The juvenile idiopathic inflammatory myopathies (JIIM) are a group of rare, chronic, autoimmune illnesses that affect muscle and, to a lesser extent, skin. The presence of new-onset weakness and, in ...juvenile dermatomyositis, typical rahes, should lead to consideration of these diagnoses. Careful evaluation to exclude alternative diagnoses is needed. Investigations include a variety of blood tests, imaging, and possibly muscle biopsy. Validated clinical assessments are available for monitoring. Standard treatment includes corticosteroids and methotrexate and often extends beyond 1 year. Outcomes are generally good, but disease persistence remains problematic. Early involvement of providers with expertise in JIIM is essential.
Significance Mass mortality events (MMEs), the rapid, catastrophic die-off of organisms, are an example of a rare event affecting natural populations. Individual reports of MMEs clearly demonstrate ...their ecological and evolutionary importance, yet our understanding of the general features characterizing such events is limited. Here, we conducted the first, to our knowledge, quantitative analysis of MMEs across the animal kingdom, and as such, we were able to explore novel patterns, trends, and features associated with MMEs. Our analysis uncovered the surprising finding that there have been recent shifts in the magnitudes of MMEs and their associated causes. Our database allows the recommendation of improvements for data collection in ways that will enhance our understanding of how MMEs relate to ongoing perturbations to ecosystems.
Mass mortality events (MMEs) are rapidly occurring catastrophic demographic events that punctuate background mortality levels. Individual MMEs are staggering in their observed magnitude: removing more than 90% of a population, resulting in the death of more than a billion individuals, or producing 700 million tons of dead biomass in a single event. Despite extensive documentation of individual MMEs, we have no understanding of the major features characterizing the occurrence and magnitude of MMEs, their causes, or trends through time. Thus, no framework exists for contextualizing MMEs in the wake of ongoing global and regional perturbations to natural systems. Here we present an analysis of 727 published MMEs from across the globe, affecting 2,407 animal populations. We show that the magnitude of MMEs has been intensifying for birds, fishes, and marine invertebrates; invariant for mammals; and decreasing for reptiles and amphibians. These shifts in magnitude proved robust when we accounted for an increase in the occurrence of MMEs since 1940. However, it remains unclear whether the increase in the occurrence of MMEs represents a true pattern or simply a perceived increase. Regardless, the increase in MMEs appears to be associated with a rise in disease emergence, biotoxicity, and events produced by multiple interacting stressors, yet temporal trends in MME causes varied among taxa and may be associated with increased detectability. In addition, MMEs with the largest magnitudes were those that resulted from multiple stressors, starvation, and disease. These results advance our understanding of rare demographic processes and their relationship to global and regional perturbations to natural systems.
Juvenile dermatomyositis (JDM) is a heterogeneous disease with new classification criteria and updates in myositis-specific autoantibody and myositis-associated antibody groups. There are many ...validated assessment tools for assessing disease activity in JDM. Future studies will optimize these tools and improve feasibility in clinical and research contexts. Genetic and environmental risk factors, mechanisms of muscle pathology, role of interferon, vascular markers, and changes in immune cells provide insights to JDM pathogenesis. Outcomes have improved, but chronic disease, damage, and mortality highlight the need for better outcome predictors and treatments. Increased collaboration of stakeholders may help overcome research barriers and improve JDM treatment.
The juvenile idiopathic inflammatory myopathies (JIIM) are systemic autoimmune diseases characterized by skeletal muscle weakness, characteristic rashes, and other systemic features. In follow-up to ...our study defining the major clinical subgroup phenotypes of JIIM, we compared demographics, clinical features, laboratory measures, and outcomes among myositis-specific autoantibody (MSA) subgroups, as well as with published data on adult idiopathic inflammatory myopathy patients enrolled in a separate natural history study. In the present study, of 430 patients enrolled in a nationwide registry study who had serum tested for myositis autoantibodies, 374 had either a single specific MSA (n = 253) or no identified MSA (n = 121) and were the subject of the present report. Following univariate analysis, we used random forest classification and exact logistic regression modeling to compare autoantibody subgroups. Anti-p155/140 autoantibodies were the most frequent subgroup, present in 32% of patients with juvenile dermatomyositis (JDM) or overlap myositis with JDM, followed by anti-MJ autoantibodies, which were seen in 20% of JIIM patients, primarily in JDM. Other MSAs, including anti-synthetase, anti-signal recognition particle (SRP), and anti-Mi-2, were present in only 10% of JIIM patients. Features that characterized the anti-p155/140 autoantibody subgroup included Gottron papules, malar rash, "shawl-sign" rash, photosensitivity, cuticular overgrowth, lowest creatine kinase (CK) levels, and a predominantly chronic illness course. The features that differed for patients with anti-MJ antibodies included muscle cramps, dysphonia, intermediate CK levels, a high frequency of hospitalization, and a monocyclic disease course. Patients with anti-synthetase antibodies had higher frequencies of interstitial lung disease, arthralgia, and "mechanic's hands," and had an older age at diagnosis. The anti-SRP group, which had exclusively juvenile polymyositis, was characterized by high frequencies of black race, severe onset, distal weakness, falling episodes, Raynaud phenomenon, cardiac involvement, high CK levels, chronic disease course, frequent hospitalization, and wheelchair use. Characteristic features of the anti-Mi-2 subgroup included Hispanic ethnicity, classic dermatomyositis and malar rashes, high CK levels, and very low mortality. Finally, the most common features of patients without any currently defined MSA or myositis-associated autoantibodies included linear extensor erythema, arthralgia, and a monocyclic disease course. Several demographic and clinical features were shared between juvenile and adult idiopathic inflammatory myopathy subgroups, but with several important differences. We conclude that juvenile myositis is a heterogeneous group of illnesses with distinct autoantibody phenotypes defined by varying clinical and demographic characteristics, laboratory features, and outcomes.
