Lupus nephritis••

Real-world effectiveness of belimumab in patients with lupus in China: RELIABLE observational cohort study protocol

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Abstract

Introduction The efficacy of belimumab in SLE has been demonstrated in randomised clinical trials, and its real-world effectiveness has been shown in studies in several countries. While belimumab was approved for treating SLE in China in 2019, data on its benefit in clinical practice are limited. This study will evaluate belimumab’s effectiveness in China, using practical clinical measures, such as Lupus Low Disease Activity State (LLDAS), to add to the body of real-world evidence.

Methods and analysis The Real-world Effectiveness of beLImumAB in patients with systemic Lupus Erythematosus in China (RELIABLE) is an ambidirectional, observational descriptive cohort study across approximately 15 centres in China. Adults with SLE newly initiating belimumab with ≥1 measure of all five LLDAS components (SLE Disease Activity Index-2000; no new lupus disease activity; Physician Global Assessment; prednisolone-equivalent dose; immunosuppressants/biologics use) in the 3 months preceding belimumab initiation (index date) will be eligible and retrospectively and/or prospectively enrolled, depending on data availability. The retrospective follow-up will be ≤6 months, and retrospective and prospective patients will have a maximum 24-month follow-up. The primary objectives will be to describe the proportion of patients achieving LLDAS at 12 and 24 months post-index. The key secondary objective will be to describe the proportion of patients achieving LLDAS and each component at 3, 6, 9 and 18 months post-index. All data will be analysed descriptively; a statistical estimand will be applied to account for intercurrent events expected in a real-world setting.

Ethics and dissemination This study will comply with all applicable laws regarding patient privacy; institutional review board approval will be obtained before the study commencement.

Conclusions This study will evaluate belimumab’s effectiveness in patients with SLE initiating belimumab in clinical practice in China. Using LLDAS will provide clinicians with valuable insights into the impact of belimumab on the treat-to-target strategy with a relevant measure that can be repeated across the clinical practice.

Introduction

SLE is a chronic, inflammatory autoimmune disease that may affect many organs or systems, resulting in a striking heterogeneity of clinical presentations.1 SLE disease activity is characterised by chronic active disease, periods of remission and relapse or sustained remission.2

The global prevalence of SLE was estimated at 43.7 per 100 000 persons, varying widely by country.3 The prevalence of SLE in China was estimated at 50.37 per 100 000 person-years, suggesting a prevalent population of 0.71 million.4 A previous study highlighted several differences in characteristics of SLE in China compared with other ethnicities. For example, more than half of patients with SLE in China (56.1%) were shown to have concurrent haematological disorders compared with 18.2% of patients in Europe, 48.8% in Malaysia and 72.5% in Latin America.5 In addition, 47.4% of patients in China experience nephropathy compared with 27.9% of patients in Europe, 40.2%–55.6% in the USA, 51.7% in Latin America and 74% in Malaysia.5

Antimalarials, corticosteroids and immunosuppressants are a mainstay in treating SLE.6 The principle of SLE treatment is early intervention and individualised treatment to minimise disease activity, prevent flares, reduce organ damage progression and reduce likelihood of mortality.6 However, patients with SLE have unsatisfactory long-term prognoses and considerable unmet needs, such as persistently active or recurrent disease, which may lead to organ damage accrual,7 8 and poor health-related quality of life.9 10 SLE was shown to significantly affect the overall productivity in work and non-work-related activity, which were associated with poor quality of life,11 and a report from China on SLE in 2020 showed that 75.8% of Chinese patients with SLE considered their health to be affecting social activities.12 Furthermore, due to persistent disease activity, many patients require long-term corticosteroid use, which was shown to be associated with an increased risk of organ damage and mortality, especially at high cumulative doses.13–16 Therefore, targeted treatment for SLE is essential to reduce the use of corticosteroid dose to ≤5 mg/day or, where possible, withdraw as recommended by EULAR 2023 recommendations.17

