Idiopathic inflammatory myopathies (IIMs) are a heterogenous group of complex muscle diseases of unknown etiology. These diseases are characterized by progressive muscle weakness and damage, together with involvement of other organ systems. It is generally believed that the autoimmune response (autoreactive lymphocytes and autoantibodies) to skeletal muscle-derived antigens is responsible for the muscle fiber damage and muscle weakness in this group of disorders. Therefore, most of the current therapeutic strategies are directed at either suppressing or modifying immune cell activity. Recent studies have indicated that the underlying mechanisms that mediate muscle damage and dysfunction are multiple and complex. Emerging evidence indicates that not only autoimmune responses but also innate immune and non-immune metabolic pathways contribute to disease pathogenesis. However, the relative contributions of each of these mechanisms to disease pathogenesis are currently unknown. Here we discuss some of these complex pathways, their inter-relationships and their relation to muscle damage in myositis. Understanding the relative contributions of each of these pathways to disease pathogenesis would help us to identify suitable drug targets to alleviate muscle damage and also improve muscle weakness and quality of life for patients suffering from these debilitating muscle diseases.
Adaptive immune; Autophagy; Cytokines; Endoplasmic reticulum stress; Innate immune; Myositis; Skeletal muscle; TLRs
Background: Identification of mononuclear cellular infiltrates in skeletal muscle tissue is the histological cornerstone of the diagnosis of idiopathic inflammatory myopathy (IIM). However, these infiltrates are not always present.
Objective: To determine whether MHC class I antigen expression on the sarcolemma, which is absent in normal muscle tissue, is upregulated in IIM and could serve as an additional diagnostic test.
Methods: Expression of MHC class I antigens was studied in 224 muscle samples of 61 adult patients with IIM (9 dermatomyositis, 23 polymyositis, 29 inclusion body myositis) and 163 controls (normal subjects and patients with various neuromuscular disorders) in a prospective blinded manner.
Results: The sensitivity of the test for diagnosing IIM was 78% (95% confidence interval (CI), 66% to 88%), with a specificity of 95% (91% to 98%). The sensitivity before the start of immunosuppressive treatment was 89% (76% to 96%). The sensitivity was not changed by including all patients who had been on immunosuppressive treatment for less than four weeks before muscle biopsy (sensitivity 90% (79% to 97%)). False positive results were found in only seven controls (4%), six of whom had a muscular dystrophy.
Conclusions: Detection of sarcolemmal MHC class I is a valid test for IIM. It is not affected by the short term use of immunosuppressive agents (less than four weeks) and it should be incorporated in the histological evaluation when the diagnosis of IIM is under consideration or needs to be excluded.
Idiopathic inflammatory myopathies (IIMs) are a rare group of autoimmune syndromes characterized by chronic muscle inflammation and muscle weakness with no known cause. Little is known about their incidence and prevalence. This study reports the incidence and prevalence of IIMs among commercially insured and Medicare and Medicaid enrolled populations in the US.
We retrospectively examined medical claims with an IIM diagnosis (ICD-9-CM 710.3 [dermatomyositis (DM)], 710.4 [polymyositis (PM)], 728.81[interstitial myositis]) in the MarketScan® databases to identify age- and gender-adjusted annual IIM incidence and prevalence for 2004–2008. Sensitivity analysis was performed for evidence of a specialist visit (rheumatologist/ neurologist/dermatologist), systemic corticosteroid or immunosuppressant use, or muscle biopsy.
We identified 2,990 incident patients between 2004 and 2008 (67% female, 17% Medicaid enrollees, 27% aged ≥65 years). Overall adjusted IIM incidence for 2004–2008 for commercial and Medicare supplemental groups combined were 4.27 cases (95% CI, 4.09-4.44) and for Medicaid, 5.23 (95% CI 4.74-5.72) per 100,000 person-years (py). Disease sub-type incidence rates per 100,000-py were 1.52 (95% CI 1.42-1.63) and 1.70 (1.42-1.97) for DM, 2.46 (2.33-2.59) and 3.53 (3.13-3.94) for PM, and 0.73 (0.66-0.81) and 0.78 (0.58-0.97) for interstitial myositis for the commercial/Medicare and Medicaid cohorts respectively. Annual incidence fluctuated over time with the base MarketScan populations. There were 7,155 prevalent patients, with annual prevalence ranging from 20.62 to 25.32 per 100,000 for commercial/Medicare (83% of prevalent cases) and from 15.35 to 32.74 for Medicaid.
