Translational glycobiology: from bench to bedside.

The importance of sugars to protein function is real and is of significant clinical relevance. Technology advances enable large population studies to be carried out, shedding light on individual sugar variation and variations with time. Three-dimensional mass spectroscopy on solid pathological specimens is going to open up a whole new world of pathology visualisation. The door is now open to exploit carbohydrate recognition in new therapeutics by identifying novel biomarkers in cancer to aid diagnosis, and also providing therapeutic targets for treatment. Glycan age correlates with biological age. This means we can map the reversal of biological age with exercise and diet.

Rheumatoid arthritis is associated with IgG antibodies to human endogenous retrovirus gag matrix: a potential pathogenic mechanism of disease?

OBJECTIVE: Human endogenous retrovirus (HERV)-K10 has been implicated in the etiology and pathogenesis of rheumatoid arthritis (RA). A secondary immune response to this virus might suggest an antigen-driven response in patients. The Gag region of HERV-K10 could provide a key epitope important for immunological reactivity. We investigated the presence of IgG antibodies to this region and assessed its significance in RA. METHODS: We determined an antigenic peptide on the matrix segment of HERV-K10 and developed an ELISA system to detect IgG antibodies in patients with RA and controls. The presence of antibodies to the matrix peptide (denoted as MAG1: RIGKELKQAGRKGNI) was correlated with patient details. RESULTS: On screening patients' serum, we found a significantly higher mean IgG antibody response to MAG1 in 30 patients with RA as compared to 23 patients with inflammatory bowel disease (p = 0.003), 29 patients with osteoarthritis (p = 0.001), and 43 healthy individuals (p = 0.002). Reactivity was not observed to a control peptide possessing a nonhomologous amino acid sequence. On evaluating clinical details with serological activity, no correlation with disease duration (p = 0.128), sex (p = 0.768), or rheumatoid factor status (p = 0.576) was found. CONCLUSION: A significantly elevated IgG antibody response to an HERV-K10 Gag matrix peptide was observed in patients with RA, suggesting that the exposure of HERV-K10 may cause a secondary, antigenic driven immune response in RA.

A double-blind, randomized, placebo-controlled study to explore the efficacy of a dietary plant-derived polysaccharide supplement in patients with rheumatoid arthritis.

OBJECTIVES: There is increased interest in the potential benefits of complementary therapies, of which dietary plant-derived polysaccharides (dPPs) are an important component. We examined the impact of oral ingestion of a pre-biotic dPP supplement active compound (AC) on serum glycosylation and clinical variables associated with inflammation and general health in patients with RA. METHODS: A double-blind, placebo-controlled, parallel-group clinical trial was used. Participants were randomly assigned to receive AC (n = 33) or placebo (n = 36) for 6 months. Serum protein N-glycosylation was determined by mass spectrometry. Patient outcomes were assessed by validated clinical trial health questionnaires. The primary clinical efficacy variable was DAS-28. RESULTS: The groups had comparable baseline clinical characteristics. AC was well tolerated with low drop-out rates. Supplementation resulted in a 12% significant drop in the levels of the agalactosylated (G0F) glycans [8.10 (0.89) to 7.16 (0.60); P = 0.03], but had no significant overall effect on patient outcomes. The placebo-treated group showed no change in G0F but exhibited a reduction in the levels of fully digalactosylated (G2) glycans (11%; P = 0.03). Although not clinically significant, DAS scores were, however, marginally lower in the placebo group [difference = 0.63 (0.23) s.e.; 95% CI 0.17, 1.10; P = 0.009], as were two of the secondary variables. CONCLUSIONS: Short-term dietary supplementation with AC resulted in a moderate, but significant, reduction in G0F levels, but did not result in any clinically significant improvement in disease activity when assessing the study group as a whole.

Prevalence of anxiety and depression in osteoarthritis: use of the Hospital Anxiety and Depression Scale as a screening tool.

