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Reumatologia/Rheumatology
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3/2021
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Review paper

Safety and efficacy of tocilizumab for rheumatoid arthritis: a systematic review and metaanalysis of clinical trial studies

Amal Saki
1
,
Elham Rajaei
2
,
Fakher Rahim
3

1.
Department of Biostatistics and Epidemiology, School of Public Health, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
2.
Department of Rheumatology, Golestan Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
3.
Research Center of Thalassemia and Hemoglobinopathies, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
Reumatologia 2021; 59, 3: 169–179
Online publish date: 2021/07/11
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Introduction

Rheumatoid arthritis (RA) is an autoimmune and long-term systemic inflammatory disorder that can cause inflammation in the lining of a person’s joints. Rheumatoid arthritis is considered as an unidentified event or a mixture of conditions that causes synovial inflammation, which leads to stiffness, soft-tissue edema, and pain [1]. Some people with RA often experience wide-range damage to body systems, including the skin, eyes, lungs, heart, and arteries [1]. Rheumatoid arthritis is the leading cause of disability worldwide, affecting one in every 100 people, according to the World Health Organization (WHO), and about half of adults with the autoimmune disorder are said to be unable to do full-time work within 10 years of being diagnosed. In RA, the body’s immune system attacks the lining of the joint capsule – the hard membrane that covers the various parts of the joint; thus, the disease process can eventually destroy cartilage and bone at the joint site [1].
Scientists have not yet found the cause of immune system changes in RA, but factors such as genetic factors, environmental factors such as viral and bacterial infections (genetically predisposed people), hormonal factors, etc. are involved in their genesis. Multiple genetic and environmental factors that increase the risk of developing RA include family history, age, gender, previous joint injury, and obesity [2]. A group of researchers believes that sudden climate change has a significant effect on the severity of RA, but so far it has not been proven that climate change is effective in reducing the effects of this disease [3, 4]. Diagnosis of RA in the early stages of the disease is difficult for several reasons. First, there is no specific test to diagnose the disease; besides, the symptoms can also be similar to other than RA types of arthritis [5].
Therefore, physicians use a variety of diagnostic methods, such as medical history, physical examination, laboratory tests, and X-rays (to determine the degree of joint damage). Rheumatoid arthritis occurs in all ethnici­ties and age groups [6], and is about two to three times more common in women than in men [7]. In the treatment of RA, conventional anti-rheumatic drugs controlling the disease are preferred and should be started immediately after the diagnosis, within 3 months after the onset of persistent symptoms [8]. This family of drugs includes methotrexate, leflunomide, hydroxychloroquine, minocycline, and sulfasalazine. Nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids are effective in the general and functional recovery of the patient and are especially used in relapses and as a bridge between courses of anti-rheumatic drugs to control the disease.
At the early stages, starting treatment with rest and movement balance training and referral to supportive social centers is recommended, then starting medical treatment using salicylates or non-steroidal anti-inflammatory agents (NSAIDs) with anti-inflammatory and analgesic effects at full dose [9]. The use of COX-2 cyclooxygenase inhibitors, new drugs from NSAIDs, inhibiting the inflammatory process, and ultimately having less toxic effects, has been suggested [10]. Most patients with RA use painkillers and anti-inflammatory drugs, and some medications also reduce the destructive process of the disease [11]. The treatment for RA has changed over the last decades. The main goal of treatment of this disease has always been to maintain a person’s functional abilities. During the last decade, the American College of Rheumatology and the European League Against Rheumatism (EULAR) have attempted to introduce new and more comprehensive treatments for RA [12, 13]. Biological drugs for the treatment of RA target specific cells that play an important role in the immune system; however, with more careful efforts and disease management in these patients, a reduction in bone and cartilage destruction of the joints is often seen [14].
Tocilizumab (TCZ) is an immunosuppressive drug used mainly for RA and widespread idiopathic arthritis treatment [15]. Tocilizumab is an interleukin 6 (IL-6) inhibitor, which is a type of cytokine that plays a vital role in the human immune system, but its overproduction and activity cause autoimmune diseases, and in some diseases, including some cancers and coronary heart disease, it causes damage to body tissues [16]. So far, exists a single systematic review/meta-analysis on treatment with TCZ in RA [17]. Studies included in this meta-analysis were published before 2016 and the literature data­bases searched were limited. Besides, Teitsma et al. [17] just synthesized the findings on TCZ as monotherapy or combination therapy, and the studies published during nearly 5 years (2016–2020) and some studies in other databases such as Scopus and Web of Science (ISI) need to be included and reanalyzed, to observe whether the results have changed. To date, several studies have suggested that this drug is effective in treating RA, but no consistent consequences were reported among these studies [18, 19]; therefore, this systematic review and meta-analysis was conducted to assess the effect of TCZ in patients with RA.

