Long-term safety and limited organ damage in patients with systemic lupus erythematosus treated with belimumab: a Phase III study extension

AbstractObjectiveThis extension study of the Phase III, randomized, placebo-controlled Belimumab International SLE Study (BLISS)-52 and BLISS-76 studies allowed non-US patients with SLE to continue belimumab treatment, in order to evaluate its long-term safety and tolerability including organ damage accrual.MethodsIn this multicentre, long-term extension study (GlaxoSmithKline Study BEL112234) patients received i.v. belimumab every 4 weeks plus standard therapy. Adverse events (AEs) were assessed monthly and safety-associated laboratory parameters were assessed at regular intervals. Organ damage (SLICC/ACR Damage Index) was assessed every 48 weeks. The study continued until belimumab was commercially available, with a subsequent 8-week follow-up period.ResultsA total of 738 patients entered the extension study and 735/738 (99.6%) received one or more doses of belimumab. Annual incidence of AEs, including serious and severe AEs, remained stable or declined over time. Sixty-nine (9.4%) patients experienced an AE resulting in discontinuation of belimumab or withdrawal from the study. Eleven deaths occurred (and two during post-treatment follow-up), including one (cardiogenic shock) considered possibly related to belimumab. Laboratory parameters generally remained stable. The mean (s.d.) SLICC/ACR Damage Index score was 0.6 (1.02) at baseline (prior to the first dose of belimumab) and remained stable. At study year 8, 57/65 (87.7%) patients had no change in SLICC/ACR Damage Index score from baseline, indicating low organ damage accrual.ConclusionBelimumab displayed a stable safety profile with no new safety signals. There was minimal organ damage progression over 8 years.Trial registrationClinicalTrials.gov, https://clinicaltrials.gov, NCT00424476 (BLISS-52), NCT00410384 (BLISS-76), NCT00732940 (BEL112232), NCT00712933 (BEL112234).

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Organ damage in patients treated with belimumab versus standard of care: a propensity score-matched comparative analysis

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2018-214043 ◽

2019 ◽

Vol 78 (3) ◽

pp. 372-379 ◽

Cited By ~ 18

Author(s):

Murray B Urowitz ◽

Robert L Ohsfeldt ◽

Ronald C Wielage ◽

Kari A Kelton ◽

Yumi Asukai ◽

...

Keyword(s):

Propensity Score ◽

Lupus Erythematosus ◽

Damage Index ◽

Standard Of Care ◽

Organ Damage ◽

Systemic Lupus ◽

American College Of Rheumatology ◽

Damage Progression

ObjectivesThe study (206347) compared organ damage progression in patients with systemic lupus erythematosus (SLE) who received belimumab in the BLISS long-term extension (LTE) study with propensity score (PS)-matched patients treated with standard of care (SoC) from the Toronto Lupus Cohort (TLC).MethodsA systematic literature review identified 17 known predictors of organ damage to calculate a PS for each patient. Patients from the BLISS LTE and the TLC were PS matched posthoc 1:1 based on their PS (±calliper). The primary endpoint was difference in change in Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) score from baseline to 5 years.ResultsFor the 5- year analysis, of 567 (BLISS LTE n=195; TLC n=372) patients, 99 from each cohort were 1:1 PS matched. Change in SDI score at Year 5 was significantly lower for patients treated with belimumab compared with SoC (−0.434; 95% CI –0.667 to –0.201; p<0.001). For the time to organ damage progression analysis (≥1 year follow-up), the sample included 965 (BLISS LTE n=259; TLC n=706) patients, of whom 179 from each cohort were PS-matched. Patients receiving belimumab were 61% less likely to progress to a higher SDI score over any given year compared with patients treated with SoC (HR 0.391; 95% CI 0.253 to 0.605; p<0.001). Among the SDI score increases, the proportion of increases ≥2 was greater in the SoC group compared with the belimumab group.ConclusionsPS-matched patients receiving belimumab had significantly less organ damage progression compared with patients receiving SoC.

