Letter: Brain natriuretic peptide is a potentially useful screening tool for the detection of cardiovascular disease in patients with rheumatoid arthritis

Patients with rheumatoid arthritis (RA) have a significantly higher risk of coronary heart disease, despite being less likely to report symptoms of angina, and are more likely to experience unrecognised myocardial infarction and sudden cardiac death than non-RA controls.1 Furthermore, left ventricular diastolic dysfunction has been described in up to 40% of patients with RA.2...

Axial spondyloarthritis: A new disease entity, not necessarily early ankylosing spondylitis

New classification criteria for axial spondyloarthritis have been developed with the goal of increasing sensitivity of criteria for early inflammatory spondyloarthritis. However these criteria substantially increase heterogeneity of the resulting disease group, reducing their value in both research and clinical settings. Further research to establish criteria based on better knowledge of the natural history of non-radiographic axial spondyloarthritis, its aetiopathogenesis and response to treatment is required. In the meantime the modified New York criteria for ankylosing spondylitis remain a very useful classification criteria set, defining a relatively homogenous group of cases for clinical use and research studies.

Is disease severity in ankylosing spondylitis genetically determined?

Objective. To assess the role of genes and the environment in determining the severity of ankylosing spondylitis. Methods: One hundred seventy-three families with >1 case of ankylosing spondylitis were recruited (120 affected sibling pairs, 26 affected parent-child pairs, 20 families with both first- and second-degree relatives affected, and 7 families with only second-degree relatives affected), comprising a total of 384 affected individuals. Disease severity was assessed by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and functional impairment was determined using the Bath Ankylosing Spondylitis Functional Index (BASFI). Disease duration and age at onset were also studied. Variance-components modeling was used to determine the genetic and environmental components Contributing to familiality of the traits examined, and complex segregation analysis was performed to assess different disease models. Results. Both the disease activity and functional capacity as assessed by the BASDAI and the BASFI, respectively, were found to be highly familial (BASDAI familiality 0.51 [P = 10-4], BASFI familiality 0,68 [P = 3 × 10-7]). No significant shared environmental component was demonstrated to be associated with either the BASDAI or the BASFI. Including age at disease onset and duration of disease as covariates made no difference in the heritability assessments. A strong correlation was noted between the BASDAI and the BASFI (genetic correlation 0.9), suggesting the presence of shared determinants of these 2 measures. However, there was significant residual heritability for each measure independent of the other (BASFI residual heritability 0.48, BASDAI 0,36), perhaps indicating that not all genes influencing disease activity influence chronicity. No significant heritability of age at disease onset was found (heritability 0.18; P = 0.2). Segregation studies suggested the presence of a single major gene influencing the BASDAI and the BASFI. Conclusion. This study demonstrates a major genetic contribution to disease severity in ankylosing spondylitis. As with susceptibility to ankylosing spondylitis, shared environmental factors play little role in determining the disease severity.

Cardiovascular disease is increased prior to onset of rheumatoid arthritis but not osteoarthritis: The population-based Nord-Trøndelag health study (HUNT)

Introduction: Patients with rheumatoid arthritis (RA) have increased risk of cardiovascular (CV) events. We sought to test the hypothesis that due to increased inflammation, CV disease and risk factors are associated with increased risk of future RA development. Methods: The population-based Nord-Trøndelag health surveys (HUNT) were conducted among the entire adult population of Nord-Trøndelag, Norway. All inhabitants 20 years or older were invited, and information was collected through comprehensive questionnaires, a clinical examination, and blood samples. In a cohort design, data from HUNT2 (1995-1997, baseline) and HUNT3 (2006-2008, follow-up) were obtained to study participants with RA (n = 786) or osteoarthritis (n = 3,586) at HUNT3 alone, in comparison with individuals without RA or osteoarthritis at both times (n = 33,567). Results: Female gender, age, smoking, body mass index, and history of previous CV disease were associated with self-reported incident RA (previous CV disease: odds ratio 1.52 (95% confidence interval 1.11-2.07). The findings regarding previous CV disease were confirmed in sensitivity analyses excluding participants with psoriasis (odds ratio (OR) 1.70 (1.23-2.36)) or restricting the analysis to cases with a hospital diagnosis of RA (OR 1.90 (1.10-3.27)) or carriers of the shared epitope (OR 1.76 (1.13-2.74)). History of previous CV disease was not associated with increased risk of osteoarthritis (OR 1.04 (0.86-1.27)). Conclusion: A history of previous CV disease was associated with increased risk of incident RA but not osteoarthritis.

