Aisha Lateef

Biologics in the treatment of systemic lupus erythematosus.

Purpose of reviewThe pathogenesis of systemic lupus erythematosus (SLE) involves aberrancy in multiple components of the immune system including B cells, T cells, cytokines and growth factors. Therapeutic agents targeting these mediators selectively have been tested for the treatment of SLE. This review summarizes the recent advances in the fast expanding field of these biological therapies. Recent findingsThe two large phase 2/3 randomized placebo-controlled trials of B-cell depletion, using anti-CD20 antibody, rituximab, in SLE, reported unexpected negative results. On the contrary, two large phase 3 trials of belimumab, the monoclonal antibody against B-lymphocyte stimulator (BLyS), showed significant clinical benefit. Response rates were 57.6 and 43.2% for 10 mg/kg belimumab, compared with 43.6 and 33.8% for placebo in BLISS-52 and BLISS-76, respectively. Studies of a co-stimulation blocker (abatacept), tumor necrosis factor inhibitor (infliximab), and interleukin-6 inhibitor (tocilizumab) were either negative (abatacept) or were associated with high rates of adverse events. Studies of T cell and interferon inhibition remain in the early development phase. SummaryDespite the enthusiasm in the field of biologic therapies, the majority of these new modalities have fallen short of expectations for various reasons. Only belimumab has recently met its primary outcome in two phase 3 trials.

Definition and initial validation of a Lupus Low Disease Activity State (LLDAS)

Aims Treating to low disease activity is routine in rheumatoid arthritis, but no comparable goal has been defined for systemic lupus erythematosus (SLE). We sought to define and validate a Lupus Low Disease Activity State (LLDAS). Methods A consensus definition of LLDAS was generated using Delphi and nominal group techniques. Criterion validity was determined by measuring the ability of LLDAS attainment, in a single-centre SLE cohort, to predict non-accrual of irreversible organ damage, measured using the Systemic Lupus International Collaborating Clinics Damage Index (SDI). Results Consensus methodology led to the following definition of LLDAS: (1) SLE Disease Activity Index (SLEDAI)-2K ≤4, with no activity in major organ systems (renal, central nervous system (CNS), cardiopulmonary, vasculitis, fever) and no haemolytic anaemia or gastrointestinal activity; (2) no new lupus disease activity compared with the previous assessment; (3) a Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLEDAI physician global assessment (scale 0–3) ≤1; (4) a current prednisolone (or equivalent) dose ≤7.5 mg daily; and (5) well tolerated standard maintenance doses of immunosuppressive drugs and approved biological agents. Achievement of LLDAS was determined in 191 patients followed for a mean of 3.9 years. Patients who spent greater than 50% of their observed time in LLDAS had significantly reduced organ damage accrual compared with patients who spent less than 50% of their time in LLDAS (p=0.0007) and were significantly less likely to have an increase in SDI of ≥1 (relative risk 0.47, 95% CI 0.28 to 0.79, p=0.005). Conclusions A definition of LLDAS has been generated, and preliminary validation demonstrates its attainment to be associated with improved outcomes in SLE.

Management of pregnancy in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoantibody-mediated systemic autoimmune disease, predominantly affecting young females. Pregnancy is increasingly common in the setting of SLE, as survival and quality of life of patients improve. Although live births can be achieved in the most cases, pregnancy in patients with SLE remains a high-risk condition. Maternal and fetal mortality and morbidity are considerably increased, compared with the general population. Aberrations in pregnancy-related maternal immune adaptations are likely contributors. Active maternal disease, renal involvement, specific autoantibody subsets and advanced organ damage are predictors of poor outcome. Therapeutic options are limited during pregnancy as maternal benefit has to be weighed against fetal risk. Prevention of preterm birth and refractory pregnancy loss, as well as management of established neonatal heart block remain unmet needs. Further research should address these important issues that affect young patients with SLE and their babies.

