L.Y. Ho

Vitamin D deficiency as marker for disease activity and damage in systemic lupus erythematosus: a comparison with anti-dsDNA and anti-C1q

Objectives: To study the sensitivity and specificity of vitamin D deficiency for predicting disease activity and damage of systemic lupus erythematosus (SLE) in comparison with anti-dsDNA and anti-C1q. Methods: Consecutive patients who fulfilled four or more ACR criteria for SLE were studied. Levels of 25-hydroxyvitamin D3, anti-C1q, anti-dsDNA and complement levels were measured. Relationship among these markers, concurrent disease activity and damage scores of SLE was studied by Spearmans rank correlation method. Results: In total, 290 SLE patients were studied (95% women; mean age 38.9 ± 13.1 years; SLE duration 7.7 ± 6.7 years). Clinical or serological lupus activity (SLEDAI ≥ 1) was present in 225 (78%) patients. Vitamin D deficiency (< 15 ng/ml) was detected in 78 (27%) patients. Levels of 25-hydroxyvitamin D3 correlated inversely with the clinical SLE disease activity score (Rho = −0.26; p < 0.001). A negative correlation was also observed between 25-hydroxyvitamin D3 and anti-dsDNA levels (Rho = −0.13; p = 0.02), or anti-C1q (Rho = −0.14; p = 0.02). However, there was no significant relationship between levels of 25-hydroxyvitamin D3 and complement C3 (Rho = 0.09; p = 0.12) or C4 (Rho = 0.09; p = 0.13). Both 25-hydroxyvitamin D3 deficiency and anti-C1q were more specific but less sensitive than anti-dsDNA for concurrent clinical renal and non-renal SLE activity. Levels of 25-hydroxyvitamin D3, anti-dsDNA or anti-C1q did not correlate significantly with the SLE damage scores. Conclusions: 25-hydroxyvitamin D3 correlated inversely and significantly with clinical SLE activity, anti-C1q and anti-dsDNA titers, but not with complement levels or damage scores. Deficiency of 25-hydroxyvitamin D3 was as specific as anti-C1q, but less sensitive than anti-dsDNA, for detecting concurrent renal and non-renal clinical activity of SLE.

Effect of disease activity and damage on quality of life in patients with systemic lupus erythematosus: a 2‐year prospective study

Objectives: To examine the effect of disease activity and damage on health‐related quality of life (HRQoL) in patients with systemic lupus erythematosus (SLE). Methods: Consecutive SLE patients and matched controls were recruited for a study of HRQoL using the Medical Outcomes Study Short Form‐36 (SF‐36). SLE activity and damage was assessed by the Safety of Oestrogens in Lupus Erythematosus National Assessment SLE Disease Activity Index (SELENA‐SLEDAI) and the American College of Rheumatology/Systemic Lupus International Collaborating Clinics (ACR/SLICC) Damage Index (SDI), respectively. Patients were prospectively followed for repeat HRQoL assessment at 2 years. The effects of cumulative disease activity and new damage on changes in SF‐36 scores were evaluated. Results: One hundred and fifty‐five patients were studied (94% women; age 37.8±11.3 years; SLE duration 7.2±5.4 years). Fifty (32%) patients had active disease and 75 (48%) had organ damage at baseline. Compared with age‐ and gender‐matched controls, SLE patients had lower SF‐36 scores, and the difference remained significant after adjustment for income and education level. SF‐36 scores in SLE patients correlated inversely with SDI but not with SELENA‐SLEDAI scores. After 2 years, there was a significant drop in the mental component score of the SF‐36. Regression analysis revealed that new damage was the only determinant for a reduction in SF‐36 scores. Patients with higher cumulative disease activity had a greater drop in bodily pain and general health subscores. Conclusions: Impaired HRQoL is more common in SLE patients than controls, regardless of age, sex, education and poverty. Pre‐existing organ damage is associated with poorer HRQoL and new damage predicts a further decline in HRQoL. Persistent disease activity is associated with deterioration in certain domains of the SF‐36.

