Factors associated with non-adherence to medications in systemic lupus erythematosus: Results from a Swedish survey.

OBJECTIVE: To identify determinants of medication non-adherence in a Swedish population of systemic lupus erythematosus (SLE). METHODS: Patients with SLE from Karolinska and Örebro University Hospitals participated in a survey-based cross-sectional study. Demographics, disease activity, organ damage, HRQoL (LupusQol, EQ-5D-5 L), medication non-adherence (<80% on CQR-19 or MASRI) and beliefs about medicines (BMQ) were registered. MASRI was used to report adherence to different drugs/drug classes, categorised into (i) antimalarial agents (AMA), (ii) glucocorticoids and (iii) other SLE medications. Multivariable logistic regression adjusted for age, sex, disease activity and organ damage. RESULTS: Among 205 respondents, the median age was 52.0 years (IQR: 34.0-70.0), 86.3% were women, 66.8% were non-adherent to their medications according to CQR-19, and 6.6% and 6.3% were non-adherent to AMA and glucocorticoids, respectively, according to MASRI. Positive beliefs about glucocorticoids (OR; 95% CI: 0.77; 0.59-0.99; p = .039) and medications overall (0.71; 0.52-0.97; p = .029) were protective against non-adherence to glucocorticoids. Anxiety/depression (3.09; 1.12-8.54; p = .029), medication concerns (1.12; 1.05-1.20; p < .001) and belief that medications are overused (1.30; 1.15-1.46; p < .001) or harmful (1.36; 1.19-1.56; p < .001) were associated with medication non-adherence (CQR-19); beliefs in the necessity of medications (0.73; 0.65-0.82; p < .001) and positive beliefs in medications were protective (0.72; 0.60-0.86; p < .001). No associations were found between other investigated factors and medication non-adherence. CONCLUSIONS: Beliefs about medications were a major determinant of medication non-adherence. Patient education may help alleviate the negative impact of misinformation/unawareness on adherence.

Sensitivity analysis of EQ-5D-3L index scores in terms of discriminative and known-groups validity in SLE: introducing Adequate Health State.

OBJECTIVES: To investigate the ability of different EuroQol 5-Dimensions 3-Levels (EQ-5D-3L) index scores to discriminate between verum drug and placebo (discriminant validity) as well as between responders and non-responders (known-groups validity) in the SLE patient population of two phase III clinical trials of belimumab. METHODS: Data from the BLISS-52 (NCT00424476) and BLISS-76 (NCT00410384) trials (N = 1684), which both showed superiority of belimumab to placebo, were utilized. Responders were defined as SLE Responder Index 4 (SRI-4) achievers at week 52. The Pearson's χ2 and Mann-Whitney U tests were used for comparisons, and logistic regression analysis was used for adjustments for confounders and assessment of independence. RESULTS: While full health state (FHS; EQ-5D index score 1) showed the best ability to discriminate between belimumab and placebo [adjusted odds ratio (OR) 1.47; 95% CI 1.11, 1.96; P = 0.008] and between SRI-4 responders and non-responders (adjusted OR 3.47; 95% CI 1.29, 10.98; P = 0.020), the discriminative ability of EQ-5D index scores 0.800 or more reached statistical significance for both discriminant validity (adjusted OR 1.29; 95% CI 1.02, 1.63; P = 0.036) and known-groups validity (adjusted OR 3.08; 95% CI 1.16, 9.69; P = 0.034). CONCLUSION: Overall, higher EQ-5D index scores were associated with increasing ability to discriminate between belimumab and placebo, and between responders and non-responders. EQ-5D index scores less stringent than FHS may be clinically relevant health-related quality of life goals of treatment in patients with SLE, introducing the concept of EQ-5D adequate health state when FHS is not achievable.

Impact of remission and low disease activity on health-related quality of life in patients with systemic lupus erythematosus.