Belimumab is a human IgG1λ monoclonal antibody that inhibits B lymphocyte stimulator (BLyS).18 The approval of intravenous belimumab in 2011 by the Food and Drug Administration signified a major step in SLE treatment, with it being the first new therapy approved for SLE in over 50 years.19 In China, belimumab was approved as an add-on treatment for adults with active, autoantibody-positive SLE with a high disease activity (eg, positive antidouble-stranded DNA and low complement, Safety of Estrogens in Lupus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) score ≥8) despite standard therapy as an intravenous formulation in 2019 and for lupus nephritis in 2022.20 This approval for use in patients with SLE was extended to children (≥5 years of age) in 2020,20 and both paediatric and adult indications have been reimbursed by national medical insurance.21 As stated in the 2020 Chinese Guidelines for Diagnosing and Treating SLE and the 2024 Chinese Expert Consensus on the Use of Biologics in SLE, belimumab is recommended for patients whose disease is poorly controlled with conventional therapy (ie, refractory or intolerant to corticosteroids and/or immunosuppressants).6 22

The efficacy of belimumab has been demonstrated previously in phase III randomised controlled trials (RCTs), and belimumab has established its position as a disease modifier in the SLE treatment paradigm over the past 10 years.19 23–25 The efficacy of belimumab in patients with SLE in China, Japan and Korea was demonstrated in a recent phase III trial,25 with an open-label North East Asia (NEA) extension study in China (NCT01345253), as measured by the SLE Responder Index (SRI, composed of the SELENA-SLEDAI, British Isles Lupus Assessment Group (BILAG) and Physician Global Assessment (PGA) indices).26 However, real-world clinical practice may involve more diversified treatment behaviour than RCTs, with populations often more heterogeneous. Furthermore, assessments undertaken during RCTs may not always be feasible in day-to-day clinical practice. For instance, the SRI measure that was used in the NEA study is not routinely used in clinical practice in China, probably because the BILAG component is very time-consuming.27

The real-world effectiveness of belimumab has been evaluated in several countries, including the USA, Canada and countries in Europe and South America, through the global OBSErve programme, consistently demonstrating clinical improvements across SLE manifestations among patients treated with belimumab for 6–24 months, measured using the physician’s assessment of improvement based on a PGA-like scale, as well as change in SELENA-SLEDAI score.28–33 Despite the evidence from these real-world studies, there is still limited real-world data on the effectiveness of belimumab in patients with SLE in China. A recent real-world study in patients with SLE in China supported the effectiveness and safety of belimumab over 12 months.34 Real-world data are important to identify the optimal treatment strategy for belimumab to reflect the patient characteristics in China, measured by instruments more commonly used by Chinese physicians.

The SLEDAI-2000 (SLEDAI-2K) and PGA have been frequently used by physicians and in real-world studies,35 and Chinese guidelines recommend using these two measures of disease activity assessment.6 The Lupus Low Disease Activity State (LLDAS) is a new instrument (defined as 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; no new lupus disease activity compared with the previous assessment; PGA score ≤1; current prednisolone-equivalent dose ≤7.5 mg/day and well-tolerated standard maintenance doses of immunosuppressants and approved biological agents).36 LLDAS was developed for the treat-to-target strategy to measure low disease activity and has been validated as a relevant outcome for patients with SLE.37 38 Recently, LLDAS and remission (as defined by the Definition Of Remission In SLE (DORIS) Task Force39) were recommended as an overarching treatment goal for biologics in SLE within the 2024 Chinese Expert Consensus on the Use of Biologics in SLE.22 Real-world data on the effectiveness of belimumab using measures that represent these more ambitious treatment goals and are more commonly used in clinical practice treating patients with SLE in China is currently limited and would be beneficial to inform clinical decision-making.

This Real-world Effectiveness of beLImumAB in patients with systemic Lupus Erythematosus in China (RELIABLE) study aims to describe the effectiveness of belimumab in patients with SLE in China to reflect the advocacy of the treat-to-target strategy, LLDAS and its components in China. This study protocol will also describe the plans to assess organ damage progression, patient-reported outcomes (PROs), treatment patterns and healthcare resource utilisation (HCRU) among patients treated with belimumab.

