Frederick W Miller

IWK Health Centre, Halifax, Nova Scotia, Canada

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Publications (167)1093.73 Total impact

  • Lisa G Rider, Katalin Dankó, Frederick W Miller
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    ABSTRACT: Clinical registries and biorepositories have proven extremely useful in many studies of diseases, especially rare diseases. Given their rarity and diversity, the idiopathic inflammatory myopathies, or myositis syndromes, have benefited from individual researchers' collections of cohorts of patients. Major efforts are being made to establish large registries and biorepositories that will allow many additional studies to be performed that were not possible before. Here, we describe the registries developed by investigators and patient support groups that are currently available for collaborative research purposes.
    Current opinion in rheumatology. 09/2014;
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    ABSTRACT: Background:Autoantibodies are of growing interest in cancer research as potential biomarkers; yet the determinants of autoimmunity are not well understood. Antinuclear antibodies (ANA) are common in the general population, and are more prevalent in women and older adults. Here we examined the relationship of ANA with reproductive and hormonal factors in a representative sample of U.S. women. Methods:We analyzed data on reproductive history and exogenous hormone use in relation to serum ANA in 2,037 females ages 12 and older from the National Health and Nutrition Examination Survey (NHANES; 1999-2004). Estimated ANA prevalences were adjusted for sampling weights. Prevalence odds ratios (POR) and 95% confidence intervals (CI) were adjusted for age, race and poverty-income-ratio, and models were stratified by menopause status. Results:In premenopausal women ages 20 and older, ANA prevalence was associated with parity (p<0.001; parous versus nulliparous POR=2.0; 95%CI 1.2, 3.4), but in parous women ANA did not vary by number of births, age at first birth, years since last birth or breastfeeding. In postmenopausal women, ANA prevalence was associated with an older age at menarche (p=0.019; age 16-20 versus 10-12 years POR=3.0, 95%CI 1.6, 5.9), but not with parity. Oral contraceptives and estrogen therapy were not associated with a higher ANA prevalence. Conclusions:Childbearing (having had one or more births) may explain age-associated elevations in ANA prevalence seen in premenopausal women. Impact:These findings highlight the importance of considering reproductive history in studies of autoimmunity and cancer in women.
    08/2014;
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    ABSTRACT: We aimed to assess changes in myositis core set measures and ancillary clinical and laboratory data from the National Institutes of Health's subset of patients enrolled in the Rituximab in Myositis trial.
    Clinical and experimental rheumatology 07/2014; · 2.66 Impact Factor
  • Annals of the rheumatic diseases 05/2014; · 8.11 Impact Factor
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    ABSTRACT: Objective Because juvenile idiopathic inflammatory myopathies (IIMs) are potentially life-threatening systemic autoimmune diseases, we examined risk factors for juvenile IIM mortality.Methods Mortality status was available for 405 patients (329 with juvenile dermatomyositis [DM], 30 with juvenile polymyositis [PM], and 46 with juvenile connective tissue disease–associated myositis [CTM]) enrolled in nationwide protocols. Standardized mortality ratios (SMRs) were calculated using US population statistics. Cox regression analysis was used to assess univariable associations with mortality, and random survival forest (RSF) classification and Cox regression analysis were used for multivariable associations.ResultsOf 17 deaths (4.2% overall mortality), 8 (2.4%) were in juvenile DM patients. Death was related to the pulmonary system (primarily interstitial lung disease [ILD]) in 7 patients, gastrointestinal system in 3, and multisystem in 3, and of unknown etiology in 4 patients. The SMR for juvenile IIMs overall was 14.4 (95% confidence interval [95% CI] 12.2–16.5) and was 8.3 (95% CI 6.4–10.3) for juvenile DM. The top mortality risk factors in the univariable analysis included clinical subgroup (juvenile CTM, juvenile PM), antisynthetase autoantibodies, older age at diagnosis, ILD, and Raynaud's phenomenon at diagnosis. In multivariable analyses, clinical subgroup, illness severity at onset, age at diagnosis, weight loss, and delay to diagnosis were the most important predictors from RSF; clinical subgroup and illness severity at onset were confirmed by multivariable Cox regression analysis.Conclusion Overall mortality was higher in juvenile IIM patients, and several early illness features were identified as risk factors. Clinical subgroup, antisynthetase autoantibodies, older age at diagnosis, and ILD are also recognized as mortality risk factors in adult myositis.
