Discussion
This observational study examined the clinical effectiveness of marketed belimumab plus SoC in patients with SLE in US clinical practice. Over the 24-month period, patients had an overall improvement in disease activity according to physician assessment of clinical response and disease severity. Furthermore, the number of patients receiving steroids and the mean dose of steroids decreased and patients with abnormal laboratory values associated with active SLE improved. Generally, the improvements were more pronounced in the first six months of treatment; however, improvements continued or were maintained through 24 months. HCRU decreased over the study period, with fewer unscheduled rheumatologist visits, ER visits and hospitalisations reported. Subgroup analyses demonstrated that patients with high disease activity and African-Americans responded to belimumab in a similar manner to the overall population. As the results from the phase 3 studies with belimumab in the African-American population were inconclusive,2 the observed positive outcomes in this subgroup provide valuable information.
Observational studies enable data collection from clinical practices across a wide geographic area and provide a more realistic reflection of treatment within clinical practice compared with clinical trials where stricter inclusion/exclusion criteria, dosing limitations and inflexible concomitant medication management can limit the generalisability of data to clinical practice.
The study design has some limitations. The lack of a control group limits the conclusions that can be made as pre-treatment and post-treatment measurements cannot account for the natural course of this highly variable disease. It is important to understand patient attrition in longitudinal analyses. Approximately half of patients did not complete the study; furthermore, the ITT population may have been enriched with patients who were more likely to respond to belimumab as only patients who received belimumab for a minimum of 6 months were included; patients who discontinued treatment early may have done so due to a lack of response or for safety and tolerability reasons. ITT analyses with the LOCF method were employed to account for missing values, but still may not provide a true picture as patients have their status artificially stabilised (favourably or unfavourably) at the point of attrition. The LOCF method assumes that attrition is not related to patient characteristics or outcomes. Analyses of the 24-month completer population show the same trends in results as the ITT population, suggesting that employing the LOCF method has not substantially affected the results.
In the BLISS-52 trial, clinically meaningful overall improvements were seen with belimumab 10 mg/kg plus SoC as early as week 16; improvements in Physician Global Assessment score were significant at week 24, and an association between belimumab and reduction in disease flare were observed.3 In this study, we also report improvements in disease severity within 6 months of initiating belimumab and the improvements were largely maintained without worsening disease throughout the study, suggesting prevention of flares.
Steroid use reduction is an important factor in treatment of SLE as prolonged use of high-dose steroids is a major cause of long-term damage and morbidity.6 ,7 In agreement with the BLISS studies, we have defined >7.5 mg/day as high dose. Post hoc analyses of the BLISS trials suggested a steroid-sparing effect of belimumab among patients with serologically active disease.8 This study also suggests that belimumab has a steroid-sparing effect (among all patients and those with high disease activity), with a reduction in both the number of patients receiving steroids and the mean dose. However, it should be noted that the reasons for steroid reduction/discontinuation were not provided and may have been due to reasons other than improved disease, (eg, side effects, patient preference); nevertheless, the steroid data provide an objective measure of disease state.
Renal involvement, experienced by up to 60% of patients with SLE, is a common source of morbidity.9 Although belimumab is not indicated for patients with severe lupus nephritis, a pooled post hoc analysis of the BLISS trials suggested that patients with renal involvement who received belimumab plus SoC had fewer renal flares (defined by increases in proteinuria) compared with patients receiving placebo.10 The present study supports this finding as the spot urine protein:creatinine ratio and serum creatinine remained stable, and for patients with abnormal values, these parameters improved at 6 months and continued to gradually improve through 24 months.
Other laboratory test results generally demonstrated that patients who had normal levels at baseline remained normal and patients who had abnormal levels at baseline improved towards normal levels, including C3, C4, white blood cell count, platelet count, haemoglobin, CRP and ESR. In addition, the proportion of patients with positive anti-dsDNA decreased over the 24 months. These objective data suggest improvements in patients’ disease state throughout the study, although without a placebo-control group this cannot be conclusively determined to be due to belimumab treatment.
This study was not designed to assess safety and tolerability. The BLISS-523 and BLISS-764 trials demonstrated an acceptable safety profile for belimumab and ongoing randomised control studies and large observational studies will provide further postmarketing data on safety and tolerability (eg, NCT0170597711 and NCT0172945512).
There is no standard disease assessment tool for SLE recommended by rheumatology professional organisations such as the American College of Rheumatology (ACR) or the European League against Rheumatism; therefore, the primary outcome of this study was physician-assessed relative interval improvement in overall clinical response. This was designed to mimic the ACR response assessment used in rheumatoid arthritis. In this study, we found that no validated disease assessment tool was routinely used in non-academic clinical practice as nearly 50% of physicians never use any tool and SELENA-SLEDAI, the most commonly used validated tool, was only used by 14.1% of physicians. The lack of any consistently used validated tool is, therefore, a general challenge when assessing SLE treatment. We have used multiple methods of assessing disease severity; improvements were observed in all measures, giving confidence in these findings.
As patient numbers were small for SELENA-SLEDAI, conclusions should be made with caution. Limited data were also available for some of the laboratory tests; nevertheless, these do provide some objective data. In addition, a limitation of the CRFs is that they were an interpretation of what was written in the charts. Furthermore, under-reporting may have occurred if not all events were reported to the physician or recorded on the patient chart.
In conclusion, the findings of this observational study provide evidence of reduced disease activity in patients with SLE who received at least 6 months of belimumab plus SoC in a clinical practice setting. In the first six months of belimumab therapy, according to physician assessment, SLE severity decreased and patients continued to improve or maintained their improvement throughout 24 months. In addition, belimumab added to SoC demonstrated reduction in SELENA-SLEDAI, flare prevention and maintenance of disease control. These favourable outcomes were achieved in the setting of objective reductions in steroid use, improvements in laboratory parameters and lower HCRU. These results from clinical practice support the findings of randomised clinical trials that have demonstrated the efficacy of belimumab.