The incidence of hip fractures in Norway -accuracy of the national Norwegian patient registry

Published version of an article in: BMC Musculoskeletal Disorders. Also available from the publisher on SpringerLink: http://dx.doi.org/10.1186/1471-2474-15-372Background Hip fractures incur the greatest medical costs of any fracture. Valid epidemiological data are important to monitor for time-dependent changes. In Norway, hip fractures are registered in the Norwegian Patient Registry (NPR), but no published national validation exists. The aim of the present study was a national validation of NPR as a register for hip fractures using diagnostic codes (ICD-10 S 72.0-2) and/or procedure codes (NOMESCO version 1.14 NFBxy (x = 0-9, y = 0-2) or NFJxy (x = 0-9, y = 0-2). Method A nationwide, population-based cohort comprising a random sub-sample of 1,000 hip fracture-related entries for the years 2008–09 was drawn from the NPR. 200 entries were defined by a combination of diagnostic and procedure codes (subsample 1), 400 entries were defined by diagnostic codes only (subsample 2) and 400 entries were defined by procedure codes only (subsample 3). Accuracy was ascertained through comparison with discharge summaries, procedure notes and X-ray reports requested from 40 health institutions. Comparisons between groups were done by chi2 for categorical and t-test for continuous variables. Results 792 health records from 32 institutions were reviewed. High accuracy (98.2%, 95% C.I. 96.5-99.9%) was found for subsample 1, a combination of diagnostic and procedure codes. Coding errors were prominent in other subsamples. Defining fractures by a combination of diagnostic and procedure codes, annual average hip fracture incidence in Norway was 9,092 (95% C.I. 8,934 -9,249), excluding only 6.5% of all hip fractures defined by wider definitions. Conclusions Based on current coding practice in Norway, a reliable national estimate of hip fracture incidences is found by a combination of relevant ICD-10 and NOMESCO codes in the NPR. This method may be used for monitoring epidemiological changes

A modeling and simulation study of siderophore mediated antagonism in dual-species biofilms

<p>Abstract</p> <p>Background</p> <p>Several bacterial species possess chelation mechanisms that allow them to scavenge iron from the environment under conditions of limitation. To this end they produce siderophores that bind the iron and make it available to the cells later on, while rendering it unavailable to other organisms. The phenomenon of siderophore mediated antagonism has been studied to some extent for suspended populations where it was found that the chelation ability provides a growth advantage over species that do not have this possibility. However, most bacteria live in biofilm communities. In particular <it>Pseudomonas fluorescens </it>and <it>Pseudomonas putida</it>, the species that have been used in most experimental studies of the phenomenon, are known to be prolific biofilm formers, but only very few experimental studies of iron chelation have been published to date for the biofilm setting. We address this question in the present study.</p> <p>Methods</p> <p>Based on a previously introduced model of iron chelation and an existing model of biofilm growth we formulate a model for iron chelation and competition in dual species biofilms. This leads to a highly nonlinear system of partial differential equations which is studied in computer simulation experiments.</p> <p>Conclusions</p> <p>(i) Siderophore production can give a growth advantage also in the biofilm setting, (ii) diffusion facilitates and emphasizes this growth advantage, (iii) the magnitude of the growth advantage can also depend on the initial inoculation of the substratum, (iv) a new mass transfer boundary condition was derived that allows to a priori control the expect the expected average thickness of the biofilm in terms of the model parameters.</p

Rare germline copy number variants (CNVs) and breast cancer risk.

Funder: CIHRGermline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P = 0.0008), ATM (P = 0.002) and BRCA2 (P = 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. To the best of our knowledge, this is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance

Interleukin-1 beta has atheroprotective effects in advanced atherosclerotic lesions of mice