OBJECTIVES: To investigate the impact of remission and lupus low disease activity state (LLDAS) on health-related quality of life (HRQoL) in systemic lupus erythematosus. METHODS: Short-Form 36 (SF-36), three-level EQ-5D (EQ-5D-3L) and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue data from the BLISS-52 (NCT00424476) and BLISS-76 (NCT00410384) trials were used. Duration in remission/LLDAS required to reach a HRQoL benefit ≥ minimal clinically important differences (MCIDs) during and post-treatment was determined using quantile regression and generalized estimating equations. RESULTS: Patients (n = 1684) were assessed every fourth week (15 visits). Four cumulative (ß = 0.60) or four consecutive (ß = 0.66) visits in remission were required to achieve a benefit ≥MCID in SF-36 physical component summary (PCS) scores, and six cumulative (ß = 0.44) or five consecutive (ß = 0.49) for a benefit ≥MCID in mental component summary (MCS) scores. Eight cumulative (ß = 0.30 for both) or eight consecutive (ß = 0.32 for both) visits in LLDAS were required for a benefit in PCS/MCS ≥MCID, respectively. For EQ-5D-3L index scores ≥MCID, six cumulative (ß = 0.007) or five consecutive (ß = 0.008) visits in remission were required, and eight cumulative (ß = 0.005) or six consecutive (ß = 0.006) visits in LLDAS. For FACIT-Fatigue scores ≥MCID, 12 cumulative (ß = 0.34) or 10 consecutive (ß = 0.39) visits in remission were required, and 17 cumulative (ß = 0.24) or 16 consecutive (ß = 0.25) visits in LLDAS. CONCLUSION: Remission and LLDAS contribute to a HRQoL benefit in a time-dependent manner. Shorter time in remission than in LLDAS was required for a clinically important benefit in HRQoL, and longer time in remission for a benefit in mental compared with physical HRQoL aspects. When remission/LLDAS was sustained, the same benefit was achieved in a shorter time.

Impact of overweight and obesity on patient-reported health-related quality of life in systemic lupus erythematosus.

OBJECTIVES: Associations between BMI and health-related quality of life (HRQoL) in SLE have been implied, but data are scarce. We determined the impact of overweight and obesity on HRQoL in a large SLE population. METHODS: We pooled cross-sectional baseline data from the BLISS-52 (NCT00424476) and BLISS-76 (NCT00410384) trials (N = 1684). HRQoL was evaluated using the 36-item Short Form Health Survey (SF-36), Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale and the European Quality of Life 5-dimension questionnaire (EQ-5D). Comparisons between BMI groups were conducted using the Mann-Whitney U test and adjustments using linear regression. Clinical relevance was determined by minimal clinically important differences (MCIDs). RESULTS: In total, 43.2% of the patients had BMI above normal and 17.4% were obese. Overweight and obese patients reported worse SF-36 physical component summary (PCS), physical functioning, role physical, bodily pain and FACIT-Fatigue scores than normal weight patients. Divergences were greater than corresponding MCIDs and more prominent with increasing BMI. Despite no clinically important difference in SF-36 mental component summary scores across BMI categories, patients experienced progressively diminished vitality and social functioning with increasing BMI. In linear regression analysis, BMI above normal and obesity were associated with worse PCS (standardized coefficient ß = -0.10, P < 0.001 and ß = -0.17, P < 0.001, respectively), FACIT-Fatigue (ß = -0.11, P < 0.001 and ß = -0.16, P < 0.001) and EQ-5D (ß = -0.08, P = 0.001 and ß = -0.12, P < 0.001) scores, independently of demographic and disease-related factors. The impact of BMI on the PCS and FACIT-Fatigue was more pronounced than that of SLE activity. CONCLUSION: Patients with SLE and BMI above normal experienced clinically important HRQoL diminutions in physical aspects, fatigue and social functioning. A survey of potential causality underlying this association is warranted.

Contribution of abnormal BMI to adverse health-related quality of life outcomes after a 52-week therapy in patients with SLE.