The aims of this study are to ascertain the prevalence of anxiety and depressive disorders in an outpatient population with osteoarthritis (OA), examine the interrelationships between severity of OA, pain, disability, and depression, and evaluate the Hospital Anxiety and Depression Scale (HADS) as a screening tool for this population. Patients with lower limb OA were evaluated with the Short Form McGill Pain and Present Pain Index Questionnaires, and a visual analogue scale, WOMAC Osteoarthritis Index-section C, and the HADS. Participants underwent a structured clinical interview by a liaison psychiatrist (AB). X-rays of affected joints were rated for disease severity. Fifty-four patients (42 females; mean age 63.3) were investigated. The prevalence of clinically significant anxiety and/or depression was 40.7% (95% confidence interval (CI), 27.6-55.0%). HADS was a good predictor of anxiety and depression with a sensitivity and specificity of 88% (95%CI, 64% to 99%) and 81% (95%CI, 65% to 92%), respectively. Pain correlated with HADS anxiety and depression scores (e.g. Rank correlation coefficients (Kendall's tau-b) between total HADS scores and Pain VAS scores 0.29; p=0.003). Disability was greater in patients with depression and/or anxiety (e.g. total HADS score; Kendall's rank correlation coefficient tau-b=0.26, p=0.007) OA severity as determined by radiological score was not a good predictor for anxiety nor depression and only weakly associated with disability. Anxiety and depression are very common in OA patients. HADS anxiety was a better predictor of diagnosed anxiety than HADS depression was of diagnosed depression. HADS is a valid and reliable screening instrument for detecting mood disorder, but not a diagnostic tool or a substitute for asking about symptoms of depression. The interrelationship between mental health, pain and disability is strong. We should therefore adopt a multidisciplinary approach to the management of OA.

Systematic review: accuracy of anti-citrullinated Peptide antibodies for diagnosing rheumatoid arthritis.

BACKGROUND: Early recognition and treatment of rheumatoid arthritis is important to prevent irreversible joint damage. Anti-citrullinated peptide antibodies (ACPA) have been suggested for early diagnosis. PURPOSE: To compare the accuracy of ACPA and rheumatoid factor in diagnosing rheumatoid arthritis in patients with early symptoms of the disease. DATA SOURCES: 10 medical databases from inception to September 2009, with no language or publication restrictions, and references of included studies. STUDY SELECTION: Two independent reviewers screened searches. Full articles were assessed by one reviewer and checked by a second reviewer to identify studies that reported 2 x 2 data on ACPA for the diagnosis of rheumatoid arthritis (by 1987 American College of Rheumatology criteria). DATA EXTRACTION: One reviewer abstracted data on patient characteristics, ACPA details, and 2 x 2 data and assessed study quality by using the QUADAS tool. A second reviewer checked extractions. DATA SYNTHESIS: 151 studies were included, with considerable heterogeneity in sensitivity (range, 12% to 93%) and specificity (range, 63% to 100%). In cohort studies that investigated second-generation anti-cyclic citrullinated peptide antibodies (anti-CCP2) in patients with early rheumatoid arthritis (<2 years), summary sensitivity and specificity were 57% (95% CI, 51% to 63%) and 96% (CI, 93% to 97%), respectively. Case-control and cross-sectional studies and studies of patients with established rheumatoid arthritis all overestimated sensitivity. Anti-CCP2 had greater specificity than rheumatoid factor (96% vs. 86%), with similar sensitivity. Evidence was insufficient to ascertain whether the combination of anti-CCP2 and rheumatoid factor provides additional benefit over anti-CCP2 alone. LIMITATIONS: Most studies used a diagnostic case-control design, which overestimated sensitivity. Items relating to study quality were rarely reported. Publication bias could not be assessed. CONCLUSION: Anti-CCP2 should be included in the work-up of patients with early symptoms of rheumatoid arthritis.

Management of knee osteoarthritis in primary care: pain and depression are the major obstacles.

OBJECTIVES: Osteoarthritis (OA) management is a challenge, as OA consists of a spectrum of pathologies requiring a multifaceted treatment approach. Patient education programmes (PEP) are attractive, as they may be cost effective and potentially efficacious. The goals of the study were to determine what may hinder the efficacy of a PEP for knee OA by determining the relevance of depression, pain, disease knowledge and physical ability in patients to their response to a PEP. METHODS: Clinical and demographic data relating to 170 patients who completed a trial of a PEP were analysed to determine how they interrelate during patient management. RESULTS: All patients showed a progressive decrease in mental health over the duration of the study (P<.001). Greater pain was associated with reduced coping, increased depression and reduced physical ability (P<.05). Women were more likely to experience disability (P<.05). Disability was associated with reduced ability to cope, increased depression and the experience of more pain (P<.05). Subjects with a Caucasian background were significantly (P<.05) more likely to possess knowledge of OA than other ethnic groups. The lowest knowledge group experienced more pain; the highest knowledge group was coping better and had less depression (P<.05). CONCLUSION: A complex interrelationship between depression, pain, disease knowledge, and physical ability in patients with knee OA has been demonstrated. Specifically, the treatment of depression and pain may be paramount to the successful treatment of knee OA, and these factors should be considered in each patient and management priorities made.

Glyco-biomarkers: potential determinants of cellular physiology and pathology.