Risk and predictors of work disability in Chinese patients with systemic lupus erythematosus

The aim of this study is to determine the risk and predictive factors for work disability in patients with SLE. A cross-sectional questionnaire study was performed to evaluate the employment status of a sample of consecutive Chinese patients with SLE. Demographic, socioeconomic data (age, gender, marital status, years of education and household income), employment status, self-reported fatigue score and disease characteristics (SLE duration, organ damage and disease activity) were collected. Work disability was defined by the failure to work due to SLE. The cumulative incidence of work disability since the time of SLE diagnosis was studied by a Kaplan Meier’s plot, and factors predictive of work disability were studied by Cox regression. A total of 147 patients with SLE were studied (mean age = 39.4 ± 11.3 years; 95% women). Among 105 patients who were working at the time of SLE diagnosis, 39 (37%) lost their ability to work as a result of SLE after a mean disease duration of 10.0 ± 6.1 years. Twenty-two (56%) patients lost their work ability within 2 years of diagnosis of SLE. The self-reported reasons for job loss were musculoskeletal pain (87%), skin disease (26%), renal problem (21%), fatigue (85%), memory deterioration (51%), anxiety or depressive symptoms (74%), too frequent sick leave (10%) and long-term hospitalisation (10%). The cumulative risk of work disability was 36% at 5 years after SLE diagnosis. In a Cox regression model, age (HR = 1.06 [1.02–1.11] per year; P = 0.008), self-reported fatigue score (HR = 1.06 [1.01–1.10] per point; P = 0.01) and mean disease activity score in the preceding two years (HR = 1.20 [1.02–1.42] per point; P = 0.03) were independently associated with working disability. In all, 37% of this group of patients with SLE lost their work ability after having the disease for 10 years. More than 50% of these patients developed work disability within the first 2 years of SLE diagnosis. Older age, fatigue and more active disease were independent predictors of work disability.

Annual incidence and standardized incidence ratio of cerebrovascular accidents in patients with systemic lupus erythematosus.

Objectives: To study the annual incidence and standardized incidence ratio (SIR) of cerebrovascular accident (CVA) in patients with systemic lupus erythematosus (SLE). Subjects and methods: The annual incidence of CVA from 1999 to 2007 in a longitudinal cohort of SLE patients was calculated each year and compared with that of the regional population within the same study period. Age-specific SIRs and outcome of CVA in SLE patients were also studied. Results: In 2007, there were 490 SLE patients in our cohort. The mean annual incidence of CVA between 1999 and 2007 was 6.45/1000 patients and no obvious trend over time was observed. Of the 20 CVAs in patients with SLE, 18 (90%) were ischaemic stroke whereas two (10%) were haemorrhagic stroke. The mean SIR of all types of CVA in SLE patients was 2.02 [95% confidence interval (CI) 1.30–3.81; p = 0.002]. The SIR of ischaemic stroke decreased with age and the stroke incidence was no longer significantly higher than that of the population in patients aged ≥ 60 years. Haemorrhagic stroke occurred mainly in younger SLE patients. The duration of hospitalization and the mortality rate for CVA was non-significantly higher in SLE than in non-SLE patients. Conclusions: The incidence of CVA in SLE remained constant over the 8 years between 1999 and 2007. Younger SLE patients are at substantially increased risk of CVA compared to age-matched population. The duration of hospitalization and the mortality rate for CVA are similar in SLE and non-SLE patients.

Switching of oral bisphosphonates to denosumab in chronic glucocorticoid users: A 12-month randomized controlled trial