OBJECTIVES: To investigate whether abnormal BMI is associated with adverse health-related quality of life (HRQoL) outcome, including severe fatigue, after 52 weeks of standard therapy plus belimumab or placebo in patients with SLE. METHODS: We analysed data from the BLISS-52 (NCT00424476) and BLISS-76 (NCT00410384) trials (n = 1684). Adverse HRQoL was defined as SF-36 scores ≤ the fifth percentile in age- and sex-matched US population-based subjects, and FACIT-F scores <30. We compared BMI groups using the Pearson's χ2 test, and assessed independence with multivariable logistic regression analysis. RESULTS: Overweight (BMI ≥25 kg/m2) and obese (BMI ≥30 kg/m2) patients showed increased likelihood to exhibit adverse SF-36 physical component summary (OR: 1.8; 95% CI: 1.4, 2.3; P <0.001 and OR: 2.4; 95% CI: 1.8, 3.2; P <0.001, respectively) and FACIT-F (OR: 1.3; 95% CI: 1.1, 1.6; P = 0.010 and OR: 1.5; 95% CI: 1.2, 2.0; P = 0.002, respectively) scores at week 52. Underweight was associated with adverse SF-36 mental component summary scores, also after adjustment for sex, ancestry, age, disease duration, disease activity, organ damage and prednisone dose during the study period (OR: 2.1; 95% CI: 1.2, 3.6; P = 0.007). Addition of belimumab to standard therapy independently protected against adverse SF-36 general health (OR: 0.8; 95% CI: 0.6, 1.0; P = 0.025) and FACIT-F < 30 (OR: 0.8; 95% CI: 0.6, 1.0; P = 0.018). CONCLUSION: Overweight and obesity contributed to adverse physical and mental HRQoL outcomes after therapeutic intervention in SLE patients, and underweight contributed to adverse mental HRQoL outcome. A protective effect of belimumab against adverse general health and severe fatigue was implicated.

EQ-5D-3L full health state discriminates between drug and placebo in clinical trials of systemic lupus erythematosus.

OBJECTIVES: The objectives of this study were to investigate the discriminative ability of EQ-5D-3L full health state (FHS) in clinical trials of SLE, and to identify factors associated with FHS after treatment. METHODS: Data from the BLISS-52 (NCT00424476) and BLISS-76 (NCT00410384) trials of belimumab (N = 1684) were utilized. FHS was defined as a response of no problems in all five EQ-5D-3L dimensions, yielding an index score of 1. The Pearson's χ2 or Fisher's exact test was employed for comparisons, and logistic regression for adjustments and assessment of independence. RESULTS: We demonstrated higher EQ-5D-3L FHS frequencies among patients given standard therapy (ST) plus the licensed belimumab dose vs ST alone (26.1% vs 19.4%; P = 0.001; week 52), and within SRI-4 responders vs non-responders (27.0% vs 19.8%; P < 0.001; week 52) from weeks 36 to 52. In multivariable regression analysis, SLEDAI-2K (OR: 0.90; 95% CI: 0.87, 0.94; P < 0.001) and SLICC/ACR Damage Index (OR: 0.79; 95% CI: 0.69, 0.91; P = 0.001) scores were independently associated with lower FHS frequencies at week 52, while adding monthly infusions of belimumab 10 mg/kg to ST favoured FHS perception (OR: 1.60; 95% CI: 1.15, 2.24; P = 0.006). Add-on belimumab 10 mg/kg yielded higher FHS frequencies in antimalarial users vs non-users (29.9% vs 20.1%; P = 0.011), and in anti-dsDNA- and anti-Sm- positive vs negative patients (31.4% vs 13.4%; P < 0.001 and 33.0% vs 22.6%; P = 0.010, respectively), whereas no significant differences were observed in patients given ST alone. CONCLUSION: EQ-5D-3L FHS distinguished belimumab from placebo and responders from non-responders, and exhibited known-group validity in subgroup analysis. FHS may prove a useful patient-reported outcome in SLE studies.

