Where possible, TCZ should be used concomitantly with MTX. In patients intolerant to MTX, TCZ is effective in monotherapy
Four-weekly monitoring of the full blood count is recommended for the first 6 months. In the absence of significant neutropenia, monitoring can be carried out less frequently thereafter
Four-weekly monitoring of liver enzymes for the first 6 months is recommended for patients on TCZ monotherapy. In patients on TCZ and MTX, 4-weekly monitoring should continue indefinitely
Tocilizumab therapy can result in elevation of serum cholesterol. All patients should have a baseline lipid profile, which should be repeated in 3 months. Treatment of high cholesterol should be initiated if necessary (based on local guidelines)
Major elective surgery should be deferred to 4 weeks after the last infusion. Clinicians must not rely entirely on fever and raised inflammatory markers when evaluating for post-operative sepsis
Treatment should be stopped 3 months before planned pregnancy, and only be re-started once breastfeeding is completed
As with other biologic DMARDs, influenza and pneumococcal vaccination is recommended in all patients on TCZ. Live and attenuated vaccines are contra-indicated
Bowel perforation is a rare but potentially life-threatening complication of TCZ therapy. Patients with diverticulitis are particularly at risk and TCZ therapy should only be initiated after careful consideration and counselling. Patients also on steroids or NSAIDS may be at a higher risk for bowel perforation.
Rheumatoid arthritis (RA) is a common and potentially devastating chronic inflammatory disease. It affects mainly women and elderly people and its prevalence in industrialised countries is thought to be 0.5%–1%. Uncontrolled, active disease causes joint damage, disability, cardiovascular and other conditions, and reduced quality of life. Fifty percent of the risk for developing RA is from genetic factors, with smoking being the main environmental risk.1
The need for the BSR guideline on tocilizumab in rheumatoid arthritis
Following the introduction of biologic disease-modifying antirheumatic drugs (bDMARDS), there has been a substantial reduction in the morbidity and mortality associated with RA. Tocilizumab (TCZ) is one such biologic DMARD and is licensed for use in the treatment of moderate to severe RA.2 With the ever-growing array of therapeutic options in RA, primary care providers are faced with new and unique challenges. The British Society for Rheumatology (BSR) has recently published a guideline for the use of TCZ in patients with RA (‘the 2013 BSR guideline’, see rheumatology.oxfordjournals.org/content/53/7/1344).3 This guideline aims to summarise other available guidelines and to provide healthcare professionals in primary care with the necessary tools to facilitate the safe and effective use of TCZ in their patients. A full version of the guideline can be found at rheumatology.oxfordjournals.org/content/53/7/1344/suppl/DC1
The 2013 BSR guideline3 provides evidence-based guidance on the use of TCZ in patients with RA, with a special emphasis on the monitoring of patients and the use of the drug in special situations, such as pregnancy and the perioperative period. It also provides guidance to clinicians on the safe use of vaccines in patients on TCZ. The main recommendations of the guideline are summarised below (see key points).
How does tocilizumab work?
Tocilizumab is a humanised antibody that targets the interleukin-6 receptor (IL-6R). Blockade of IL-6R disrupts the downstream effects of interleukin-6 (IL-6). Because IL-6 is a potent pro-inflammatory cytokine, the use of TCZ in patients with RA significantly suppresses inflammation and thereby prevents disease progression.
Tocilizumab has been approved by NICE for use in adult patients with severe RA (as evidenced by a disease activity score [DAS28] >5.1) whose RA has responded inadequately to two conventional DMARDS.4,5
Tocilizumab as monotherapy
Methotrexate (MTX) is a very effective treatment for RA; however, patients are often concerned about remaining on the drug in the long term because it is a chemotherapeutic agent. Despite these concerns, when appropriately monitored MTX has been found to be safe and effective in the treatment of RA. A proportion of patients, however, are intolerant to MTX. There is considerable clinical trial evidence suggesting that TCZ in monotherapy is effective in patients with RA.6–9
The guidelines working group for the 2013 BSR guideline reviewed all the available evidence and concluded that where possible, TCZ should be used in combination with methotrexate (MTX). In patients who were intolerant to MTX, tocilizumab could be used in monotherapy (i.e. without MTX).
