When to use belimumab in SLE

KEYWORDS:

• Acute disease manifestations
• belimumab
• damage
• disease activity
• flare rate
• systemic lupus erythematosus

1. Introduction

Belimumab is a monoclonal IgGʎ antibody targeting soluble B lymphocyte stimulator (BLyS) and aimed at lowering available BLyS levels for autoreactive B cells selection and survival.

Belimumab was approved in recent years for systemic lupus erythematosus (SLE) treatment and notably it was the only approved drug in the last 60 years, since the time corticosteroids, hydroxychloroquine, and nonsteroidal anti-inflammatory drugs were released for SLE. Hence, treatment of lupus until 2011 was only based on corticosteroid and antimalarial use together with traditional immunosuppressants, to whom off-label use of a restricted panel of biologics was added, mainly rituximab. Accordingly, management of such an heterogeneous disease did not benefit from optimized treatment schedules and this may be a reason for the prognosis of SLE patients having remained poor in the long term, with a 4.6-fold-increased mortality compared to matched population [1]. Indeed, satisfactory disease control with prolonged remission is still scarcely achieved among different lupus cohorts, and risk of organ deterioration in SLE patients has reached a plateau in the last 10 years, suggesting a balance between therapy-related benefits and harm has been accomplished.

Approval of belimumab raised great expectations for SLE despite the size effect in the successful phase 3 randomized controlled trials (RCT) being not that great. However, beside the measurable effect obtained in those studies, we should now point out whether belimumab is able to really ameliorate patients’ prognosis. As the follow-up is still short since its approval, we may focus on major predictors of damage in SLE and analyze whether belimumab is able to dampen those predictors.

2. Unmet needs in SLE

Several unmet needs are still present among SLE patients as they suffer from deteriorated quality of life, mood disorders, decreased work productivity, need for unscheduled medical visits due to uncontrolled disease activity, and increased mortality. All of those unmet needs rely on a common ground, which is the increased organ damage provided to SLE patients by persistent disease activity and drug-related side effects, especially those linked to chronic corticosteroid intake. Moreover, no shared treatment protocol exists in SLE regarding long-term management which is often dependent on a single physician’s experience; in this regard, the relevance of a treat-to-target approach applicable to SLE is emerging, and the need for novel steroid-sparing therapeutic strategies and confidence in their administration are paramount.

3. Observations on belimumab use in clinical practice

Several case series and case reports and subsequently a large multicenter observational study have been carried out after BLISS trials [2–10] (Table 1), all converging on belimumab being able to improve control of disease activity and reduce daily corticosteroid intake, which are indeed expected to reduce organ damage in the long term. Unfortunately, those studies did not systematically measure disease activity according to approved scores, as retrospective observations were performed that were influenced by clinical practice. Nevertheless, improvement in disease activity was judged relevant by all physicians involved, even though clinical manifestations were not dissected in detail. Interestingly, by improving control of disease activity belimumab was shown to reduce work disability, being thus cost-effective both in terms of employment and in decreasing health resource utilization and emergency room visits [11,12], and to ameliorate fatigue as well, which is among the major complaints of SLE patients [6,9,10,13,14].

Table 1. Summary of studies (all types) carried out on belimumab use in real life after RCT.