Whole blood transcriptional profiling in ankylosing spondylitis identifies novel candidate genes that might contribute to the inflammatory and tissue-destructive disease aspects

Introduction: A number of genetic-association studies have identified genes contributing to ankylosing spondylitis (AS) susceptibility but such approaches provide little information as to the gene activity changes occurring during the disease process. Transcriptional profiling generates a 'snapshot' of the sampled cells' activity and thus can provide insights into the molecular processes driving the disease process. We undertook a whole-genome microarray approach to identify candidate genes associated with AS and validated these gene-expression changes in a larger sample cohort. Methods: A total of 18 active AS patients, classified according to the New York criteria, and 18 gender- and age-matched controls were profiled using Illumina HT-12 whole-genome expression BeadChips which carry cDNAs for 48,000 genes and transcripts. Class comparison analysis identified a number of differentially expressed candidate genes. These candidate genes were then validated in a larger cohort using qPCR-based TaqMan low density arrays (TLDAs). Results: A total of 239 probes corresponding to 221 genes were identified as being significantly different between patients and controls with a P-value <0.0005 (80% confidence level of false discovery rate). Forty-seven genes were then selected for validation studies, using the TLDAs. Thirteen of these genes were validated in the second patient cohort with 12 downregulated 1.3- to 2-fold and only 1 upregulated (1.6-fold). Among a number of identified genes with well-documented inflammatory roles we also validated genes that might be of great interest to the understanding of AS progression such as SPOCK2 (osteonectin) and EP300, which modulate cartilage and bone metabolism. Conclusions: We have validated a gene expression signature for AS from whole blood and identified strong candidate genes that may play roles in both the inflammatory and joint destruction aspects of the disease.

Clinical factors associated with the humoral immune response to influenza vaccination in chronic obstructive pulmonary disease

Background and objective Individuals with chronic obstructive pulmonary disease (COPD) are at a high risk of developing significant complications from infection with the influenza virus. It is therefore vital to ensure that prophylaxis with the influenza vaccine is effective in COPD. The aim of this study was to assess the immunogenicity of the 2010 trivalent influenza vaccine in persons with COPD compared to healthy subjects without lung disease, and to examine clinical factors associated with the serological response to the vaccine. Methods In this observational study, 34 subjects (20 COPD, 14 healthy) received the 2010 influenza vaccine. Antibody titers at baseline and 28 days post-vaccination were measured using the hemagglutination inhibition assay (HAI) assay. Primary endpoints included seroconversion (≥4-fold increase in antibody titers from baseline) and the fold increase in antibody titer after vaccination. Results Persons with COPD mounted a significantly lower humoral immune response to the influenza vaccine compared to healthy participants. Seroconversion occurred in 90% of healthy participants, but only in 43% of COPD patients (P=0.036). Increasing age and previous influenza vaccination were associated with lower antibody responses. Antibody titers did not vary significantly with cigarette smoking, presence of other comorbid diseases, or COPD severity. Conclusion The humoral immune response to the 2010 influenza vaccine was lower in persons with COPD compared to non-COPD controls. The antibody response also declined with increasing age and in those with a history of prior vaccination.

Immunogenetic characteristics of immunoglobulin E in allergic disease

Patients with allergic diseases produce an excess of allergen-specific IgE, the specific effector molecule that triggers allergic reactions. The provocation for this excess IgE production is still uncertain. Current ideas include oligoclonal expansion of allergen-specific B cells emanating from germinal centres, activation by superantigen of a subset of B cells, or polyclonal B cells class switching to IgE due to an IL-4 predominance. Additionally, genetic elements contribute to a propensity for increased allergen-specific IgE production. The procedure of RT-PCR allows for amplification of infrequent IgE mRNA transcripts from B cells of atopic individuals, and so facilitates examination of expressed Ig cDNA sequences. Better knowledge of the molecular characteristics of IgE produced by patients with allergic diseases would elucidate the immunogenetic basis for elevated allergen-specific IgE levels. The 'immunogenetic footprint' of IgE transcripts may elucidate the origin and activation of IgE-producing B cells in allergic disease. Here we review studies of the immunogenetic features of IgE in allergic diseases, highlighting the major advances and the experimental limitations.