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Comparative analysis of long-term organ damage in patients with systemic lupus erythematosus using belimumab versus standard therapy: a post hoc longitudinal study

Lupus Science & Medicine ◽

10.1136/lupus-2020-000412 ◽

2020 ◽

Vol 7 (1) ◽

pp. e000412

Author(s):

Murray B Urowitz ◽

Robert L Ohsfeldt ◽

Ronald C Wielage ◽

John J Dever ◽

Mehdi Zakerifar ◽

...

Keyword(s):

Propensity Score ◽

Propensity Score Matching ◽

Standard Therapy ◽

Organ Damage ◽

Systemic Lupus ◽

Damage Progression ◽

Damage Accrual ◽

Post Hoc

ObjectiveLong-term extension (LTE) studies of belimumab in SLE do not include a comparator arm, preventing comparisons between belimumab plus standard therapy and standard therapy alone for organ damage accrual. Propensity score matching can be used to match belimumab-treated patients from LTE studies with standard therapy–treated patients from observational cohort studies. This analysis was designed to compare organ damage progression between treatment groups (belimumab plus standard therapy vs standard therapy alone) in patients with SLE with ≥5 years of follow-up, reproducing our previous study with more generalisable data.MethodsThis exploratory post hoc analysis used a heterogeneous population of US and non-US patients receiving monthly intravenous belimumab from pooled BLISS LTE trials (BEL112234/NCT00712933) and standard therapy–treated patients from the Toronto Lupus Cohort. Sixteen clinical variables were selected to calculate the propensity score.ResultsThe 592 LTE and 381 Toronto Lupus Cohort patients were highly dissimilar across the 16 variables; an adequately balanced sample of 181 LTE and 181 matched Toronto Lupus Cohort patients (mean bias=3.7%) was created using propensity score matching. Belimumab treatment was associated with a smaller increase in Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) over 5 years than standard therapy alone (mean treatment difference=–0.453 (95% CI –0.646 to –0.260); p<0.001). Patients treated with belimumab were 60% less likely to progress to a higher SDI score over any given year of follow-up, compared with standard therapy alone (HR (95% CI) 0.397 (0.275 to 0.572); p<0.001).ConclusionUsing propensity score matching, this highly heterogeneous sample was sufficiently matched to the Toronto Lupus Cohort, suggesting that patients treated with intravenous belimumab may have reduced organ damage progression versus standard therapy alone. This analysis of a large and diverse pooled SLE population was consistent with our previously published US-focused study.

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Clinical profile of systemic lupus erythematosus among children less than 12 years

International Journal of Contemporary Pediatrics ◽

10.18203/2349-3291.ijcp20180458 ◽

2018 ◽

Vol 5 (2) ◽

pp. 343

Author(s):

Senthil Kumar Andy ◽

Elayaraja Kandasamy

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Damage Index ◽

Organ Damage ◽

Clinical Profile ◽

Connective Tissues ◽

Systemic Lupus ◽

Initial Manifestation ◽

Double Stranded Dna

Background: Systemic lupus erythematosus (SLE) is an episodic multisystem autoimmune disease characterized by widespread inflammation of blood vessels and connective tissues and by the presence of antinuclear antibodies especially antibodies to native double stranded DNA. The aim was to study the clinical profile of SLE among children less than 12 years attending an urban referral hospital, SLEDAI scoring at onset and follow up at 1 year and SLICC/ACR damage index at 1 year.Methods: A descriptive, prospective and observational study was conducted in Medical, Nephrology, Rheumatology OPD wards, in ICH and HC, from November 2007 to August 2009 among all children diagnosed to have SLE. Results: In this study there were 50 cases over the last 2 years. Majority of the children were diagnosed within a year of their initial manifestation. The mean age at the time of onset of symptoms was 7.94 years. Female to male ratio in our study is 2.5:1.Conclusions: Efforts should be directed in diagnosing at earlier stage itself for better outcome. SLEDAI and SLICC/ACR DI can be incorporated in routine follow up to detect mild to moderate and severe flare and extent of organ damage.