Predictors of low disease activity and clinical remission following belimumab treatment in systemic lupus erythematosus.

OBJECTIVES: To identify predictors of low disease activity and clinical remission following belimumab treatment in SLE. METHODS: SLE patients who received belimumab 10 mg/kg (N = 563) in the BLISS-52 and BLISS-76 clinical trials were surveyed. The performance of baseline factors in predicting attainment of low disease activity (defined as Lupus Low Disease Activity State) or clinical remission [defined as clinical (c)SLEDAI-2K = 0] at week 52 from treatment initiation was evaluated using logistic regression. Organ damage was assessed using the SLICC/ACR Damage Index (SDI). RESULTS: We demonstrated a negative impact of established organ damage on attainment of Lupus Low Disease Activity State [SDI > 0; odds ratio (OR): 0.44; 95% CI 0.22, 0.90; P = 0.024] and the primary Lupus Low Disease Activity State condition, i.e. SLEDAI-2K ⩽ 4 with no renal activity, pleurisy, pericarditis or fever (SDI > 1; OR: 0.46; 95% CI 0.27, 0.77; P = 0.004); cognitive impairment/psychosis was found to mainly account for the latter association. Baseline SDI scores > 1 predicted failure to attain cSLEDAI-2K = 0 (OR: 0.53; 95% CI 0.30, 0.94; P = 0.030), with cutaneous damage mainly driving this association. Anti-dsDNA positivity increased (OR: 1.82; 95% CI 1.08, 3.06; P = 0.025) and cardiovascular damage reduced (OR: 0.13; 95% CI 0.02, 0.97; P = 0.047) the probability of attaining cSLEDAI-2K = 0 along with a daily prednisone equivalent intake restricted to ⩽7.5 mg. CONCLUSION: Belimumab might be expected to be more efficacious in inducing low disease activity and clinical remission in SLE patients with limited or no organ damage accrued prior to treatment initiation. Patients with positive anti-dsDNA titres might be more likely to achieve clinical remission along with limited or no CS use.

Efficacy of glucocorticoids, conventional and targeted synthetic disease-modifying antirheumatic drugs: a systematic literature review informing the 2016 update of the EULAR recommendations for the management of rheumatoid arthritis.

OBJECTIVES: To perform a systematic literature review (SLR) informing the 2016 update of the recommendations for the management of rheumatoid arthritis (RA). METHODS: An SLR for the period between 2013 and 2016 was undertaken to assess the efficacy of glucocorticoids (GCs), conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and targeted synthetic DMARDs (tsDMARDs) (tofacitinib and baricitinib) in randomised clinical trials. RESULTS: For GCs, four studies were included in the SLR. Patients without poor prognostic factors experienced benefit when GCs were added to methotrexate (MTX). Lower doses of GCs were similar to higher doses. For csDMARDs, two new studies comparing MTX monotherapy with combination csDMARD were included in the SLR. In the tREACH trial at the end of 12 months no difference between the groups in disease activity, functional ability and radiographic progression was seen, using principles of tight control (treat-to-target). In the CareRA trial, combination therapy with csDMARDs was not superior to MTX monotherapy and monotherapy was better tolerated.For tsDMARDs, tofacitinib and baricitinib were shown to be more effective than placebo (MTX) in different patient populations. CONCLUSIONS: Addition of GCs to csDMARD therapy may be beneficial but the benefits should be balanced against the risk of toxicity. Under tight control conditions MTX monotherapy is not less effective than combination csDMARDs, but better tolerated. Tofacitinib and baricitinib are efficacious in patients with RA, including those with refractory disease.

Obesity is associated with pain and impaired mobility despite therapy in systemic lupus erythematosus.