We found higher IIM incidence than historically reported. Employer turnover, miscoding and misdiagnosing, care seeking behavior, and fluctuations in database membership over time can influence the results. Further studies are needed to confirm the incidence and prevalence of IIM.
Objective. To investigate expression of vascular endothelial growth factor (VEGF) antiangiogenic isoform A-165b on human muscle in idiopathic inflammatory myopathies (IIM) and to compare distribution of angiogenic/antiangiogenic VEGFs, as isoforms shifts are described in other autoimmune disorders. Subjects and Methods. We analyzed VEGF-A165b and VEGF-A by western blot and immunohistochemistry on skeletal muscle biopsies from 21 patients affected with IIM (polymyositis, dermatomyositis, and inclusion body myositis) and 6 control muscle samples. TGF-β, a prominent VEGF inductor, was analogously evaluated. Intergroup differences of western blot bands density were statistically examined. Endomysial vascularization, inflammatory score, and muscle regeneration, as pathological parameters of IIM, were quantitatively determined and their levels were confronted with VEGF expression. Results. VEGF-A165b was significantly upregulated in IIM, as well as TGF-β. VEGF-A was diffusely expressed on unaffected myofibers, whereas regenerating/atrophic myofibres strongly reacted for both VEGF-A isoforms. Most inflammatory cells and endomysial vessels expressed both isoforms. VEGF-A165b levels were in positive correlation to inflammatory score, endomysial vascularization, and TGF-β. Conclusions. Our findings indicate skeletal muscle expression of antiangiogenic VEGF-A165b and preferential upregulation in IIM, suggesting that modulation of VEGF-A isoforms may occur in myositides.
Muscle inflammation and weakness are the key features of idiopathic inflammatory myopathies (IIMs). In addition IIMs are frequently associated with cutaneous and pulmonary involvement. In clinical practice the three common inflammatory myopathies we come across are polymyositis (PM), dermatomyositis (DM) and inclusion body myositis (IBM). The Bohan and Peter criteria combine clinical, laboratory, and pathologic features to define PM and DM. They did not recognize inclusion body myositis (IBM) or other inflammatory myopathies, such as granulomatous and eosinophilic myositis. Thus the disease spectrum is wide and IIMs are a heterogeneous group of autoimmune disorders. To address these issues in this article we have discussed the currently developing newer classifications of IIMs.
Polymyositis; dermatomyositis; classification; disease spectrum
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.
Muscle; Magnetic Resonance Elastography (MRE); Myositis; Muscle Stiffness; Noninvasive
Objective. Serum cytokines play an important role in the pathogenesis of myositis by initiating and perpetuating various cellular and humoral autoimmune processes. The aim of the present study was to describe a broad spectrum of T- and B-cell cytokines, growth factors and chemokines in patients with idiopathic inflammatory myopathies (IIMs) and healthy individuals.
Methods. A protein array system, denoted as multiplex cytokine assay was utilized to measure simultaneously the levels of 24 circulating cytokines, including B-cell activating factor (BAFF) and a proliferation inducing ligand (APRIL) of patients with IIMs and healthy individuals. Additionally, correlational clustering and discriminant function analysis (DFA), two multivariate, supervised analysis methods were employed to identify a subset of biomarkers in order to describe potential functional interrelationships among these pathological cytokines.
Results. Univariate analysis demonstrated that a complex set of immune and inflammatory modulating cytokines are significantly up-regulated in patients with IIMs relative to unaffected controls including IL-10, IL-13, IFN-α, epidermal growth factor (EGF), VEGF, fibroblast growth factor (FGF), CCL3 [macrophage inflammatory protein (MIP-1α)], CCL4 (MIP-1β) and CCL11 (eotaxin), whereas G-CSF was significantly reduced in IIM patients. Correlational clustering was able to discriminate between, and hence sub-classify patients with IIMs. DFA identified EGF, IFN-α, VEGF, CCL3 (MIP-1α) and IL-12p40, as analytes with the strongest discriminatory power among various myositis patients and controls.
Conclusions. Our findings suggest that these factors modulate myositis pathology and help to identify differences between subsets of the disease.
