Rajalingham Sakthiswary

The Clinical Significance of Vitamin D in Systemic Lupus Erythematosus: A Systematic Review

Background Vitamin D deficiency is more prevalent among SLE patients than the general population. Over the past decade, many studies across the globe have been carried out to investigate the role of vitamin D in SLE from various clinical angles. Therefore, the aim of this systematic review is to summarise and evaluate the evidence from the published literature; focusing on the clinical significance of vitamin D in SLE. Methods The following databases were searched: MEDLINE, Scopus, Web of Knowledge and CINAHL, using the terms “lupus”, “systemic lupus erythematosus”, “SLE and “vitamin D”. We included only adult human studies published in the English language between 2000 and 2012.The reference lists of included studies were thoroughly reviewed in search for other relevant studies. Results A total of 22 studies met the selection criteria. The majority of the studies were observational (95.5%) and cross sectional (90.9%). Out of the 15 studies which looked into the association between vitamin D and SLE disease activity, 10 studies (including the 3 largest studies in this series) revealed a statistically significant inverse relationship. For disease damage, on the other hand, 5 out of 6 studies failed to demonstrate any association with vitamin D levels. Cardiovascular risk factors such as insulin resistance, hypertension and hypercholesterolaemia were related to vitamin D deficiency, according to 3 of the studies. Conclusion There is convincing evidence to support the association between vitamin D levels and SLE disease activity. There is paucity of data in other clinical aspects to make firm conclusions.

Methotrexate in systemic lupus erythematosus: a systematic review of its efficacy

Objective The objective of this review is to evaluate the evidence for efficacy of methotrexate (MTX) in systemic lupus erythematosus (SLE). Methods A comprehensive, computerized search was performed in MEDLINE (PubMed), EMBASE and the Cochrane Controlled Trials registry to screen for studies that examined the efficacy of MTX in adult SLE patients. The Jadad scoring system was used to assess study quality, and data were pooled using the random effects model. Results Of the 53 articles that were identified, 44 were excluded. Nine studies (including three randomized controlled and six observational) were eligible for inclusion. All of the included studies predominantly involved patients with arthritis or mucocutaneous features. There was significant reduction of the SLE Disease Activity Index (SLEDAI) among MTX-treated patients when compared with controls (p = 0.001, odds ratio (OR) 0.444, 95% confidence interval (CI) 0.279 to 0.707). There was also significant reduction in the average dose of corticosteroids among MTX-treated patients when compared with controls (p = 0.001, OR 0.335, 95% CI 0.202 to 0.558). The effect of MTX on laboratory and serological markers, including erythrocyte sedimentation rate, anti-dsDNA and complement levels (C3 and C4), could not be determined because of the limited numbers of controlled trials. Conclusion The use of MTX is associated with significant reductions in SLEDAI and the average dose of corticosteroids in adult patients with SLE.

Effects of Tumour Necrosis Factor Antagonists on Insulin Sensitivity/Resistance in Rheumatoid Arthritis: A Systematic Review and Meta-Analysis.

Objective Beyond the joints, TNFi (tumour necrosis factor inhibitor) therapy may confer systemic benefits in rheumatoid arthritis (RA). Several studies have investigated the role of TNFi on insulin resistance/sensitivity (IR/IS). This question is of general interest given the emerging evidence linking inflammation and insulin resistance. The main aim of this review was to summarise the published data and to determine the effects of TNFi on IR/IS. Methods We searched the PubMed and ISI Web of Knowledge databases for studies which examined the effects of TNFi on IR/IS. The studies were assessed independently by two reviewers according to a pre-specified protocol. The data on Homeostatic Model Assessment for Insulin resistance (HOMA) and Quantitative Insulin Sensitivity Check Index (QUICKI) were pooled and reported as standard difference in means (SDM) with 95% confidence interval (CI) using a random-effects model. Results A total of eight studies with 260 subjects met the selection criteria. The duration of the studies was from 8 weeks to 12 months. There was statistically significant reduction in HOMA index in six out of eight studies and four reported significant increment in QUICKI. The pooled analysis revealed significant reduction in HOMA [SDM-0.148, 95%CI[-0.278 to -0.017], p=0.026] and increment in QUICKI [SDM 0.312, 95%CI[0.019 to 0.606], p=0.037] with TNFi. Conclusion There is emerging evidence to support that TNFi therapy improves IS and reduces IR in RA. Further, well conducted trials are needed to determine if such effects translate to lower incidence of diabetes in RA or other autoimmune conditions on biologic therapy.