OBJECTIVES To evaluate the effect of switching from oral bisphosphonates to denosumab on bone mineral density (BMD) in long-term glucocorticoid users. METHODS Adult patients who were receiving long-term prednisolone (≥2.5 mg/day for ≥1 year) and oral bisphosphonates (≥2 years) were recruited. Participants were randomized to either continue oral bisphosphonates or switch to denosumab (60 mg subcutaneously every 6 months) for 12 months. Serial BMD (lumbar spine, hip) and bone turnover markers (serum osteocalcin, P1NP, β-CTX) were measured. RESULTS 42 women were recruited (age 54.7±12.9 years; 21 shifted to denosumab and 21 continued on bisphosphonates). The duration of prednisolone therapy was 101±66.3 months and the daily dose was 4.4±2.1 mg. Baseline demographic data, osteoporosis risk factors, and BMD at various sites were similar between the two groups of patients. At month 12, BMD of the spine and hip increased by +3.4±0.9% (p=0.002) and +1.4±0.6% (p=0.03), respectively, in the denosumab group; whereas the corresponding change was +1.5±0.4% (p=0.001) and +0.80±0.5% (p=0.12) in the bisphosphonate group. The spinal BMD at month 12 was significantly higher in the denosumab than bisphosphonate group after adjustment for baseline BMD and β-CTX values, and other confounding factors (p=0.01). Bone turnover markers (β-CTX and P1NP) were more strongly suppressed by denosumab than the bisphosphonates. Minor infections were more common in denosumab-treated patients while other adverse events occurred at similar frequencies between the two groups. CONCLUSIONS In patients receiving long-term glucocorticoids, switching from oral bisphosphonates to denosumab resulted in greater gain of the spinal BMD and suppression of bone turnover markers after 12 months of therapy. The results have to be confirmed by a larger clinical trial with fracture as endpoint.

Raloxifene for prevention of glucocorticoid-induced bone loss: a 12-month randomised double-blinded placebo-controlled trial

Objectives To study the efficacy of raloxifene in preventing bone mineral density (BMD) loss in women receiving long-term glucocorticoids (GC). The study took the form of a parallel-group randomised double-blinded placebo-controlled trial. Methods Postmenopausal women without hypercoagulability risk factors who were prevalent GC users were randomised to receive either raloxifene (60 mg/day) or placebo (1 tablet/day) on top of calcium (1000 mg/day) and calcitriol (0.25 μg/day). BMD of the hip and spine (primary outcome), bone turnover markers and new vertebral fractures (secondary outcomes) at month 12 were assessed. Results Between December 2006 and December 2008, 114 patients were recruited (age 55.3±7.7 years). The duration and dose of prednisolone received was 62.2±64 months and 6.7±5.9 mg/day, respectively. Baseline vertebral fracture was present in six (5%) patients. In all, 57 patients were allocated to each of the treatment arms. Demographic data, osteoporotic risk factors and BMD at various sites were similar between the two groups of patients. At month 12, a significant gain in the lumbar spine (+1.3±0.4%; p=0.004) and total hip BMD (+1.0±0.4%; p=0.01) was observed in patients treated with raloxifene but a significant decrease in BMD of the lumbar spine (−0.9±0.4%; p=0.045) and hip (−0.8±0.3%; p=0.01) occurred in the placebo group. The femoral neck BMD did not change significantly in favour of raloxifene. Three new fractures developed exclusively in the patients treated with placebo. Bone formation (serum osteocalcin and procollagen type I N-terminal) and resorption (urine deoxypyridinoline and type I collagen) markers decreased significantly in the raloxifene group but not in patients treated with placebo. Leg cramps were numerically more frequent in the raloxifene group (7% vs 0%) but thromboembolism was not reported in any patients. Conclusions In postmenopausal women receiving long-term GCs, raloxifene is well tolerated and significantly increases spinal and hip BMD after 12 months of treatment.

Combined low-dose mycophenolate mofetil and tacrolimus for lupus nephritis with suboptimal response to standard therapy: a 12-month prospective study