Idiopathic inflammatory myopathies; Circulating cytokines; B-cell activating factor; A proliferation inducing ligand
The lung is one of the most common extra-muscular targets in idiopathic inflammatory myopathies (IIM) and interstitial lung disease (ILD) is a prevalent and often devastating manifestation of IIM. IIM-associated ILD (IIM-ILD) contributes to nearly 80% of the mortality in IIM with a reported prevalence of 65% of newly diagnosed IIM cases. Although ILD frequently accompanies clinical and laboratory findings of myositis, overt signs of muscle disease may be absent in the setting of significant lung disease. Understanding the varied scope of presentation of these diseases is essential to providing optimal patient care. This review will provide an in depth examination of ILD in IIM both from a rheumatologic and pulmonary perspective and will discuss the scope of disease, presenting features, genetic associations, pathogenesis, diagnosis, radiographic and histopathologic findings, along with biomarker assessment and a rationale for therapeutic intervention.
Myopathy; polymyositis; dermatomyositis; myositis; interstitial lung disease
Objective. Treatment-resistant muscle wasting is an increasingly recognized problem in idiopathic inflammatory myopathy (IIM). TNF-α is thought to induce muscle catabolism via activation of nuclear factor-kappa B (NF-κB). Several genes share homology with the NF-κB family of proteins. This study investigated the role of NF-κB-related genes in disease susceptibility in UK Caucasian IIM.
Methods. Data from 362 IIM cases [274 adults, 49 (±14.0) years, 72% female; 88 juveniles, 6 (±3.6) years, 73% female) were compared with 307 randomly selected Caucasian controls. DNA was genotyped for 63 single nucleotide polymorphisms (SNPs) from NF-κB-related genes. Data were stratified by IIM subgroup/serotype.
Results. A significant allele association was observed in the overall IIM group vs controls for the IKBL-62T allele (rs2071592, odds ratio 1.5, 95% CI 1.21, 1.89, corrected P = 0.0086), which strengthened after stratification by anti-Jo-1 or -PM-Scl antibodies. Genotype analysis revealed an increase for the AT genotype in cases under a dominant model. No other SNP was associated in the overall IIM group. Strong pairwise linkage disequilibrium was noted between IKBL-62T, TNF-308A and HLA-B*08 (D′ = 1). Using multivariate regression, the IKBL-62T IIM association was lost after adjustment for TNF-308A or HLA-B*08.
Conclusion. An association was noted between IKBL-62T and IIM, with increased risk noted in anti-Jo-1- and -PM-Scl antibody-positive patients. However, the IKBL-62T association is dependent on TNF-308A and HLA-B*08, due to strong shared linkage disequilibrium between these alleles. After adjustment of the 8.1 HLA haplotype, NF-κB genes therefore do not independently confer susceptibility in IIM.
polymyositis; dermatomyositis; single nucleotide polymorphisms; immunogenetics; autoantibodies; NF-κB; TNF
Interstitial lung disease (ILD) is a common and severe complication of idiopathic inflammatory myopathies (IIM). The aim of our study was to identify risk factors for ILD by evaluating both clinical and biochemical features in IIM patients with or without ILD. From January 2008 to December 2011, medical records of 134 IIM patients in our rheumatology unit were reviewed. The patients were divided into ILD group (83 patients) and non-ILD group (51 patients). The clinical features and laboratory findings were compared. The univariable analyses indicated that arthritis/arthralgia (54.2% versus 17.6%, P < 0.05), Mechanic's hand (16.9% versus 2.0%, P < 0.05), Raynaud's phenomenon (36.1% versus 2.0%, P < 0.05), heliotrope rash (44.6% versus 19.6%, P < 0.05), fever (43.4% versus 21.6%, P < 0.05), elevated ESR (60.2% versus 35.3%, P < 0.05), elevated CRP (55.4% versus 31.4%, P < 0.05), or anti-Jo-1 antibody (20.5% versus 5.9%, P < 0.05) were risk factors for developing ILD in IIM. Multivariable unconditional logistic regression analysis that showed arthritis/arthralgia (OR 7.1, 95% CI 2.8–18.1), Raynaud's phenomenon (OR 29.1, 95% CI 3.6–233.7), and amyopathic dermatomyositis (ADM) (OR 20.2, 95% CI 2.4–171.2) were the independent risk factors for developing ILD in IIM.
