Vitamin D has the potential to modulate the immune system resulting in an inflammatory response which could lead to improved clinical outcomes for individuals diagnosed with systemic lupus erythematosus (SLE). The overall aim of this research was to investigate vitamin D status in SLE patients residing in Northern Ireland, to determine whether there was a relationship with disease activity, bone mineral density (BMD) and quality of life (QoL). To achieve this we undertook a pilot study in SLE patients (n=19) and age-and-sex matched control participants (n= 19), to investigate the vitamin D status of SLE patients. This was followed by a larger observational study to examine vitamin D status in SLE patients during winter months (November-March) and again in the summer months (June-July). A total of 52 SLE patients were recruited, of which, 50 completed the study. Serum 25-hydroxyvitamin D (25(OH)D) was assessed by liquid chromatography mass spectrometry and disease activity and damage were scored using Systemic Lupus Activity Measure (SLAM), British Isles Lupus Assessment Group (BILAG), Safety of Estrogen in Lupus Erythematosus National Assessment Trial Systemic Lupus Erythematosus Disease Activity Index (SELENA SLEDAI) and Systemic Lupus International Collaborative Clinics/American College of Rheumatology (SLICC/ ACR). BMD was measured by Dual Energy X-ray absorptiometry, fatigue was assessed by the fatigue severity score and percieved QoL was assessed using the 36-item short form health survey. BMD was measured during the winter assessment of the observational study and at both time points, associations between vitamin D, disease activity, fatigue and QoL were examined by means of correlation and regression analysis. Vitamin D inadequacy was prevalent in this cohort of SLE patients residing in Northern Ireland, although no significant difference in vitamin D status was observed between winter and summer (P=0.439). Some 98% of SLE patients presented with serum 25(OH)D concentration < 75 nmol/L at both timepoints and vitamin D concentration was inversely associated with BILAG during winter. Fatigue was present in 98% of the cohort during both time points and patients with fatigue had significantly lower vitamin D status compared to those without fatigue (P=0.030). Furthermore, BILAG was a useful predictor of future fatigue in this cohort. Osteoporosis and osteopenia were identified in 8% and 45% of the SLE patients respectively, none of whom were prescribed calcium/vitamin D supplements. The social functioning (P=0.023) and mental component scores (P=0.049) of the 36-item short form questionnaire were significantly decreased during the summer. This cohort of SLE patients appeared to have much lower QoL throughout the year than that of SLE patients reported in other studies and both fatigue and disease activity were shown to be associated with QoL. The findings of this research could impact on patient care, given the high prevalence of vitamin D inadequacy and its relationship with disease activity and fatigue. These novel results provide some evidence of a potential relationship between vitamin D and disease activity. If proven, increased vitamin D status could improve clinical outcomes such as fatigue and disease activity thereby indirectly improving QoL. Future research involving vitamin D supplementation in SLE patients to optimise status would strengthen the evidence for beneficial effects of vitamin D in SLE.

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Discoid Lupus Erythematosus (DLE) is the most common form of cutaneous lupus and causes irreversible facial scarring and disfigurement. Hydroxychloroquine is the oral therapy of choice. The factors influencing clinical response to hydroxychloroquine are unclear. Patients with Systemic Lupus Erythematosus (SLE) treated with hydroxychloroquine demonstrate a positive correlation between whole-blood hydroxychloroquine levels and clinical response. Variation in response to hydroxychloroquine might, in part, be due to genetic differences in the CYP450 genes responsible for hepatic metabolism of hydroxychloroquine between individuals, which therein could influence whole-blood hydroxychloroquine levels. The influence of genetic polymorphisms on the therapeutic response to hydroxychloroquine, in comparison with host or disease attributes such as smoking status or disease extent, is unknown. A multicentre retrospective cohort study was conducted in 200 patients with DLE treated with hydroxychloroquine. The outcomes of interest were: (i) the clinical response to hydroxychloroquine by 6 months and (ii) the effects of disease attributes, smoking, and CYP450 polymorphisms on clinical response. Although the majority of patients responded to hydroxychloroquine, a significant proportion (39%) either failed to respond or was intolerant of the drug. Cigarette smoking and CYP 206 and 2CB genotypes did not have any Significant influence on response to hydroxychloroquine. Multivariate analysis indicated that disseminated disease and concomitant SLE at baseline were both Significantly associated with lack of response to hydroxychloroquine. These findings suggest that baseline lupus severity and SLE are important predictors of response to hydroxychloroquine. A prospective study is required to further explore the response of DLE to hydroxychloroquine and to investigate the relationships between disease activity and eventual response. A validated scoring instrument was designed to specifically measure activity and damage attributable to DLE and will be essential for quantifying disease and appraising responsiveness to hydroxychloroquine in future prospective studies. Following peer review, pilot work and two reliability studies, the Score of Activity and Damage in DLE (SADDLE) was developed as a measure of disease severity in DLE. Activity is measured using erythema, induration and scaling and damage is represented by scarring and dyspigmentation. SADDLE demonstrates evidence of inter and intra-rater reliability and construct validity. In summary, these inter-related studies not only indicate that 1 in 3 patients with DLE do not respond to hydroxychloroquine by 6 months, but also show that lack of response may be associated with disease extent and concomitant SLE at baseline. Cigarette smoking did not influence response, casting doubt on the results of previous small single-site retrospective studies, which did not assess confounding variables such as disease extent and SLE and suggested smoking was associated with poor response to therapy. A disease activity score has been developed for future use in prospective trials to help investigate these findings further.