Atherogenic serum lipid profile is an independent predictor for gouty flares in patients with gouty arthropathy

OBJECTIVE Atherogenic serum lipid profile possesses pro-inflammatory properties and is associated with more active RA. While prevalent in patients with gout, whether atherogenic lipid profile is associated with gouty flares is unknown. This study aims to investigate whether atherogenic serum lipid predicts gouty flares in patients with gout. METHODS Adult patients (age > or =21 yrs) who suffered from gout were prospectively followed between September 2006 and November 2007 and their demographic, clinical and laboratory data were collected. Episodes of gouty flares over this observation period were recorded and factors predictive of gouty flares were studied by regression models. RESULTS Of the 100 patients, 80 were men, 65 were ethnic Chinese, 31 were Malay and the rest were Indian and Caucasian. The mean age and duration of gout (+/-S.D.) were 61.9 +/- 14.0 and 6.6 +/- 7.8 yrs, respectively. The mean serum uric acid and creatinine levels were 537.6 +/- 142.8 and 173.6 +/- 119.9 micromol/l, respectively. In univariate analysis, longer duration of gout, higher adjusted mean serum creatinine, lower adjusted mean fasting serum, total cholesterol and high-density lipoprotein cholesterol (HDL-C) levels were associated with gouty flares. After adjustment for potential confounders in multivariate regression models, longer duration of gout and lower adjusted mean fasting serum HDL-C level remained independently predictive of gouty flares. CONCLUSIONS Low serum high-density lipoprotein cholesterol level was an independent predictor for gouty flares. Whether optimizing serum HDL-C level can benefit patients with gout in terms of reducing gouty flares needs to be addressed by controlled trials.

A randomized controlled trial for improving patient self-assessment of synovitis in rheumatoid arthritis with education by ultrasonography: the RAEUS Study

OBJECTIVE Patients can potentially monitor disease activity of RA through self-assessed swollen joints (clinical synovitis), but reliability is poor. The objective is to evaluate the use of education by US feedback on the ability of patients to assess for clinical synovitis in RA. METHODS We performed a 6 month, single-centre, randomized controlled trial on patients with established RA to study the effect of education on self-assessment of joints that included initial brief patient training on tender (TJC) and swollen (SJC) joint counts followed by US feedback every 3 months vs standard care without education. Patient and physician independently performed 28-joint counts at each visit. Outcome variables included the percentage of patients with good agreement with physician-derived swollen joints [prevalence-adjusted bias-adjusted kappa (PABAK) >0.6] as well as agreement in the SJC (Bland and Altman 95% limits of agreement), feasibility/patient satisfaction survey and disease activity at 6 months. RESULTS Of the 101 randomized patients, 95 were included (51 in the education arm and 44 in the standard care arm). At 6 months there was a significant difference in the proportion of patients with swollen joint PABAK >0.6 in the education arm compared with standard care (98 vs 85%, P = 0.02). Limits of agreement for the SJC difference between physician and patients were reduced only in the education arm. The training method is considered feasible, with 94% of patients reporting it as useful. A trend of higher rates of disease remission (28-joint DAS <2.6) in the education arm vs standard care (47% vs 29%, P = 0.07) was seen. CONCLUSION A short course of education with US feedback may be helpful in educating patients to assess for clinical synovitis. TRIAL REGISTRATION Clinical trials.gov, https://clinicaltrials.gov, NCT02351401.

Does expert opinion match the operational definition of the Lupus Low Disease Activity State (LLDAS)? A case-based construct validity study