    Arthritis Care & Research. 05/2014; 66(5).
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    ABSTRACT: In environmental epidemiology, measurements of exposure biomarkers often fall below the assay's limit of detection. Existing methods for handling this problem, including deletion, substitution, parametric regression, and multiple imputation, can perform poorly if the proportion of "nondetects" is high or parametric models are misspecified. We propose an approach that treats the measured analyte as the modeled outcome, implying a role reversal when the analyte is a putative cause of a health outcome. Following a scale reversal as well, our approach uses Cox regression to model the analyte, with confounder adjustment. The method makes full use of quantifiable analyte measures, while appropriately treating nondetects as censored. Under the proportional hazards assumption, the hazard ratio for a binary health outcome is interpretable as an adjusted odds ratio: the odds for the outcome at any particular analyte concentration divided by the odds given a lower concentration. Our approach is broadly applicable to cohort studies, case-control studies (frequency matched or not), and cross-sectional studies conducted to identify determinants of exposure. We illustrate the method with cross-sectional survey data to assess sex as a determinant of 2,3,7,8-tetrachlorodibenzo-p-dioxin concentration and with prospective cohort data to assess the association between 2,4,4'-trichlorobiphenyl exposure and psychomotor development.
    American journal of epidemiology 04/2014; 179(8):1018-24. · 5.59 Impact Factor
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    ABSTRACT: Studies of twin pairs discordant for autoimmune conditions provide a unique opportunity to explore contributing factors triggered by complex gene-environment interactions. In this cross-sectional study, thirty-one monozygotic or dizygotic twin pairs discordant for myositis or systemic lupus erythematosus (SLE), along with matched healthy controls were evaluated for antibodies against a panel of 21 autoantigens. Autoantibody profiling revealed that 42% of the affected twins showed significant seropositivity against autoantigens in the panel. In many of these affected twins, but none of healthy controls, there were high levels of autoantibodies detected against two or more autoantigens commonly seen in systemic autoimmune diseases including Ro52, Ro60, RNP-70 K and/or RNP-A. In contrast, only 10% (3/31) of the unaffected twins showed seropositivity and these immunoreactivities were against single autoantigens not seen in systemic autoimmune diseases. While no significant differences in autoantibodies were detected between the affected or unaffected twins against thyroid peroxidase, transglutaminase and several cytokines, 23% of the affected twins with myositis showed autoantibodies against the gastric ATPase. Analysis of the monozygotic twins separately also revealed a higher frequencies of autoantibodies in the affected twins compared to the unaffected twins (P = 0.046). Lastly, clinical analysis of both the affected monozygotic and dizygotic twins revealed that the autoantibody seropositive affected twins had a greater global disease activity score compared to seronegative affected twins (P = 0.019). The findings of significantly more autoantibodies in the affected twins with myositis and SLE compared to the unaffected twins are consistent with potential non-genetic factors playing a role in autoantibody production and pathogenesis of these autoimmune disorders.