Objective: To investigate whether abnormal BMI is associated with health-related quality of life (HRQoL) impairments, defined as patient-reported problems within the different dimensions of the three-level EQ-5D (EQ-5D-3L), before and after treatment for active systemic lupus erythematosus (SLE). Patients and methods: We conducted a post-hoc analysis of data from two phase III clinical trials of belimumab in SLE, i.e., BLISS-52 (n = 865) and BLISS-76 (n = 819). Underweight was defined as BMI <18.5 kg/m2, normal weight as BMI ≥18.5 but <25 kg/m2, pre-obesity as BMI ≥25 but <30 kg/m2, and obesity as BMI ≥30 kg/m2. We investigated associations between BMI groups and problems (level 2 or 3) within each one of the five EQ-5D dimensions before treatment initiation and at week 52, using logistic regression analysis adjusting for age, ethnicity, disease activity, and glucocorticoid dose, and for the post-treatment analysis also for belimumab treatment and baseline EQ-5D-3L responses. Results: Of 1,684 patients included, 73 (4%) were classified as underweight, 850 (50%) as normal weight, 438 (26%) as pre-obese, and 323 (19%) as obese. At baseline, obesity was associated with mild to severe problems in all EQ-5D dimensions (p < 0.05 for all), yielding the strongest association with problems in mobility (adjusted odds ratio, aOR: 2.1; 95% confidence interval, CI: 1.6-2.8; p < 0.001). Pre-obesity was also associated with problems in mobility (aOR: 1.4; 95% CI: 1.1-1.8; p = 0.005). Post-intervention, obesity was associated with problems in mobility and pain/discomfort, and pre-obesity with problems in mobility and self-care (p < 0.05 for all). Conclusion: Our study adds to the evidence that high BMI negatively affects SLE patients' HRQoL, with obesity being associated with pain and impaired mobility despite therapy.

How Can We Enhance Adherence to Medications in Patients with Systemic Lupus Erythematosus? Results from a Qualitative Study.

Medication non-adherence is common among patients with systemic lupus erythematosus (SLE) and may lead to poor clinical outcomes. Our aim was to identify influenceable contributors to medication non-adherence and suggest interventions that could increase adherence. Patients with SLE from two Swedish tertiary referral centres (n = 205) participated in a survey assessing self-reported adherence to medications. Responses were used to select patients for qualitative interviews (n = 15). Verbatim interview transcripts were analysed by two researchers using content analysis methodology. The median age of the interviewees was 32 years, 87% were women, and their median SLE duration was nine years. Reasons for non-adherence were complex and multifaceted; we categorised them thematically into (i) patient-related (e.g., unintentional non-adherence due to forgetfulness or intentional non-adherence due to disbelief in medications); (ii) healthcare-related (e.g., untrustworthy relationship with the treating physician, authority fear, and poor information about the prescribed medications or the disease); (iii) medication-related (e.g., fear of side-effects); and (iv) disease-related reasons (e.g., lacking acceptance of a chronic illness or perceived disease quiescence). Interventions identified that healthcare could implement to improve patient adherence to medications included (i) increased communication between healthcare professionals and patients; (ii) patient education; (iii) accessible healthcare, preferably with the same personnel; (iv) well-coordinated transition from paediatric to adult care; (v) regularity in addressing adherence to medications; (vi) psychological support; and (vii) involvement of family members or people who are close to the patient.

EQ-5D full health state after therapy heralds reduced hazard to accrue subsequent organ damage in systemic lupus erythematosus.