Once dismissed as just the icing on the cake, sugar molecules are emerging as vital components in life's intricate machinery. Our understanding of their function within the context of the proteins and lipids to which they are attached has matured rapidly, and with it the far reaching clinical implications are becoming understood. Recent advances in high-throughput glycomic techniques, glyco biomarker profiling, glyco-bioinformatics and development of increasingly sophisticated glyco-arrays, combined with our increased understanding of the molecular details of glycosylation have facilitated the linkage between aberrant glycosylation and human diseases, and highlighted the possibility of using glyco-biomarkers as potential determinants of disease and its progression. The focus of this review is to give an insight into the biological significance of these glycomodifications, highlight some specific examples of glyco-biomarkers in relation to autoimmunity and in particular rheumatoid arthritis, and to explore the exciting possibility of exploiting these for diagnostic and prognostic strategies.

The pivotal nature of sugars in normal physiology and disease.

Glycopathology has become the focus of considerable research in recent years as the role of glycosylation in the development, regulation, and progression of disease has come under increased scrutiny. Cracking the 'sugar-code' in biological systems that relate to both health and disease holds tremendous promise for deciphering disease mechanisms such as the link between the glycomodification of immunoglobulins and various autoimmune diseases, notably IgG in rheumatoid arthritis (RA), and has exciting implications for the development of novel diagnostic and therapeutic interventions.

Imaging in CNS lupus.

The diagnosis of neuropsychiatric systemic lupus erythematosus (NPSLE) is complex not only on account of the heterogeneous nature of neurological presentation but also because of the difficulty of differentiating lupus-related pathology from other neuropsychiatric diseases. Magnetic resonance imaging (MRI) remains the gold standard for the non-invasive assessment of NPSLE but there are problems, both with sensitivity and specificity. Both T(2) quantitation and the use of gadolinium have shown promise in differentiating acute from chronic lesions. Nonetheless, the lack of sensitivity of conventional MRI has led to the exploration of other MR-based techniques. Magnetic resonance spectroscopy (MRS) allows the measurement of brain metabolites, whereas diffusion weighted imaging and diffusion tensor imaging allow assessment of white matter structure and integrity. MRS studies in NPSLE have consistently shown a reduction in N-acetyl aspartate (a neuronal marker). Diffusion weighted imaging has had only limited application in lupus and the results to date have shown abnormal diffusivity in lupus patients consistent with inflammation and loss of white matter structure. These techniques remain research tools at this early stage. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) have also been explored as functional imaging tools in lupus and both appear to be more sensitive in detecting subtle brain changes in NPSLE but there are issues with specificity which deter their use in the clinical setting.

Lack of benefit of a primary care-based nurse-led education programme for people with osteoarthritis of the knee.

Osteoarthritis (OA) is the commonest cause of locomotor disability and forms a major element of the workload of the primary care team. There is evidence that patient education may improve quality of life, physical functioning, mental health and coping as well as reducing health service use. The aim of this study was to evaluate the effectiveness of a primary care-based patient education programme (PEP) using a randomised controlled trial. A cluster randomised controlled trial, involving 22 practices, was used to determine the efficacy of a nurse-led education programme. The programme consisted of a home visit and four 1-h teaching sessions. Patients were assessed at baseline and then 1, 3, 6 and 12 months post intervention using 36-item Short Form (SF-36), Western Ontario and McMaster Universities Arthritis Index (WOMAC), arthritis helplessness index and a patient knowledge questionnaire. Direct interviews were used at baseline and at the 12-month follow-up. There were no differences in depression, OA knowledge, pain or physical ability at either 1 month or 1 year between the two groups. Control practices (65 patients from 12 practices) recruited significantly fewer patients than intervention practices (105 patients from ten practices, p = 0.02). Control practices had more doctors (p = 0.02), more non-white patients (p = 0.007), fewer patients living alone (p = 0.005) and lower levels of disability (p = 0.008). We detected a lack of benefit of PEP for people with OA of the knee. This was thought to be due in part to the short intervention time employed and the heterogeneous nature of the disease and the population studied.

Serum galactosyltransferase isoform changes in rheumatoid arthritis.

OBJECTIVE: To investigate glycosylation changes associated with rheumatoid arthritis (RA) by determining whether there are beta1,4-galactosyltransferase (GTase) isoforms specific to or altered in the serum of patients with RA. Methods. Serum GTase isoform profiles were determined using isoelectric focusing (IEF) in patients with active RA (n = 9), disease controls (DC; n = 9), and healthy individuals (HI; n = 10). RESULTS: There was a highly significant difference (p < 0.0001) between the IEF profiles. The RA IEF profile was significantly (p < 0.0001) different from that of the DC or the HI group. There was, however, no significant difference between the DC and HI profiles. Serum GTase samples from 8/9 RA, 9/9 DC, and 9/10 HI resolved into 2 distinct peaks of activity. The RA isoform profile was associated with an acidic shift. There were no significant differences in the pH value of the first peak; the second peak was found to be significantly more acidic in the RA group (mean pH 5.02) compared to the DC and HI group (mean pH 5.20; p < 0.05). The RA associated isoform constituted a significantly greater proportion of total enzymatic activity in the RA sera (16.1%) compared to DC and HI (13.5%; p < 0.05 and 12.6%; p < 0.01, respectively). RA and HI serum GTase desialylation resulted in an alkaline shift of the isoforms into similar pH bands: 5.25-5.50, 5.70-5.85, and 6.20-6.40. GTase was found to be on average 75% more active in its desialylated form than in its sialylated state. CONCLUSION: RA is associated with a differential expression of GTase isoforms. This may be due to increased hypersialylation, which has the potential to adversely affect the catalytic activity of the enzyme, thus providing a possible mechanism for posttranslational regulation of GTase activity in RA.