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SAT0179 ADHERENCE TO HYDROXYCHLOROQUINE INFLUENCES THE INCIDENCE OF ORGAN DAMAGE DURING FOLLOW-UP IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.1656 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1031.1-1031

Author(s):

J. H. Kang ◽

S. E. Choi ◽

H. Xu ◽

D. J. Park ◽

S. S. Lee

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Damage Index ◽

Clinical Manifestations ◽

Medication Possession Ratio ◽

Organ Damage ◽

Systemic Lupus ◽

Laboratory Findings ◽

The Impact

Background:Objectives:Hydroxychloroquine (HCQ) is a cornerstone drug in patients with systemic lupus erythematosus (SLE), decreasing the risk of flares and comorbidities and improving survival. This study investigated the effects of HCQ adherence on clinical manifestations, disease activity, and organ damage in Korean patients with SLE.Methods:Data on 299 SLE patients were obtained from the Korean Lupus Network registry. Demographic variables, clinical manifestations, laboratory findings, PGA, and SLEDAI-2000 and SLICC damage index scores were recorded at the time of enrollment and repeated annually for 4 consecutive years. Patients were divided into two groups according to the level of HCQ adherence. Adherence was defined by the medication possession ratio and dichotomized as ≤ 80% vs. > 80%. Univariate and multivariate analyses were performed to assess the impact of adherence to HCQ on clinical outcomes.Results:Of the 299 patients, 31 (10.4%) showed poor drug adherence during the follow-up period. Patients with poor HCQ adherence were older (P=0.011), less insured (P=0.024), experienced lower employment (P=0.033), and had a higher rate of comorbidities such as hypertension (P=0.048) and depression (P<0.001). The non-adherent group had higher mean and changed SLICC damage index scores than the adherent group across all 4 years. In the multivariate analysis, HCQ non-adherence was significantly associated with older age (OR, 1.043; 95% CI, 1.006–1.081; P=0.021), depression (OR, 11.98; 95% CI, 1.099–130.6; P=0.042), and an annual increase in the SLICC damage index score (OR, 2.275; 95% CI, 1.369–3.779; P=0.002).Conclusion:HCQ adherence might be influenced by age and depressive mood. Additionally, the poor adherence to HCQ in SLE patients was correlated with higher cumulative organ damage. Therefore, patients with SLE should be educated to take HCQ appropriately to improve their clinical outcome in clinical practice.Disclosure of Interests:None declared

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Childhood Systemic Lupus Erythematosus: Presentation, management and long-term outcomes in an Australian cohort

Lupus ◽

10.1177/09612033211069765 ◽

2022 ◽

pp. 096120332110697

Author(s):

Megan P Cann ◽

Anne M Sage ◽

Elizabeth McKinnon ◽

Senq-J Lee ◽

Deborah Tunbridge ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Incidence Rate ◽

Lupus Erythematosus ◽

Renal Involvement ◽

Damage Index ◽

Organ Damage ◽

Systemic Lupus ◽

End Organ Damage ◽

American College Of Rheumatology

Objectives Systemic Lupus Erythematosus (SLE) is a serious autoimmune disease often resulting in major end-organ damage and increased mortality. Currently, no data exists focussing on the presentation, long-term management and progression of SLE in the Australian paediatric population. We conducted the first Australian longitudinal review of childhood SLE, focussing on response to treatment and outcomes. Methods Detailed clinical and laboratory data of 42 children diagnosed with SLE before 16 years from 1998 to 2018 resident in Western Australia was collected. Data was collected at diagnosis and key clinical review time points and compared using the Systemic Lupus Collaborating Clinics (SLICC) and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) criteria. End organ damage was assessed against Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). Incidence rates of disease complications and end organ damage were determined. Results Of the 42 children, 88% were female with average age at diagnosis of 12.5 years. Indigenous Australians were over represented with an incidence rate 18-fold higher than non-Indigenous, although most children were Caucasian, reflecting the demographics of the Australian population. Median duration of follow-up was 4.25 years. On final review, 28.6% had developed cumulative organ damage as described by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (incidence rate: 0.08/PY (95% CI 0.04–0.14)), and one child died. Twenty-nine children had renal involvement (incidence rate: 0.38/PY (95% CI 0.26–0.56)). Of the 27 patients with biopsy proven lupus nephritis, 70% had Class III or IV disease. Average length of prednisolone use from diagnosis was 32.5 months. Hydroxychloroquine ( n = 36) and mycophenolate mofetil ( n =21) were the most widely used steroid sparing agents. 61.9% received rituximab and/or cyclophosphamide. Conclusion This is the first longitudinal retrospective review of Australian children with SLE, with a markedly higher incidence in Indigenous children. Although improving, rates of end organ complications remain high, similar to international cohort outcomes. Longitudinal multi-centre research is crucial to elucidate risk factors for poor outcomes, and identifying those warranting early more aggressive therapy.