    BMC Musculoskeletal Disorders 03/2014; 15(1):67. · 1.88 Impact Factor
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    ABSTRACT: Background/Purpose:Three disease courses can be distinguished in patients with juvenile idiopathic inflammatory myopathies (JIIM): monocyclic (M), polycyclic (P), and chronic continuous (CC). Predictors of disease course could result in improved therapy and help focus research efforts. We examined the association of immunogenetic and environmental factors with disease course in a large JIIM cohort.Methods:We enrolled 240 Caucasian patients with JIIM (204 dermato-, 21 poly-, and 15 overlap myositis) diagnosed from 1980–2010 in the US and Canada into IRB-approved studies. The ratio of girls to boys was 3:1. Median age at diagnosis was 7 years (IQR: 5–12). Physician questionnaires with clinical and demographic data and patient blood samples were obtained. Follow-up was through medical record review. The disease course classification was as follows: M—no active disease and off medication within 2 years of diagnosis (n = 62); P—disease recurrence after definite remission (n = 62); and CC—persistent disease or continuation of medication for more than 2 years (n = 116). Genetic data included: high resolution HLA-DRB1 and HLA-DQA1 alleles, and peptide binding motifs; immunoglobulin gamma heavy and kappa light chain phenotypes and allotypes; and TNFα (−238, −308), IL-1α (−889, +4845), and IL-1β (−511, −3953) polymorphisms. Environmental data included: documentation of infections within 6 months prior to illness onset; average and highest ultraviolet (UV) index for the month prior to illness onset and prior to diagnosis based on residential location; season of illness onset; and geoclimatic regions and planting zones of residential location at illness onset.Results:HLA-DRB1*1501 was present more frequently in the M group (22%) compared to the P (5%; OR [95% CI]=5.7 [1.1–29.0]; p=0.04) and CC groups (7%; OR=4.0 [12.4–1.3]; p=0.02). In patients with dermatomyositis only, the F25 peptide binding was present less frequently in the M group (18%) compared to the P (41%; OR = 0.3 [0.1–0.8]; p = 0.02) and CC groups (39%; OR = 0.3 [0.1–0.8]; p = 0.02). The other HLA alleles and peptide binding motifs, immunoglobulin gamma heavy and kappa light chain phenotypes and allotypes, and cytokine polymorphisms (including TNFα-308) were not associated with disease course. Infections 6 months prior to illness onset were more often present in the P group (40%) compared to the M (18%; OR = 3.0 [1.3–7.2]; p = 0.01) and CC groups (21%; OR = 2.5 [1.2–5.2]; p = 0.01). Three-quarter of these infections were respiratory. In girls, the average UV index in the month before diagnosis was higher in the P group (median [IQR] = 5.7 [4.0–6.6]) compared to the M group (median [IQR] = 4.3 [1.2–5.6]; p = 0.01). Season of illness onset, geoclimatic regions, and planting zones did not differ among the 3 disease courses.Conclusion:Immunogenetic factors, including HLA alleles, and environmental factors, including a history of preceding infections and the UV index at diagnosis, were significantly associated with disease course in this population of Caucasian patients with JIIM. Future studies are needed to confirm these associated factors and to identify the value of these factors in determining prognosis.
    Arthritis & Rheumatology. 03/2014; 66(S11).
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    ABSTRACT: Background/Purpose:Inadequate classification criteria for IIM are a fundamental limitation in clinical studies. An international, multidisciplinary collaboration, the International Myositis Classification Criteria Project (IMCCP), supported by ACR and EULAR, was established to address this problem.Methods:Identification and definition of potential criterionCandidate variables to be included in classification criteria were assembled from published criteria and inclusion criteria in controlled trials of myositis and refined using Nominal Group Technique. Comparator groups confused with IIM were defined.Data collectionWithin this retrospective case control study, clinical and laboratory data from IIM and comparator patients were collected from 47 rheumatology, dermatology, neurology and pediatrics clinics worldwide from 2008–2011.AnalysisCrude pair-wise associations among all variables measured and between each variable and clinician's diagnosis were assessed. Three approaches for derivation of classification criteria were explored: Traditional: case defined by specified number of items from a set Risk score: patient assigned a probability risk score by summing score-points associated with the variables (Probability model 1 and 2) Classification tree: case defined by a decision treeA random forest algorithm explored the most important variables. Results obtained with each approach were utilized to improve others iteratively.ValidationInternal validation