John S. Axford

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.

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.

THE ROLE OF IGG GLYCOFORMS IN THE PATHOGENESIS OF RHEUMATOID-ARTHRITIS

ConclusionsIn conclusion, there is a shift in the population of IgG glycoforms towards those with a higher content of agalactosyl biantennary N-linked oligosaccharides in active rheumatoid arthritis (both juvenile and adult), tuberculosis, and Crohns disease, but not in a variety of other rheumatological, inflammatory, or infectious conditions. This shift may contribute to disease pathogenesis both through immune-complex formation and through disturbance of a cellular network directed against the non-reducing terminal G1cNAc epitope. The precise pathology would in each case be modulated by the anatomical site(s) of production of such IgG, and also by the precise mechanism inducing this change in IgG glycosylation. Important amongst such mechanisms may be cross-reactivity between environmental and endogenous carbohydrate epitopes. It will be interesting to see if future research supports the idea that groups of diseases (e. g., rheumatoid arthritis, tuberculosis, Crohns) are indeed related by a common aetiopathogenesis [i. e., G(0)].

Increased apoptosis of bone marrow CD34+ cells and impaired function of bone marrow stromal cells in patients with systemic lupus erythematosus

The changes in bone marrow (BM) stem cell reserve and function and stromal cell function in patients with active systemic lupus erythematosus (SLE) were investigated. The study was carried out on seven SLE patients and 28 healthy controls using flow cytometry and in vitro cell culture assays. We found that patients had low CD34+ cells, compared with the control group, reflecting the decrease of both CD34+/CD38− and CD34+/CD38+ cells. Patient CD34+/Fas+ but not CD34−/Fas+ cells were significantly increased. Apoptotic (7AADdim) cells were higher among CD34+/Fas+ than among CD34+/Fas− cells, and individual values of apoptotic CD34+ cells strongly correlated with the number of CD34+/Fas+ cells. These findings are suggestive of a Fas‐mediated apoptosis accounting for the low CD34+ cells in SLE patients. Moreover, we found that patients had low numbers of granulocyte‐macrophage colony‐forming units (CFU‐GM) and erythroid burst‐forming units (BFU‐E), compared with the control group, and that the generation of colony‐forming cells in long‐term BM cultures was significantly reduced. Patient BM stroma failed to support allogeneic progenitor cell growth. In one patient, CD34+ cells were increased, apoptotic CD34+/Fas+ cells were normalized and defective stromal cell function was restored after autologous stem cell transplantation. We concluded that defective haemopoiesis in SLE patients is probably caused, at least in part, to the presence of autoreactive lymphocytes in BM.

Glycosylation and rheumatic disease.

Abstract Rheumatoid arthritis (RA) and other rheumatic diseases are associated with a significant defect in the galactosyltransferase enzyme that results in a profound change in the galactosylation of immunoglobulin G. This change has been demonstrated to be integrally associated with pathogenic mechanisms associated with inflammation in RA. It is not thought that these changes are unique to RA, but it is thought that there may be subtle changes in the disruption of glycosylation homeostasis causing a unique sugar change to be associated with a number of other rheumatic diseases. This is referred to as ‘sugar printing the rheumatic diseases’ and may be a concept useful both diagnostically and therapeutically.

Sugar printing rheumatic diseases: a potential method for disease differentiation using immunoglobulin G oligosaccharides.

OBJECTIVE To look for oligosaccharide structural variants of IgG that may be unique to specific rheumatic diseases. METHODS Using normal-phase high-performance liquid chromatography technology, a comparison was made of the oligosaccharide pools released from serum IgG from patients with systemic lupus erythematosus (SLE) (n = 10), ankylosing spondylitis (AS) (n = 10), primary Sjögrens syndrome (n = 6), juvenile chronic arthritis (JCA) (n = 13), psoriatic arthritis (n = 9), rheumatoid arthritis (RA) (n = 5), and healthy control individuals (n = 19). RESULTS The oligosaccharide pools were resolved into 13 peaks and the relative proportions of the peaks in each disease group was significantly different from that in healthy controls (P < 0.0001-0.05). A characteristic serum IgG oligosaccharide profile, or sugar print, for each of the rheumatic diseases was found. The sugar prints exhibited a range of glycosylation patterns whereby all RA (P < 0.0001) and JCA (P < 0.006) patients had predominantly agalactosyl structures, while SLE (P < 0.03-0.0001) and AS (P < 0.025-0.0001) patients had predominantly digalactosyl structures. CONCLUSION The data suggest that each disease is associated with a specific mechanism that gives rise to alterations in the normal glycosylation pattern of IgG. Sugar printing of IgG is therefore a potential means for the differentiation of rheumatic diseases and may provide insight into disease pathogenesis.

