TIF1-γ, -MJ, other and no autoantibodies). All measures were univariately assessed for association with improvement using time-to-event analyses. A multivariable time-dependent proportional hazards model was used to evaluate the association of individual predictive factors with improvement.
In the final multivariable model, the presence of an anti-synthetase [primarily anti-Jo-1 (HR 3.08, p<0.01)], anti-Mi-2 (HR 2.5, p<0.01), or other autoantibody (HR 1.4, p=0.14) predicted a shorter time to improvement compared to the autoantibody negative subset. Lower physician global damage (HR 2.32, p< 0.01) and JDM (vs. adult myositis, HR 2.45, p<0.01) also predicted improvement. Unlike the autoantibody subset, the predictive effect of physician global damage and JDM diminished by week 20. Rituximab treatment did not affect these associations.
The presence of an anti-synthetase and anti-Mi-2 autoantibodies, JDM subset and lower disease damage strongly predicted clinical improvement in refractory myositis patients.
PMCID: PMC3987896  PMID: 24574235
predictor; clinical improvement; myositis; autoantibody
7.  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
12.  Premature cell senescence and T cell receptor-independent activation of CD8T cells in Juvenile Idiopathic Arthritis* 
Arthritis and rheumatism  2013;65(8):2201-2210.
CD8T cells lacking CD28 were originally reported by Wedderburn and colleagues as a characteristic feature of JIA, but the relevance of these unusual cells to JIA remains to be elucidated. Because of recent evidence that CD28 loss is typical of terminally differentiated lymphocytes, we examined for functional subsets of CD8T cells in JIA.
Following informed consent/assent, blood and/or waste synovial fluid were collected from children with definite diagnosis of JIA (n = 98). De-identified blood (n = 33) and cord blood (n = 13) samples from healthy donors were also collected. CD8T and CD4T cells were screened for novel receptors, and where indicated, bioassays were performed to determine functional relevance of the identified receptor.
Patients had a naïve T cell compartment with shortened telomeres, and their entire T cell pool had reduced proliferative capacity. They had an over abundance of CD31+CD28null CD8T cells, which was a significant feature of oligoarticular JIA (n = 62) compared to polyarticular JIA (n = 36). CD31+CD28null CD8T cells had limited mitotic capacity, and expressed high levels of the senescence antigens γH2Ax and/or p16. Ligation of CD31, independent of the TCR, sufficiently induced tyrosine phosphorylation, vesicle exocytosis, and production of IFN-γ and IL-10.
These data provide the first evidence for cell senescence, represented by CD31+CD28null CD8T cells, in the pathophysiology of JIA. Activation of these unusual cells in a TCR-independent manner suggests they are maladaptive, and could be potential targets for immunotherapy.
PMCID: PMC3729743  PMID: 23686519
not included in the title: CD28; CD31; cell senescence
13.  Secondary analysis of APPLE study suggests atorvastatin may reduce atherosclerosis progression in pubertal lupus patients with higher C reactive protein 
Annals of the rheumatic diseases  2013;73(3):557-566.
Participants in the Atherosclerosis Prevention in Paediatric Lupus Erythematosus (APPLE) trial were randomised to placebo or atorvastatin for 36 months. The primary endpoint, reduced carotid intima medial thickness (CIMT) progression, was not met but atorvastatin-treated participants showed a trend of slower CIMT progression. Post-hoc analyses were performed to assess subgroup benefit from atorvastatin therapy.
Subgroups were prespecified and defined by age (> or ≤15.5 years), systemic lupus erythematosus (SLE) duration (> or ≤24 months), pubertal status (Tanner score ≥4 as post-pubertal or <4 as pre-pubertal), low density lipoprotein cholesterol (LDL) (≥ or <110 mg/dl) and high-sensitivity C reactive protein (hsCRP) (≥ or <1.5 mg/l). A combined subgroup (post-pubertal and hsCRP≥1.5 mg/l) was compared to all others. Longitudinal linear mixed-effects models were developed using 12 CIMT and other secondary APPLE outcomes (lipids, hsCRP, disease activity and damage, and quality of life). Three way interaction effects were assessed for models.