using bootstrap methods was performed. External validation using extracted data from the Euromyositis register and an UK juvenile myositis register was performed.Results:Data from 973 IIM patients (74% adults;26% children), representing subgroups of IIM (245 polymyositis, 239 dermatomyositis, 176 inclusion body myositis and 246 juvenile dermatomyositis cases) and 629 comparators (81% adults; 19% children) were obtained. The comparators include other myopathies and systemic rheumatic diseases.Two probability score models were developed (Table 2): Model 1 comprised clinical variables on muscles, skin, and laboratory measures; Model 2 additionally comprised muscle biopsy variables. Model 1 performed nearly as well as Model 2 and both models performed as well as and often better than, the classification tree that was developed and published criteria.External validation using data on 2363 myositis patients in the Euromyositis register resulted in >99% sensitivity, and using 332 juvenile myositis cases resulted in 100% sensitivity for both probability models.1Table 1. PERFORMANCE OF NEW AND EXISITING CLASSIFICATION/DIAGNOSTIC CRITERIA FOR IIMProbability model†Performance(%)Without muscle biopsy data(Model 1)With muscle biopsy data (Model 2)Classification TreePeter & Bohan [1]‡Tanimoto et al. [2]Targoff et al.[3]‡Dalakas & Hohlfeld [4]‡Hoogendijk et al.[5]‡aCut point for probability: 55%bDefinite and probable polymyositis and dermatomyositisSensitivity878888989693651Specificity8889725531889996Correctly classified8788848679914570Table 2. New model for classification criteria for IIM and performance of criteriaProbability modelVariableScore pointsaWhen muscle biopsies are available, multiply the score-sum of all other variables by 0.9 and then add the scores of the positive biopsies. Probability of disease can be obtained using the web calculator: www.imm.ki.se/biostatistics/calculators/iim18 ≤ Age of onset of first symptom < 401.6Age of onset of first symptom ≥ 402.3Clinical Muscle Variables Objective symmetric weakness, usually progressive, of the proximal upper extremities0.7Objective symmetric weakness, usually progressive, of the proximal lower extremities0.6Neck flexors are relatively weaker than neck extensors1.6In the legs proximal muscles are relatively weaker than distal muscles1.5Skin Variables Heliotrope rash3.3Gottronxs papules2.3Gottron's sign3.4Other Clinical Variables Dysphagia or esophageal dysmotility0.7Laboratory Variables Serum creatine kinase activity (CK) activity1.2Serum lactate dehydrogenase (LDH) activity or Serum aspartate aminotransferase (ASAT/AST/SGOT) activity or Serum alanine aminotransferase (ALAT/ALT/SGPT) activity Anti-Jo-1 (anti-His) antibody positivity4.2Score-sum from above items§0.9Muscle Biopsy Variables Endomysial infiltration of mononuclear cells surrounding, but not invading, myofibers1.4Perimysial and/or perivascular infiltration of mononuclear cells1.2Perifascicular atrophy1.6Rimmed vacoules2.2Conclusion:New classification criteria for IIM with readily clinically assessable measurements and symptoms have been developed. They generally show superior performance compared with existing criteria.
    Arthritis & Rheumatology. 03/2014; 66(S11).
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    ABSTRACT: Background/Purpose:The myositis syndromes are rare systemic autoimmune diseases with poorly understood etiologies. We present the demographics, illness features and treatments of patients with juvenile dermatomyositis (JDM) who enrolled in a newly created national registry.Methods:Using a patient database from The Myositis Association and supplemental advertisements, a national registry of myositis patients was established. Between December 2010 and July 2012 questionnaires were mailed to 8847 myositis patients in the US and Canada. The questionnaire queried demographics, clinical features, environmental exposures, and quality of life. Descriptive statistics and multivariable logistic regression analysis were computed using GraphPad Prysm and SAS.Results:1956 patients (22%) returned the questionnaire and consented to participate; 1806 who met probable or definite Bohan and Peter criteria for myositis were included (708 DM, 483 PM, 466 IBM, 139 JDM, 10 JPM); juvenile patients were diagnosed before age 18 years. Of the 139 JDM patients, the median age at diagnosis was 6.9 years and median disease duration at enrollment was 10.3 years. Most JDM patients were female (78%) and Non-Hispanic Caucasian (88%), and the remainder were Hispanic (6.5%), Asian (2.9%), multiple races (2.2%), and Black (0.7%). Patients or their parents often completed a graduate degree (23%) or college degree (29%). JDM patients were primarily diagnosed by a pediatric rheumatologist (48%), with adult and pediatric dermatologists (22%), pediatric neurologists and primary care physicians (11% each) diagnosing most of the remaining patients; 67% were under the care of a pediatric rheumatologist. JDM patients frequently had skin rashes as a major manifestation (86%); arthritis (35%) and dysphagia (32%) were also common, whereas lung disease (12%) was less frequent. An additional autoimmune disease was present in 18% of JDM patients, with JIA (8%) and SLE and celiac disease (3% each) the most frequent. There were no recorded associated malignancies. 