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.

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.