The Effects of TNF α Antagonist Therapy on Bone Metabolism in Rheumatoid Arthritis: A Systematic Review

Osteoporosis is a common complication observed in rheumatoid arthritis (RA). Accelerated bone loss is always a matter of concern. The pathogenesis of RA may be important for better understanding of the bone loss. The mechanism involved in the bone loss in RA is not well understood although cytokines such as interleukin 1 and tumour necrosis factor α (TNF α) have been strongly implicated. TNF α antagonists have revolutionised the treatment of RA in the recent years. Beyond the control of disease activity in RA, accumulating evidence suggests that this form of therapy may provide beneficial effects to the bone metabolism and remodeling. An extensive search of the literature was performed in the Medline, Scopus and EBSCO databases to evaluate the documented research on the effects of TNF α antagonists in RA on bone mineral density and bone turnover markers. The available data based on our systematic review, depict a significant association between TNF α antagonists treatment and suppression of bone resorption.

Bone metabolism and histomorphometric changes in murine models treated with sclerostin antibody: a systematic review.

Preventing osteoporotic fractures in millions of individuals may significantly reduce the associated morbidity and health-care expenditures incurred. As such, the search for newer anti-osteoporotic agents has been ongoing for years. Genetic studies have proven that the secreted protein sclerostin is one of the main culprits, which negatively regulates the bone formation. Recently, sclerostin-neutralizing monoclonal antibodies (Scl-Ab) in rodent studies have shown positive effects on bone homeostasis. An extensive search of the literature was performed in the BIOSIS, Cinahl, EMBASE, Pub- Med, Web of Science and Cochrane Library databases to evaluate the published murine studies on the effects of Scl-Ab on the bone metabolism and histomorphometric parameters. Our systematic review depicts a significant association between Scl-Ab administration and improvement in bone formation, bone density, bone volume and trabecular thickness.

Interleukin-23 and its correlation with disease activity, joint damage, and functional disability in rheumatoid arthritis

The purpose of this study was to compare the serum interleukin (IL)‐23 levels between rheumatoid arthritis (RA) patients and healthy controls and to determine the correlation of IL‐23 levels with disease activity, joint damage and functional disability in RA. Serum samples were obtained from 45 patients with RA and 45 healthy controls. The enzyme‐linked immunosorbent assay method was used for quantitative analysis of IL‐23. All the RA patients were assessed for disease activity based on the 28‐joint disease activity score, joint damage based on modified Sharp score, and functional ability using the Health Assessment Questionnaire–Disability Index. The mean serum IL‐23 level was much higher among the RA patients (24.50 ± 13.98 pg/mL) compared to the controls (5.98 ± 3.40 pg/mL; p < 0.01). There was a significant positive relationship between IL‐23 levels and disease activity and questionnaire scores (p = 0.003 and 0.020, respectively). On logistic regression analysis, IL‐23 levels were significantly higher in patients with moderate to high disease activity (p = 0.008, odds ratio = 1.073, 95% confidence interval = 1.019–1.130) and patients with significant functional disability (p = 0.008, odds ratio = 1.085, 95% confidence interval = 1.021–1.153). RA patients have significantly higher levels of serum IL‐23. The IL‐23 levels correlate well with disease activity and functional disability but not with radiographic joint damage.

Left atrial volume index is an independent predictor of major adverse cardiovascular events in acute coronary syndrome.