Objective The objective of this paper is to evaluate the efficacy of combined mycophenolate mofetil (MMF) and tacrolimus (TAC) for lupus nephritis with suboptimal response to standard therapy. Methods Inclusion criteria for patients: (1) biopsy-confirmed active lupus nephritis; and (2) inadequate response to ≥2 immunosuppressive regimens. While prednisolone (≤10 mg/day) and angiotensin-converting enzyme inhibitors were continued, immunosuppressive agents were replaced by combined MMF (1 g/day) and TAC (4 mg/day). Patients were followed every 2 months for the clinical response and adverse events at 12 months. Results Twenty-one patients were recruited (20 women; age 35.8 ± 9.2 years; systemic lupus erythematosus (SLE) duration 111 ± 51 months). The histological classes of lupus nephritis were: IV/III (33%), V + III/IV (33%) and pure V (33%). The creatinine clearance (CrCl), urine protein-to-creatinine ratio (uP/Cr) and serum albumin was 82.4 ± 33 ml/min (<90 ml/min in 57%), 3.27 ± 1.5 and 30.1 ± 5.9 g/l, respectively. Thirteen (62%) patients had active urinary sediments and 17 (81%) patients had active lupus serology. At 12 months, eight (38%) patients had very good response, one (5%) patient had good response and five (24%) patients had partial response. Significant improvement in uP/Cr, albumin, complement C3 and anti-dsDNA titer, and stabilization of CrCl was observed in the responders. Thirty-three adverse events were reported in 18 patients: major infection requiring hospitalization (6%), infection not requiring hospitalization (27%), herpes infection (9%), diarrhea (12%), cramps (9%), dyspepsia (6%), transient increase in serum Cr (6%), alopecia (4%), facial twitching (3%), tremor (3%) and diabetes mellitus (3%). None of these had led to protocol withdrawal. Conclusions Combined low-dose MMF and TAC is an option for lupus nephritis that fails to respond adequately to standard regimens, with two-thirds of patients improving after 12 months. Longer-term observation is needed to confirm its efficacy and safety.

Effect of golimumab and pamidronate on clinical efficacy and MRI inflammation in axial spondyloarthritis: a 48-week open randomized trial

Objectives: To compare the effect of golimumab (GLM) and pamidronate (PAM) on clinical efficacy and magnetic resonance imaging (MRI) inflammation in axial spondyloarthritis (aSpA). Method: Patients who fulfilled the Assessment of SpondyloArthritis Society (ASAS) criteria for aSpA and had active disease [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score ≥ 4] were randomized in a 2:1 ratio to receive either GLM (50 mg) or PAM (60 mg) 4 weekly for 48 weeks. Clinical efficacy was assessed at intervals. Inflammation of the spine and sacroiliac joints (SIJs) on MRI was graded by the Spondyloarthritis Research Consortium of Canada (SPARCC) scoring system. Results: Twenty patients were assigned to GLM and 10 to PAM (83% men; age 33.4 ± 10.9 years; disease duration 4.4 ± 3.4 years). The baseline characteristics of the two groups were similar. At week 48, the proportions of patients who achieved an ASAS20 response were not significantly different between the GLM and PAM groups (65% vs. 56%; p = 0.69). Although there were no differences in BASDAI, spinal pain, and Medical Outcomes Study 36-item Short Form Health Survey (SF-36) scores between the two groups at week 48, the Ankylosing Spondylitis Disease Activity Score (ASDAS), Bath AS Functional Index (BASFI), C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) levels were significantly lower in GLM-treated patients. The SPARCC scores of the spine and SIJs decreased significantly in GLM- but not in PAM-treated patients. The differences in SPARCC scores between the two groups at week 48 were statistically significant. The frequency of adverse events (AEs) was similar in both arms. Conclusions: In patients with aSpA, the clinical response rate and improvement in pain and quality of life (QoL) were similar between GLM and PAM groups after 48 weeks. However, significant reduction in inflammatory markers and MRI inflammation was only observed with GLM treatment.

SAT0216 Relationship between individual organ damage and mortality of systemic lupus erythematosus (SLE): A prospective cohort study of 679 patients