98% of JDM patients received prednisone therapy. Methotrexate was the most common steroid-sparing agent (84%), followed by hydroxychloroquine (60%), IV pulse solumedrol (54%), IVIG (48%), cyclosporine (19%), rituximab and anti-TNFs (10% each). Predictors of which agents were received varied among medications, but included age, year of JDM diagnosis, gender, and region of country. Pulse solumedrol and cyclosporine were more likely to be used in JDM patients with dysphagia, hydroxychloroquine in patients with skin rashes and less likely in those with fevers, and azathioprine was less likely in patients with arthritis. Of medications utilized, 45% of JDM patients reported responding best to IVIG, 39% responded best to prednisone, 33% to anti-TNFs, and 29% to cyclophosphamide.Conclusion:A nationwide myositis registry has been established and includes a subsample of JDM patients that appears demographically and clinically representative of other US populations. This registry may help identify environmental exposures associated with myositis, elucidate factors associated with quality of life, and serve as an important resource for future clinical investigations.
    Arthritis & Rheumatology. 03/2014; 66(S11).
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    ABSTRACT: Autoimmune diseases include 80 or more complex disorders characterized by self-reactive, pathologic immune responses in which genetic susceptibility is largely insufficient to determine disease onset. In September 2010, the National Institute of Environmental Health Sciences (NIEHS) organized an expert panel workshop to evaluate the role of environmental factors in autoimmune diseases, and the state of the science regarding relevant mechanisms, animal models, and human studies. The objective of the workshop was to analyze the existing data to identify conclusions that could be drawn regarding environmental exposures and autoimmunity and to identify critical knowledge gaps and areas of uncertainty for future study. This consensus document summarizes key findings from published workshop monographs on areas in which "confident" and "likely" assessments were made, with recommendations for further research. Transcribed notes and slides were reviewed to synthesize an overview on exposure assessment and questions addressed by interdisciplinary panels. Critical advances in the field of autoimmune disease research have been made in the past decade. Collaborative translational and interdisciplinary research is needed to elucidate the role of environmental factors in autoimmune diseases. A focus on exposure assessment methodology is needed to improve the effectiveness of human studies, and more experimental studies are needed to focus on causal mechanisms underlying observed associations of environmental factors with autoimmune disease in humans.
    International Journal of Molecular Sciences 01/2014; 15(8):14269-14297. · 2.46 Impact Factor
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    ABSTRACT: Clinical trial design in interstitial lung diseases (ILDs) has been hampered by lack of consensus on appropriate outcome measures for reliably assessing treatment response. In the setting of connective tissue diseases (CTDs), some measures of ILD disease activity and severity may be confounded by non-pulmonary comorbidities. The Connective Tissue Disease associated Interstitial Lung Disease (CTD-ILD) working group of Outcome Measures in Rheumatology-a non-profit international organisation dedicated to consensus methodology in identification of outcome measures-conducted a series of investigations which included a Delphi process including >248 ILD medical experts as well as patient focus groups culminating in a nominal group panel of ILD experts and patients. The goal was to define and develop a consensus on the status of outcome measure candidates for use in randomised controlled trials in CTD-ILD and idiopathic pulmonary fibrosis (IPF). A core set comprising specific measures in the domains of lung physiology, lung imaging, survival, dyspnoea, cough and health-related quality of life is proposed as appropriate for consideration for use in a hypothetical 1-year multicentre clinical trial for either CTD-ILD or IPF. As many widely used instruments were found to lack full validation, an agenda for future research is proposed. Identification of consensus preliminary domains and instruments to measure them was attained and is a major advance anticipated to facilitate multicentre RCTs in the field.