Significant interaction effects with trends of less CIMT progression in atorvastatin-treated participants were observed in pubertal (3 CIMT segments), high hsCRP (2 CIMT segments), and the combined high hsCRP and pubertal group (5 CIMT segments). No significant treatment effect trends were observed across subgroups defined by age, SLE duration, LDL for CIMT or other outcome measures.
Pubertal status and higher hsCRP were linked to lower CIMT progression in atorvastatin-treated subjects, with most consistent decreases in CIMT progression in the combined pubertal and high hsCRP group. While secondary analyses must be interpreted cautiously, results suggest further research is needed to determine whether pubertal lupus patients with high CRP benefit from statin therapy. identifier
PMCID: PMC4104199  PMID: 23436914
14.  Clinical Characteristics of Children With Juvenile Dermatomyositis: The Childhood Arthritis and Rheumatology Research Alliance Registry 
Arthritis care & research  2014;66(3):404-410.
To investigate aspects of juvenile dermatomyositis (DM), including disease characteristics and treatment, through a national multicenter registry.
Subjects meeting the modified Bohan and Peter criteria for definite juvenile DM were analyzed from the cross-sectional Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry between 2010 and 2012 from 55 US pediatric rheumatology centers. Demographics, disease characteristics, diagnostic assessments, and medication exposure data were collected at enrollment.
A total of 384 subjects met the criteria for analysis. At enrollment, the median Childhood Myositis Assessment Scale score was 51 (interquartile range [IQR] 46–52), the median Childhood Health Assessment Questionnaire score was 0 (IQR 0–0.5), and the median physician and subject global assessment scores were 1 (IQR 0–2) and 1 (IQR 0–3), respectively, out of a maximum of 10. Of the diagnostic assessments, magnetic resonance imaging was more likely than electromyography or muscle biopsy to show abnormalities. A total of 329 subjects had ≥2 diagnostic studies performed, and >34% of these subjects reported ≥1 negative study. Ninety-five percent had been treated with corticosteroids and 92% with methotrexate, suggesting that these medications were almost universally prescribed for juvenile DM in the US.
In 2 years, the ongoing CARRA Registry has collected clinical data on 384 children with juvenile DM and has the potential to become one of the largest juvenile DM cohorts in the world. More research is needed about prognostic factors in juvenile DM, and differences in therapy based on manifestations of disease need to be explored by practitioners. This registry provides the infrastructure needed to advance clinical and translational research and represents a major step toward improving outcomes of children with juvenile DM.
PMCID: PMC4078654  PMID: 23983017
15.  Susceptibility to childhood onset rheumatoid arthritis: Investigation of a weighted genetic risk score that integrates cumulative effects of variants at five genetic loci 
Arthritis and rheumatism  2013;65(6):1663-1667.
Children with rheumatoid-factor or anti-citrullinated peptide antibody positive juvenile idiopathic arthritis represent the childhood onset of RA (CORA). To test the hypothesis that adult-onset RA-associated variants are also associated with CORA, we investigated RA-associated variants at five loci in our CORA cohort. We also assessed the cumulative association of these variants in the susceptibility to CORA using a weighted genetic risk score (wGRS).
155 children with CORA and 684 healthy controls were genotyped for five variants in PTPN22, TRAF1/C5, STAT4, and TNFAIP3 loci. High-resolution HLA-DRB1 genotypes were available for 149 cases and 373 controls. We tested each locus for association with CORA via logistic regression. We also computed a wGRS for each subject, with weights based on the natural log of the published odds ratios for the alleles investigated, and used logistic regression to test the wGRS for association with CORA.
CORA was associated with TNFAIP3-rs10499194 [OR 0.60 (95%CI 0.44–0.83)], PTPN22-rs2476601 [OR 1.61 (1.11–2.31)], and STAT4-rs7574865 [OR 1.41 (1.06–1.87)] variants. The wGRS was significantly different between cases and controls (P<2×10−16). Individuals in the third to fifth quintiles of wGRS had a significantly increased disease risk compared to the baseline. Higher wGRS associated with increased risk of CORA, especially among males.
TNFAIP3, STAT4 and PTPN22 variants are associated with CORA in a similar magnitude and direction as in RA, suggesting that adult-onset RA and CORA share common genetic risk factors. Utilizing a wGRS, we have demonstrated the cumulative association of RA-associated variants in the susceptibility to CORA.
