Predictors of survival in a cohort of patients with polymyositis and dermatomyositis: effect of corticosteroids, methotrexate and azathioprine

Introduction: The idiopathic inflammatory myopathies are rare diseases for which data regarding the natural history, response to therapies and factors affecting mortality are needed. We performed this study to examine the effects of treatment and clinical features on survival in polymyositis and dermatomyositis patients. Methods: A total of 160 consecutive patients (77 with polymyositis and 83 with dermatomyositis) seen at the University of Michigan from 1997 to 2003 were included. Medical records were abstracted for clinical, laboratory and therapeutic data, including initial steroid regimen and immunosuppressive use. State vital records were utilized to derive mortality and cause of death data. Survival was modeled by left-truncated Kaplan-Meier estimation and Cox regression. Results: The 5- and 10-year survival estimates were 77% (95% CI = 66 to 85), and 62% (95% CI = 48 to 73), respectively, and the rates were similar for polymyositis and dermatomyositis. Survival between the sexes was similar through 5 years and significantly lower thereafter for males (10-year survival: 18% male, 73% female; P = 0.002 for 5- to 10-year interval). The sex disparity was restricted to the polymyositis group. Increased age at diagnosis and non-Caucasian race were associated with lower survival. Intravenous versus oral corticosteroid use was associated with a higher risk of death among Caucasians (HR = 10.6, 95% CI = 2.1 to 52.8). Early survival between patients treated with methotrexate versus azathioprine was similar, but survival at 10 years was higher for the methotrexate-treated group (76% vs 52%, P = 0.046 for 5- to 10-year interval). Conclusions: Patients treated initially with intravenous corticosteroids had higher mortality, which was likely related to disease severity. Both methotrexate and azathioprine showed similar early survival benefits as first-line immunosuppressive drugs. Survival was higher between 5 and 10 years in the methotrexate-treated group, but could not be confirmed in multivariable modeling for the full follow-up period. Other important predictors of longterm survival included younger age, female sex and Caucasian race.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90025/1/IIM_ART2012.pdf1611

Phase distortions of attosecond pulses produced by resonance-enhanced high harmonic generation

Resonant enhancement of high harmonic generation can be obtained in plasmas containing ions with strong radiative transitions resonant with harmonic orders. The mechanism for this enhancement is still debated. We perform the first temporal characterization of the attosecond emission from a tin plasma under near-resonant conditions for two different resonance detunings. We show that the resonance considerably changes the relative phase of neighbouring harmonics. For very small detunings, their phase locking may even be lost, evidencing strong phase distortions in the emission process and a modified attosecond structure. These features are well reproduced by our simulations, allowing their interpretation in terms of the phase of the recombination dipole moment

A national registry for juvenile dermatomyositis and other paediatric idiopathic inflammatory myopathies: 10 years' experience; the Juvenile Dermatomyositis National (UK and Ireland) Cohort Biomarker Study and Repository for Idiopathic Inflammatory Myopathies

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

Biomarkers in Inflammatory Myopathies – An Expanded Definition

Biomarkers as parameters of pathophysiological conditions can be of outmost relevance for inflammatory myopathies. They are particularly warranted to inform about diagnostic, prognostic, and therapeutic questions. As biomarkers become more and more relevant in daily routine, this review focusses on relevant aspects particularly addressing myopathological features. However, the level of evidence to use them in daily routine at presence is low, still since none of them has been validated in large cohorts of patients and rarely in independent biopsy series. Hence, they should be read as mere expert opinions. The evaluation of biomarkers as well as key biological parameters is an ongoing process, and we start learning about relevance of them, as we must recognize that pathophysiology of myositis is biologically incompletely understood. As such this approach should be considered an essay toward expansion of the definition “biomarker” to myositis, an emerging field of interest in biomedical research

Disease course, frequency of relapses and survival of 73 patients with juvenile or adult dermatomyositis

Objective Our aim is to present the disease course, frequency of relapses and survival of juvenile and adult dermatomyositis (JDM/DM) patients. Methods Analysis was performed using data on 73 patients. The median follow-up for 38 JDM patients was 32 months and 78 months for 35 adult DM patients. Results 23/38 JDM patients (60%) had monophasic, 12/38 (31.6%) had polycyclic and 3138 (7.9%) had chronic disease. Among children treated only with glucocorticoids, 12/20 (60%) had monophasic and 8/20 (40%) had polycyclic disease. 10/17 (58.8%) children, who required second-line immunosuppressive agents, had monophasic and 4/17 (23.5%) had polycyclic disease. 18/35 DM (51.4%) patients had monophasic, 13/35 (37.1%) had polycyclic, 1/35 (2.9%) had chronic disease and 3135 (8.6%) had fulminant myositis. Among DM patients requiring only glucocorticoids, 12/20 (60%) were monophasic and 8/20 (40%) were polycyclic. In patients requiring second-line immunosuppressive agents, 6/15 patients (40%) had monophasic and 5/15 (33.3%) had polycyclic disease. Among patients with polycyclic disease, the risk of relapse was higher during first year than later in the disease course. None of the JDM patients have died, while 4 disease-specific deaths occurred in adult patients. There was no significant difference between the survival of JDM and DM patients. Discussion There was no correlation between relapse-free survival and the initial therapeutic regimen. Many of our patients had polycyclic or chronic disease. As relapses can occur after a prolonged disease-free interval, patients should be followed for at least 2 years. Although we found a favourable survival rate, further investigations are needed to assess functional outcome

