Introduction
Tocilizumab (TCZ), a monoclonal antibody targeting the IL-6 receptor, has become a cornerstone therapy in rheumatoid arthritis (RA) management. It effectively reduces inflammation and joint damage by inhibiting IL-6 signaling pathways. Approved in both intravenous and subcutaneous forms, TCZ has demonstrated significant benefits in patients who do not respond adequately to methotrexate or TNF inhibitors, as shown in key clinical trials like SAMURAI and OPTION. Real-world data support its long-term efficacy and safety, particularly in biologic-naïve and overweight individuals. However, monitoring is essential due to potential adverse effects, including altered lipid profiles and an increased risk of infections.
While TCZ and sarilumab are both IL-6 receptor inhibitors with proven efficacy in RA, they differ in structure, administration routes, and dosing schedules. TCZ is humanized and available in both IV and SC formulations, while sarilumab is fully human and given only subcutaneously. Biosimilars of TCZ have shown comparable efficacy and safety. Importantly, TCZ also holds promise beyond RA, being approved for other inflammatory conditions like juvenile idiopathic arthritis and COVID-19. Its ability to block both classic and trans-signaling of IL-6 underscores its wide-ranging anti-inflammatory potential, reinforcing its position as a key therapeutic option in RA and other cytokine-mediated diseases.
Method
A comprehensive literature search was conducted using PubMed and EMBASE databases to identify full-text English-language articles on tocilizumab (TCZ) in rheumatoid arthritis (RA), published between January 1, 2005, and December 31, 2023. The search used keywords and terms such as “tocilizumab,” “IL-6,” “IL-6 receptor,” “IL-6 inhibitor,” and “rheumatoid arthritis,” incorporating relevant MeSH and Emtree terms to ensure accurate results. Articles with available abstracts were included for review.
Results
TCZ efficacy and safety profile emerging from randomized controlled trials
Over the past 18 years, several Phase III clinical trials have consistently demonstrated the efficacy and safety of tocilizumab (TCZ) in treating rheumatoid arthritis (RA), both as monotherapy and in combination with csDMARDs. Trials such as SAMURAI, OPTION, RADIATE, TOWARD, and AMBITION confirmed TCZ’s effectiveness in patients who were either intolerant or unresponsive to methotrexate or TNF inhibitors. Long-term studies like STREAM and MUSASHI further supported sustained clinical improvement, safety, and quality of life. Subcutaneous (SC) and intravenous (IV) formulations showed comparable results in SUMMACTA and BREVACTA, while FUNCTION and LITHE emphasized TCZ’s benefits in early RA and in halting radiographic progression. ADACTA showed TCZ monotherapy to be superior to adalimumab.
Despite concerns about lipid elevations and cardiovascular risk, the ENTRACTE trial found no significant increase in major cardiovascular events with TCZ versus etanercept. The ‘lipid paradox’ in RA—where low lipid levels still coincide with high cardiovascular risk due to systemic inflammation—has made TCZ’s lipid impact a topic of interest. Nonetheless, data show that TCZ’s cardiovascular risk remains comparable to other biologics. Across studies, the safety profile remains consistent, with infections and neutropenia being notable concerns but manageable. Overall, TCZ remains a well-supported and effective option for managing RA.
TCZ’s broader implications or cardiovascular benefits
Emerging research indicates that tocilizumab (TCZ) may offer cardiovascular (CV) benefits beyond controlling RA inflammation. By targeting IL-6, TCZ reduces systemic inflammation and positively affects endothelial function, monocyte activity, NETosis, and oxidative stress—key contributors to atherosclerosis. Ruiz-Limón et al. showed that TCZ improves endothelial function, reduces oxidative stress, and limits NET formation, while also reversing pro-inflammatory and pro-thrombotic monocyte behavior in RA patients.
Additionally, TCZ has been found to reduce arterial stiffness and improve HDL cholesterol levels, both of which are beneficial for cardiovascular health. By stabilizing atherosclerotic plaques and improving vascular function, TCZ may lower CV risk in RA patients, particularly those with subclinical atherosclerosis or metabolic syndrome. These findings suggest TCZ’s potential role in CV risk management, warranting further exploration in broader at-risk populations.