BACKGROUND Left atrial volume index (LAVI) is well proven to be a reliable method of determining left atrial size, which has prognostic implications in cardiovascular diseases. Studies demonstrate that increased LAVI is a predictor of mortality in myocardial infarction, but its association with other major adverse cardiovascular events (MACEs) among patients post acute coronary syndrome (ACS) has not been adequately evaluated. METHODS We calculated the baseline LAVI for all patients who were admitted with ACS between December 2010 and August 2011. The patients were stratified into 2 arms: normal LAVI and increased LAVI, with a cutoff value of 28 mL/m(2). All patients were prospectively followed up during 6 months for development of MACEs. RESULTS Of the 75 patients who completed the study, 32 had increased LAVI, and 43 had normal LAVI. More than half (55%) of the patients were diagnosed with unstable angina. During the follow-up period of 6 months, 30 patients (93.8%) in the increased-LAVI arm and 23 patients (53.5%) in the normal-LAVI arm developed at least a single MACE. Patients with increased LAVI had significantly more MACEs (P = 0.021). The occurrence of MACE remained significantly higher in the increased-LAVI group even when atrial fibrillation was excluded (P = 0.016). After adjusting for confounding variables by multivariate analysis, LAVI was found to have a significant association with MACEs (P = 0.030, odds ratio = 1.229 (95% confidence interval, 1.020-1.481). CONCLUSION LAVI is a useful tool for prognostication and an independent predictor of MACEs post ACS.

IgA rheumatoid factor as a serological predictor of poor response to tumour necrosis factor α inhibitors in rheumatoid arthritis

The main objective of this study is to elucidate the role of immunoglobulin A (IgA) rheumatoid factor (RF) in predicting the clinical response to tumour necrosis factor α inhibitors (TNFi) among patients with rheumatoid arthritis (RA).

Stem cell therapy in neurodegenerative diseases: From principles to practice.

The lack of curative therapies for neurodegenerative diseases has high economic impact and places huge burden on the society. The contribution of stem cells to cure neurodegenerative diseases has been unraveled and explored extensively over the past few years. Beyond substitution of the lost neurons, stem cells act as immunomodulators and neuroprotectors. A large number of preclinical and a small number of clinical studies have shown beneficial outcomes in this context. In this review, we have summarized the current concepts of stem cell therapy in neurodegenerative diseases and the recent advances in this field, particularly between 2010 and 2012. Further studies should be encouraged to resolve the clinical issues and vague translational findings for maximum optimization of the efficacy of stem cell therapy in neurodegenerative diseases.

The Clinical Significance of Interleukin–1 Receptor Antagonist +2018 Polymorphism in Rheumatoid Arthritis

Objective Interleukin-1 receptor antagonist (IL-1Ra) acts as an inhibitor of IL-1; which is one of the culprit cytokines in rheumatoid arthritis (RA). Although +2018 polymorphism of IL-1Ra has been implicated in the pathogenesis of RA, its importance remains poorly understood. Hence, the purpose of this study was to determine the clinical significance of interleukin-1 receptor antagonist (IL-1Ra) +2018 polymorphism in RA. Methods Polymerase chain reaction (PCR) and sequencing were used to determine the genotypes of the IL-1Ra +2018 for 77 RA patients and 18 healthy controls. All RA patients were assessed for the disease activity score that includes 28 joints (DAS28) and radiographic disease damage based on Modified Sharp Score (MSS). Results The frequency of the T/T and C/T genotypes did not differ significantly (p = 0.893) between the RA patients and the controls. The C/T genotype had significantly higher mean disease activity (DAS 28) and disease damage (MSS) scores with p values of 0.017 and 0.004, respectively. Additionally, the ESR (erythrocyte sedimentation rate), CRP (C-reactive protein), the number of swollen and tender joints were higher for the C/T individuals. On multivariate analysis the CRP, swollen joint count and MSS remained significant with the following p values i.e. 0.045, 0.046 and less than 0.05. Conclusions C/T genotype of IL-1Ra +2018 prognosticates more aggressive disease in RA.