Methods and analysis

Study design

RELIABLE is a multicentre, ambidirectional, observational cohort study (GSK Study 214958) across approximately 15 study sites across all the geographical regions in China. The enrolled sites will be tertiary hospitals with extensive experience in the management of SLE, which have been selected based on good data availability, their ability to recruit patients and whether there are appropriate personnel and facilities to conduct study activities.

The index date will be defined as the belimumab initiation date, for which the date of first administration will be used, unless missing, whereby a prescription date will be used instead. Otherwise, patients will be considered unexposed to belimumab for all time prior to the index date. The baseline period is the time before the index date. The observations will be retrospective and prospective, depending on whether the patient was on belimumab at enrolment (figure 1). The maximum retrospective follow-up will be 6 months, with a maximum total follow-up of 24 months.

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Figure 1

Study design.

The exposure of patients to belimumab in this study will be defined as 10 mg/kg intravenous dose every 2 weeks for the first three administrations and then every 4 weeks, according to the label in China. However, the study will not intervene in treatment decisions made by physicians or patients, and the dosing and treatment interval will be the real-world practice. Therefore, the treatment regimens in this study will be a group of treatment options with belimumab as the mainstay, reflecting the real-world treatment behaviour in China. As a targeted add-on treatment for SLE, the duration of belimumab treatment is based on ongoing clinical assessment of the patient’s disease activity and response to therapy, and it should be administered for as long as the patient continues to benefit from it.

Belimumab treatment end date will be defined as 28 days following the last belimumab administration, and the end of the study for each patient will be the earliest of the following: end of the maximum total follow-up period; death; withdrawal of consent; diagnosis of severe CNS manifestations (including seizures, psychosis, organic brain syndrome, cerebrovascular accident, cerebritis or CNS vasculitis) requiring therapeutic intervention; co-enrolment into another study of an investigational agent or non-drug therapy or lost to follow-up.

Patient population

To minimise selection bias, study sites will be encouraged to invite all potentially eligible patients consecutively, and a screening log will be recorded. Eligible patients will be adults (≥18 years of age at first belimumab infusion) with documented SLE based on physician’s judgement, who are new users of belimumab and have ≥1 available assessment of each of the following components of LLDAS in the 3 months preceding belimumab initiation: SLEDAI-2K, new lupus disease activity compared with the previous assessment (yes/no), PGA (yes/no), prednisolone-equivalent dose or well-tolerated maintenance doses of immunosuppressants and/or biological agents (yes/no). Patients will be excluded if they are enrolled in any other medicinal SLE interventional clinical trial at the time of study entry or have a diagnosis of severe CNS manifestations requiring therapeutic intervention before study entry. Since this is a real-world study, concomitant treatments, including those commonly used for treating SLE in clinical practice in China or those that may impact SLE treatment effectiveness, will be permitted.

Due to the ambidirectional design of this study, there are three possible scenarios for patient enrolment: (1) retrospective only (patient initiated and discontinued belimumab within the 6-month period prior to enrolment), (2) retrospective and prospective (patient initiated belimumab ≤6 months prior to enrolment) or (3) prospective only (patient initiated belimumab at enrolment). The study objectives will be analysed for all patients enrolled in the study.

Data collection

An overview of the data collection schedule for outcomes assessments is shown in table 1. Baseline data will include demographics at the index date, medical and treatment history 3 years prior to the index date and SLE-related measures and PROs up to 3 months prior to the index date and laboratory data up to 1 week prior to the index date.

Table 1

Data collection schematic

For retrospectively identified patients, in the retrospective phase of the follow-up (ie, up to 6 months post-index), pre-enrolment data will be extracted from medical records. Retrospective patients may or may not have a prospective phase of follow-up; during the prospective phase of the follow-up (ie, the period between enrolment and 24 months post-index), post-enrolment data will be collected by the investigator through the medical records system or paper questionnaires. Baseline data for prospectively identified patients will be collected at the initial visit at enrolment using patient medical records, and follow-up data will be collected by the investigator through the medical records system and paper questionnaires. Prospective patients may discontinue belimumab either before or after enrolment, as long as they continue to be followed up until the end of the study.

