Systemic lupus erythematosus (SLE) is characterised by a dysregulated immune system, which leads to an ongoing autoimmune reaction. Many different cytokines are produced during an autoimmune response causing chronic inflammation, and studies in both animal models of lupus and patients with SLE have revealed a number of cytokine pathways important in the disease process.¹Amongst these is the B lymphocyte stimulator (BLyS), which promotes B-cell survival and autoantibody production, the interferons that activates most immune cells, tumor necrosis factor (TNF), which contributes to organ inflammation and interleukin (IL)-17, which can induce the production of additional inflammatory cytokines and chemokines. Most cytokines have pleiotropic effects and can either positively or negatively affect the expression or function of other cytokines. Thus, a cytokine can both promote organ inflammation and at the same time down regulate a central autoimmune process. Furthermore, different cytokines may be operative during early or longstanding SLE, as well as in different disease subsets. Consequently, the precise role of a single cytokine in SLE as well as other autoimmune diseases has proved difficult to determine. Despite this difficulty, targeting cytokines in several rheumatic diseases, such as rheumatoid arthritis and ankylosing spondylitis, has been a remarkably successful approach. However, in SLE it has been far more difficult to demonstrate clinical efficacy with drugs targeting a single cytokine and a large number of studies have, after early promising results, failed in Phase III trials. At the moment only belimumab, a human mAb that binds to BLyS, is the only approved specific anticytokine treatment in SLE.² Targeting cytokine receptors or downstream signaling molecules, such as the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway, is at the moment intensively studied as therapeutic possibilities.³ Another approach is administration of a regulatory cytokine, and induction of regulatory T cells by low dose IL-2 is now explored as new therapy for SLE.⁴ However, In order to be successful in obtaining remission in our patients, we need to better understand the cytokine network in the disease and stratify patients not only on organ manifestations, but also on involved molecular pathways.⁵

Learning objectives

• Understand the pleiotropic effects of cytokines and their possible role in autoimmunity

• Review key cytokines involved in the SLE disease process

• Discuss different possibilities to modulate cytokine effects in SLE

References

1. Ronnblom L, Elkon KB. Cytokines as therapeutic targets in SLE. Nature reviews Rheumatology 2010;6(6):339–47.

2. Manzi S, Sanchez-Guerrero J, Merrill JT, et al. Effects of belimumab, a B lymphocyte stimulator-specific inhibitor, on disease activity across multiple organ domains in patients with systemic lupus erythematosus: combined results from two phase III trials. Ann Rheum Dis 2012;71(11):1833–8.

3. Baker KF, Isaacs JD. Novel therapies for immune-mediated inflammatory diseases: What can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn’s disease and ulcerative colitis?Ann Rheum Dis 2018;77(2):175–87.

4. Mizui M, Tsokos GC. Targeting Regulatory T Cells to Treat Patients With Systemic Lupus Erythematosus. Frontiers in immunology 2018;9:786.

5. Dorner T, Furie R. Novel paradigms in systemic lupus erythematosus. Lancet (London, England) 2019;393(10188):2344–58.