Idiopathic inflammatory myopathies (IIMs), comprising of polymyositis, dermatomyositis, and inclusion-body myositis, are characterized by muscle weakness and various types of inflammatory changes in muscle cells. They also show non-inflammatory changes, including perifascicular atrophy, mitochondrial changes, and amyloid protein accumulation. It is possible that some molecules/mechanisms bridge the extracellular inflammatory stimulation and intracellular non-inflammatory changes. One such mechanism, Ca2+ influx leading to calpain activation has been proposed. In this study, we demonstrated that post-treatment with calpeptin (calpain inhibitor) attenuated intracellular changes to prevent apoptosis (Wright staining) through both mitochondrial pathway (increase in Bax:Bcl-2 ratio) and endoplasmic reticulum stress pathway (activation of caspase-12), which were induced by interferon-gamma (IFN-γ) stimulation in rat L6 myoblast cells. Our results also showed that calpeptin treatment inhibited the expression of calpain, aspartyl protease cathepsin D, and amyloid precursor protein. Thus, our results indicate that calpain inhibition plays a pivotal role in attenuating muscle cell damage from inflammatory stimulation due to IFN-γ, and this may suggest calpain as a possible therapeutic target in IIMs.
Apoptosis; Calpain; Inflammation; Interferon-gamma; Mitochondria; Myoblast cells; Myositis
Idiopathic inflammatory myopathies (IIMs), comprising polymyositis, dermatomyositis, and inclusion-body myositis, are characterized by inflammatory cell infiltrates in skeletal muscle tissue, muscle weakness, and muscle fatigue. The cellular infiltrates often consist of T lymphocytes and macrophages but also, in some cases, B lymphocytes. Emerging data have led to improved phenotypic characterization of the inflammatory cells, including their effector molecules, in skeletal muscle, peripheral blood, and other organs that are frequently involved, such as skin and lungs. In this review we summarize the latest findings concerning the role of T lymphocytes, B lymphocytes, dendritic cells, and other antigen-presenting cells in the pathophysiology of IIMs.
Introduction. Idiopathic inflammatory myopathies (IIMs) are a group of chronic systemic autoimmune diseases that mainly affect the skeletal muscle. The common subtypes include adult dermatomyositis (DM), polymyositis (PM), and inclusion body myositis (IBM). Most of the earlier studies that described the clinical characteristics of IIM as well as their association with cancer were conducted in Western population. Our study is the first systematic review that summarizes the clinical data of DM/PM in Asian population. Methods. We identified 14 case series of DM/PM that met our eligibility criteria. We then compared this data with that from previous reports from Europe and North America. Results. Our systematic review included 2518 patients. Dermatomyositis is more common, with the ratio of dermatomyositis to polymyositis being 1.36 : 1. 69% of them were females with mean age of 45.5 years. Extramuscular manifestations, including arthritis/arthralgia, dysphagia, and interstitial lung disease, are found in one-third of the patients. Malignancy was found in 10% of patients, with lung and nasopharyngeal carcinomas being the most common malignancies associated with these myopathies. Conclusion. Clinical presentation of PM/DM appears to be similar in both Western and Asian populations. However, the type of associated malignancies in Asians differs from that in Caucasians. Ethnic background should be one of the factors that clinicians should consider while screening for malignancy.
We assessed birth patterns of patients with idiopathic inflammatory myopathies (IIM), hypothesizing that seasonal early environmental exposures influence later development of autoimmune disease.
Juvenile-onset patients (n = 307) and healthy controls (n = 3,942) were born from 1970−1999, and adult-onset patients (n = 668) and controls (n = 6,991) from 1903−1982. Birth dates were analyzed as circular data. Seasonal clustering was assessed by the Rayleigh test, and differences between groups by a rank-based Uniform-Scores Test.
The overall birth distributions of juvenile IIM patients and controls did not significantly differ nor did those of adult IIM patients vs. controls. Subgroups of juvenile IIM showed seasonal birth distributions: Hispanic juvenile IIM patients had a seasonal birth pattern (mean October 16), differing (p = 0.002) from those of Hispanic controls (uniform birth distribution) and from non-Hispanic juvenile patients (mean May 2, p < 0.001). Juvenile dermatomyositis patients with p155 autoantibody differed in birth distribution (p = 0.003) from p155 antibody-negative juvenile dermatomyositis patients. Juvenile IIM patients with the human leukocyte antigen (HLA) risk factor allele DRB1*0301 differed in birth distribution (p = 0.021) from those without the allele. Similar results were observed for juvenile and adult IIM patients with the linked allele DQA1*0501. No significant seasonal birth patterns were found for other subgroups.