Objectives To study the relationship between damage in different organ systems and mortality in patients with SLE. Methods 679 patients who fulfilled at least 4 of the ACR criteria for SLE between 1995 and 2011 were prospectively followed. The cumulative rate of survival was studied by Kaplan-Meier’s plot. For those who died during the disease course, data were censored at the time of death. For other patients, including those who were lost follow-up, data were censored at the time of last clinic visits. Organ damage was assessed by the ACR SLICC damage scores (SDI). Cox regression models were established to study the association between damage in individual systems and mortality in this cohort of patients. Results 679 SLE patients were studied (623 women, 92%). All were ethnic Chinese. The mean age of onset of SLE was 32.5±13.6 years and the mean follow-up time of the entire cohort of patients was 117±89 months. 67 (9.9%) patients died during the course of illness and 33 (4.9%) patients were lost to follow-up. 23 (3.4%) patients developed end stage renal failure (ESRF). The main contributing causes of death were: infection (51%), cardiovascular events (12%), cerebrovascular events (16%), cancer (9%), suicide (3%) and others (8%). Infective complications were the commonest causes of death both in patients with disease duration of less (55%) and more than 5 years (47%). In patients with SLE for less than 5 years, 19% of all deaths were caused by vascular events, which was lower than those with disease for more than 5 years (36%). The cumulative survival rate of the patients was 94.8% at 5 years, 91.3% at 10 years and 88% at 15 years. 301 (44%) patients had organ damage (SDI score ≥1). Among patients who had organ damage, the frequency of damage in individual systems was, in decreasing order: neuropsychiatric (N=102, 15%), musculoskeletal (N=93, 14%), renal (N=78, 11%), ocular (N=46, 6.8%), cardiovascular (N=38, 5.6%), pulmonary (N=36, 5.3%), gonadal (N=32, 4.7%), endocrine (N=23, 3.4%), peripheral vascular (N=22, 3.2%), malignancy (N=19, 2.8%) and gastrointestinal (N=8, 1.1%). Within the first 5 years of onset of SLE, neuropsychiatric damage was most frequent (10%), followed by renal (7.9%) and dermatological (7%) damage. In patients with SLE duration of more than 5 years, the commonest cause of damage was in the musculoskeletal system (18.4%), followed by neuropsychiatric (17%) and renal damage (13.3%). The presence of any organ damage was strongly and significantly associated with mortality (HR 6.42[3.05-13.5]; p<0.001). Cox regression analysis revealed that damage in the neuropsychiatric system (HR 1.74[1.31-2.32]; p<0.001), renal (HR 1.97 [1.61-2.42]; p<0.001), cardiovascular (HR 1.75 [1.21-2.53]; p=0.03) and pulmonary (HR 2.63 [1.50-4.62]; p=0.001) systems was significantly associated with mortality. Conclusions In patients with SLE, organ damage predicts mortality, in particular damage in the renal, nervous, cardiovascular and pulmonary systems. Neuropsychiatric damage is most common in early disease while musculoskeletal damage is most frequent in long-standing disease. Prevention of infective and cardiovascular complications, and minimization of renal damage is important in improving the survival of SLE. Disclosure of Interest None Declared

Long-term immunogenicity of a quadrivalent human papillomavirus vaccine in systemic lupus erythematosus

OBJECTIVES To evaluate the 5-year immunogenicity of a quadrivalent human papillomavirus (HPV) vaccine (GARDASIL) in patients with systemic lupus erythematosus (SLE). METHODS Female SLE patients and controls, aged 18-35 years, who received GARDASIL in 2011 and sero-converted 12 months post-vaccination were followed for persistence of immunogenicity. Antibody measurement to HPV serotypes 6, 11, 16, 18 was repeated at 5 years. The rate of sero-reversion was compared between patients and controls, and factors associated with sero-reversion of the anti-HPV antibodies were studied. RESULTS 50 SLE patients and 50 controls were vaccinated with GARDASIL. Among subjects who sero-converted at 1 year and consented for this study, antibodies to HPV serotypes 6, 11, 16 and 18 at 5 years were persistent in 24/27 (89%), 26/31 (84%), 32/34 (94%) and 24/25 (96%) of the SLE patients; and 32/33 (97%), 32/33 (97%), 32/32 (100%) and 23/24 (96%) of the controls, respectively. Antibody titers to HPV-6 and 16 were significantly lower in patients than controls. Seven (21%) SLE patients had sero-reversion of ≥1 anti-HPV antibodies. Sero-reverted patients experienced significantly more SLE flares, particularly renal, and had received significantly higher cumulative doses of prednisolone, mycophenolate mofetil and tacrolimus than those with persistent immunogenicity. The cumulative doses of prednisolone correlated inversely and significantly with the anti-HPV 6, 11, and 16 titers at 5 years. CONCLUSIONS Immunogenicity of the quadrivalent HPV vaccine was retained in a high proportion of SLE patients at 5 year. Patients with more SLE renal flares and had received more immunosuppression were more likely to have sero-reversion of the anti-HPV antibodies. CLINICAL TRIAL REGISTRATION NUMBER US ClinicalTrials.gov (NCT00911521 & NCT02477254).