Introduction: Epitope mimicry as a component cause of autoimmune disease

The causes of autoimmune diseases have yet to be fully elucidated. Autoantibodies, autoreactive T cell responses, the presence of a predisposing major histocompatibility complex (MHC) haplotype and responsiveness to corticosteroids are features, and some are possibly contributory causes of autoimmune disease. The most challenging question is how autoimmune diseases are triggered. Molecular mimicry of host cell determinants by epitopes of infectious agents with ensuing cross-reactivity is one of the most popular yet still controversial theories for the initiation of autoimmune diseases [1]. Throughout the 1990s, hundreds of research articles focusing to various extents on epitope mimicry, as it is more accurately described in an immunological context, were published annually. Many of these articles presented data that were consistent with the hypothesis of mimicry but that did not actually prove the theory. Other equally convincing reports indicated that epitope mimicry was not the cause of the autoimmune disease despite sequence similarity between molecules of infectious agents and the host. Some 20 years ago, Rothman [2] proposed a model for disease causation and I have used this as a framework to examine the role of epitope mimicry in the development of autoimmune disease. The thesis of Rothman’s model is that an effect, in this instance autoimmune disease, arises as a result of a cause. In most cases, multiple-component causes contribute synergistically to yield the effect, and each of these components alone is insufficient as a cause. Logically, some component causes, such as the presence of a particular autoimmune response, are also necessary causes.

Towards the pathogenesis of autoimmune liver disease

There have been recent improvements in the clinical understanding and definition of the major types of autoimmune liver disease. However, still lacking is knowledge of their prevalence and pathogenesis. Three areas of study are in progress in our laboratory. First, in type 1 autoimmune hepatitis, the search continues to identify a liver/disease-specific autoantigenic reactant. Using hepatocyte membrane preparations, immunoblotting has underlined the problem of distinguishing, among multiple reactants, those that may be causally rather than consequentially related to hepatocellular damage. Second, in primary biliary cirrhosis (PBC), the need for population screening to ascertain prevalence and detect preclinical cases can be met by a rapid automated procedure for detection, by specific enzyme inhibition in microtitre wells, of antibody (anti-M2) to the pyruvate dehydrogenase complex E2 subunit (PDC-E2). Third, the structure of the conformational epitope within the inner lipoyl domain of PDC-E2 is being investigated by screening random phage-displayed peptide libraries using PBC sera. This has yielded phage clones in which the sequence of the peptide insert portrays the structure of this epitope, as judged by clustering of PBC-derived sequences to particular branches of a guide-tree that shows relatedness of peptides, and by reactivity of selected phage clones with anti-PDC-E2. Thus phage display identifies a peptide 'mimotope' of the antibody epitope in the inner lipoyl domain of PDC-E2.

Molecular mimicry: Can epitope mimicry induce autoimmune disease?

Mimicry of host antigens by infectious agents may induce cross-reactive autoimmune responses to epitopes within host proteins which, in susceptible individuals, may tip the balance of immunological response versus tolerance toward response and subsequently lead to autoimmune disease. Epitope mimicry may indeed be involved in the pathogenesis of several diseases such as post-viral myocarditis or Chagas disease, but for many other diseases in which it has been implicated, such as insulin-dependent diabetes mellitis or rheumatoid arthritis, convincing evidence is still lacking. Even if an epitope mimic can support a cross-reactive T or B cell response in vitro, its ability to induce an autoimmune disease in vivo will depend upon the appropriate presentation of the mimicked host antigen in the target tissue and, in the case of T cell mimics, the ability of the mimicking epitope to induce a proliferative rather than anergizing response upon engagement of the MHC-peptide complex with the T cell receptor. B cell presentation of mimicking foreign antigen to T cells is a possible mechanism for instigating an autoimmune response to self antigens that in turn can lead to autoimmune disease under particular conditions of antigen presentation, secondary signalling and effector cell repertoire. In this review evidence in support of epitope mimicry is examined in the light of the necessary immunological considerations of the theory.

Kits and methods for diagnosis, screening, treatment and disease monitoring [WO 2015048852 A1]

Disclosed are methods for detecting the presence of a carcinoma or an increased likelihood that a carcinoma is present in a subject. More particularly, the present invention discloses methods for diagnosis, screening, treatment and monitoring of carcinomas associated with aberrant DNA methylation of the MED15 promoter region

Genetic factors in the pathogenesis of CPPD crystal deposition disease

Crystal deposition is a very complex process ruled by numerous factors. A small but important proportion of cases of chondrocalcinosis are monogenic, and many of the genes involved have been identified. These genetic findings strongly point to control of the level of extracellular inorganic pyrophosphate as the primary mechanism for their association with either calcium pyrophosphate dihydrate or hydroxyapatite deposition. However, effects on extracellular inorganic pyrophosphate levels do not explain the mechanism of association in all of these monogenic diseases. Further, there are likely to be several as yet unidentified genes that are important in this common condition. This review highlights what genetic studies have demonstrated about the processes involved in these diverse but related disorders.