Birth distributions appear to have stronger seasonality in juvenile than adult IIM subgroups, suggesting greater influence of perinatal exposures on childhood-onset illness. Seasonal early-life exposures may influence the onset of some autoimmune diseases later in life.
Myositis; Environmental Factors; Autoimmune Diseases
This review summarizes the previous and current literature on the immunogenetics of idiopathic inflammatory myopathy (IIM) and updates the research progress that has been made over the past decade. A substantial part of the genetic risk for developing adult- and juvenile-onset IIM lies within the major histocompatibility complex (MHC), and a tight relationship exists between individual human leukocyte antigen alleles and specific serological subtypes, which in turn dictate clinical disease phenotypes. Multiple genetic regions outside of the MHC are increasingly being identified in conferring IIM disease susceptibility. We are still challenged with the task of studying a serologically and clinically heterogeneous disorder that is rarer by orders of magnitude than the likes of rheumatoid arthritis. An ongoing and internationally coordinated IIM genome-wide association study may provide further insights into IIM immunogenetics.
HLA-DRB1*03 is strongly associated with anti-Jo-1-positive idiopathic inflammatory myopathies (IIM) and there is now increasing evidence that Jo-1 antigen is preferentially expressed in lung tissue. This study examined whether smoking was associated with the development of anti-Jo-1 antibodies in HLA-DRB1*03-positive IIM.
IIM cases were selected with concurrent information regarding HLA-DRB1 status, smoking history and anti-Jo-1 antibody status. DNA was genotyped at DRB1 using a commercial sequence-specific oligonucleotide kit. Anti-Jo-1 antibody status was established using a line blot assay or immunoprecipitation.
557 Caucasian IIM patients were recruited from Hungary (181), UK (99), Sweden (94) and Czech Republic (183). Smoking frequency was increased in anti-Jo-1-positive IIM cases, and reached statistical significance in Hungarian IIM (45% Jo-1-positive vs 17% Jo-1-negative, OR 3.94, 95% CI 1.53 to 9.89, p<0.0001). A strong association between HLA-DRB1*03 and anti-Jo-1 status was observed across all four cohorts (DRB1*03 frequency: 74% Jo-1-positive vs 35% Jo-1-negative, OR 5.55, 95% CI 3.42 to 9.14, p<0.0001). The frequency of HLA-DRB1*03 was increased in smokers. The frequency of anti-Jo-1 was increased in DRB1*03-positive smokers vs DRB1*03-negative non-smokers (42% vs 8%, OR 7.75, 95% CI 4.21 to 14.28, p<0.0001) and DRB1*03-positive non-smokers (42% vs 31%, p=0.08). In DRB1*03-negative patients, anti-Jo-1 status between smokers and non-smokers was not significantly different. No significant interaction was noted between smoking and DRB1*03 status using anti-Jo-1 as the outcome measure.
Smoking appears to be associated with an increased risk of possession of anti-Jo-1 in HLA-DRB1*03-positive IIM cases. The authors hypothesise that an interaction between HLA-DRB1*03 and smoking may prime the development of anti-Jo-1 antibodies.
Macrophages play a critical role in both innate and acquired immunity because of their unique ability to internalize, kill, and degrade bacterial pathogens through the process of phagocytosis. The adaptor protein, amphiphysin IIm, participates in phagocytosis and is transiently associated with early phagosomes. Certain pathogens, including Chlamydia pneumoniae, have evolved mechanisms to subvert macrophage phagosome maturation and, thus, are able to survive within these cells. We report here that, although amphiphysin IIm is usually only transiently associated with the phagosome, it is indefinitely retained on vacuoles containing C. pneumoniae. Under these wild-type conditions, C. pneumoniae do not elicit significant nitric oxide (NO) production and are not killed. Abrogation of amphiphysin IIm function results in C. pneumoniae–induced NO production and in the sterilization of the vacuole. The data suggest that C. pneumoniae retains amphiphysin IIm on the vacuole to survive within the macrophage.
innate immunity; bacterial infection; pathogen; phagocytosis; nitric oxide
Objectives. The paediatric idiopathic inflammatory myopathies (IIMs) are a group of rare chronic inflammatory disorders of childhood, affecting muscle, skin and other organs. There is a severe lack of evidence base for current treatment protocols in juvenile myositis. The rarity of these conditions means that multicentre collaboration is vital to facilitate studies of pathogenesis, treatment and disease outcomes. We have established a national registry and repository for childhood IIM, which aims to improve knowledge, facilitate research and clinical trials, and ultimately to improve outcomes for these patients.