Objectives: To investigate whether self-reported EQ-5D full health state (FHS) after therapeutic intervention for active systemic lupus erythematosus (SLE) is associated with a reduced risk to accrue organ damage. In a separate analysis, we sought to investigate associations between experience of "no problems" in each one of the five dimensions of EQ-5D and the risk to accrue damage. Methods: Data from the open-label extension periods of the BLISS-52 and BLISS-76 trials of belimumab in SLE (NCT00724867; NCT00712933) were used (N = 973). FHS was defined as an experience of "no problems" in all five EQ-5D dimensions. Organ damage was assessed annually using the Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) Damage Index (SDI). Associations between the three-level version of the EQ-5D (EQ-5D-3L) responses at open-label baseline and the first documented increase in organ damage were investigated using Cox regression accounting for age, sex, ancestry, SDI at baseline, and background therapy, and associations with SDI items were investigated using phi (φ) correlation analyses. Results: A total of 147 patients (15.1%) accrued organ damage during follow-up, with the first increase in their SDI score occurring after a mean time of 29.1 ± 19.6 months. Lower proportions of FHS respondents accrued damage over a course of up to 7.9 years of open-label follow-up compared with no FHS respondents (p = 0.004; derived from the logrank test). FHS was associated with a reduced hazard to accrue subsequent organ damage (HR: 0.60; 95% CI: 0.38-0.96; p = 0.033) after adjustments, as was experience of "no problems" in mobility (HR: 0.61; 95% CI: 0.43-0.87; p = 0.006). "No problems" in mobility was negatively correlated with musculoskeletal damage accrual (φ = -0.08; p = 0.008) and associated with a lower hazard to accrue musculoskeletal damage in Cox regression analysis (HR: 0.38; 95% CI: 0.19-0.76; p = 0.006). Conclusion: Experience of EQ-5D-3L FHS and "no problems" in mobility after therapeutic intervention heralded reduced hazard to accrue subsequent organ damage, especially musculoskeletal damage, suggesting that optimisation of these health-related quality of life aspects constitutes a clinically relevant treatment target in patients with SLE, along with clinical and laboratory parameters.

Adverse Health-Related Quality of Life Outcome Despite Adequate Clinical Response to Treatment in Systemic Lupus Erythematosus.

Objective: To determine the prevalence of adverse health-related quality of life (HRQoL) outcomes in patients with SLE who achieved an adequate clinical response after a 52-week long standard therapy plus belimumab or placebo, and identify contributing factors. Methods: We included patients who met the primary endpoint of the BLISS-52 (NCT00424476) and BLISS-76 (NCT00410384) trials, i.e., SLE Responder Index 4 (total population: N = 760/1,684; placebo: N = 217/562; belimumab 1 mg/kg: N = 258/559; belimumab 10 mg/kg: N = 285/563). Adverse HRQoL outcomes were defined as SF-36 scale scores ≤ the 5th percentile derived from age- and sex-matched population-based norms, and FACIT-Fatigue scores <30. We investigated factors associated with adverse HRQoL outcomes using logistic regression analysis. Results: We found clinically important diminutions of HRQoL in SLE patients compared with matched norms and high frequencies of adverse HRQoL outcomes, the highest in SF-36 general health (29.1%), followed by FACIT-Fatigue (25.8%) and SF-36 physical functioning (25.4%). Overall, frequencies were higher with increasing age. Black/African American and White/Caucasian patients reported higher frequencies than Asians and Indigenous Americans, while Hispanics experienced adverse HRQoL outcome less frequently than non-Hispanics. Established organ damage was associated with adverse physical but not mental HRQoL outcomes; particularly, damage in the cardiovascular (OR: 2.12; 95% CI: 1.07-4.21; P = 0.032) and musculoskeletal (OR: 1.41; 95% CI: 1.01-1.96; P = 0.041) domains was associated with adverse SF-36 physical component summary. Disease activity showed no impact on HRQoL outcomes. In multivariable logistic regression analysis, addition of belimumab to standard therapy was associated with lower frequencies of adverse SF-36 physical functioning (OR: 0.59; 95% CI: 0.39-0.91; P = 0.016) and FACIT-F (OR: 0.53; 95% CI: 0.34-0.81; P = 0.004). Conclusions: Despite adequate clinical response to standard therapy plus belimumab or placebo, a substantial proportion of SLE patients still reported adverse HRQoL outcomes. While no impact was documented for disease activity, established organ damage contributed to adverse outcome within physical HRQoL aspects and add-on belimumab was shown to be protective against adverse physical functioning and severe fatigue.