Study	Type of study	No. of patients	Length of follow-up	Primary endpoint or study outcome	% responders	Outcome achieved	Ref.
RCT
NCT00071487	Phase 2 RCT	449	52 weeks	SELENA-SLEDAI at week 24 and time to first flare during 52 weeks	19.5	–	[2]
BLISS52	Phase 3 RCT	865	52 weeks	SRI-4 at week 52	58	–	[2]
BLISS76	Phase 3 RCT	819	52 weeks	SRI-4 at week 52	43.2	–	[2]
Non-randomized, real-life studies
OBSErve Germany	Retrospective data collection on belimumab-naïve patients after 6 months on treatment	102	6 months	Physician’s judgment scale for disease activity of 20% improvement	78	–	[3]
				Physician’s judgment scale for disease activity of 50% improvement	42
OBSErve USA	Observational cohort study	ITT 501 Completers at 24 months: 277	24 months	Physician assessed change in clinical response to belimumab at each 6-month interval
				20% improvement at 6 months	88.4	–	[4]
				50% improvement at 6 months	48.7
				20% continued improvement months 18–24	54.9
				50% continued improvement months 18–24	32.1
Scheinberg et al.	Prospective monitoring of steroid-dependent SLE treated with belimumab	48	12 months	Significant decrease in mean SLEDAI-2k score after treatment vs. baseline	79	–	[5]
Iaccarino et al.	Prospective multicenter cohort study	188	24 months	SRI4 at 12 months	71.3	–	[6]
				SRI4 at 24 months	68.7
Iaccarino et al.	Prospective cohort study	67	24 months	Decrease in SLEDAI score	NA	Yes	[7]
				Decrease in DAS28 score
				Decrease in CLASI score
				Decrease in SFI
				No progression in damage during FU
Hui-Yuen et al.	Observational study	195	6 months	Clinical response (according to treating physician) of ≥50% improvement in the initial manifestation(s) being treated and no worsening in other organ systems.	51	–	[8]
Andreoli et al.	Case series	18	9 months	Decrease in SLEDAI-2k	NA	Yes	[9]
				Decrease in corticosteroid intake
Scheinberg and Golmia	Case series	20	6 months	Decrease in SELENA-SLEDAI	NA	Yes	[10]
				Improvement in FACIT-fatigue
				Decrease in corticosteroid intake

RCT, randomized controlled trial; SLEDAI-2k, SLE-activity index 2000; SELENA-SLEDAI, Safety of Estrogens in Lupus Erythematosus National Assessment–SLEDAI; FACIT, Functional Assessment of Chronic Illness Therapy; DAS28, Disease Activity Score in 28 joints; CLASI, Cutaneous Lupus Erythematosus Disease Area and Severity Index; SFI, SLE Flare Index; SRI, SLE Responder Index; ITT, intention to treat.

Following the success of phase 3 RCT, a pooled analysis and a post hoc analysis focused on patient features able to predict belimumab response were performed, pointing out that a greater disease activity score, a higher corticosteroid intake, active serology and more refractory manifestations (especially musculoskeletal and mucocutaneous) were best predictors for belimumab response [13,14].

So, putting together real-life and post hoc observations, some SLE features are emerging which should be considered when prescribing belimumab, pertinent to disease activity and serological abnormalities. However, those aspects may not be sufficient in identifying the best candidate to belimumab treatment, owing to heterogeneousness in SLE course and manifestations.

In 2014 we had prospectively followed 188 patients on belimumab and shown a significant improvement in SLE Responder Index-4 (SRI4) in the majority of them [6]. Subsequently, we published the first prospective study on belimumab use as on-top treatment in SLE with a 24-month follow-up, including a real-world population, that is, patients attending our outpatient clinic, with no restrictions in previous drug use or comorbidities, except the presence of severe SLE manifestations that per se prevent patients from accessing belimumab in our cohort [7].

Our results were in line with those from pioneer studies and post hoc analysis on the BLISS population, finding out that belimumab is able to reduce disease flares, control disease activity in the mid- and long term, and significantly decrease daily corticosteroid intake. As the study was prospective, we were able to routinely measure disease activity and damage according to official scores, that is, SLE Activity Index-2000 (SLEDAI-2K), Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI), Disease Activity Score in 28 joints (DAS28), and mean Systemic Lupus International Collaborating Clinics Damage Index (SLICC-DI), and above all to stratify patients according to their disease phenotype (i.e. major manifestations for which belimumab was used) and importantly by disease activity patterns. Indeed, we recently noticed that patients with SLE may present with different patterns of disease activity, that is, often relapsing remitting or chronic active, that deserve different therapeutic approaches [15]. By doing this, we pointed out a dramatic decrease in disease flares during the follow-up which is fairly useful in patients displaying a relapsing-remitting course, that is, presenting with increased SLEDAI-2K (≥2) in one out of three annual visits. Among clinical manifestations, a striking improvement was observed in acute and subacute skin manifestations as well as in classic lupus arthritis, that is, the acute, nonerosive phenotype, while chronic cutaneous manifestations and rheumatoid-like arthritis were more refractory. Moreover, encouraging results were seen in moderately active lupus nephritis with a progressive decrease observed in 24-hour proteinuria over time and no worsening in renal function, in keeping with previous data on BLISS population.