    Thorax 12/2013; · 8.38 Impact Factor
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    ABSTRACT: Objective To differentiate juvenile polymyositis (PM) and muscular dystrophy, both of which may present with chronic muscle weakness and inflammation. Methods We studied 39 patients with probable or definite juvenile PM and 9 patients with muscular dystrophies who were initially misdiagnosed as having juvenile PM. Differences in demographic, clinical, and laboratory results; outcomes; and treatment responses were evaluated by Fisher's exact and rank sum tests. Random forests classification analysis and logistic regression were performed to examine significant differences in multivariable models. ResultsClinical features and serum muscle enzyme levels were similar between juvenile PM and dystrophy patients, except 89% of dystrophy patients had muscle atrophy compared with 46% of juvenile PM patients. Dystrophy patients had a longer delay to diagnosis (median 12 versus 4 months) and were less frequently hospitalized than juvenile PM patients (22% versus 74%). No dystrophy patients, but 54% of juvenile PM patients, had a myositis autoantibody. Dystrophy patients more frequently had myopathic features on muscle biopsy, including diffuse variation of myofiber size, fiber hypertrophy, and myofiber fibrosis (44–100% versus 8–53%). Juvenile PM patients more frequently had complex repetitive discharges on electromyography and a complete response to treatment with prednisone or other immunosuppressive agents than dystrophy patients (44% versus 0%). Random forests analysis revealed that the most important features in distinguishing juvenile PM from dystrophies were myositis autoantibodies, clinical muscle atrophy, and myofiber size variation on biopsy. Logistic regression confirmed muscle atrophy, myofiber fibrosis, and hospitalization as significant predictors. Conclusion Muscular dystrophy can present similarly to juvenile PM. Selected clinical and laboratory features are helpful in combination in distinguishing these conditions.
    Arthritis Care & Research. 12/2013; 65(12).
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    ABSTRACT: Objective To identify new genetic associations with juvenile and adult dermatomyositis (DM). Methods We performed a genome-wide association study (GWAS) of adult and juvenile DM patients of European ancestry (n = 1,178) and controls (n = 4,724). 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. ResultsCompared to controls, patients with DM had a strong signal in the MHC region consisting of GWAS-level significance (P < 5 × 10–8) at 80 genotyped SNPs. An analysis of 141 non-MHC SNPs previously associated with autoimmune diseases showed that 3 SNPs linked with 3 genes were associated with DM, with a false discovery rate (FDR) of
    Arthritis & Rheumatology 12/2013; 65(12). · 7.48 Impact Factor
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    ABSTRACT: Objective: The aim was to identify the clinical and laboratory predictors of clinical improvement in a cohort of myositis patients treated with rituximab. Methods: 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. Results: 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. Conclusion: 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. © 2013 American College of Rheumatology.
    Arthritis & Rheumatology 11/2013; · 7.48 Impact Factor
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    ABSTRACT: Objective. Genetic and environmental factors may contribute to the etiology of the juvenile idiopathic inflammatory myopathies (JIIM), systemic autoimmune diseases characterized by muscle and skin inflammation. We investigated the association between ultraviolet radiation (UVR) exposure and the clinical and autoantibody expression of JIIM. Methods. We assessed the relationship between UVR exposure in the month before symptom onset and prevalence of juvenile dermatomyositis (JDM) versus polymyositis (JPM) in 298 patients. Among JDM patients, the association between UVR exposure and myositis autoantibodies was assessed. Regression models were stratified by sex and race. The association between regional UV index in U.S. geoclimatic zones and the clinical and autoantibody subgroups was examined by weighted least squares regression analysis. Results. We observed increasing odds of JDM compared with JPM per unit increase in the patients' highest UV index in the month before symptom onset in girls (OR = 1.18; 95% CI = 1.00-1.40). The average and highest UV indices were associated with increasing odds of anti-p155/140 autoantibodies, which was strongest in white males (OR 1.30 and 1.23, respectively). No association was observed between the UV index and anti-MJ autoantibodies or patients without myositis autoantibodies. Across US geoclimatic regions, the average UV index was associated with increasing odds of JDM and anti-p155/140 autoantibodies but decreasing odds of anti-MJ autoantibodies. Conclusion. Short-term UVR exposure prior to illness onset may have a role in the clinical and serologic expression of juvenile myositis. Research examining mechanisms of UVR in JIIM pathogenesis is suggested from these findings. © 2013 American College of Rheumatology.