The use of TCZ in patients with RA has been associated with abnormalities in blood counts, liver function tests, and the lipid profile.
Impact of tocilizumab on the neutrophil count
Intravenous TCZ at a dose of 8 mg/kg results in a significant reduction in the absolute neutrophil count (ANC) and initiation of TCZ is not recommended in patients with a pre-treatment ANC <2x109. In a meta-analysis of six clinical trials and five long-term extensions, an ANC <1x109 was seen at least once in about 6% of patients and an ANC of between 1–2x109 was seen in about 15% of patients.10ccording to the TCZ summary of product characteristics (SPC),2 50% of grade 3/4 neutropenia (i.e. ANC <1x109) occurs within the first 8 weeks of therapy. Despite these lower neutrophil counts, there is no specific association between the occurrence of infections and a low neutrophil count and indeed neutropenic sepsis has been very rarely encountered. Studies have demonstrated that the neutrophil counts reached their lowest point in the middle of the 4-weekly infusion cycles.9
Based on this evidence, the 2013 BSR guideline recommends as follows:
Patients on TCZ should have 4-weekly monitoring of their ANC during the first 6 months. If grade 3/4 neutropenia is not encountered during this time, monitoring can be less frequent thereafter and should be based on the concomitant use of other DMARDS.
[The use of other DMARDS, such as MTX, increases the risk of neutropenia. When TCZ is used along with other DMARDS such as MTX, monitoring after the first 6 months can be less frequent, but must take into account the higher risk with combination therapy.]
For the purpose of monitoring, the full blood count should be checked in the week prior to the next infusion.
Impact of tocilizumab on liver enzymes
Clinical trials in RA have demonstrated that the use of TCZ is associated with an elevation in liver enzymes. When TCZ is used in combination with MTX, the elevation in liver enzymes can be up to three times the upper limit of normal in 41%–50% of patients.11–13 Abnormalities in liver enzymes are less frequent when TCZ is used as monotherapy and the incidence has been found to be similar to that with MTX monotherapy.14 Changes in alanine transaminase (ALT) follow a saw-tooth pattern with the peak levels in between the 4-weekly infusions.9 The TCZ SPC2recommends that when ALT levels are found to be between 1–3 times the upper limit of normal, the dose of concomitant medications such as MTX should be altered. If these levels persist, it is recommended that the dose of TCZ be reduced to 4 mg/kg. When ALT levels are between 3–5 times the upper limit of normal, it is recommended that treatment is interrupted. When the levels are >5 times the upper limit of normal, treatment with TCZ should be discontinued.
Based on the available evidence, the 2013 BSR guideline recommends the following:
It is recommended that all patients on TCZ have liver function tests every 4 weeks for the first 6 months. For patients on TCZ monotherapy, monitoring tests can be carried out less frequently after that. In patients that are on TCZ and MTX, 4-weekly monitoring should be continued indefinitely.
Impact of tocilizumab on the lipid profile
The use of TCZ in RA has been associated with elevations in total cholesterol, HDL cholesterol, and LDL cholesterol. In most randomised controlled trials, the levels have been found to stabilise after the first few months.8,9 Despite the higher absolute values, the net effect on the atherogenic index (total cholesterol/HDL cholesterol) is neutral. The impact of the alteration of lipid profile on cardiovascular disease is currently unclear and is being studied in an ongoing clinical trial.15
The 2013 BSR guideline recommends that all patients should have a baseline fasting lipid profile and if this is abnormal, treatment should be initiated based on local guidelines. A further check of the lipid profile is recommended at 3 months.
In addition to increasing the risk of infections, TCZ poses an additional challenge that is particularly relevant in the post-operative period. As indicators of sepsis (such as fever, C-reactive protein [CRP]) depend at least in part on IL-6 expression, suppression of IL-6 with TCZ makes assessment of post-operative sepsis particularly difficult. Equally, withdrawal of TCZ several months before planned major surgery is likely to result in an RA flare, and the use of corticosteroids to treat such a flare would put patients at risk of infection and impaired wound-healing.
