Considering new lessons about the use of IL-6 inhibitors in arthritis

Interleukin (IL)−6 represents one of several possible targets for the treatment of rheumatoid arthritis. Drugs targeting IL-6 can be divided into monoclonal antibodies against IL-6 itself and monoclonal antibodies against the IL-6 receptor. Both types of agent inhibit both classical signalling through membrane­-bound IL-6 receptor, and trans-signalling via formation of a complex between IL-6 and soluble IL-6 receptor. The IL-6 receptor blockers tocilizumab and sarilumab inhibit the low affinity binding of IL-6 to its receptor. The anti-IL-6 agents clazakizumab and vobarilizumab also block binding of IL-6 to the receptor, while olokizumab blocks the higher affinity interaction of the IL-6-receptor complex with gp130. The doses and dosing intervals of the biologics targeting different elements vary, but no major differences in efficacy or safety have yet been seen between the two approaches, although more studies are needed in this area. In addition to the different blocking actions of monoclonal antibodies, we consider therapeutic strategies including the timing of IL-6 blockade and the use of monotherapy versus the addition of methotrexate.

Targeting IL-6: A review of data

Compounds that target interleukin (IL)−6 pathways include antibodies against the IL-6 receptor or ligand, and inhibitors of IL-6 signal transduction. The anti-IL-6 receptor (IL-6R) monoclonal antibody tocilizumab has been licensed for several years; data from multiple studies demonstrate its efficacy and tolerability in rheumatoid arthritis as monotherapy or in combination with methotrexate. In addition, another anti-IL-6R monoclonal antibody, sarilumab, has recently been approved in both the US and EU. Anti-IL-6 monoclonal antibodies include olokizumab and clazakizumab, which both have data from phase II studies, as well as sirukumab which has completed phase III trials but may not be brought to the market. Comparative data for olokizumab versus tocilizumab intervention in rheumatoid arthritis suggest no difference in efficacy between blocking the receptor or the ligand. Head-to-head studies are needed to determine whether inhibition of the Janus kinase pathway is similar in its overall efficacy to direct inhibition of IL-6 or its receptor. The IL-6 inhibitors appear to be more effective when combined with methotrexate. However, they have shown superiority to tumour necrosis factor inhibitors when used as monotherapy, and may have an advantage in patients who cannot use methotrexate or any other conventional synthetic disease modifying anti-rheumatic drug. Regarding disease activity assessment, CDAI is a more appropriate measure than DAS28 when looking at the effect of IL-6 inhibition, as these agents interfere with the acute phase response, which is heavily weighted in the formula of DAS28.

IL-6: To immunity and beyond

Interleukin (IL)−6 inhibition has been approved for the treatment of rheumatoid arthritis, systemic juvenile arthritis, polyarticular juvenile idiopathic arthritis, giant cell arteritis, and, in some countries, Castleman’s disease. IL-6 has also been implicated in several non-rheumatoid arthritis inflammatory and immune conditions such as systemic sclerosis, vasculitides, systemic lupus erythematous, and psoriatic arthritis. In orphan diseases, such as systemic sclerosis, which are associated with significant morbidity and mortality and for which there are no approved treatments, IL-6 inhibition may offer a promising treatment strategy. It is also becoming clear that IL-6 may have an important role not only in inflammatory and immune diseases but also in non-immune mediated diseases such as endogenous depression and depression associated with chronic inflammatory conditions. Several studies have explored the effect of IL-6 pathway inhibition in Crohn’s disease and adult-onset Still’s disease, suggesting that IL-6 may be important in their pathogenesis.

Interleukin 6: The biology behind the therapy

The cytokine interleukin (IL)−6 performs a diverse portfolio of functions in normal physiology and disease. These functions extend beyond the typical role for an inflammatory cytokine, and IL-6 often displays hormone-like properties that affect metabolic processes associated with lipid metabolism, insulin resistance, and the neuroendocrine system. Consequently, the biology of IL-6 is complex. Recent advances in the field have led to novel interpretations of how IL-6 delivers immune homeostasis in health and yet drives disease pathology during infection, autoimmunity, and cancer. Various biological drugs that target IL-6 are in clinical practice or emerging in clinical trials and pre-clinical development programmes. The challenge is knowing how and when to apply these therapies. In this review, we will explore the biology behind IL-6 directed therapies and identify some key hurdles for future investigation.