Methods. A UK-wide network of centres and research group was established to contribute to the study. Standardized patient assessment, data collection forms and sample protocols were agreed. The Biobank includes collection of peripheral blood mononuclear cells, serum, genomic DNA and biopsy material. An independent steering committee was established to oversee the use of data/samples. Centre training was provided for patient assessment, data collection and entry.
Results. Ten years after inception, the study has recruited 285 children, of which 258 have JDM or juvenile PM; 86% of the cases have contributed the biological samples. Serial sampling linked directly to the clinical database makes this a highly valuable resource. The study has been a platform for 20 sub-studies and attracted considerable funding support. Assessment of children with myositis in contributing centres has changed through participation in this study.
Conclusions. This establishment of a multicentre registry and Biobank has facilitated research and contributed to progress in the management of a complex group of rare muscloskeletal conditions.
Juvenile myositis; Dermatomyositis; Idiopathic inflammatory myopathy; Paediatric; Registry; Biobank; Multicentre
In idiopathic inflammatory myopathies (IIMs), extracellular inflammatory stimulation is considered to induce secondary intracellular inflammatory changes including expression of major histocompatibility complex class-I (MHC-I) and to produce self-sustaining loop of inflammation. We hypothesize that activation of calpain, a Ca2+-sensitive protease, bridges between these extracellular inflammatory stress and intracellular secondary inflammatory changes in muscle cells. In this study, we demonstrated that treatment of rat L6 myoblast cells with interferon-gamma (IFN-γ) caused expression of MHC-I and inflammation related transcription factors (phosphorylated-extracellular signal-regulated kinase 1/2 and nuclear factor-kappa B). We also demonstrated that treatment with tumor necrosis factor-alpha (TNF-α) induced apoptotic changes and activation of calpain and cyclooxygenase-2. Further, we found that post-treatment with calpeptin attenuated the intracellular changes induced by IFN-γ or TNF-α. Our results indicate that calpain inhibition attenuates apoptosis and secondary inflammatory changes induced by extracellular inflammatory stimulation in the muscle cells. These results suggest calpain as a potential therapeutic target for treatment of IIMs.
Calpain; Immune inflammatory myopathy; Interferon-gamma; Myoblast cells; Tumor necrosis factor-alpha
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.
Juvenile Idiopathic Inflammatory Myopathy; Juvenile Dermatomyositis; Skin Disease; Cutaneous Assessment Tool; CAT; Assessment
The idiopathic inflammatory myopathies (IIMs) are rare disorders with the unifying feature of proximal muscle weakness. These diseases include polymyositis(PM), dermatomyositis (DM) and inclusion body myositis (IBM) as the most common. The diagnosis is based on the finding of weakness on exam, elevated muscles enzymes, characteristic histopathology of muscle biopsies, electromyography abnormalities and rash in DM. Myositis-specific antibodies have been helpful in defining subsets of patients with different responses to treatment and prognosis. The cornerstone of therapy is corticosteroids with the addition of other immunosuppressives in severe or refractory disease or patients with intolerable side effects. IBM is particularly difficult to treat but is more slowly progressive as compared with PM or DM. There is still a great need to find more effective and less-toxic therapies.
dermatomyositis; inclusion body myositis; idiopathic inflammatory myopathies; polymyositis
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.
Little is known about the clinical features and true survival risk factors in Chinese Han population. We conducted the current study to investigate the clinical features, long-term outcome and true potential indicators associated with mortality of idiopathic inflammatory myopathies (IIM) in China.
We restrospectvely investigated 188 patients diagnosed with IIM at our hospital from January 1986 to April 2009. The primary outcome was determined with mortality. The secondary outcomes for survival patients were organ damage and disease activity, health status, and disability, which were assessed with Myositis Damage Index, Myositis Disease Activity Assessment Visual Analogue Scales, Health Assessment Questionnaire Disability Index, and the Modified Rankin Scale, respectively. Potential prognostic factors for mortality were analyzed with the multivariate Cox regression model.