The accrual of organ damage was measured before and after belimumab initiation, and notably no damage accrued during the 2-year follow-up period, which is in line with data reported by the group of Bruce, where only a small increase in SLICC-DI after 5 years of belimumab treatment was observed in patients who terminated the two phase 3 RCT and entered in the long-term extension study [16]. Importantly, relevant real-life experience [4,6,7,9] as well as a 7-year long-term extension study involving patients coming from the phase 2 RCT who had had an improvement in physician global assessment (PGA) since baseline proved a long-standing disease control and decrease in flare rate during the overall 7-year observation on belimumab treatment [17], suggesting such positive effects are long-lasting.

Notably, published studies including RCT, long-term extensions studies and real-life experience underlined a good safety and tolerability profile of belimumub use even when added to immunosuppressive therapy.

It has to be pointed out that although the majority of our patients (73.1%) as well as patients included in previous studies, including BLISS52 and BLISS76 (42% and 56%, respectively), were undergoing an immunosuppressive therapy while receiving belimumab, a relevant percentage was not; accordingly, the question is pending whether belimumab should only be used after immunosuppressants have failed or even before immunosuppressants use at least in selected patients. In this regard, it is worth noting that acute manifestations, for example, skin or joint disease, benefit best from belimumab treatment if compared with chronic manifestations; as such, it is reasonable to look at belimumab as a fruitful tool when facing active disease symptoms before they get chronic. Moreover, the use of an in-label drug as a first choice in suitable patients is preferable to the use of the familiar, yet never-approved-for-SLE, traditional immunosuppressants.

4. Expert opinion

In this editorial we tried to summarize real-life experience obtained with belimumab in recent years. The landscape looks encouraging, yet it is likely that no single drug will ever be enough for SLE; hence, rheumatologists should maximize the benefits obtainable by any available drug. Standard treatment of SLE should always include hydroxychloroquine – if no strong contraindications exist – as many positive effects were proven; an adequate steroid intake is currently nearly unavoidable, especially in active phases of disease. After this is done, some patients may already be suitable for belimumab use; for example, patients bearing active arthritis, skin rash, or any mucocutaneous manifestations, especially if they are young females in whom we do not want to lavish methotrexate or other traditional immunosuppressants. Moreover, the time of onset of disease symptoms matters: the earlier the onset, the more indicated may be belimumab use, as it was shown to better impact on acute disease manifestations. Alternatively, belimumab may be used as on-top treatment when refractory manifestations persist despite immunosuppressants use. More convincing evidence was so far reported concerning musculoskeletal and mucocutaneous disease; however, due to real-life experience belimumab should be kept into account in a wide spectrum of disease symptoms, including suboptimal control of lupus nephritis and in cases of SLE-related thrombocytopenia.

Importantly, as a reduction in SLE flares was extensively reported [2–8], it looks advisable to prompt belimumab especially in patients displaying a relapsing-remitting disease pattern, in whom a significant decrease in flare rate is among the fundamental treatment goals.

In summary, the best belimumab patient displays an active disease with acute mucocutaneous and musculoskeletal manifestations, active serology and disproportionate corticosteroid intake, with a relapsing-remitting course (Table 2). However, any patient without active neuropsychiatric SLE or severe lupus nephritis or life-threatening SLE-related manifestations may be eligible for belimumab use due to its positive effects in sparing corticosteroids and improve control of disease activity.

Table 2. Best responders to belimumab according to RCTs and real-life experience.

Patients with the following characteristics

Active disease High prednisone intake (≥7.5 mg/day) required to control disease activity Clinical phenotypes: Musculoskeletal Mucocutaneous Relapsing-remitting disease-activity profile

Patients with chronic active disease-activity profile can also benefit from belimumab, but in order to maximize the effectiveness it should be started as early as possible

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

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