PMCID: PMC3683854  PMID: 23450725
juvenile idiopathic arthritis; rheumatoid arthritis; genetics; association
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
17.  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
18.  Rituximab in the Treatment of Refractory Adult and Juvenile Dermatomyositis and Adult Polymyositis: A Randomized, Placebo-phase Trial 
Arthritis and rheumatism  2013;65(2):314-324.
To assess the safety and efficacy of rituximab in a randomized, double-blind, placebo-phase, trial of adult and pediatric myositis.
Adults with refractory polymyositis and adults and children with refractory dermatomyositis were enrolled. Entry criteria included muscle weakness and ≥2 additional abnormal core set measures (CSM) for adults. JDM patients required ≥ 3 abnormal CSM with or without muscle weakness. Patients were randomized to either ‘rituximab early’ or ‘rituximab late’ and glucocorticoid and immunosuppressive therapy were allowed at entry. The primary endpoint compared the time to achieve the preliminary International Myositis Assessment and Clinical Studies Group definition of improvement (DOI) between the 2 groups. The secondary endpoints were time to achieve ≥20% improvement in muscle strength, and the proportion of early and late rituximab patients achieving DOI at week 8.
Among 200 randomized patients (76 PM/76 DM/48 JDM), 195 showed no difference in the time to DOI between the rituximab late (n=102) and rituximab early (n=93) groups (p=0.74, log rank) with a median time to DOI of 20.2 weeks and 20.0 weeks respectively. The secondary endpoints also did not significantly differ between the two treatment groups. However, 161 (83%) of randomized patients met the DOI and individual CSM improved in both groups throughout the 44-week trial.
Although there were no significant differences in the two treatment arms for the primary and secondary endpoints, 83% of refractory adult and juvenile myositis patients met the DOI. The role of B cell depleting therapies in myositis warrants further study with consideration for a different trial design.
PMCID: PMC3558563  PMID: 23124935
19.  MRI guided wire localization muscle biopsy in a child with juvenile dermatomyositis 
A novel technique for preoperative MRI guided wire localization for targeted surgical excisional biopsy of muscle is described in a pediatric patient with juvenile dermatomyositis (JDM). This technique allows for preoperative localization of abnormalities seen only with MRI. Using this technique, the patient underwent successful targeted muscle biopsy for confirmation of the diagnosis and staging of dermatomyositis.
PMCID: PMC3635941  PMID: 23566445
Juvenile dermatomyositis; Myopathy; MRI; Guide wire localization
20.  Consensus Treatments for Moderate Juvenile Dermatomyositis: Beyond the First Two Months 
Arthritis care & research  2012;64(4):546-553.
To use consensus methods and the considerable expertise contained within the Children’s Arthritis and Rheumatology Research Alliance (CARRA) organization, to extend the 3 previously developed treatment plans for moderate juvenile dermatomyositis (JDM) to span the full course of treatment.
A consensus meeting was held in Chicago on April 23–24, 2010 involving 30 pediatric rheumatologists and 4 lay participants. Nominal group technique was used to achieve consensus on treatment plans which represented typical management of moderate JDM. A pre-conference survey of CARRA, completed by 151/272 (56%) members, was used to provide additional guidance to discussion.
Consensus was reached on timing and rate of steroid tapering, duration of steroid therapy, and actions to be taken if patients were unchanged, worsening, experiencing medication side effects or disease complications. Of particular importance, a single, consensus steroid taper was developed.
We were able to develop consensus treatment plans which describe therapy for moderate JDM throughout the treatment course. These treatment plans can now be used clinically, and data collected prospectively regarding treatment effectiveness and toxicity. This will allow comparison of these treatment plans and facilitate the development of evidence-based treatment recommendations for moderate JDM.
PMCID: PMC3315594  PMID: 22076847
21.  An Interferon Signature in the Peripheral Blood of Dermatomyositis Patients is Associated with Disease Activity 
Molecular Medicine  2007;13(1-2):59-68.