Patient demographic data collected will include sex, age at SLE diagnosis, age at belimumab initiation and treatment history, among other data. The clinical outcomes assessments will include: LLDAS (defined as SLEDAI-2K score ≤4, with no major organ system involvement including renal, CNS, cardiopulmonary, vasculitis and fever components; no increase in any SLEDAI-2K components since the previous visit; PGA score ≤1; prednisone-equivalent dose ≤7.5 mg/day; tolerated maintenence use of immunosuppressants and biologics); SLEDAI-2K; SELENA-SLEDAI Flare Index (SFI) flares40; remission (as defined by DORIS Task Force39: clinical SLEDAI score=0 (irrespective of serology); SELENA-SLEDAI PGA score <0.5 (0–3 scale); current prednisolone-equivalent dose ≤5 mg/day and stable antimalarials, immunosuppressants and biologics); Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI); PGA; concomitant medications (eg, steroids, antimalarials, immunosuppressants and biologics) and PROs (Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) and Work Productivity and Activity Impairment Questionnaire (WPAI)). For baseline data, except for flares, if multiple records are available, the one closest to the index date will be selected. For the follow-up period, the one closest to the time point will be recorded if multiple records are available within the allowable window. For patients with ≥3 months of baseline data, the flare number during this baseline period will be collected. HCRU, treatment patterns and laboratory testing will not be linked to the time points for data collection outcome assessments but will be collected throughout the study.

Objectives

The primary objective of this study will be to describe the LLDAS attainment in patients with SLE in China treated with belimumab. The secondary objectives will be to describe the changes in multiple SLE disease activity measures, organ involvement measures and PROs during the 24 months following belimumab initiation, alongside whether LLDAS attainment or discontinuation of belimumab have a predictable pattern. The study outcomes will also be described in patients stratified by the point of belimumab initiation in the treatment pathway (ie, early vs late).

Outcomes

The primary outcome will be the attainment of LLDAS, defined as the proportion of patients achieving LLDAS at both 12-month and 24-month time points post-index. The secondary outcomes will include: (1) the proportion of patients achieving LLDAS and each of its components at 3, 6, 9 and 18 months post-index; (2) time to achieve LLDAS in patients who are not in LLDAS at baseline; (3) time spent in LLDAS in patients who achieve LLDAS any time during baseline or follow-up; (4) the proportion of patients achieving ≥4-point reduction in SLEDAI-2K at 3, 6, 9, 12, 18 and 24 months post-index; (5) change from baseline in SDI score at 12 and 24 months post-index; (6) the proportion of patients achieving DORIS remission on medication at 12, 18 and 24 months post-index; (7) time to achieve DORIS remission in patients who are not in remission at baseline; time spent on remission in patients who achieve remission any time during baseline or follow-up; (8) change from baseline in flare rate (adapted from SFI40) at 3, 6, 9, 12, 18 and 24 months post-index; (9) change from baseline in FACIT-Fatigue and WPAI at 3, 6, 9, 12, 18 and 24 months post-index. As part of the secondary outcomes, the treatment patterns surrounding the use of belimumab, including prior and concomitant treatments and subsequent SLE treatments if applicable, and HCRU associated with belimumab initiation within the study period, including all-cause and SLE-related HCRU over the 2-year follow-up period, will be described.

Precision estimation

Considering the descriptive nature of the study, statistical hypothesis is not necessary; however, precision estimation was considered under a pre-assumed sample size of 400 patients. Based on previous real-world studies, it is expected to see 30.0%–50.0% missing data for 12 and 24 months post-index.33 41 Informed by a previous real-world study in Greece42 and a post hoc analysis of the BLISS studies,38 a range of 8.0%, 20.0% and 30.0% of patients achieving LLDAS at 12 and 24 months post-index is assumed. Using this imputation for missing data, the estimated width of precision is estimated to vary from 5.3% to 9.0% but would not exceed the maximum width 9.8%.