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Long-Term Follow Up of Patients with Mild-to-Moderate Alzheimer’s Disease Treated with Bapineuzumab in a Phase III, Open-Label, Extension Study

Journal of Alzheimer s Disease ◽

10.3233/jad-171157 ◽

2018 ◽

Vol 64 (3) ◽

pp. 689-707 ◽

Cited By ~ 3

Author(s):

Stephen P. Salloway ◽

Reisa Sperling ◽

Nick C. Fox ◽

Marwan N. Sabbagh ◽

Lawrence S. Honig ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Phase Iii ◽

Extension Study ◽

Open Label ◽

Open Label Extension ◽

Long Term Follow Up

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The majority of Swedish systemic lupus erythematosus patients are still affected by irreversible organ impairment: factors related to damage accrual in two regional cohorts

Lupus ◽

10.1177/0961203319860198 ◽

2019 ◽

Vol 28 (10) ◽

pp. 1261-1272 ◽

Cited By ~ 6

Author(s):

M Frodlund ◽

S Reid ◽

J Wetterö ◽

Ö Dahlström ◽

C Sjöwall ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Causes Of Death ◽

Age At Onset ◽

Damage Index ◽

Organ Damage ◽

Antiphospholipid Antibody ◽

Antiphospholipid Antibody Syndrome ◽

Systemic Lupus ◽

Damage Accrual

Background Although the survival of patients with systemic lupus erythematosus (SLE) has improved, irreversible organ damage remains a critical concern. We aimed to characterize damage accrual and its clinical associations and causes of death in Swedish patients. Methods Accumulation of damage was evaluated in 543 consecutively recruited and well-characterized cases during 1998−2017. The Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology damage index (SDI) was used to estimate damage. Results Organ damage (SDI ≥ 1) was observed in 59%, and extensive damage (SDI ≥ 3) in 25% of cases. SDI ≥ 1 was significantly associated with higher age at onset, SLE duration, the number of fulfilled SLICC criteria, neurologic disorder, antiphospholipid antibody syndrome (APS), hypertension, hyperlipidemia, depression and secondary Sjögren's syndrome (SS). In addition, SDI ≥ 3 was associated with serositis, renal and haematological disorders and interstitial lung disease. A multiple regression model identified not only well-known risk factors like APS, antihypertensives and corticosteroids, but pericarditis, haemolytic anaemia, lymphopenia and myositis as being linked to SDI. Malignancy, infection and cardiovascular disease were the leading causes of death. Conclusions After a mean SLE duration of 17 years, the majority of today's Swedish SLE patients have accrued damage. We confirm previous observations and report some novel findings regarding disease phenotypes and damage accrual.