Mean age at disease onset was 43.8 ± 15.8 years and male to female ratio was 1:2.1 in this cohort. The 1-, 5-, 10-, 15- and 20-year survival rates were 93.6%, 88.7%, 81%, 73.6% and 65.6%. The independent predicators for mortality were age at disease onset [hazard ratio (HR):1.05, 95% CI 1.02 - 1.08], presence of cancer (HR:3.68, 95%CI 1.39 - 9.74), and elevated IgA level at diagnosis (HR:2.80, 95% CI 1.16-6.74). At the end of the follow-up, 29 patients manifested drug withdrawal within an average 4.1 years (range 0.5-15.2 year), most patients (85.9%) had no disease activity and 130 patients (83.4%) had no disability.
The long-term outcomes of IIM patients in our cohort have improved dramatically. Those patients most likely to survive had a high chance of reaching stable disease status, and obtained long-term or possibly permanent remission to a large extent.
The objective of this study is to determine if multiple systemic autoimmune diseases (SAID) share gene expression pathways that could provide insights into pathogenic mechanisms common to these disorders.
RNA microarray analyses (Agilent Human 1A(V2) 20K oligo arrays) were used to quantify gene expression in peripheral blood cells from 20 monozygotic (MZ) twin pairs discordant for SAID. Six affected probands with systemic lupus erythematosus (SLE), six with rheumatoid arthritis (RA), eight with idiopathic inflammatory myopathies (IIM), and their same-gendered unaffected twins, were enrolled. Comparisons were made between discordant twin pairs and these were also each compared to 40 unrelated control subjects (matched 2:1 to each twin by age, gender and ethnicity) using statistical and molecular pathway analyses. Relative quantitative PCR was used to verify independently measures of differential gene expression assessed by microarray analysis.
Probands and unrelated, matched controls differed significantly in gene expression for 104 probes corresponding to 92 identifiable genes (multiple-comparison adjusted P values < 0.1). Differentially expressed genes involved several overlapping pathways including immune responses (16%), signaling pathways (24%), transcription/translation regulators (26%), and metabolic functions (15%). Interferon (IFN)-response genes (IFI27, OASF, PLSCR1, EIF2AK2, TNFAIP6, and TNFSF10) were up-regulated in probands compared to unrelated controls. Many of the abnormally expressed genes played regulatory roles in multiple cellular pathways. We did not detect any probes expressed differentially in comparisons among the three SAID phenotypes. Similarly, we found no significant differences in gene expression when comparing probands to unaffected twins or unaffected twins to unrelated controls. Gene expression levels for unaffected twins appeared intermediate between that of probands and unrelated controls for 6535 probes (32% of the total probes) as would be expected by chance. By contrast, in unaffected twins intermediate ordering was observed for 84 of the 104 probes (81%) whose expression differed significantly between probands and unrelated controls.
Alterations in expression of a limited number of genes may influence the dysregulation of numerous, integrated immune response, cell signaling and regulatory pathways that are common to a number of SAID. Gene expression profiles in peripheral blood suggest that for genes in these critical pathways, unaffected twins may be in a transitional or intermediate state of immune dysregulation between twins with SAID and unrelated controls, perhaps predisposing them to the development of SAID given the necessary and sufficient environmental exposures.
Purpose of review
Recent literature in inflammatory myopathies suggests that both immune (cell-mediated and humoral) and non-immune (endoplasmic reticulum (ER) stress and autophagy) mechanisms play a role in muscle fiber damage and dysfunction. This review describes these findings and discusses their relevance to disease pathogenesis and therapy.
Recent data highlights the role of ER stress response especially the roles of Hexose-6-phosphate dehydrogenase and ER-anchored RING finger E3 ligase in the activation of unfolded protein response and the formation of vacuoles and inclusions in myopathies. Several studies investigated the link between inflammation and the beta amyloid associated muscle fiber degeneration and loss of muscle function. Likewise, the roles of ER stress and autophagy in skeletal muscle damage have been explored in multiple muscle diseases.
Current data indicate that the ER stress, NF-kB pathway and autophagy are active in the skeletal muscle of myositis patients, and the pro-inflammatory NF-kB pathway connects the immune and non-immune pathways of muscle damage. The relative contributions of each of these pathways to muscle fiber damage are presently unclear. Therefore further defining the role of these pathways in disease pathogenesis should help to design effective therapeutic agents for these diseases.
endoplasmic reticulum; idiopathic myopathy; skeletal muscle; cell death; autophagy and NF-kB activation