OBJECTIVE To evaluate the construct validity of the Lupus Low Disease Activity State (LLDAS), a treatment target in systemic lupus erythematosus (SLE). METHODS Fifty SLE case summaries based on real patients were prepared and assessed independently for meeting the operational definition of LLDAS. Fifty international rheumatologists with expertise in SLE, but with no prior involvement in the LLDAS project, responded to a survey in which they were asked to categorize the disease activity state of each case as remission, low, moderate, or high. Agreement between expert opinion and LLDAS was assessed using Cohens kappa. RESULTS Overall agreement between expert opinion and the operational definition of LLDAS was 77.96% (95% CI: 76.34-79.58%), with a Cohens kappa of 0.57 (95% CI: 0.55-0.61). Of the cases (22 of 50) that fulfilled the operational definition of LLDAS, only 5.34% (59 of 22 × 50) of responses classified the cases as moderate/high activity. Of the cases that did not fulfill the operational definition of LLDAS (28 of 50), 35.14% (492 of 28 × 50) of responses classified the cases as remission/low activity. Common reasons for discordance were assignment to remission/low activity of cases with higher corticosteroid doses than defined in LLDAS (prednisolone ≤ 7.5mg) or with SLEDAI-2K >4 due to serological activity (high anti-dsDNA antibody and/or low complement). CONCLUSIONS LLDAS has good construct validity with high overall agreement between the operational definition of LLDAS and expert opinion. Discordance of results suggests that the operational definition of LLDAS is more stringent than expert opinion at defining a low disease activity state.

THU0298 Consensus Definition of a Low Disease Activity State in Systemic Lupus Erythematosus

Background In systemic lupus erythematosus (SLE), organ damage, morbidity and mortality are the result of acute or sustained disease activity. The diversity of clinical features of active SLE makes quantification of disease activity problematic. The definition of a low disease activity state in rheumatoid arthritis has resulted in it being widely applied in research and clinical practice, but in SLE there is currently no such definition and thus no related outcome data. In contrast, clinicians often intuitively recognize a state of low SLE disease activity, wherein patients’ disease activity is low and treatment burden acceptable. No empirical definition of a low disease activity state in SLE has been described. Objectives To define a ‘lupus low disease activity state’ (LLDAS), for subsequent validation using prospective cohort data. Methods Firstly, we defined LLDAS conceptually as follows: ‘A state which, if sustained, is associated with a low likelihood of adverse outcome’, considering both disease activity and medication safety. Next, a panel of experts from Hong Kong, China, Philippines, Thailand, Singapore, Indonesia and Australia individually generated items for potential inclusion in a definition of LLDAS. These items were scored on a 5-point scale, then reduced using the Delphi method. Six experts participated in the first round of Delphi, and items with a mean score ≥ 3 were retained. Eleven experts then participated in a consensus meeting using the nominal group technique, and in a second round of Delphi, in which items with an mean score ≥ 4 were retained. Results Fifty-six ‘unique’ items were initially generated. These fell into two domains: (i) descriptions of disease activity, and (ii) descriptions of medication use. Following two rounds of Delphi, unanimous agreement on the preliminary definition of LLDAS was reached. The final list of five items defining LLDAS comprised: SLEDAI-2K ≤4, with no SLEDAI activity in major organ systems (renal, CNS, cardiopulmonary, vasculitis, hemolytic anemia, fever) and no gastrointestinal activity); No new features of lupus disease activity compared to the previous assessment; SELENA-SLEDAI physician global assessment (PGA, scale 0-3) ≤1; Current prednisolone (or equivalent) dose ≤ 7.5 mg daily; and Well-tolerated standard maintenance doses of immunosuppressive drugs and/or approved biologic agents, excluding investigational drugs. Conclusions We have generated a definition of LLDAS. The definition of LLDAS will be validated in a large prospective multicenter Asian-Pacific lupus cohort, using outcomes including organ damage and death, and refined in response to subsequent findings. Once validated, LLDAS may serve alone, or in combination with variables such as patient reported outcomes, as a treatment target in SLE clinical practice, research, and clinical trials. Disclosure of Interest None Declared

SAT0282 Frequency and Predictors of Attainment of The Lupus Low Disease Activity State (LLDAS) in A Cross Sectional Study of Sle Patients in The Asia Pacific