    Arthritis & Rheumatology 05/2013; · 7.48 Impact Factor
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    ABSTRACT: Although historically considered as junk-DNA, tandemly repeated sequence motifs can affect human phenotype. For example, variable number tandem repeats (VNTR) with embedded enhancers have been shown to regulate gene transcription. The post-zygotic variation is the presence of genetically distinct populations of cells in an individual derived from a single zygote, and this is an understudied aspect of genome biology. We report somatically variable VNTR with sequence properties of an enhancer, located upstream of IFNAR1. Initially, SNP genotyping of 63 monozygotic twin pairs and multiple tissues from 21 breast cancer patients suggested a frequent post-zygotic mosaicism. The VNTR displayed a repeated 32 bp core motif in the center of the repeat, which was flanked by similar variable motifs. A total of 14 alleles were characterized based on combinations of segments, which showed post-zygotic and inter-individual variation, with up to 6 alleles in a single subject. Somatic variation occurred in ∼24% of cases. In this hypervariable region, we found a clustering of transcription factor binding sites with strongest sequence similarity to mouse Foxg1 transcription factor binding motif. This study describes a VNTR with sequence properties of an enhancer that displays post-zygotic and inter-individual genetic variation. This element is within a locus containing four related cytokine receptors: IFNAR2, IL10Rβ, IFNAR1 and IFNGR2, and we hypothesize that it might function in transcriptional regulation of several genes in this cluster. Our findings add another level of complexity to the variation among VNTR-based enhancers. Further work may unveil the normal function of this VNTR in transcriptional control and its possible involvement in diseases connected with these receptors, such as autoimmune conditions and cancer.
    PLoS ONE 01/2013; 8(9):e67752. · 3.53 Impact Factor
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    ABSTRACT: The juvenile idiopathic inflammatory myopathies (JIIM) are systemic autoimmune diseases characterized by skeletal muscle weakness, characteristic rashes, and other systemic features. Although juvenile dermatomyositis (JDM), the most common form of JIIM, has been well studied, the other major clinical subgroups of JIIM, including juvenile polymyositis (JPM) and juvenile myositis overlapping with another autoimmune or connective tissue disease (JCTM), have not been well characterized, and their similarity to the adult clinical subgroups is unknown. We enrolled 436 patients with JIIM, including 354 classified as JDM, 33 as JPM, and 49 as JCTM, in a nationwide registry study. The aim of the study was to compare demographics; clinical features; laboratory measures, including myositis autoantibodies; and outcomes among these clinical subgroups, as well as with published data on adult patients with idiopathic inflammatory myopathies (IIM) enrolled in a separate natural history study.We used random forest classification and logistic regression modeling to compare clinical subgroups, following univariate analysis. JDM was characterized by typical rashes, including Gottron papules, heliotrope rash, malar rash, periungual capillary changes, and other photosensitive and vasculopathic skin rashes. JPM was characterized by more severe weakness, higher creatine kinase levels, falling episodes, and more frequent cardiac disease. JCTM had more frequent interstitial lung disease, Raynaud phenomenon, arthralgia, and malar rash. Differences in autoantibody frequency were also evident, with anti-p155/140, anti-MJ, and anti-Mi-2 seen more frequently in patients with JDM, anti-signal recognition particle and anti-Jo-1 in JPM, and anti-U1-RNP, PM-Scl, and other myositis-associated autoantibodies more commonly present in JCTM. Mortality was highest in patients with JCTM, whereas hospitalizations and wheelchair use were highest in JPM patients. Several demographic and clinical features were shared between juvenile and adult IIM subgroups. However, JDM and JPM patients had a lower frequency of interstitial lung disease, Raynaud phenomenon, "mechanic's hands" and carpal tunnel syndrome, and lower mortality than their adult counterparts. We conclude that juvenile myositis is a heterogeneous group of illnesses with distinct clinical subgroups, defined by varying clinical and demographic characteristics, laboratory features, and outcomes.
