Although the concept of disease modification is well-established in several immune-mediated diseases, there is no widely accepted definition of disease modification in systemic lupus erythematosus (SLE). A group of international lupus experts recently proposed a framework for the definition of disease modification in SLE that includes minimizing disease activity with the fewest treatment associated toxicities and slowing/preventing organ damage progression.¹ Achieving this goal in SLE will require a multifaceted approach including the use of therapies that target key immunologic pathways important to disease pathogenesis and shared decision making between patients and physicians to encourage therapeutic adherence.

The successful development and approval of two targeted biologic agents, belimumab and anifrolumab, will hopefully accelerate our ability to achieve disease modification in SLE. Both agents target key mechanisms that contribute to ongoing SLE disease activity and damage. Belimumab is a fully human IgG1l antibody against soluble B cell activating factor (BAFF) and anifrolumab is a fully human IgG1k against subunit 1 of the Type I Interferon receptor. In large scale international phase III trials of participants with SLE, both agents reduced disease activity across multiple organ domains and enabled tapering of glucocorticoids.^2–5 The agents differ in kinetics of response, with anifrolumab demonstrating a faster time to response, particularly in people with cutaneous lupus manifestations. The availability of belimumab over the past decade has enabled studies demonstrating reduction in damage progression with belimumab compared to matched controls receiving conventional therapies. Such long-term studies are not yet available with anifrolumab. In terms of the critical issue of predictors of response, serologic activity predicts response to belimumab and to anifrolumab compared to conventional therapies. As a result of the distinct effects on pathways involved with host defence, the safety profile between belimumab and anifrolumab is quite distinct. Belimumab has consistently demonstrated a reassuring safety profile in comparison to conventional therapies with one exception being the increased risk of depression-related adverse events. In contrast, anifrolumab has been associated with an increased risk of mild-moderate infections, including herpes zoster and influenza. Thus, all patients should be strongly encouraged to receive appropriate vaccinations prior to start of therapy.

The pipeline of therapies for the treatment of SLE is full of promising agents targeting a variety of important immunologic pathways. An ongoing area of active investigation is learning how to select the right therapy for the right patient at the right stage of their disease. In this way, we will continue to make significant progress towards disease modification in SLE.

References

1. van Vollenhoven R, et al. Conceptual framework for defining disease modification in systemic lupus erythematosus: a call for formal criteria. Lupus Sci Med. 2022 Mar;9(1):e000634. doi: 10.1136/lupus-2021-000634.

2. Navarra SV, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet. 2011 Feb 26;377(9767):721–31. doi: 10.1016/S0140-6736(10)61354-2.

3. Furie R, et al. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum. 2011 Dec;63(12):3918–30. doi: 10.1002/art.30613. PMID: 22127708; PMCID: PMC5007058.

4. Morand EF, et al. Trial of Anifrolumab in Active Systemic Lupus Erythematosus. N Engl J Med. 2020 Jan 16;382(3):211–221. doi: 10.1056/NEJMoa1912196.

5. Furie RA, et al. Type I interferon inhibitor anifrolumab in active systemic lupus erythematosus (TULIP-1): a randomised, controlled, phase 3 trial. Lancet Rheumatol. 2019;1(4):E208-E219.Idoi:10.1016/S2665-9913(19)30076-1.

Learning Objectives

• Describe the evolving framework for disease modification in SLE

• Distinguish the mechanisms of action of belimumab and anifrolumab

• Explain the key differences in efficacy and safety between belimumab and anifrolumab