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Osteopontin and Disease Activity in Patients with Recent-onset Systemic Lupus Erythematosus: Results from the SLICC Inception Cohort

The Journal of Rheumatology ◽

10.3899/jrheum.180713 ◽

2019 ◽

Vol 46 (5) ◽

pp. 492-500 ◽

Cited By ~ 1

Author(s):

Lina Wirestam ◽

Helena Enocsson ◽

Thomas Skogh ◽

Leonid Padyukov ◽

Andreas Jönsen ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Disease Activity ◽

Lupus Erythematosus ◽

Renal Involvement ◽

Damage Index ◽

Organ Damage ◽

Inception Cohort ◽

Systemic Lupus ◽

Recent Onset ◽

Damage Accrual

Objective.In cross-sectional studies, elevated osteopontin (OPN) levels have been proposed to reflect, and/or precede, progressive organ damage and disease severity in systemic lupus erythematosus (SLE). We aimed, in a cohort of patients with recent-onset SLE, to determine whether raised serum OPN levels precede damage and/or are associated with disease activity or certain disease phenotypes.Methods.We included 344 patients from the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort who had 5 years of followup data available. All patients fulfilled the 1997 American College of Rheumatology (ACR) criteria. Baseline sera from patients and from age- and sex-matched population-based controls were analyzed for OPN using ELISA. Disease activity and damage were assessed at each annual followup visit using the SLE Disease Activity Index 2000 (SLEDAI-2K) and the SLICC/ACR damage index (SDI), respectively.Results.Compared to controls, baseline OPN was raised 4-fold in SLE cases (p < 0.0001). After relevant adjustments in a binary logistic regression model, OPN levels failed to significantly predict global damage accrual defined as SDI ≥ 1 at 5 years. However, baseline OPN correlated with SLEDAI-2K at enrollment into the cohort (r = 0.27, p < 0.0001), and patients with high disease activity (SLEDAI-2K ≥ 5) had raised serum OPN (p < 0.0001). In addition, higher OPN levels were found in patients with persistent disease activity (p = 0.0006), in cases with renal involvement (p < 0.0001) and impaired estimated glomerular filtration rate (p = 0.01).Conclusion.The performance of OPN to predict development of organ damage was not impressive. However, OPN associated significantly with lupus nephritis and with raised disease activity at enrollment, as well as over time.

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AB0447 IRREVERSIBLE ORGAN DAMAGE IN PERI- AND POSTMENOPAUSAL WOMEN WITH SYSTEMIC LUPUS ERYTHEMATOSUS IN REMISSION

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.2420 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1522.2-1522

Author(s):

S. Shkireeva ◽

E. Zotkin ◽

O. Lesnyak

Keyword(s):