Use of Antimalarial Agents is Associated with Favourable Physical Functioning in Patients with Systemic Lupus Erythematosus.

Impaired health-related quality of life (HRQoL) is a major problem in patients with systemic lupus erythematosus (SLE). Antimalarial agents (AMA) are the cornerstone of SLE therapy, but data on their impact on HRQoL are scarce. We investigated this impact using baseline data from the BLISS-52 (NCT00424476) and BLISS-76 (NCT00410384) trials (n = 1684). HRQoL was self-reported using the Medical Outcomes Study short-form 36 (SF-36), functional assessment of chronic illness therapy (FACIT)-Fatigue and 3-level EuroQoL 5-Dimension (EQ-5D) questionnaires. Patients on AMA (n = 1098/1684) performed better with regard to SF-36 physical component summary, physical functioning, role physical, bodily pain, FACIT-Fatigue, EQ-5D utility index and EQ-5D visual analogue scale scores. The difference in SF-36 physical functioning (mean ± standard deviation (SD): 61.1 ± 24.9 versus 55.0 ± 26.5; p < 0.001) exceeded the minimal clinically important difference (≥5.0). This association remained significant after adjustment for potential confounding factors in linear regression models (standardised coefficient, ß = 0.07; p = 0.002). Greater proportions of AMA users than non-users reported no problems in the mobility, self-care, usual activities and anxiety/depression EQ-5D dimensions. AMA use was particularly associated with favourable HRQoL in physical aspects among patients with active mucocutaneous and musculoskeletal disease, and mental aspects among patients with active renal SLE. These results provide support in motivating adherence to AMA therapy. Exploration of causality in the relationship between AMA use and favourable HRQoL in SLE has merit.

Clinical SLEDAI-2K zero may be a pragmatic outcome measure in SLE studies.

Objectives: Development of therapies for systemic lupus erythematosus (SLE) has in part been limited by the lack of suitable outcome measures in clinical trials. In the present post-hoc analysis of two clinical trials of belimumab, we investigated two potential outcomes, the Lupus Low Disease Activity State (LLDAS) and clinical SLE disease activity index 2000 (cSLEDAI-2K) zero, in relation to SLE responder index 4 (SRI-4). Methods: A total of 1684 SLE patients from the BLISS-52 (n = 865) and BLISS-76 (n = 819) trials were surveyed. Physician's Global Assessment (PGA) scores <0.5 (3-point scale) were used for comparisons. We used the chi-square test for comparisons and the phi coefficient for correlations. Results: At week 52, LLDAS was achieved by 8.6% of patients, cSLEDAI-2K = 0 by 34.5% and SRI-4 by 45.1%. cSLEDAI-2K = 0 showed the strongest correlation with PGA <0.5 (rφ = 0.36, P < 0.001). cSLEDAI-2K = 0 unveiled the superiority of belimumab 10 mg/kg over placebo (P = 0.003) with a magnitude which was comparable to that of SRI-4 (P < 0.001). LLDAS displayed a more moderate separation (P = 0.033). Conclusions: LLDAS was a stringent measure. cSLEDAI-2K = 0 showed the strongest correlation with the clinician-based evaluation. Being based on the SLEDAI-2K only, cSLEDAI-2K = 0 may be considered a more pragmatic outcome measure in SLE studies compared with composite tools.

Definitions of remission in systemic lupus erythematosus: a post-hoc analysis of two randomised clinical trials.