TCZ efficacy and safety profile emerging from real-world studies
Real-world evidence (RWE) studies have confirmed the efficacy and safety of tocilizumab (TCZ) in routine clinical practice for rheumatoid arthritis (RA), often involving more diverse patient populations than clinical trials. A French multicenter study found better TCZ response in younger patients with high CRP and no cardiovascular disease (CVD), emphasizing the value of personalized treatment. Other RWE studies using ultrasound and clinical assessments also confirmed TCZ’s rapid anti-inflammatory effects. The SURPRISE study showed over 90% remission with TCZ, and disease control was maintained with methotrexate (MTX) post-TCZ withdrawal.
Further RWE, including the FIRST registry, underlined TCZ’s effectiveness and safety, especially in patients under 75 years, while noting increased caution for elderly patients with comorbidities like lung disease. The SIMPACT study in Hungary showed significant disease activity reduction with subcutaneous TCZ, particularly in biologic-naïve and younger patients, along with reduced use of corticosteroids and other medications. These findings support TCZ as a well-tolerated, effective therapy across diverse RA populations, particularly when tailored to individual patient profiles.
Tocilizumab efficacy and safety on specific populations
Interstitial Lung Disease (ILD):
ILD is a serious extra-articular manifestation of RA that can significantly impact patient outcomes. It may present early in RA, sometimes even before joint symptoms, and can be worsened by some DMARDs. Tocilizumab (TCZ) has shown a favorable safety profile in RA-associated ILD, making it a suitable treatment in patients where methotrexate (MTX) is not recommended due to lung involvement.
Secondary Amyloidosis:
AA amyloidosis, a severe RA complication, is driven by prolonged inflammation and IL-6. It commonly affects the kidneys and other organs. TCZ has shown effectiveness in reducing amyloid burden, improving proteinuria, and preserving renal function in patients with RA-related amyloidosis. Its efficacy may surpass that of anti-TNF therapies in such cases.
Overweight/Obesity:
Obesity contributes to systemic inflammation through cytokine release, particularly IL-6 and TNF. While obesity can reduce the efficacy of some biologics, TCZ maintains its effectiveness regardless of BMI, making it a good option for overweight RA patients. By controlling RA, TCZ may also help reduce obesity-related inflammation.
Pregnancy and Breastfeeding:
TCZ use during pregnancy and breastfeeding should be considered with caution. Though some reports show successful outcomes, data is limited, and contraception is advised during treatment and up to three months after discontinuation. Disease control during pregnancy is essential and often outweighs potential risks of biologics like TCZ.
Elderly Patients:
TCZ is effective and generally well-tolerated in elderly RA patients, although infections are more common in this group. Age-related comorbidities and immunosenescence can complicate treatment, but TCZ’s ability to target IL-6 makes it beneficial in reducing chronic inflammation and disease activity in older patients.
Tocilizumab adverse effects and general considerations
Infections:
Infections are common with TCZ, especially respiratory and urinary tract infections, due to IL-6 inhibition. Serious infections like pneumonia, herpes zoster, and diverticulitis have been reported but are generally manageable. TCZ has a lower or comparable infection risk to corticosteroids. Hepatitis B reactivation is possible, especially in HBsAg+ patients, emphasizing the need for screening and antiviral prophylaxis.
Neutropenia:
TCZ can cause transient neutropenia by affecting neutrophil survival and distribution. Grade 3 neutropenia occurs in a small percentage (about 3.7%) but is usually not linked to infections. Long-term monitoring is recommended, though it rarely requires treatment adjustment or leads to discontinuation.
Malignancies:
Malignancy rates with TCZ are generally low and comparable to placebo or other biologics. A slightly higher rate was seen in the 4 mg/kg group in one study, but not consistently across trials. RA itself increases cancer risk, and current evidence doesn’t suggest TCZ significantly raises this risk. Regular monitoring remains essential.