Despite decades of research, our understanding of the processes controlling late-stage atherosclerotic plaque stability remains poor. A prevailing hypothesis is that reducing inflammation may improve advanced plaque stability, as recently tested in the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) trial, in which post-myocardial infarction subjects were treated with an IL-1β antibody. Here, we performed intervention studies in which smooth muscle cell (SMC) lineage-tracing Apoe-/- mice with advanced atherosclerosis were treated with anti-IL-1β or IgG control antibodies. Surprisingly, we found that IL-1β antibody treatment between 18 and 26 weeks of Western diet feeding induced a marked reduction in SMC and collagen content, but increased macrophage numbers in the fibrous cap. Moreover, although IL-1β antibody treatment had no effect on lesion size, it completely inhibited beneficial outward remodeling. We also found that SMC-specific knockout of Il1r1 (encoding IL-1 receptor type 1) resulted in smaller lesions nearly devoid of SMCs and lacking a fibrous cap, whereas macrophage-selective loss of IL-1R1 had no effect on lesion size or composition. Taken together, these results show that IL-1β has multiple beneficial effects in late-stage murine atherosclerosis, including promotion of outward remodeling and formation and maintenance of an SMC- and collagen-rich fibrous cap

Preclinical Characterization and Clinical Development of ILARIS® (canakinumab) for the Treatment of Autoinflammatory Diseases

Interleukin-1beta (IL-1) is a pro-inflammatory cytokine which is part of the first line innate response in vertebrates and is induced in injury, infection, and immunity. While temporally limited induction of IL-1 is believed to protect the organisms against traumatic or infectious insults, its aberrant expression in chronic inflammation is detrimental. Therefore, pharmacological neutralization of IL-1 in chronic inflammatory diseases is a meaningful strategy to treat inflammation and to alleviate respective clinical symptoms in man. Canakinumab is a high-affinity human monoclonal antibody designed to target human IL-1 in inflammatory diseases. Indeed, canakinumab has shown excellent efficacy in rare genetic autoinflammatory diseases or pathological conditions associated with aberrant production of IL-1. This review focusses on the molecular and clinical mode of action and pharmaceutical development of canakinumab in (auto)inflammatory diseases

Commentary: Preclinical characterization and clinical development of ILARIS (canakinumab) for the treatment of autoinflammatory diseases