Genetic association study of NF-κB genes in UK caucasian adult and juvenile onset idiopathic inflammatory myopathy

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

Decreased expression of breast cancer resistance protein in the duodenum in patients with obstructive cholestasis

Background/Aims: The expression of transporters involved in bile acid homeostasis is differentially regulated during obstructive cholestasis. Since the drug efflux transporter breast cancer resistance protein (BCRP) is known to transport bile acids, we investigated whether duodenal BCRP expression could be altered during cholestasis. Methods: Using real-time RT-PCR analysis we determined mRNA expression levels in duodenal tissue of 19 cholestatic patients. Expression levels were compared to 14 healthy subjects. BCRP protein staining was determined in biopsies of 6 cholestatic and 6 healthy subjects by immunohistochemistry. Results: We found that in patients with obstructive cholestasis mean duodenal BCRP mRNA levels were significantly reduced to 53% and mean protein staining was reduced to 57%. Conclusions: BCRP, a transporter for bile acids and numerous drugs, appears to be down-regulated in the human duodenum during cholestasis. The clinical impact of these results has to be investigated in further studies. Copyright (c) 2006 S. Karger AG, Basel

A dermatopathic Juvenile Dermatomyositis; An Unexpected Case in Childhood

Abstract Juvenile dermatomyositis (JDM) is a rare idiopathic inflammatory disease which usually presents with skin rashes along with muscle weakness. We report a case of JDM in a 10- year-old girl with no skin manifestations.She was presented with progressive muscle weakness and fatigue. Further laboratory investigation along with a muscle biopsy confirmed the diagnosis of Adermathopathic Juvenile Dermatomyositis. The patient was treated with intravenous immunoglobulin, corticosteroids, methotrexate, hydroxychloroquine, pamidronate, and Rituximab.Following treatment, patients symptoms subsided and she gained normal muscular strength over the course of a year

Validation of a score tool for measurement of histological severity in juvenile dermatomyositis and association with clinical severity of disease.

OBJECTIVES: To study muscle biopsy tissue from patients with juvenile dermatomyositis (JDM) in order to test the reliability of a score tool designed to quantify the severity of histological abnormalities when applied to biceps humeri in addition to quadriceps femoris. Additionally, to evaluate whether elements of the tool correlate with clinical measures of disease severity. METHODS: 55 patients with JDM with muscle biopsy tissue and clinical data available were included. Biopsy samples (33 quadriceps, 22 biceps) were prepared and stained using standardised protocols. A Latin square design was used by the International Juvenile Dermatomyositis Biopsy Consensus Group to score cases using our previously published score tool. Reliability was assessed by intraclass correlation coefficient (ICC) and scorer agreement (α) by assessing variation in scorers' ratings. Scores from the most reliable tool items correlated with clinical measures of disease activity at the time of biopsy. RESULTS: Inter- and intraobserver agreement was good or high for many tool items, including overall assessment of severity using a Visual Analogue Scale. The tool functioned equally well on biceps and quadriceps samples. A modified tool using the most reliable score items showed good correlation with measures of disease activity. CONCLUSIONS: The JDM biopsy score tool has high inter- and intraobserver agreement and can be used on both biceps and quadriceps muscle tissue. Importantly, the modified tool correlates well with clinical measures of disease activity. We propose that standardised assessment of muscle biopsy tissue should be considered in diagnostic investigation and clinical trials in JDM

Polimiosite : investigação clínica em duas irmãs

We present an investigation of a case of polymyositis affecting two sisters of one same parenthood. Their cases have been documented for almost two decades, being investigated by means of a diagnostic protocol which combined clinical findings as well as laboratorial, histopathological and image tests. In both cases, clinical manifestations started in childhood, without signs of involvement of the central and peripheral nervous system. Both patients proved to respond to a therapeutics based on corticosteroids. The degree of relatedness between their parents corroborate the notion that genetic factors may contribute to the development of the disease. ___________________________________________________________________________________________________ RESUMOApresentamos a investigação de dois casos de polimiosite, ocorridos entre irmãs de uma mesma filiação. Seus casos foram documentados ao longo de quase duas décadas, tendo sido diagnosticados utilizando- se de protocolo diagnóstico que combinou achados clínicos, exames laboratoriais, histopatológicos e por imagem. Em ambos os casos, as manifestações clínicas se iniciaram ainda na infância, sendo constatada ausência de acometimento do sistema nervoso central ou periférico. Ambas as pacientes responderam satisfatoriamente a terapia baseada em corticosteróide. O grau de parentesco entre os genitores das pacientes sugere que fatores genéticos podem predispor ao desenvolvimento da doença