Intestinal Injuries:
TCZ may increase the risk of gastrointestinal perforation, especially in patients with diverticulosis. It may mask symptoms and delay diagnosis by suppressing CRP and pain response. Though rare, intestinal complications can be serious. The risk is still lower than with corticosteroids but should be considered in at-risk patients.
Conclusion
Clinical trials have demonstrated that TCZ (tocilizumab) offers a strong efficacy and safety profile, comparable or even superior to TNF inhibitors and other bDMARDs, and is effective as monotherapy in both subcutaneous and intravenous forms. Importantly, it does not increase cardiovascular risk compared to other biologics. Real-world evidence supports these findings, highlighting that smoking does not impact treatment response, and that TCZ is more effective in younger, biologic-naïve patients. In special populations, TCZ has shown a favorable safety profile in RA-associated interstitial lung disease (RA-ILD), helps reduce AA amyloid deposits in affected organs, and remains effective in overweight or obese individuals. While data in pregnant and breastfeeding women is limited, its use requires cautious consideration. In elderly patients with comorbidities, TCZ has been associated with reduced RA disease activity. The most frequently reported adverse effects include serious infections, neutropenia, and diverticulitis, making careful monitoring essential to optimize treatment safety and effectiveness.
References
1. Strand V, Burmester GR, Ogale S, Devenport J, John A, Emery P. Improvements in health-related quality of life after treatment with tocilizumab in patients with rheumatoid arthritis refractory to tumour necrosis factor inhibitors: results from the 24-week randomized controlled RADIATE study. Rheumatol (Oxford). (2012) 51:1860–9. doi: 10.1093/rheumatology/kes131
2. Cacciapaglia F, Spinelli FR, Bartoloni E, Bugatti S, Erre GL, Fornaro M, et al. Clinical features of diabetes mellitus on rheumatoid arthritis: data from the Cardiovascular Obesity and Rheumatic DISease (CORDIS) study group. J Clin Med. (2023) 12:2148. doi: 10.3390/jcm12062148
3. Pandolfi F, Franza L, Carusi V, Altamura S, Andriollo G, Nucera E. Interleukin-6 in rheumatoid arthritis. Int J Mol Sci. (2020) 21:5238. doi: 10.3390/ijms21155238
4. Deane KD, Demoruelle MK, Kelmenson LB, Kuhn KA, Norris JM, Holers VM. Genetic and environmental risk factors for rheumatoid arthritis. Best Pract Res Clin Rheumatol. (2017) 31:3–18. doi: 10.1016/j.berh.2017.08.003
5. Burmester GR, Rigby WF, van Vollenhoven RF, Kay J, Rubbert-Roth A, Kelman A, et al. Tocilizumab in early progressive rheumatoid arthritis: FUNCTION, a randomised controlled trial. Ann Rheum Dis. (2016) 75:1081–91. doi: 10.1136/annrheumdis-2015-207628
6. Iorio GC, Ammendolia A, Marotta N, Ricardi U, de Sire A. A bond between rheumatic diseases and cancer in the elderly: the interleukin-6 pathway. Int J Rheum Dis. (2021) 24:1317–20. doi: 10.1111/1756-185X.14194
7. Aliyu M, Zohora FT, Anka AU, Ali K, Maleknia S, Saffarioun M, et al. Interleukin-6 cytokine: an overview of the immune regulation, immune dysregulation, and therapeutic approach. Int Immunopharmacol. (2022) 111:109130. doi: 10.1016/j.intimp.2022.109130
8. Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol. (2014) 6:a016295. doi: 10.1101/cshperspect.a016295
9. Rose-John S. IL-6 trans-signaling via the soluble IL-6 receptor: importance for the pro-inflammatory activities of IL-6. Int J Biol Sci. (2012) 8:1237–47. doi: 10.7150/ijbs.4989
10. Avci AB, Feist E, Burmester GR. Targeting IL-6 or IL-6 receptor in rheumatoid arthritis: what have we learned? BioDrugs. (2024) 38:61–71. doi: 10.1007/s40259-023-00634-1
