Effect of Vitamin D on serum markers of bone turnover in SLE in a randomised controlled trial

© 2019 Author(s). Objective Bone health in SLE is adversely affected by vitamin D deficiency, inflammatory cytokines and glucocorticoid use. We hypothesised that vitamin D supplementation would increase markers of bone formation and decrease markers of bone resorption in SLE subjects. Methods We studied 43 vitamin D-deficient SLE subjects who participated in a 12-week randomised controlled trial of 2000-4000 IU/day vitamin D supplementation versus placebo. Subjects had inactive SLE (SLE Disease Activity Index ≤4) and were taking D, N-terminal propeptide of type 1 collagen (P1NP) and C-telopeptide (CTX). We tested the effect of vitamin D versus placebo on change (δ) in P1NP and δCTX in an intention-to-treat analysis. Secondary analyses evaluated whether vitamin D affected bone turnover among subjects achieving vitamin D repletion (≥30 ng/mL) or currently taking glucocorticoids. Results 28 subjects were randomised to vitamin D and 15 to placebo. Mean age was 39 years and 40% were using glucocorticoids at enrolment. Repletion was achieved by 46% in the vitamin D group versus none in the placebo group. Changes in bone turnover markers were not significantly different in the vitamin D group versus placebo group (median δP1NP -0.2 vitamin D group vs -1.1 placebo group (p=0.83); median δCTX +3.5 vitamin D group vs -37.0 placebo group (p=0.50)). The effect of vitamin D did not differ based on achieving vitamin D repletion or baseline glucocorticoid use. Conclusion Vitamin D supplementation did not affect the 12-week change in bone turnover markers among SLE subjects in this trial

Brain metabolism and autoantibody titres predict functional impairment in systemic lupus erythematosus

OBJECTIVE: We investigated whether systemic lupus erythematosus (SLE) disease duration or serology associate with abnormal regional glucose metabolism as measured with [(18)F]2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) and deficits on neuropsychological testing. METHODS: Subjects with SLE with stable disease activity, without brain damage or clinical symptoms of neuropsychiatric (NP) SLE, stratified by disease duration (short-term (ST)-SLE=disease/=10 years), underwent clinical assessments, neuropsychological testing, resting FDG-PET scan imaging and measurement of serum titres of antibody to N-methyl-d-aspartate receptor (DNRAb). FDG-PET scans were compared with age-matched and gender-matched healthy controls. RESULTS: Subjects with LT-SLE demonstrated hypometabolism in the prefrontal and premotor cortices that correlated with accrued SLE-related damage, but not with DNRAb titre or performance on NP testing. Independent of disease duration, subjects with SLE demonstrated hypermetabolism in the hippocampus and orbitofrontal cortex that correlated with impaired memory performance and mood alterations (depression, anxiety, fatigue). Serum DNRAb also correlated independently with impaired memory performance and increased anxiety. Together, serum DNRAb titre and regional hypermetabolism were more powerful predictors of performance than either alone. INTERPRETATION: The presence of serum DNRAbs can account for some aspects of brain dysfunction in patients with SLE, and the addition of regional measurements of resting brain metabolism improves the assessment and precise attribution of central nervous system manifestations related to SLE

Attainment of treat-to-target endpoints in SLE patients with high disease activity in the atacicept phase 2b ADDRESS II study

OBJECTIVE Low disease activity (LDA) and remission are emerging treat-to-target (T2T) endpoints in SLE. However, the rates at which these endpoints are met in patients with high disease activity (HDA) are unknown. Atacicept, which targets B lymphocyte stimulator and a proliferation-inducing ligand, improved disease outcomes in SLE patients with HDA (SLEDAI-2K ≥10) at baseline in the phase 2b ADDRESS II study. This is a post hoc analysis of T2T endpoints in these patients. METHODS Patients received weekly atacicept (75 or 150 mg s.c.) or placebo for 24 weeks (1:1:1 randomization). Attainment of three T2T endpoints, LDA (SLEDAI-2K ≤ 2), Lupus Low Disease Activity State (LLDAS) and remission (clinical SLEDAI-2K = 0, prednisone-equivalent ≤5mg/day and Physician’s Global Assessment <0.5), was assessed and compared with SLE Responder Index (SRI)-4 and SRI-6 response. RESULTS Of 306 randomized patients, 158 (51.6%) had baseline HDA. At week 24, 37 (23.4%) HDA patients attained LDA, 25 (15.8%) LLDAS and 17 (10.8%) remission. Each of these endpoints was more stringent than SRI-4 (n = 87; 55.1%) and SRI-6 (n = 67; 42.4%). Compared with placebo (n = 52), at week 24, patients treated with atacicept 150 mg (n = 51) were more likely to attain LDA [odds ratio (OR) 3.82 (95% CI: 1.44, 10.15), P = 0.007], LLDAS [OR 5.03 (95% CI: 1.32, 19.06), P = 0.018] or remission [OR 3.98 (95% CI: 0.78, 20.15), P = 0.095]. CONCLUSION At week 24, LDA, LLDAS and remission were more stringent than SRI-4 and SRI-6 response, were attainable in the HDA population and discriminated between treatment with atacicept 150 mg and placebo. These results suggest that T2T endpoints are robust outcome measures in SLE clinical trials and support further evaluation of atacicept in SLE. TRAIL REGISTRATION ClinicalTrials.gov, http://clinicaltrials.gov, NCT01972568