IL-1 is an ancient cytokine found in the entire vertebrate lineage1. It is part of the innate response towards infections, and in mammals it is essential part of the fever response2. IL-1b has been recognized or proposed as pathogenic factor causing or contributing to numerous of diseases, clinical conditions, or syndromes3,4. It is not surprising that more than two decades ago pharmaceutical research towards the inhibition of IL-1 started. Three marketed drugs resulted from these endeavors: Anakinra, a recombinant form of the endogenous IL-1 receptor antagonist, was approved first by the FDA in 2001 for the treatment of rheumatoid arthritis; Rilonacept, a recombinant soluble IL-1 receptor, achieved market authorization for Cryopyrin Associated Periodic Syndrome (CAPS) in 2008; and canakinumab, a monoclonal antibody targeting IL-1, obtained its first market authorization for CAPS in 2009. It is surprising that despite ample evidence for the role of IL-1b in a large number of preclinical and experimental conditions resulted in relatively few successful development programs and approved clinical indications, such as CAPS (Anakinra, Rilonacept, Canakinumab), rheumatoid arthritis (Anakinra), systemic juvenile idiopathic arthritis (sJIA, Canakinumab) and refractory gout (Canakinumab) for these IL-1 targeting drugs. The reasons for this discrepancy may lie in the translation of mechanistic animal models to complex diseases in the clinical setting. Indeed, IL-1 blockers failed to show a clinically relevant benefit over placebo or standard of care in a number of clinical trials e.g., in sepsis, osteoarthritis, or COPD5–7. However, IL-1 targeting drugs have shown unprecedented efficacy in rare autoinflammatory diseases8,9. Amongst those, CAPS can be considered as the prototypic disease which is intimately linked to a dysfunctional regulation of IL-1 production. CAPS is a rare disease with an incidence of about 1-2 cases per million, and mostly caused by mutations in the NLRP3 gene which leads to activation of the inflammasome, a multi-protein complex directly controlling the secretion of active IL-1 from cells. CAPS patients are characterized by overproduction of IL-1 by their lymphocytes, and by recurrent fevers, rash, arthralgia, progressive hearing loss and amyloidosis in some cases. Canakinumab is a human monoclonal antibody potently and specifically neutralizing the activity of human IL-110. It was derived from hybridomas generated from genetically engineered mice carrying part of the human immunoglobulin genes. Biochemical and structural analysis revealed that glutamine 64 in human IL-1b is a key residue for the interaction with canakinumab. This residue is rarely conserved in mammalian species, explaining the narrow species crossreactivity only to marmoset, a small non-human primate species suitable for toxicological assessments. Canakinumab is the only approved drug which specifically targets IL-1, but not IL-1 or IL-1Ra. The first full clinical development of canakinumab was performed in CAPS, where it induced a long-term clinical remission and normalization of C-reactive protein, a marker of systemic inflammation. Clinical relapse and recurrence of symptoms occurred in patients treated with a single injection of canakinumab after several months. Time to relapse was related to the dose of canakinumab used, and clinical remission could be restored upon re-treatment with canakinumab. A pivotal phase III clinical trial using a withdrawal design was conceived based on the observation of the clinical relapse pattern in seven patients treated with canakinumab. A combination of the relapse pattern with a pharmacokinetic/ pharmacodynamic (PK/PD) model predicted the probability of a clinical relapse within a given time for a given dose of canakinumab. The model derived proposal for a dosing scheme of a subcutaneous injection of 150 mg of canakinumab every two months was confirmed in a phase III study, resulting in lasting suppression of clinical symptoms. As CAPS represents a wide spectrum of clinical manifestations, dose adjustments up to 300 mg/months might be required for severe or very young patients to achieve full clinical and sustained efficacy. A growing list of autoinflammatory syndromes have been identified and associated with specific genetic defects11. Many of these identified syndromes, mostly characterized by fever attacks of variable length, respond to some extent to IL-1 blockade, but systematic studies are lacking for most of these syndromes. Most of the evidence for a clinical benefit by IL-1 targeting was generated in open label studies for Familial Mediterranean Fever (FMF), TNF Receptor Associated Periodic Syndrome (TRAPS) and Hyper IgD Syndrome /Mevalonate Kinase Deficiency (HIDS/MKD). Interestingly, the respective genetic defects in these diseases affect cellular pathways and molecules which are not directly upstream of IL-1, but their physiological consequences appear to converge on the overproduction of IL-1. Indeed, Canakinumab had shown highly encouraging results in small open label clinical studies in these diseases. Canakinumab is the first IL-1 targeted therapy in a controlled phase III study which enrolled FMF, TRAPS, and MVKD/HIDS patients under a combined protocol. Excellent efficacy was observed in all three sub-studies, and first results have just been reported at the EULAR meeting in June this year12. Respective applications for market authorization in these three autoinflammatory diseases are currently pending. Genetic diagnosis of an autoinflammatory disease will aid today a physician’s decision to treat the disease with an IL-1 targeted therapy, however, there are autoinflammatory diseases without a clear cut genetic cause, but characterized by spiking fever, e.g., sJIA or Schnitzler’s syndrome, which both show excellent response to neutralization of IL-113,1415. While fever is indicative of high systemic IL-1 activity in autoinflammation, IL-1 may play a pivotal role in endothelial dysfunction which is accompanied by sub clinical inflammation. Atherosclerosis has been recognized as an inflammatory disease in which IL-1 is postulated to play a pathogenic role by different mechanisms16. Notably, the inflammasome can be activated in the atherosclerotic plaque by deposits of cholesterol crystals, leading to the induction of IL-1 and creating an inflammatory environment favoring plaque instability and rupture. Canakinumab is currently tested in a large cardiovascular outcome trial to test the contention that neutralization of IL-1 specifically reduces the risk of a secondary cardiovascular event in patients with a previous myocardial infarction17. Blockade of IL-1 by Anakinra in provided initial evidence of a potential clinical benefit in small studies with heart failure patients displaying an increased inflammatory burden18,19. Further, IL-1 may play a major role ischemia and reperfusion induced small vessel occlusion, leucocyte extravasation and endothelial activation in the vasculature, which is a major clinical problem occurs in sickle cell anemia20. Indeed, IL-1 neutralization in a mouse model of sickle cell disease provided a significant improvement in vessel occlusion, granulocyte extravasation and hemodynamics21. It remains to be seen whether these predicted benefits can be verified in clinical studies

The long and winding road in pharmaceutical development of canakinumab, a human anti-IL-1 antibody