Background Systemic lupus erythematosus (SLE) is a heterogeneous disease characterised by fluctuating disease activity. A low disease activity endpoint, the Lupus Low Disease Activity State (LLDAS), was recently reported and retrospective validation showed that time spent in LLDAS translated into reduced damage accrual (Franklyn, Ann Rheum Dis, 2015). A large prospective study to validate LLDAS in a multiethnic cohort of lupus patients from the Asia Pacific Region is underway. Objectives To describe the frequency and identify the predictors of fulfilling criteria for LLDAS in baseline visit data from a large multinational multiethnic cohort of patients with SLE in nine Asia Pacific countries. Methods Prospectively collected baseline visit data from 1846 SLE patients enrolled in a longitudinal study were analysed cross sectionally against the recently published definition of LLDAS, and patient characteristics associated with LLDAS attainment determined. Results LLDAS criteria were met by 44% of patients at a single baseline visit. Stepwise multivariable logistic regression revealed that patients with shorter disease duration were less likely to be in LLDAS (OR 0.31, 95% CI 0.19–0.49, p<0.001). Likewise, discoid rash (OR 0.66, 95% CI 0.49–0.89, p=0.006), renal disease (OR 0.60, 95% CI 0.48–0.75, p<0.001), elevated double stranded DNA (OR 0.65, 95% CI 0.53–0.81, p<0.001) or hypocomplementaemia (OR 0.52, 95% CI 0.40–0.67, p<0.001) were negatively associated with LLDAS attainment. Significant differences in LLDAS attainment between countries were observed, and higher national social wealth as measured by the Gross Domestic Product per capita was positively associated with LLDAS (OR 1.57, 95% CI 1.25–1.98, p<0.001). Conclusions Low disease activity was observed in less than half of SLE patients at a single point in time. Disease duration and phenotype, as well as national social wealth, were predictive of LLDAS attainment. Disclosure of Interest None declared

OP0053 A Randomized Controlled TRIAL of Improving Patient Self-Assessment of Synovitis in Rheumatoid Arthritis with Education by Ultrasonography: the Raeus Study

Background Patients can potentially monitor disease activity in rheumatoid arthritis (RA) by performing self-assessment of joint counts. However, reliability of self-assessed swollen joint count is generally poor [1]. Objectives To evaluate the use of education by using feedback from ultrasound (US) images on the ability of patients to assess swollen joints in RA. Methods Study design: 6-month single centre unblinded randomized controlled trial, stratified by age and disease activity. Patients: Consecutive patients with established RA. Intervention: (i) education on self-assessment of joints: initial brief patient training on tender (TJC) and swollen (SJC) joint counts, followed by US feedback for areas of active synovitis every 3 months (EUS) versus (ii) standard care (no education on self-assessment and feedback with US). Patient and physician independently performed 28-joint counts at each study visit, with US feedback for areas of active synovitis provided for patients in the intervention arm only, at end of each visit. Outcome variables: Primary: Agreement at “joint” level - Proportion of patients with good agreement with physician derived swollen joints (i.e. prevalence-adjusted bias adjusted kappa, PABAK more than 0.6). Secondary: Agreement at “patient” level: i.e. SJC between patients and physician using Bland and Altman 95% limits of agreement, disease activity indices between the 2 groups, proportion of patients achieving remission, feasibility and patient satisfaction survey according to a 5-point Likert scale on the joint count training method by US. Results Ninety-two out of 101 patients completed the study (n=48 EUS, n=44 standard care). There were no differences in baseline characteristics. Mean age was 54.5±12.8 yrs, disease duration 6.3±6.0 yrs, with mean Disease Activity Score (DAS28) 3.3±1.1 (26% in DAS28 remission). At 6 months, the proportion of patients with swollen joint PABAK>0.6 was greater in the EUS arm compared to standard care (98% vs. 82%, p=0.009). The Bland and Altman limits of agreement for SJC difference between physician and patients were reduced only in the EUS arm. At 6 months, there were no significant inter-group differences in disease activity although a trend to higher DAS28 remission in the EUS arm (46% vs. 28% in standard care, p=0.08). Training with US was considered feasible (15-20 minutes) with 94% of patients reporting it as useful for appreciating their own disease activity. Conclusions A short course of patient education with US feedback can improve patient-physician reliability for the assessment of swollen joints. Larger studies with longer follow up are required to evaluate the clinical benefits. References Cheung et al. Sem Arthritis Rheum 2013 (nov 13) [Epub ahead of print] Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.2203