Safety and clinical activity of atacicept in the long-term extension of the Phase IIb ADDRESS II study in systemic lupus erythematosus

Objectives: Atacicept reduced SLE disease activity in the Phase IIb ADDRESS II study, particularly in patients with high disease activity (HDA; SLEDAI-2K ≥10) at screening. We assessed long-term safety and efficacy of atacicept in the long-term extension (LTE) of ADDRESS II. Methods: In the 24-week, randomised, double-blind, placebo-controlled ADDRESS II study, patients received weekly atacicept (75 or 150 mg) or placebo. Atacicept was continued at the same dose in atacicept-treated patients in the LTE; placebo-treated patients switched to atacicept 150 mg. Long-term safety was the primary end point. Secondary endpoints included SLE responder index (SRI)-4 and SRI-6 response rates and flares. Results: 253 patients entered the ADDRESS II LTE; 88 received atacicept 150 mg, 82 atacicept 75 mg and 83 placebo/atacicept 150 mg. Median active treatment duration in the LTE was 83.8 weeks. Frequencies of treatment-emergent adverse events (TEAEs) were similar across groups (90.4–93.2%). 12.5%, 14.6% and 21.7% of patients in the atacicept 150 mg, atacicept 75 mg and placebo/atacicept 150 mg groups reported serious TEAEs during the treatment period. The proportions of patients with TEAEs leading to discontinuation were 5.7%, 4.9% and 10.8%, respectively. SRI-4 and SRI-6 response rates were maintained with atacicept in the modified intent-to-treat and HDA populations and those on continuous 150 mg had a reduced risk of first severe flare and longer time to first severe flare vs those who initially received placebo. Conclusion: Long-term treatment with atacicept 150 mg in SLE patients had an acceptable safety profile, with durable efficacy

Soluble urokinase plasminogen activator receptor (suPAR) levels predict damage accrual in patients with recent-onset systemic lupus erythematosus

© 2019 The Authors Objective: The soluble urokinase plasminogen activator receptor (suPAR) has potential as a prognosis and severity biomarker in several inflammatory and infectious diseases. In a previous cross-sectional study, suPAR levels were shown to reflect damage accrual in cases of systemic lupus erythematosus (SLE). Herein, we evaluated suPAR as a predictor of future organ damage in recent-onset SLE. Methods: Included were 344 patients from the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort who met the 1997 American College of Rheumatology classification criteria with 5-years of follow-up data available. Baseline sera from patients and age- and sex-matched controls were assayed for suPAR. Organ damage was assessed annually using the SLICC/ACR damage index (SDI). Results: The levels of suPAR were higher in patients who accrued damage, particularly those with SDI≥2 at 5 years (N = 32, 46.8% increase, p = 0.004), as compared to patients without damage. Logistic regression analysis revealed a significant impact of suPAR on SDI outcome (SDI≥2; OR = 1.14; 95% CI 1.03–1.26), also after adjustment for confounding factors. In an optimized logistic regression to predict damage, suPAR persisted as a predictor, together with baseline disease activity (SLEDAI-2K), age, and non-Caucasian ethnicity (model AUC = 0.77). Dissecting SDI into organ systems revealed higher suPAR levels in patients who developed musculoskeletal damage (SDI≥1; p = 0.007). Conclusion: Prognostic biomarkers identify patients who are at risk of acquiring early damage and therefore need careful observation and targeted treatment strategies. Overall, suPAR constitutes an interesting biomarker for patient stratification and for identifying SLE patients who are at risk of acquiring organ damage during the first 5 years of disease

Study of Flare Assessment in Systemic Lupus Erythematosus Based on Paper Patients