Capturing lay perspectives in a randomized control trial of a health promotion intervention for people with osteoarthritis of the knee.

Osteoarthritis (OA) is a common and often disabling condition that predominately affects older adults. It is the commonest cause of locomotor disability and forms a major element of the workload in primary care. Previous studies suggest that there are both deficits in the knowledge patients have about their disease and extensive 'unmet' information needs. This paper explores the patients' perspective on the meaning and significance of living with arthritis, identified through quantitative and qualitative approaches undertaken during a trial that evaluated the effectiveness of a primary care-based patient education programme. This paper draws on qualitative and quantitative data from: the baseline interview (knowledge of arthritis, satisfaction with services and support received in primary care); patient diaries (individual goals and reflections on treatment); and group teaching sessions (themes describing the patient's experience). The different data sources were interrogated for common and divergent themes. One hundred and ninety-four participants were identified and 170 completed baseline interviews. Participants were predominantly female (73%), with a mean age of 63 and arthritis of long-standing; 55% reported that they had had it for 5 years or more. Use of primary care services was high, with 41% consulting their GP in the 2 weeks before interview. Levels of information were low, with less than 25% receiving support/advice about the disease, pain management or its impact upon daily life. Set against negative perceptions of the quality of services, patients' personal priorities were for improved pain management and enhanced mobility/functional ability. The combined quantitative and qualitative data provide insight into the patients' perspective on the causes and impact of knee OA, individual goals desired from treatment and the quality of care. There is consistent evidence of unmet needs for information and support and the priority placed by patients on finding strategies to cope with OA and maintaining independence. Even within a tightly defined study sample participating in the intervention, a diversity of experience and goals were revealed, which highlights the importance of taking account of contextual factors and individual differences when evaluating complex interventions.

Rheumatic disease differentiation using immunoglobulin G sugar printing by high density electrophoresis.

OBJECTIVE: To determine whether immunoglobulin G (IgG) sugar printing using high density electrophoresis can be a diagnostic and prognostic test to rapidly differentiate early rheumatoid arthritis (ERA), rheumatoid arthritis (RA), and other rheumatic diseases from each other. METHODS: One hundred fifty-three patients with ERA/RA, psoriatic arthritis (PsA), early psoriatic arthritis (EPsA) ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), juvenile idiopathic arthritis (JIA), early undifferentiated seronegative arthritis (UA), and osteoarthritis (OA) were investigated. Samples of their serum IgG were purified, and sugars were released enzymatically and fluorophore-labelled, then subjected to high density electrophoresis, and relative quantities of each sugar were determined by optical density. RESULTS: Sugar prints of 9 sugars were compiled for each of the 9 disease groups. Specific disease-associated sugar changes were determined by comparison with OA. For example, agalactosylated structures were increased in ERA/RA and EPsA/PsA (p = 0.0001-0.004) and digalactosylated structures were decreased in PsA, AS, and JIA (p = 0.0001-0.04). When the disease groups were compared, each disease was characterized by a unique sugar print comprising 7 of the 9 sugars (p = 0.001-0.005); only g0fb and a1f were not associated. ERA/RA differed in the quantities of monogalactosyl and sialylated sugars (p = 0.006-0.007). The presence of agalactosyl sugars enabled correct prediction of RA in 71.2% of individuals, with a specificity of 84.2% and sensitivity of 50.0%. The area under the sensitivity versus specificity curve was 0.7812. CONCLUSION: IgG sugar printing was found to be effective in differentiation of rheumatic diseases and can differentiate ERA and RA from each other and from other rheumatic diseases; and hence may constitute a relatively rapid diagnostic and prognostic test for patients presenting with arthritis.

Evaluation of education for people with osteoarthritis of the knee: recruitment and retention issues in study design.

Osteoarthritis (OA) is a common and often disabling condition affecting older adults. Treatment using anti-inflammatory drugs (NSAIDs) often contributes to morbidity ( 1 ). It is a common reason for people seeking help from primary care ( 2 ). However, unfortunately management approaches often reflect the ageist view that OA is an inevitable consequence of ageing.