Wound infection in patients undergoing joint replacement surgery is rare and hence it is difficult to assess the impact that biologic therapy might have on this. Two studies looked at febrile response and CRP levels in patients on TCZ undergoing elective joint replacement surgery.16,17 Both demonstrated a blunted inflammatory response with lower temperatures and lower CRP levels. Based on the available evidence, the 2013 BSR guideline made the following recommendations:
In patients undergoing elective joint replacement or any other major non-orthopaedic surgery, TCZ therapy should be interrupted 4 weeks prior to surgery. During the post-operative period, clinicians are advised not to rely on traditional indicators of sepsis (fever, high CRP), and even a small elevation in inflammatory markers and the neutrophil count should warrant further evaluation for sepsis.
Pregnancy and breastfeeding
As with all other biologic DMARDs, it is unclear whether use of TCZ is safe during pregnancy and breastfeeding. Tocilizumab is likely to be able to pass through the placental barrier and into breast milk. There is some data to suggest that high levels of IL-6 are associated with adverse effects on the fetus,18 but the data are not robust enough to recommend the use of TCZ during pregnancy.
The 2013 BSR guideline recommends that TCZ be stopped at least 3 months prior to planned conception and that it be restarted once breastfeeding is completed.
The safety of live vaccination for people on TCZ and all other biologic DMARDs has never been studied. One study has looked at seroconversion rates following influenza vaccination in patients on TCZ. Seroconversion rates were found to be in excess of 70% in these patients and no significant adverse events were reported.19
The 2013 BSR guideline recommends that all patients on TCZ have annual influenza and pneumococcal vaccinations, unless there are other contra-indications. Live or attenuated vaccines are contraindicated.
Risk of bowel perforation
Patients with RA have been found to have a higher risk of bowel perforation than the general population. The risk seems to be highest in people who are taking non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids.20 Patients with a pre-existing history of diverticulitis are particularly at risk. Gastrointestinal perforation has been reported in patients on TCZ and the risk is deemed to be higher than that in patients taking anti-TNF medications, but lower than in patients taking NSAIDs and corticosteroids.21
Based on this evidence, the 2013 BSR guideline recommends that TCZ be used cautiously in patients with a history of diverticulitis. In patients who are also on NSAIDS and/or steroids, the risk of bowel perforation is likely to be much higher and it is recommended that such patients be counselled about this risk before TCZ therapy is started.
Tocilizumab is an effective biologic drug with a favourable safety profile, endorsed by NICE for use in adult patients with RA.5 In addition to TCZ, there are currently seven other biologic DMARDs approved for use in RA. Biomarkers that can accurately predict response to specific biologic agents remain an unmet need at the present time. As a result, local treatment guidelines are heavily influenced by NICE guidance, which takes into account cost-effectiveness of these high-cost therapies.
With a wide range of therapeutic options available, clinicians are expected to develop local guidelines within the broader framework of NICE guidance. This will require an active dialogue between clinicians in secondary care and clinical commissioners. The purpose of this review is to familiarise primary care clinical commissioners with TCZ in order to help facilitate this dialogue. In addition, with the growing number of patients on biologic therapy, it is envisaged that primary care practitioners might choose to take over the monitoring of stable patients on biologic DMARDs in the future; it is hoped that this article will provide them with the necessary tools to do so.
- Scott D, Wolfe F, Huizinga T. Rheumatoid arthritis. Lancet 2010; 376 (9746): 1094–1108.
- Tocilizumab (RoActemra) Summary of Product Characteristics. www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000955/WC500054890.pdf (accessed 20 October 2014).