© 2017, The Authors. Arthritis Care & Research published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology. Objective: To determine the level of agreement of disease flare severity (distinguishing severe, moderate, and mild flare and persistent disease activity) in a large paper-patient exercise involving 988 individual cases of systemic lupus erythematosus. Methods: A total of 988 individual lupus case histories were assessed by 3 individual physicians. Complete agreement about the degree of flare (or persistent disease activity) was obtained in 451 cases (46%), and these provided the reference standard for the second part of the study. This component used 3 flare activity instruments (the British Isles Lupus Assessment Group [BILAG] 2004, Safety of Estrogens in Lupus Erythematosus National Assessment [SELENA] flare index [SFI] and the revised SELENA flare index [rSFI]). The 451 patient case histories were distributed to 18 pairs of physicians, carefully randomized in a manner designed to ensure a fair case mix and equal distribution of flare according to severity. Results: The 3-physician assessment of flare matched the level of flare using the 3 indices, with 67% for BILAG 2004, 72% for SFI, and 70% for rSFI. The corresponding weighted kappa coefficients for each instrument were 0.82, 0.59, and 0.74, respectively. We undertook a detailed analysis of the discrepant cases and several factors emerged, including a tendency to score moderate flares as severe and persistent activity as flare, especially when the SFI and rSFI instruments were used. Overscoring was also driven by scoring treatment change as flare, even if there were no new or worsening clinical features. Conclusion: Given the complexity of assessing lupus flare, we were encouraged by the overall results reported. However, the problem of capturing lupus flare accurately is not completely solved

A double-blind, placebo-controlled, phase II, randomized study of lovastatin therapy in the treatment of mildly active rheumatoid arthritis

© 2019 The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. 3-hydroxy-3-methylglutaryl coenzyme-A (HMG Co-A) reductase inhibitors (statins) are standard treatment for hyperlipidaemia. In addition to lipid-lowering abilities, statins exhibit multiple anti-inflammatory effects. The objectives of this study were to determine whether treatment of patients with RA with lovastatin decreased CRP or reduced disease activity. Methods: We conducted a randomized double-blind placebo-controlled 12 week trial of lovastatin vs placebo in 64 RA patients with mild clinical disease activity but an elevated CRP. The primary efficacy end point was the reduction in mean log CRP. Secondary end points included disease activity, RF and anti-CCP antibody titres. Mechanistic end points included levels of serum cytokines. Safety was assessed; hepatic and muscle toxicities were of particular interest. Results: Baseline features were similar between groups. No significant difference in mean log CRP reduction between the two groups was observed, and disease activity did not change from baseline in either treatment group. Mechanistic analyses did not reveal significant changes in any biomarkers. A post hoc analysis of subjects not using biologic therapy demonstrated a significantly greater proportion achieving ≥20% reduction in CRP from baseline in the lovastatin group compared with placebo (P-value = 0.007). No difference was observed in subjects receiving biologics. Lovastatin was well tolerated with no serious safety concerns. Conclusion: This study showed no anti-inflammatory or clinical effects on RA disease activity after 12 weeks of treatment with lovastatin. Lovastatin had a modest effect on CRP in subjects not using biologics, suggesting statins may be anti-inflammatory in selected patients. Trial registration: ClinicalTrials.gov, http://clinicaltrials.gov, NCT00302952

Peripheral Nervous System Disease in Systemic Lupus Erythematosus: Results From an International Inception Cohort Study

© 2019, American College of Rheumatology Objective: To determine the frequency, clinical characteristics, associations, and outcomes of different types of peripheral nervous system (PNS) disease in a multiethnic/multiracial, prospective inception cohort of systemic lupus erythematosus (SLE) patients. Methods: Patients were evaluated annually for 19 neuropsychiatric (NP) events including 7 types of PNS disease. SLE disease activity, organ damage, autoantibodies, and patient and physician assessment of outcome were measured. Time to event and linear regressions were used as appropriate. Results: Of 1,827 SLE patients, 88.8% were female, and 48.8% were white. The mean ± SD age was 35.1 ± 13.3 years, disease duration at enrollment was 5.6 ± 4.2 months, and follow-up was 7.6 ± 4.6 years. There were 161 PNS events in 139 (7.6%) of 1,827 patients. The predominant events were peripheral neuropathy (66 of 161 [41.0%]), mononeuropathy (44 of 161 [27.3%]), and cranial neuropathy (39 of 161 [24.2%]), and the majority were attributed to SLE. Multivariate Cox regressions suggested longer time to resolution in patients with a history of neuropathy, older age at SLE diagnosis, higher SLE Disease Activity Index 2000 scores, and for peripheral neuropathy versus other neuropathies. Neuropathy was associated with significantly lower Short Form 36 (SF-36) physical and mental component summary scores versus no NP events. According to physician assessment, the majority of neuropathies resolved or improved over time, which was associated with improvements in SF-36 summary scores for peripheral neuropathy and mononeuropathy. Conclusion: PNS disease is an important component of total NPSLE and has a significant negative impact on health-related quality of life. The outcome is favorable for most patients, but our findings indicate that several factors are associated with longer time to resolution