Ability of commonly used prediction equations to predict resting energy expenditure in children with inflammatory bowel disease

Background: Paediatric onset inflammatory bowel disease (IBD) may cause alterations in energy requirements and invalidate the use of standard prediction equations. Our aim was to evaluate four commonly used prediction equations for resting energy expenditure (REE) in children with IBD. Methods: Sixty-three children had repeated measurements of REE as part of a longitudinal research study yielding a total of 243 measurements. These were compared with predicted REE from Schofield, Oxford, FAO/WHO/UNU, and Harris-Benedict equations using the Bland-Altman method. Results: Mean (±SD) age of the patients was 14.2 (2.4) years. Mean measured REE was 1566 (336) kcal per day compared with 1491 (236), 1441 (255), 1481 (232), and 1435 (212) kcal per day calculated from Schofield, Oxford, FAO/WHO/UNU, and Harris-Benedict, respectively. While the Schofield equation demonstrated the least difference between measured and predicted REE, it, along with the other equations tested, did not perform uniformly across all subjects, indicating greater errors at either end of the spectrum of energy expenditure. Smaller differences were found for all prediction equations for Crohn's disease compared with ulcerative colitis. Conclusions: Of the commonly used equations, the equation of Schofield should be used in pediatric patients with IBD when measured values are not able to be obtained. (Inflamm Bowel Dis 2010;) Copyright © 2010 Crohn's & Colitis Foundation of America, Inc.

Quality of life in children with Crohn disease

Objectives: Quality of life (QOL) is reportedly poor in children with Crohn disease (CD) but improves with increasing disease duration. This article aims to detail QOL in a cohort of Australian children with CD in relation to disease duration, disease activity, and treatment. MATERIALS AND METHODS: QOL, assessed using the IMPACT-III questionnaire, and disease activity measures, assessed using the Pediatric Crohn's Disease Activity Index (PCDAI), were available in 41 children with CD. For this cohort, a total of 186 measurements of both parameters were available. Results: QOL was found to be significantly lower, and disease activity significantly higher (F = 31.1, P = 0.00), in patients within 6 months of their diagnosis compared with those up to 2.5 years, up to 5 years, and beyond 5 years since diagnosis. Higher disease activity was associated with poorer QOL (r =-0.51, P = 0.00). Total QOL was highest in children on nil medications and lowest in children on enteral nutrition. The PCDAI (t =-6.0, P = 0.00) was a significant predictor of QOL, with the clinical history (t =-6.9, P = 0.00) and examination (t =-2.9, P = 0.01) sections of the PCDAI significantly predicting QOL. Disease duration, age, or sex was neither related to nor significant predictors of QOL, but height z score and type of treatment approached significance. Conclusions: Children with CD within 6 months of their diagnosis have impaired QOL compared with those diagnosed beyond 6 months. These patients, along with those with growth impairment, ongoing elevated disease activity with abdominal pain, diarrhoea and/or perirectal and extraintestinal complications, may benefit from regular assessments of QOL as part of their clinical treatment. © 2010 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.

Bone health in children with inflammatory bowel disease : adjusting for bone age

OBJECTIVES: Clinical results of bone mineral density for children with inflammatory bowel disease are commonly reported using reference data for chronological age. It is known that these children, particularly those with Crohn disease, experience delayed growth and maturation. Therefore, it is more appropriate to compare clinical results with bone age rather than chronological age. MATERIALS AND METHODS: Areal bone mineral density (aBMD) was measured using dual energy x-ray absorptiometry, and bone age was assessed using the Tanner-Whitehouse 3 method from a standard hand/wrist radiograph. Results were available for 44 children ages 7.99 to 16.89 years. Areal bone mineral density measurements were converted to z scores using both chronological and bone ages for each subject. RESULTS: Areal bone mineral density z scores calculated using bone age, as opposed to chronological age, were significantly improved for both the total body and lumbar spine regions of interest. When subjects were grouped according to diagnosis, bone age generated z scores remained significantly improved for those with Crohn disease but not for those diagnosed with ulcerative colitis. Grouping of children with Crohn disease into younger and older ages produced significantly higher z scores using bone age compared with chronological for the older age group, but not the younger age group. CONCLUSIONS: Our findings, in accordance with those presented in the literature, suggest that aBMD results in children with Crohn disease should include the consideration of bone age, rather than merely chronological age. Bone size, although not as easily available, would also be an important consideration for interpreting results in paediatric populations. © 2009 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.