Systemic Lupus Erythematosus ◽

Disease Activity ◽

Postmenopausal Women ◽

Lupus Erythematosus ◽

Damage Index ◽

Osteoporotic Fractures ◽

Organ Damage ◽

Systemic Lupus ◽

Low Disease Activity ◽

Damage Accrual

Background:Although the survival of patients with systemic lupus erythematosus (SLE) has improved, irreversible organ damage remains a critical concern. Long-standing inflammation, drug-related side effects and comorbidities may eventually cause permanent organ damage even in remission[1].Objectives:To describe irreversible organ damage in peri- and postmenopausal women with SLE in remission and low disease activity, to find predictors of damage progression.Methods:234 peri- and postmenopausal women with SLE were included (mean age 49,94±9,1 years) in our study. All women were under outpatient observation in St.Petersburg State Clinical Rheumatology Hospital #25 (Russia). Mean disease duration was 8,9±7,5 years. We analyzed treatment regimens and doses of glucocorticoids (GC) based on source medical documents. To assess disease activity, we used SLEDAI-2K and LLDAS. To assess organ damage, we used SLICC damage index (SDI).Results:94,3% of women have been taking GC during our study. Median of maintenance dose was 12,5 mg per day. Almost a half of all women (44,8%, n=105) in our study were postmenopausal (mean duration of menopause was 11,1±7,1 years). A half of all patients had low disease activity (44,4%, n=111) or were in remission (18,8%, n=44) according to SLEDAI-2K. 26,5% (n=65) of patients had all 5 criteria and 45,1 % (n=115) of patients had 4 of 5 criteria according to LLDAS. Critical organ damage (SDI>4) was observed in 68,8% (n=161) of women with SLE. Moderate (1≤SDI≤4) and low (SDI=1) damage had 25,6% (n=60) and 6,4% (n=15) of patients respectively. Musculoskeletal damage was on the first place among others: 37,6% (n=88) of patients had osteoporosis with fractures and 34,2% (n=80) had muscle weakness. In 75 women with SLE of osteoporotic fractures occurred in remission or low disease activity (LLDAS). Progression of irreversible organ damage in remission or low disease activity (LLDAS) had 62% (n=145) of women with SLE. Multifactorial logistic regression analysis of factors associated with organ damage in SLE showed that only patients age (р=0.013215), cumulative dose of GC (р=0.000047) and therapy with cyclophosphamide (р=0.041505) were statistically significant.Conclusion:Progression of irreversible organ damage in peri- and postmenopausal women with SLE may occur despite remission or low disease activity. There are no doubts that organ damage accrual is associated with CG therapy. Correction of GC dose or discontinuation of GC treatment in remission can predict organ damage accrual in SLE including osteoporosis and osteoporotic fractures.References:[1]Frodlund M, Reid S, Wetterö J, Dahlström Ö, Sjöwall C, Leonard D. The majority of Swedish systemic lupus erythematosus patients are still affected by irreversible organ impairment: factors related to damage accrual in two regional cohorts. Lupus. 2019;28(10):1261–1272. doi:10.1177/0961203319860198Disclosure of Interests:None declared

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ALCAM and VCAM-1 as urine biomarkers of activity and long-term renal outcome in systemic lupus erythematosus

Rheumatology ◽

10.1093/rheumatology/kez528 ◽

2019 ◽

Vol 59 (9) ◽

pp. 2237-2249 ◽

Cited By ~ 4

Author(s):

Ioannis Parodis ◽

Sirisha Gokaraju ◽

Agneta Zickert ◽

Kamala Vanarsa ◽

Ting Zhang ◽

...

Keyword(s):

Lupus Erythematosus ◽

Renal Involvement ◽

Organ Damage ◽

Population Based ◽

Renal Outcome ◽

Urine Biomarkers ◽

Increased Risk ◽

Function Loss

Abstract Objectives We investigated the cell adhesion molecules (CAMs) Vascular CAM 1 (VCAM-1) and Activated Leucocyte CAM (ALCAM) as urinary biomarkers in SLE patients with and without renal involvement. Methods Female SLE patients (n = 111) and non-SLE population-based controls (n = 99) were enrolled. We measured renal activity using the renal domain of the BILAG index and urine (U) and plasma (P) concentrations of soluble (s)VCAM 1 and U-sALCAM using ELISA. U-sCAM levels were next corrected by U-creatinine. Results U-sVCAM-1/creatinine and U-sALCAM/creatinine ratios were higher in SLE patients vs non-SLE controls (P < 0.001 for both), as well as in patients with active/low-active (BILAG A–C; n = 11) vs quiescent (BILAG D; n = 19) LN (P = 0.023 and P = 0.001, respectively). U-sALCAM/creatinine but not U-sVCAM-1/creatinine ratios were higher in patients with nephritis history (BILAG A–D; n = 30) vs non-renal SLE (BILAG E; n = 79) (P = 0.014). Patients with baseline U-sVCAM-1/creatinine ratios ≥75th percentile showed a 23-fold increased risk of a deterioration in estimated glomerular filtration rate by ≥25% during a 10-year follow-up (odds ratio: 22.9; 95% CI: 2.8, 189.2; P = 0.004); this association remained significant after adjustments for age, disease duration and organ damage. Traditional markers including anti-dsDNA antibodies did not predict this outcome. Conclusion While high U-sVCAM-1 levels appear to reflect SLE disease activity, sALCAM might have particular importance in renal SLE. Both U-sVCAM-1 and U-sALCAM showed ability to distinguish SLE patients with active renal involvement from patients with quiescent or no prior nephritis. High U-sVCAM-1 levels may indicate patients at increased risk for long-term renal function loss.

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