Recent studies have shown increased expression of interferon (IFN)-regulated genes in the peripheral blood cells of patients with systemic lupus erythematosus. A similar interferon signature has been observed in affected muscle tissue from patients with dermatomyositis (DM), but it has not yet been determined if this signature extends to the peripheral blood in DM. We performed global gene expression profiling of peripheral blood cells from adult and juvenile DM patients and healthy controls. Several interesting groups of genes were differentially expressed in DM, including genes with immune function, and others that function in muscle or are involved in mitochondrial/oxidative phosphorylation. Investigation of type I IFN-regulated transcripts revealed a striking interferon signature present in most DM patients studied. Levels of type I IFN-regulated proteins were also elevated in DM serum samples. Furthermore, both the transcript and serum protein IFN signatures were associated with disease activity. These data suggest that the IFN signature may be a useful marker for DM disease activity, and that sampling peripheral blood may be a more practical alternative to muscle biopsy for measuring this signature.
PMCID: PMC1869622  PMID: 17515957
22.  Type I interferon pathway in adult and juvenile dermatomyositis 
Gene expression profiling and protein studies of the type I interferon pathway have revealed important insights into the disease process in adult and juvenile dermatomyositis. The most prominent and consistent feature has been a characteristic whole blood gene signature indicating upregulation of the type I interferon pathway. Upregulation of the type I interferon protein signature has added additional markers of disease activity and insight into the pathogenesis of the disease.
PMCID: PMC3334651  PMID: 22192711
23.  Evaluation of Muscles Affected by Myositis Using Magnetic Resonance Elastography 
Muscle & nerve  2011;43(4):585-590.
Idiopathic inflammatory myopathies (IIM or myositis), is a group of autoimmune diseases that result in decreased muscle strength and/or endurance. Non-invasive tools to assess muscle may improve our understanding of the clinical and functional consequences of myopathies and their response to treatment. This study examined Magnetic Resonance Elastography (MRE), a non-invasive technique that assesses the shear modulus (stiffness) of muscle, in IIM subjects.
Nine subjects with active myositis completed the MRE protocol. Participants lay in a positioning device, and scans of the vastus medialis (VM) were taken in the relaxed state and at two contraction levels. Manual inversion was used to estimate the stiffness.
A significant reduction in muscle stiffness was seen in myositis subjects compared with healthy controls during the ‘relaxed’ condition.
The use of non-invasive technologies such as MRE may provide greater understanding of the pathophysiology of IIM and improve assessment of treatment efficacy.
PMCID: PMC3059125  PMID: 21319167
Muscle; Magnetic Resonance Elastography (MRE); Myositis; Muscle Stiffness; Noninvasive
24.  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
25.  The Cutaneous Assessment Tool (CAT): Development and Reliability in Juvenile Idiopathic Inflammatory Myopathy 
Rheumatology (Oxford, England)  2007;46(10):1606-1611.
Clinical care and therapeutic trials in idiopathic inflammatory myopathies (IIM) require accurate and consistent assessment of cutaneous involvement. The Cutaneous Assessment Tool (CAT) was designed to measure skin activity and damage in IIM. We describe the development and inter-rater reliability of the CAT, and the frequency of lesions endorsed in a large population of juvenile IIM patients.
The CAT includes 10 activity, 4 damage and 7 combined lesions. Thirty-two photographic slides depicting IIM skin lesions were assessed by 11 raters. One hundred and twenty three children were assessed by 11 pediatric rheumatologists at ten centers. Inter-rater reliability was assessed using simple agreements and intra-class correlation coefficients (ICC).
Simple agreements in recognizing lesions as present or absent were generally high (0.5 – 1.0). ICC's for CAT lesions were moderate (0.4 – 0.75) in both slides and real patients. ICC's for the CAT activity and damage scores were 0.71 and 0.81, respectively. CAT activity scores ranged from 0 – 44 (median 7, potential range 0 – 96) and CAT damage scores ranged from 0 – 13 (median 1, potential range 0 – 22). The most common cutaneous lesions endorsed were periungual capillary loop changes (63%), Gottron's papules/sign (53%), heliotrope rash (49%) and malar/facial erythema (49%).
Total CAT activity and damage scores have moderate to good reliability. Assessors generally agree on the presence of a variety of cutaneous lesions. The CAT is a promising, semi-quantitative tool to comprehensively assess skin disease activity and damage in IIM.
PMCID: PMC2598780  PMID: 17890275
Juvenile Idiopathic Inflammatory Myopathy; Juvenile Dermatomyositis; Skin Disease; Cutaneous Assessment Tool; CAT; Assessment

Results 1-25 (27)