    Medicine 12/2012; · 4.35 Impact Factor
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    ABSTRACT: OBJECTIVE: To assess the safety and efficacy of rituximab in a randomized, double-blind, placebo-phase, trial of adult and pediatric myositis. METHODS: 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. RESULTS: 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. CONCLUSION: 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. © 2012 American College of Rheumatology.
    Arthritis & Rheumatology 11/2012; · 7.48 Impact Factor
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    ABSTRACT: Increasing evidence supports a role for the environment in the development of autoimmune diseases, as reviewed in the accompanying three papers from the National Institute of Environmental Health Sciences Expert Panel Workshop. An important unresolved issue, however, is the development of criteria for identifying autoimmune disease phenotypes for which the environment plays a causative role, herein referred to as environmentally associated autoimmune diseases. There are several different areas in which such criteria need to be developed, including: 1) identifying the necessary and sufficient data to define environmental risk factors for autoimmune diseases meeting current classification criteria; 2) establishing the existence of and criteria for new environmentally associated autoimmune disorders that do not meet current disease classification criteria; and 3) identifying in clinical practice specific environmental agents that induce autoimmune disease in individual patients. Here we discuss approaches that could be useful for developing criteria in these three areas, as well as factors that should be considered in evaluating the evidence for criteria that can distinguish individuals with such disorders from individuals without such disorders with high sensitivity and specificity. Current studies suggest that multiple lines of complementary evidence will be important and that in many cases there will be clinical, serologic, genetic, epigenetic, and/or other laboratory features that could be incorporated as criteria for environmentally associated autoimmune diseases to improve diagnosis and treatment and possibly allow for preventative strategies in the future.
    Journal of Autoimmunity 07/2012; · 8.15 Impact Factor

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Institutions

  • 2004–2014
    • IWK Health Centre
      Halifax, Nova Scotia, Canada
    • The Ohio State University
      Columbus, Ohio, United States
    • University College London
      • Division of Medicine
      London, ENG, United Kingdom
  • 2003–2014
    • National Institute of Environmental Health Sciences
      • Epidemiology Branch
      Durham, North Carolina, United States
  • 1988–2013
    • National Institutes of Health
      • • Center for Clinical Research
      • • National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
      • • Department of Laboratory Medicine
      • • Laboratory of Cellular and Molecular Immunology
      Maryland, United States
  • 2012
    • University of Florida
      • Department of Medicine
      Gainesville, FL, United States
  • 2009
    • National Institute of Standards and Technology
      Maryland, United States
    • Oregon State University
      Corvallis, Oregon, United States
    • Georgetown University
      • Division of Dermatology
      Washington, D. C., DC, United States
    • Tokyo Dental College
      • Department of Internal Medicine
      Edo, Tōkyō, Japan
  • 2008
    • George Washington University
      • School of Medicine and Health Sciences
      Washington, D. C., DC, United States
  • 2007
    • Dalhousie University
      Halifax, Nova Scotia, Canada
  • 1990–2006
    • University of Oklahoma Health Sciences Center
      Oklahoma City, Oklahoma, United States
  • 2005
    • University of Pittsburgh
      Pittsburgh, Pennsylvania, United States
  • 2001–2003
    • Thomas Jefferson University
      • Division of Rheumatology
      Philadelphia, PA, United States
  • 1993–2003
    • U.S. Food and Drug Administration
      • • Center for Biologics Evaluation and Research
      • • Division of Monoclonal Antibodies
      • • Laboratory of Molecular Virology
      • • Center for Food Safety and Applied Nutrition
      Washington, D. C., DC, United States
  • 1987–2003
    • National Institute of Arthritis and Musculoskeletal and Skin Diseases
      Maryland, United States
  • 2000
    • Stanford University
      Palo Alto, California, United States
  • 1995
    • Columbia Memorial Hospital
      Hudson, New York, United States