Statistical analyses

Due to the descriptive nature of this study, no comparative analyses will be performed. Descriptive statistics will be used to describe the study sample for demographic and clinical information. The number of non-missing values, mean, median and measures of variance will be summarised for continuous variables; the number of non-missing patients, frequency and percentages will be summarised for categorical variables. Any missing data for primary outcomes will be assumed to be missing at random and imputed using multiple imputation methods. For the primary analysis, the 95% CI will be estimated using the Clopper-Pearson method. For all time-to-event analyses listed in the secondary outcomes, Kaplan-Meier curves will be used. Unless otherwise specified, all analyses will be based on data from all enrolled patients, including retrospective and prospective patients.

A primary statistical estimand of Treatment Policy strategy will be applied to allow for intercurrent events expected in a real-world setting, including belimumab discontinuation and use of concomitant treatments. For patients discontinuing belimumab, defined as ≥60 days between infusions, patients will be followed up, assessed and analysed irrespective of belimumab discontinuation. If a patient discontinues belimumab and data are continued to be collected, their data will be analysed. If data are not continued to be collected, missing data will be imputed using multiple imputations. Given that concomitant treatment may affect SLE treatment effectiveness, patients will be followed up, assessed and analysed irrespective of combination, discontinuation or switch of concomitant treatment post-index. In addition to the primary analysis, there will be additional analyses conducted for outcomes in the subpopulation of patients who remain on belimumab for at least 3, 6, 9, 12, 18 and 24 months postbelimumab initiation, with available assessments for LLDAS and SLEDAI-2K.

For exploratory outcomes, predictors of belimumab discontinuation and LLDAS attainment will be analysed using Cox proportional hazard models; key covariates will be selected in a data-driven approach, and a p value of <0.05 will indicate statistical significance.

Ethics and dissemination

This study will comply with all applicable laws regarding patient privacy, and results will omit patient identification. Local Ethics Committee and Human Genetic Resources Administration of China regulations approval will be obtained before patient enrolment commences. Informed consent forms will be signed by all patients before their participation in the study. An interim analysis is planned after the last patient’s last visit. Further dissemination and communication of study results will be determined by the study sponsor (GSK).

Patients and public involvement

Patients or the public will not be involved in the design, conduct, reporting, or dissemination plans of this study.

Discussion

The effectiveness of belimumab in real-world clinical practice in patients with SLE has been demonstrated in the OBSErve programme of multinational cohort studies28–30 32 33; however, there is limited real-world data from China. This multicentre, ambidirectional, observational cohort study on the effectiveness of belimumab in patients with SLE in China will build on the evidence generated from real-world studies in other countries and help inform physicians on clinical decision-making regarding patients with SLE in China.

LLDAS and remission have been developed as potential treatment targets that allow for low levels of disease activity and treatment in patients with SLE.36 43 The association between LLDAS and remission achievements and improved clinical outcomes and lower risk of organ damage accrual has been demonstrated previously, supporting the clinical utility of these outcomes and remission in a treat-to-target strategy.37 44–46 Previous research has shown the attainment of LLDAS through belimumab.42 47 48 A prospective observational study of 188 patients in Greece demonstrated achievement of LLDAS and remission by 33.5% and 17.8% of patients, respectively, following 24 months of belimumab therapy.48 A prospective study of 91 patients in the USA demonstrated that 33.3% and 25.0% of patients achieved LLDAS and remission, respectively, following 24 months of belimumab therapy.42 The studies in the USA and Greece, however, do not clearly report the definition of LLDAS, especially since LLDAS can be achieved and then lost during the course of the disease. A recent real-world study in patients with SLE in China used LLDAS and remission as the key outcome measurements and demonstrated that, following 12 months of belimumab therapy, 54.76% of patients attained LLDAS and 28.6% cumulatively attained remission.34 Furthermore, a previous study in Toronto Lupus Cohort has demonstrated the association between the achievement of LLDAS and remission and low organ damage progression, and even a small percentage of time spent by patients in these low disease activity states led to approximately 50% reduction in organ damage.49 Our study will add to the growing body of evidence supporting the effectiveness of belimumab and provide important data regarding the achievement of LLDAS after belimumab initiation in patients with SLE in China, expanding on the previous work. The planned population size of 400 patients in this study is larger than in the previous studies investigating LLDAS,34 42 47 48 which will increase the population diversity and enhance the strength of the obtained results. This diversity is further enhanced by the multicentre design, which will capture any differences in patient characteristics and SLE treatment regimens across China.