BACKGROUND: The Definitions Of Remission In Systemic Lupus Erythematosus (DORIS) international task force has proposed remission definitions that are amenable to scientific testing. In this study, we aimed to evaluate their suitability as outcome measures in studies of systemic lupus erythematosus. METHODS: In this post-hoc study, we applied remission definitions as specified by DORIS criteria at multiple timepoints in the BLISS-52 (n=865) and BLISS-76 (n=819) clinical trials. All definitions required physician's global assessment scores less than 0·5 (possible range 0-3). The DORIS 1 definitions required clinical systemic lupus erythematosus disease activity index 2000 (SLEDAI-2K)=0 (with serological items excluded). The DORIS 2 definitions required a score of D or E in all British Isles Lupus Assessment Group (BILAG) domains. The definitions were assessed in the trial populations both with (on therapy) and without (off therapy) treatment allowance-ie, low-dose glucocorticoids (prednisone ≤5 mg/day) and maintenance immunosuppressive and biological agents. Antimalarial agents were allowed in all definitions. The definitions were applied irrespective of serological activity (anti-double stranded DNA positivity, or low C3 or C4) and with normal serology. Finally, we applied modifications similar to DORIS on therapy but allowing higher prednisone doses (≤10 mg/day). FINDINGS: In the pooled dataset, the remission definition most frequently attained was the modified (prednisone ≤10 mg/day) DORIS 1a on therapy definition, which required a SLEDAI-2K score of 0 and permitted serological activity (237 [17·8%] of 1333 participants at week 52), followed by the unmodified (predisone ≤5 mg/day) DORIS 1 on therapy definition (140 [10·5%] of 1336 participants at week 52) based on these two definitions. We detected no significant difference between the placebo and belimumab groups. Proportions of patients achieving off therapy and BILAG-based definitions were low (≤0·9% at all timepoints). Sustained attainment of certain on therapy definitions showed an ability to discriminate between patients who received belimumab 10 mg/kg and patients who received placebo. INTERPRETATION: Attainment of DORIS remission definitions was infrequent overall. Use of clinical SLEDAI-2K=0 in the definitions yielded higher proportions of attainment than did use of BILAG D or E. Attainment was also higher using definitions that allowed for serological activity and maintenance treatment. Addition of the durability aspect to on therapy definitions led to an ability to discriminate between belimumab and placebo. FUNDING: Swedish Rheumatism Association, Professor Nanna Svartz Foundation, Ulla and Roland Gustafsson Foundation, Region Stockholm, and Karolinska Institutet Foundations.

Induction maintenance with tumour necrosis factor-inhibitor combination therapy with discontinuation versus methotrexate monotherapy in early rheumatoid arthritis: a systematic review and meta-analysis of efficacy in randomised controlled trials.

OBJECTIVE: To determine whether an induction-maintenance strategy of combined therapy (methotrexate (MTX)+tumour necrosis factor (TNF) inhibitor (TNFi)) followed by withdrawal of TNFi could yield better long-term results than a strategy with MTX monotherapy, since it is unclear if the benefits from an induction phase with combined therapy are sustained if TNFi is withdrawn. METHODS: We performed a meta-analysis of trials using the initial combination of MTX+TNFi in conventional synthetic disease-modifying antirheumatic drug-naïve patients with early rheumatoid arthritis (RA). A systematic literature search was performed for induction-maintenance randomised controlled trials (RCTs) where initial combination therapy was compared with MTX monotherapy in patients with clinically active early RA. Our primary outcome was the proportion of patients who achieved low disease activity (LDA; Disease Activity Score (DAS)28<3.2) and/or remission (DAS28<2.6) at 12-76 weeks of follow-up. A random-effects model was used to pool the risk ratio (RR) for LDA and remission and heterogeneity was explored by subgroup analyses. RESULTS: We identified 6 published RCTs, 4 of them where MTX+adalimumab was given as initial therapy and where adalimumab was withdrawn in a subset of patients after LDA/remission had been achieved. 2 additional trials used MTX+infliximab as combination therapy. The pooled RRs for achieving LDA and clinical remission at follow-up after withdrawal of TNFi were 1.41 (95% CI 1.05 to 1.89) and 1.34 (95% CI 0.95 to 1.89), respectively. There was significant heterogeneity between trials due to different treatment strategies, which was a limitation to this study. CONCLUSIONS: Initial therapy with MTX+TNFi is associated with a higher chance of retaining LDA and/or remission even after discontinuation of TNFi.