Abstract Interleukin-1beta (IL-1) is an ancient and evolutionary conserved cytokine, which orchestrates in vertebrates innate immune responses triggered by infections. While temporally limited induction of IL-1 protects the organism against traumatic or infectious insults, its chronic production in unabated inflammation causes or enhances clinical manifestations of disease in almost all organ systems. Therefore, pharmacological targeting of IL-1 in a variety of clinical inflammatory conditions may provide symptomatic relief or profound disease modification. The discovery of proteolytic processing of the inactive pro-IL-1to mature, active and secreted IL-1 by the inflammasome/caspase I complex inspired drug discovery programs towards low molecular weight inhibitors across the Pharma industry. Approved and marketed IL-1 pathway drugs today, however, are biologics targeting either IL-1, or the IL-1 receptor. Canakinumab is a human monoclonal antibody that binds to human IL-1 with high affinity and neutralizes its biological activity. This review describes the unique preclinical and clinical development journey of canakinumab starting from a rare genetic autoinflammatory disease and a systemic juvenile form of arthritis to further rare monogenetic periodic fever syndromes, and leading to non-orphan diseases, such as gout, myocardial infarction, and lung cancer

Biomarkers in systemic juvenile idiopathic arthritis: A comparison with biomarkers in cryopyrin-associated periodic syndromes

PURPOSE OF REVIEW: This review summarizes biomarkers in systemic juvenile idiopathic arthritis (sJIA). Broadly, the markers are classified under protein, cellular, gene expression and genetic markers. We also compare the biomarkers in sJIA to biomarkers in cryopyrin-associated periodic syndrome (CAPS). RECENT FINDINGS: Recent publications showing the similarity of clinical response of sJIA and CAPS to anti-interleukin 1 therapies prompted a comparison at the biomarker level. SUMMARY: sJIA traditionally is classified under the umbrella of juvenile idiopathic arthritis. At the clinical phenotypic level, sJIA has several features that are more similar to those seen in CAPS. In this review, we summarize biomarkers in sJIA and CAPS and draw upon the various similarities and differences between the two families of diseases. The main differences between sJIA and CAPS biomarkers are genetic markers, with CAPS being a family of monogenic diseases with mutations in NLRP3. There have been a small number of publications describing cellular biomarkers in sJIA with no such studies described for CAPS. Many of the protein marker's characteristics of sJIA are also seen to characterize CAPS. The gene expression data in both sJIA and CAPS show a strong upregulation of innate immunity pathways. In addition, we describe a strong similarity between sJIA and CAPS at the gene expression level in which several genes that form a part of the erythropoiesis signature are upregulated in both sJIA and CAPS. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins

The molecular mode of action and species specificity of canakinumab, a human monoclonal antibody neutralizing IL-1β

Interleukin-1β (IL-1β) plays a key role in autoinflammatory diseases, such as systemic juvenile idiopathic arthritis (sJIA) or hereditary periodic fevers. Canakinumab, a human monoclonal anti-IL-1β antibody was recently approved for human use under the trade name Ilaris. Canakinumab does not cross-react with IL-1β from mouse, rat, rabbit, or macaques. The crystal structure of the canakinumab Fab bound to human IL-1β was determined in an attempt to rationalize the species specificity. The X-ray analysis reveals a complex surface epitope with an intricate network of well-ordered water molecules at the antibody-antigen interface. The canakinumab paratope is largely pre-organized, as demonstrated by the structure determination of the free Fab. Glu 64 of human IL-1β is a pivotal epitope residue explaining the exquisite species specificity of canakinumab. We identified marmoset as the only non-human primate species that carries Glu 64 in its IL-1β and demonstrates full cross-reactivity of canakinumab, thereby enabling toxicological studies in this species. The X-ray study further reveals the mechanism of action at the molecular level. Canakinumab binds IL-1β on the opposite side with respect to the IL-1RAcP binding site and in an approximately orthogonal orientation with respect to IL-1RI. However, the antibody and IL-1RI binding sites slightly overlap and the VH region of canakinumab would sterically interfere with the D1 domain of IL-1RI, as shown by a structural overlay with the IL-1β:IL-1RI complex. Therefore, direct competition with IL-1RI for IL-1β binding is the molecular mechanism of neutralization by canakinumab. Biochemical assays with recombinant IL-1RI and IL-1RII confirmed the proposed mode of action