The aim of the study «Schoels MM, van der Heijde D, Breedveld FC, et al....»1 was to review published evidence on safety and efficacy of IL-6i in inflammatory diseases.
A systematic literature research of Medline and Cochrane, each from their inception to January 2012. Also the abstract archives of European League Against Rheumatism (EULAR) (2010–2012) and American College of Rheumatology (ACR) (2010 and 2011) conferences and accessed the National Institutes of Health database on clinical trialsfor preliminary results from on-going trials were searched.
Meta-analyses of comparable randomised controlled trial (RCT) data were performed by using Meta-Analyst software. The heterogeneity among the included trials (Cochrane's Q) were tested.
Data Extraction, Quality Assessment: We extracted efficacy data on clinical, functional and radiographic outcomes as well as safety data from all included studies. We evaluated all RCTs according to the Jadad scoring system and followed PRISMA reporting guidelines.
Concerning rheumatoid arthritis following results:
ACR20/50/70 responses at 24 weeks were 69/45/27 % using tocilizumab monotherapy in DMARD-naïve patients, compared with 54/33/14 % on methotrexate (MTX) monotherapy, and 56–80/30–64/4–44 % (ACR20/50/70) in DMARD-IR, when compared with placebo arms (usually continued or de novo MTX therapy, with ACR20/50/70 response rates of 17–34/21–26/2–20%). Finally, in TNFi-IR, tocilizumab achieved 50/27–29/10–12 % (ACR20/50/70) at 24 weeks versus 10/4/1 % in the MTX plus placebo arm.
Comment: This study was made possible by a grant from Roche.
In a systematic literature review «Navarro-Millán I, Singh JA, Curtis JR. Systematic ...»2, 10 clinical trials (7 phase III and 3 phase II studies) were evaluated. These were identified through a literature search of English-language publications in PubMed and the Cochrane Library covering the years 1989–2011 and addressing treatment with tocilizumab. The literature search included randomized controlled trials, controlled trials, and open-label studies with a duration of more than six months and approved outcomes of ACR20, ACR50, or ACR70 response. Adverse events were also assessed.
Patients receiving tocilizumab monotherapy at a dose of 8 mg/kg intravenously every four weeks showed better ACR20, ACR50, and ACR70 responses than patients receiving oral methotrexate. Prior treatment with methotrexate or a TNF inhibitor had been insufficient. Patients treated with tocilizumab 8 mg/kg showed less radiographic progression (Genant-modified Sharp score) at 52 weeks compared with the group receiving methotrexate combined with placebo (85% vs 67%).
In phase III studies, at least one elevation in liver enzyme levels was observed in 34–41% of patients receiving tocilizumab in combination with methotrexate or another conventional disease-modifying antirheumatic drug. Corresponding elevations of liver enzymes (>3× the upper limit of normal) occurred in 17% of patients in the comparator groups.
The rate of serious infections was 4.7 per 100 patient-years in the tocilizumab groups. Tocilizumab treatment was also associated with higher rates of thrombocytopenia, neutropenia, and hyperlipidaemia
In a Cochrane meta-analysis «Singh JA, Beg S, Lopez-Olivo MA. Tocilizumab for r...»3, eight randomized controlled trials were included after a comprehensive and reproducible search. A total of 3,334 patients were included, of whom 2,233 were in the intervention groups and 1,101 in the comparator groups. Eligible participants were adults (>18 years) with rheumatoid arthritis fulfilling the ACR 1987 criteria.
Treatment effects were observed for both ACR20 and ACR70 outcomes as follows:
For ACR50 response at 16–24 weeks, tocilizumab 8 mg/kg every four weeks in combination with methotrexate or another DMARD, compared with placebo combined with methotrexate or a DMARD, showed a relative risk (RR) of 3.17 (95% confidence interval [CI] 2.72–3.65), with a number needed to treat for benefit (NNTB) of 5. This analysis included four trials, one of which enrolled patients with an inadequate response to TNF inhibitors, while the others included patients with an inadequate response to methotrexate or other DMARDs.
In three studies (total n = 1,961), the risk of serious adverse events in the treatment group compared with the control group was RR 1.17 (95% CI 0.83–1.64); the certainty of evidence was moderate.
In addition, an increased risk of infections, gastrointestinal perforations, and elevated cholesterol levels was observed in the intervention group compared with the control group. The risk of infection was RR 1.18 (95% CI 1.04–1.34), the risk of gastrointestinal adverse events RR 1.42 (95% CI 1.18–1.71), and a 30% increase in the LDL/HDL ratio RR 1.66 (95% CI 1.24–2.23)
Based on a systematic literature review «Campbell L, Chen C, Bhagat SS, et al. Risk of adve...»4 (ad 2009), eight studies were selected to assess the risk associated with tocilizumab treatment of developing infections, serious infections, adverse events, or serious adverse events. The study populations consisted of adults (>18 years) with rheumatoid arthritis fulfilling the ACR 1987 criteria.
In the intervention groups, patients received tocilizumab either as monotherapy or in combination with methotrexate. The comparator groups received methotrexate. The follow-up period ranged from 20 to 24 weeks.
The risk of adverse events was increased with tocilizumab 8 mg/kg in combination with methotrexate (odds ratio [OR] 1.53; 95% confidence interval [CI] 1.26–1.86). Reported adverse events included neutropenia, elevated lipid levels, and elevated liver enzymes. In the combination therapy group receiving 4 mg/kg, the risk of serious adverse events was not significantly increased compared with the control group (OR 0.78; 95% CI 0.45–1.33), and no significant difference was observed between the 8 mg/kg and 4 mg/kg dose groups (OR 1.18; 95% CI 0.69–2.02).
In the monotherapy group receiving 8 mg/kg, the risk of serious adverse events was increased compared with the control group (OR 1.39; 95% CI 0.67–2.89).
The risk of serious infections was not significantly increased in the tocilizumab monotherapy group compared with the control group (OR 2.03; 95% CI 0.50–8.21). In patients receiving tocilizumab 8 mg/kg in combination with methotrexate, the risk of serious infections was OR 1.78 (95% CI 0.98–3.23) compared with the comparator group.
General comment: No cases of tuberculosis reactivation were observed in the studies; however, the follow-up period was too short to assess the overall risk. A systematic review and meta-analysis showed that tocilizumab was effective in the treatment of rheumatoid arthritis (OR 9.83, 95% confidence interval 5.85–16.52, compared with placebo) «Schoels MM, van der Heijde D, Breedveld FC, et al....»1. The results are considered applicable to the Finnish population
Parts of the text were translated from Finnish into English using artificial intelligence. The translation was reviewed by an expert.