- Malaviya A, Ledingham J, Bloxham J et al on the behalf of the BSR Clinical Affairs Committee & Standards, Audit and Guidelines Working Group and the BHPR. The 2013 BSR and BHPR guideline for the use of intravenous tocilizumab in the treatment of adult patients with rheumatoid arthritis (Executive summary). Rheumatol 2014; 53 (10): 1914. Available at: rheumatology.oxfordjournals.org/content/53/7/1344
NICE. Tocilizumab for the treatment of rheumatoid arthritis. Technology Appraisal 198. NICE, 2010. Available at: www.nice.org.uk/guidance/ta198
NICE. Tocilizumab for the treatment of rheumatoid arthritis (rapid review of Technology Appraisal Guidance 198). Technology Appraisal 247. NICE, 2011. Available at: www.nice.org.uk/guidance/ta247
Nishimoto N, Yoshizaki K, Miyasaka N et al. Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo controlled trial. Arthritis Rheum 2004; 50 (6): 1761–1769.
- Nishimoto N, Miyasaka N, Yamamoto K et al. Study of active controlled tocilizumab monotherapy for rheumatoid arthritis patients with an inadequate response to methotrexate (SATORI): significant reduction in disease activity and serum vascular endothelial growth factor by IL-6 receptor inhibition therapy. Mod Rheumatol 2009; 19: 12–19.
- Nishimoto N, Miyasaka N, Yamamoto K et al. Long-term safety and efficacy of tocilizumab, an anti-IL-6 receptor monoclonal antibody, in monotherapy, in patients with rheumatoid arthritis (the STREAM study): evidence of safety and efficacy in a 5-year extension study. Ann Rheum Dis 2009; 68 (10): 1580–1584.
- Maini R, Taylor P, Szechinski J et al. Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. Arthritis Rheum 2006; 54 (9): 2817–2829.
- Nishimoto N, Ito K, Takagi N. Safety and efficacy profiles of tocilizumab monotherapy in Japanese patients with rheumatoid arthritis: meta-analysis of six initial trials and five long-term extensions. Mod Rheumatol 2010; 20: 222–232.
- Dougados M, Kissel K, Sheeran T et al. Adding tocilizumab or switching to tocilizumab monotherapy in methotrexate inadequate responders: 24-week symptomatic and structural results of a 2-year randomised controlled strategy trial in rheumatoid arthritis (ACT-RAY). Ann Rheum Dis 2013; 72 (1): 43–50.
- Genovese M, McKay J, Nasonov E et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum 2008; 58 (10): 2968–2980.
- Kremer J, Blanco R, Brzosko M et al. Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate: results from the double-blind treatment phase of a randomized placebo-controlled trial of tocilizumab safety and prevention of structural joint damage at one year. Arthritis Rheum 2011; 63 (3): 609–621.
- Jones G, Sebba A, Gu J et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis 2010; 69 (1): 88–96.
- A study of RoActemra/Actemra (tocilizumab) in comparison to etanercept in patients with rheumatoid arthritis and cardiovascular disease risk factors. ClinicalTrials.gov NCT01331837.
- Hirao M, Hashimoto J, Tsuboi H et al. Laboratory and febrile features after joint surgery in patients with rheumatoid arthritis treated with tocilizumab. Ann Rheum Dis 2009; 68 (5): 654–657.
Hiroshima R, Kawakami K, Iwamoto T et al. Analysis of C-reactive protein levels and febrile tendency after joint surgery in rheumatoid arthritis patients treated with a perioperative 4-week interruption of tocilizumab. Mod Rheumatol 2011; 21 (1): 109–111.
de Steenwinkel F, Hokken-Koelega A, de Man Y et al. Circulating maternal cytokines influence fetal growth in pregnant women with rheumatoid arthritis. Ann Rheum Dis 2013;72 (12): 1995–2001.
- Mori S, Ueki Y, Hirakata N et al. Impact of tocilizumab therapy on antibody response to influenza vaccine in patients with rheumatoid arthritis. Ann Rheum Dis 2012; 71 (12): 2006–2010.
- Curtis J, Xie F, Chen L et al. The incidence of gastrointestinal perforations among rheumatoid arthritis patients. Arthritis Rheum 2011; 63 (2): 346–351.
Gout T, Ostör A, Nisar M. Lower gastrointestinal perforation in rheumatoid arthritis patients treated with conventional DMARDs or tocilizumab: a systematic literature review. Clin Rheumatol 2011; 30 (11): 1471–1474.