As would be expected in any real-world study, patients are unlikely to adhere perfectly to the treatment schedule for the entire 24-month follow-up period, and it is expected that between 30.0% and 50.0% of patients enrolled will have missing data owing to treatment discontinuation.33 41 Using the statistical estimand for the primary objective will mitigate the effect of missing data from patients potentially lost to follow-up alongside the reduced patient size with available data after 24 months of follow-up, although it is a non-comparative study. The estimand has also helped to clearly define the research question, which is the outcomes achieved after belimumab initiation. Previously, this statistical estimand framework has rarely been used in real-world studies of SLE in China; thus, this study may also serve as a case for results interpretation for future real-world studies in China.

Belimumab discontinuation has been previously reported to range from 4.3% to 26.2% within 6 months following initiation,50 51 although discontinuation rates as high as 49.4% have been reported over longer periods (median 15 months).48 The reasons for treatment discontinuation have been suggested as ineffective treatment but are not well-reported, since real-world studies frequently use administrative claims databases that may not capture these data.28 42 51 However, belimumab’s long-term safety, tolerability and efficacy in patients with SLE have been examined in open-label extension studies of the phase II study, BLISS-52, BLISS-76, BLISS-SC and NEA.19 A notable proportion of the patients who completed the original clinical trials continued belimumab treatment in open-label extensions, which consistently demonstrated maintained disease control, suggesting sustained efficacy of belimumab that was well tolerated, with no new safety signals observed.19 In China, based on local insight, patients with SLE may sometimes discontinue their treatment when they perceive an improvement in their symptoms, which could be driven by various reasons, including cultural beliefs, financial constraints or simply feeling better and assuming treatment is no longer necessary. The collection of treatment pattern data in patients treated with belimumab in this study will help understand the pattern of belimumab use and how the concomitant drugs, such as corticosteroids or immunosuppressants, would vary in combination with belimumab. Therefore, this study can potentially capture new, important data on patients in China to shape targets for future research.

There are potential limitations of this study to be acknowledged. The lack of comparator groups restricts the interpretation of the results; due to the descriptive nature of this study, the effectiveness of belimumab compared with other treatments, including conventional SLE therapy, cannot be assessed, nor can the results definitively state any causal relationships between belimumab and the outcome variables. Due to the real-world nature of this study, no study visits will be scheduled, and data will be obtained from routine clinical visits or medical records. Therefore, there is a potential for missing data for outcome assessments, especially for data collected from the retrospective period, which may lead to uncertainty in the measured changes from baseline analyses. However, since LLDAS availability at baseline is one of the inclusion criteria, this limits the potential impact of missing retrospective data. In addition, the maximum retrospective follow-up period is only 6 months, lessening the impact of retrospective data on long-term outcomes. Applying multiple imputation methods will also help mitigate the impact of missing data. As patients will be enrolled from tertiary hospitals rather than those treated in primary practice, the patient population may not fully represent all patients with SLE in China. However, the use of tertiary hospitals is necessary in this study to ensure adequate data availability.

In conclusion, the RELIABLE study may provide important evidence for the effectiveness of belimumab in patients with SLE in China. Using LLDAS will provide clinicians with valuable insights into the impact of belimumab on the treat-to-target strategy with a relevant and practical measure that can be repeated across the clinical practice in China.

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Overview

Abstract
Introduction
Methods and analysis
Discussion
References

Footnotes
Publication history
Rapid Responses

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