Introduction
Interleukin-6 (IL-6) is a key cytokine driving inflammation across multiple organ systems. Sarilumab (SAR), a fully human IL-6 receptor antibody, binds both monomeric and dimeric IL-6Rα with ~20 times higher affinity than tocilizumab (TCZ). It shows low immunogenicity, and anti-drug antibodies do not affect its efficacy or safety, even with DMARDs like methotrexate. At steady state, SAR achieves high IL-6Rα occupancy (98% at 200 mg), showing stronger IL-6 inhibition and greater disease activity reduction than TCZ in RA patients.
IL-6R blockade increases T-helper 2 and regulatory T cells, especially resting Tregs, correlating with better treatment response. While overall T and B cell counts stay stable, IL-6 inhibition reduces memory B cells and IgG, IgA, and IgM levels, with a rise in IgE. Neutrophil antibacterial function remains intact; IL-6 blockade merely redistributes them within the vascular system without functional loss.
Clinical evidence and expert opinion
Clinical trials have confirmed the efficacy and safety of sarilumab (SAR) in treating rheumatoid arthritis (RA), with no new safety concerns reported. SAR shows similar effectiveness in patients with or without methotrexate and has additional benefits, such as improving RA-associated anemia and stabilizing interstitial lung disease. It has also shown success in achieving remission and reducing glucocorticoid use in polymyalgia rheumatica. Approved by the FDA and EMA for juvenile idiopathic arthritis, SAR holds promise for broader use across immune-mediated inflammatory diseases, similar to tocilizumab (TCZ).
The PROFILE study demonstrated SAR’s real-world effectiveness, showing significant improvement in disease activity through week 52, both as monotherapy and in combination therapy, with a safety profile consistent with clinical trials. Post-marketing data from Japan involving 678 RA patients revealed neutropenia and infections as the most frequent serious adverse events, though neutropenia did not increase infection risk. No malignancy cases were reported, and existing evidence suggests IL-6 blockade does not compromise tumor immunity or interfere with checkpoint inhibitors, supporting its long-term safety.
SAR was also well-tolerated among older RA patients, with infection rates only slightly higher in those aged ≥75 years. As it can suppress CRP elevation during infections, alternative biomarkers like leucine-rich α2-glycoprotein may be useful for monitoring. Compared to TCZ, SAR 200 mg biweekly shows superior efficacy, and given its stable receptor targeting, it may be the most effective IL-6 therapy currently available. It is recommended for patients with inadequate response to methotrexate or conventional DMARDs and may be used as a first- or later-line biologic option—especially for elderly patients—before considering Janus kinase inhibitors.
Conclusion
In conclusion, SAR has demonstrated favorable effectiveness and safety in routine clinical practice for RA management. Its clinical indications have the potential to expand, as seen with TCZ, to a variety of IMIDs, including glucocorticoid-refractory conditions. Future studies should investigate the safety profile of SAR in patients with comorbidities such as malignancies, chronic pulmonary infections, and cardiovascular diseases, as well as the identification of biomarkers useful for the precision medicine by predicting and monitoring the treatment response.
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