Quantitation of the oligosaccharides of human serum IgG from patients with rheumatoid arthritis: a critical evaluation of different methods

Several different chromatographic methods and a lectin-based assay have been compared for the quantitation of oligosaccharides released from immunoglobulin G (IgG). The analysis of a series of IgG samples purified from the serum of rheumatoid arthritis patients was carried out by these methods to evaluate the percentage of the glycoforms having 0, 1 or 2 galactose residues (G0, G1 and G2) in order to (a) identify the method that can be most widely used for quantitation, (b) accurately define the range of G0 values found in patients with rheumatoid arthritis, and (c) make available a series of characterised standards for distribution to clinical chemistry laboratories. The chromatographic methods involved: release of oligosaccharides by glycoamidase A after protease digestion followed by HPLC analysis of aminopyridine derivatives on reverse phase and normal phase columns; hydrazinolysis treatment with exoglycosidases (G0 mix) and Biogel P4 chromatography of 2-aminobenzamide (2-AB) derivatives; hydrazinolysis and weak anion exchange or normal phase HPLC of 2-AB derivatives; release of oligosaccharides by PNGase F and either Biogel P4 chromatography of 2-AB derivatives or HPAEC-PAD analysis of native oligosaccharides. The G0 values given by these methods compared favourably with each other and a dot blot assay of denatured IgG interaction with Ricinus communis agglutinin and Bandeiraea simplicifolialectin II. The HPLC and HPAEC methods give additional information that may be important in less routine assays.

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.

The relationship between exposed galactose and N-acetylglucosamine residues on IgG in rheumatoid arthritis (RA), juvenile chronic arthritis (JCA) and Sjogren's syndrome (SS)

The relationship between exposed galactose and N‐acetylglucosamine on IgG in RA, JCA and SS was investigated. This was achieved using IgG isolated from serum where the levels of galactose and N‐acetylglucosamine (GlcNAc) were detected using biotinylated lectins. Galactose and GlcNAc on IgG from patients with RA and JCA are inversely related, but in contrast, in SS, galactose expression on IgG decreased while GlcNAc expression remained similar to normal levels. Alterations in IgG glycosylation are closely associated with the development of adult and juvenile chronic arthritis and SS, but the changes involved are different in RA compared with SS, suggesting that the precise pattern of exposed sugars is associated with different rheumatological diseases.

A role for human endogenous retrovirus‐K (HML‐2) in rheumatoid arthritis: investigating mechanisms of pathogenesis

Human endogenous retroviruses (HERVs) are remnants of ancient retroviral infections within the human genome. These molecular fossils draw parallels with present‐day exogenous retroviruses and have been linked previously with immunopathology within rheumatoid arthritis (RA). Mechanisms of pathogenesis for HERV‐K in RA such as molecular mimicry were investigated. To clarify a role for HERVs in RA, potential autoantigens implicated in autoimmunity were scanned for sequence identity with retroviral epitopes. Short retroviral peptides modelling shared epitopes were synthesized, to survey anti‐serum of RA patients and disease controls. A novel real‐time polymerase chain reaction (PCR) assay was also developed to quantify accurately levels of HERV‐K (HML‐2) gag expression, relative to normalized housekeeping gene expression. Both serological and molecular assays showed significant increases in HERV‐K (HML‐2) gag activity in RA patients, compared to disease controls. The real‐time PCR assay identified significant up‐regulation in HERV‐K mRNA levels in RA patients compared to inflammatory and healthy controls. Exogenous viral protein expression and proinflammatory cytokines were also shown to exert modulatory effects over HERV‐K (HML‐2) transcription. From our data, it can be concluded that RA patients exhibited significantly elevated levels of HERV‐K (HML‐2) gag activity compared to controls. Additional factors influencing HERV activity within the synovium were also identified. The significant variation in RA patients, both serologically and transcriptionally, may be an indication that RA is an umbrella term for a number of separate disease entities, of which particular HERV polymorphisms may play a role in development.