The G protein-coupled receptor (GPCR) rhodopsin self-assembles into supramolecular structures in native bilayers, but the structural determinants of receptor oligomerization are not known. We carried ...out multiple self-assembly coarse-grained molecular dynamics (CGMD) simulations of model membranes containing up to 64 molecules of the visual receptor rhodopsin over time scales reaching 100 μs. The simulations show strong preferential interaction modes between receptors. Two primary modes of receptor–receptor interactions are consistent with umbrella sampling/potential of mean force (PMF) calculations as a function of the distance between a pair of receptors. The preferential interfaces, involving helices (H) 1/8, 4/5 and 5, present no energy barrier to forming a very stable receptor dimer. Most notably, the PMFs show that the preferred rhodopsin dimer exists in a tail-to-tail conformation, with the interface comprising transmembrane H1/H2 and amphipathic H8 at the extracellular and cytoplasmic surfaces, respectively. This dimer orientation is in line with earlier electron microscopy, X-ray, and cross-linking experiments of rhodopsin and other GPCRs. Less stable interfaces, involving H4 and H6, have a free energy barrier for desolvation (delipidation) of the interfaces and appear to be designed to stabilize “lubricated” (i.e., lipid-coated) dimers. The overall CGMD strategy used here is general and can be applied to study the homo- and heterodimerization of GPCRs and other transmembrane proteins. Systematic extension of the work will deepen our understanding of the forces involved in the membrane organization of integral membrane proteins.
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.
To describe clinical outcomes of juvenile idiopathic arthritis (JIA) in a prospective inception cohort of children managed with contemporary treatments.
Children newly diagnosed with JIA at 16 ...Canadian paediatric rheumatology centres from 2005 to 2010 were included. Kaplan-Meier survival curves for each JIA category were used to estimate probability of ever attaining an active joint count of 0, inactive disease (no active joints, no extraarticular manifestations and a physician global assessment of disease activity <10 mm), disease remission (inactive disease >12 months after discontinuing treatment) and of receiving specific treatments.
In a cohort of 1104 children, the probabilities of attaining an active joint count of 0 exceeded 78% within 2 years in all JIA categories. The probability of attaining inactive disease exceeded 70% within 2 years in all categories, except for RF-positive polyarthritis (48%). The probability of discontinuing treatment at least once was 67% within 5 years. The probability of attaining remission within 5 years was 46-57% across JIA categories except for polyarthritis (0% RF-positive, 14% RF-negative). Initial treatment included joint injections and non-steroidal anti-inflammatory drugs for oligoarthritis, disease-modifying antirheumatic drugs (DMARDs) for polyarthritis and systemic corticosteroids for systemic JIA.
Most children with JIA managed with contemporary treatments attain inactive disease within 2 years of diagnosis and many are able to discontinue treatment. The probability of attaining remission within 5 years of diagnosis is about 50%, except for children with polyarthritis.
Introduction: Juvenile dermatomyositis (JDM) is a rare, chronic autoimmune illness with primary features of symmetric, proximal muscle weakness and involvement of the skin with a number of ...identifiable rashes. Evidence to support treatment decisions is limited, given the paucity of clinical trials. Consensus based methods, informed by available data, play an important role in treatment recommendations.
Areas covered: This review focuses on evidence and consensus opinion regarding therapeutic options in JDM and identifies gaps where future research is needed.
Expert commentary: The combination of trial evidence (as limited as it is) and consensus opinion support standard initial management for children with JDM to consist of high-dose corticosteroids, either intravenous or oral, and methotrexate. Several other agents have preliminary support, either through clinical trials or case series for their use in patients who either fail to respond adequately, have severe disease or have contraindications to standard initial therapy. One of the important goals of management in JDM will be to reduce the corticosteroid exposure experienced by patients. To meet this goal, progress in a number of key areas is needed: increased international collaboration, advances in study design and increased translational research.
PDF