This research to develop and validate the BILAG-2004 index for the assessment of disease activity in patients with [systemic lupus erythematosus] SLE had involved several validation studies. The reliability of this index was shown in 2 exercises, as assessed by level of agreement, kappa statistic, ICC and disagreement between physicians. This study also highlighted the importance of training in ensuring optimal performance of the index. This index had construct validity as higher scores in the index were significantly associated increasing ESR, decreasing C3, decreasing C4, elevated anti-dsDNA antibody and increasing SLEDAI-2000 scores. Active disease scores were significantly associated with increase in therapy, confirming the criterion validity of the index. Sensitivity to change was demonstrated as changes in the score of the index were differentially related to change in therapy, with greater change in score having greater predictive power. Rasch analysis showed that this index had a good fit to the Rasch model, indicating that it is a unidimensional ordinal scale index with internal construct validity. The validation studies led to revisions of the index to ensure it had face and content validity. The results of this research have shown that the revised BILAG-2004 index is valid for use to assess SLE disease activity.

Introduction: SLE is associated with pro-atherogenic metabolic derangement and an elevated cardiovascular risk. The vascular endothelium may be a key interface between active SLE and premature atherosclerosis. Improved understanding of the contribution of inflammation and its management to cardiovascular risk in SLE will inform personalised treatment decisions in SLE patients. Methods: Data from an international inception cohort was used to investigate the relationship between inflammatory disease activity, lupus phenotype and corticosteroid exposure and the metabolic syndrome (MetS) over 2 years in SLE patients. The relationship between disease activity (BILAG-2004) and markers of endothelial function (flow-mediated dilatation (FMD) of the brachial artery) and endothelial damage (endothelial microparticles (EMPs)) following a change in anti-inflammatory therapy was investigated in a longitudinal cohort of patients with active SLE. Results: MetS was common in young SLE patients (12.6-16.0%) over the initial 2 years of disease. Factors independently associated with developing MetS over the 2-year study period were (odds ratio (95% CI)) Hispanic ethnicity (3.47 (1.76, 6.86)), higher initial peak corticosteroid dose (1.02 (1.01,1.03)), and elevated anti-dsDNA antibodies at study entry (1.86(1.19,2.81)). MetS was often persistent and preceding MetS strongly predicted future MetS (4.83 (2.93, 7.87)). Patients with active SLE had reduced FMD (median (IQR) FMD 1.63% (-1.22, 5.32) vs. 5.40% (3.02, 8.57); p = 0.05) and elevated EMPs (157,548/ml (59,906, 272,643) vs. 41,025 (30,179, 98,082); p = 0.003) compared to age-matched controls. Both improved following a change in anti-inflammatory therapy, and correlated moderately with change in disease activity over time. Conclusions: Inflammatory disease activity and higher doses of corticosteroids in very early disease influence the development of MetS in SLE, which can become persistent. Endothelial dysfunction is common in patients with active SLE but can be improved with better disease control. Therefore even from disease onset, therapeutic regimes should be individually tailored to achieve good disease control whilst minimising corticosteroid doses, to improve cardiovascular risk surrogates in SLE.