Material and methods

This systematic review protocol and data extraction were conducted following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) [20], and the Cochrane Handbook of Systematic Reviews of Interventions [21].

Search strategy

All potential articles were initially identified through a systematic search in main databases, including PubMed, Scopus, EMBASE, ISI Web of Sciences and Cochrane Center using MeSH key words, including “tocilizumab”, “RHPM-1”, “RG-1569”, “R-1569”, “MSB11456”, “MSB-11456”, “monoclonal antibody, MRA”, “RO-4877533”, “actemra”, “roactemra”, “atlizumab”, “sarilumab”, “kevzara”, “siltuximab”, “sylvan”, and “rheumatoid arth­ritis” or “arthritis, rheumatoid” [MeSH]”. Further search for relevant studies was performed through the reference lists of the selected and review articles. Also, additional records were identified through searching medRxiv, bioRxiv, Research square, and Social Science Research Network (SSRN). The search was not restricted by language. The most recent or complete report was used when multiple reports were published describing the same sample. The search was subsequently updated in December 2020.

Study selection

Studies on patients 18 years of age and older with active RA comparing the clinical efficacy of TCZ and its comparators were selected. Inclusion criteria were patients with RA according to the American College of Rheumatology (ACR) 1987 modified criteria; intervention, use of TCZ; comparison, American College of Rheumatology 20%, 50%, and 70% improvement criteria ACR20, ACR50, ACR70, respectively, overall complication rate; and study design, randomized controlled trial (RCT). We excluded articles in different formats such as reviews, case reports, short communications, letters or opinions, as well as studies in which an animal model was used.

Data extraction

The initial review and extraction of information were performed independently by two authors (FR and ER) to collect the first author and publication year; sample size; mean age of the intervention and control groups; the dose of TCZ; and the follow-up duration. Outcomes of interest including the ACR20, ACR50, ACR70, total complication rate, and the occurrence of remission were recorded. Any disagreements between the reviewers were resolved by discussion and re-check of the article and consultation with a third reviewer (ASM).

Methodological quality and bias assessment

The risk of bias (ROB) for every single study was evaluated using the Cochrane Collaboration’s tool, which has 7 categories: random sequence generation-defining selection bias, allocation concealment defining selection bias, blinding of participants and personnel defining performance bias, blinding of outcome assessment defining detection bias, incomplete outcome data defining attribution bias, selective reporting defining reporting bias, and other bias [22]. The quality assessment findings were revealed as one of the three pre-specified categories: including low, unclear, and high. The publication bias was measured qualitatively using the funnel plot.

Statistical analysis

The number of clinical responses ACR20, ACR50, ACR70, and remission patients as well as DAS28 (good) and DAS28 (good or moderate) per treated and control groups of patients were used to calculate the odds ratio (OR). The odds ratio and its 95% confidence intervals (CI) were calculated to assess the improvement and clini­cal efficacy of TCZ versus comparators in the treatment of patients with RA. The heterogeneity and inconsistency were evaluated using Cochrane Q and I2 statistics, respectively [23]. The p-value < 0.01 was considered as indicating significant heterogeneity. Furthermore, I2 < 25% showed homo­geneity between studies, and I2 > 50% showed high heterogeneity [23]. According to the results of the heterogeneity test, either DerSimonian and Laird’s random-effects method or Mantel-Haenszel’s fixed-effects method was used to estimate the overall OR and 95% confidence intervals [24, 25]. Moreover, subgroup analysis was performed based on the dose (4 mg, 8 mg), type of TCZ group (TCZ, TCZ + MTX and TCZ + DMARD) and follow-up time (less than or equal to 24 weeks and more than 24 weeks) as an important variable which may cause heterogeneity between studies. Egger’s regression test was implemented to assess small study effects due to potential publication bias. Statistical analysis was performed using STATA 16 software (STATA Corporation, College Station, Texas).

Results

Characteristics of the studies

The initial search yielded 25,869 potentially relevant studies, of which following the exclusion of 17,117 duplicate articles, 8,752 studies were subsequently eva­luated. Then, 835 articles were recognized for full-text screening according to pre-defined eligibility criteria when eliminating the rest of the 7,917 studies by title/abstract. Finally, 821 articles were excluded after the full-text screening, and only 15 clinical trials comparing the clinical efficacy of TCZ and its comparators in the treatment of patients with RA entered qualitative and quantitative synthesis (Fig. 1). Overall, this systematic review and meta-analysis involved a total of 10,314 patients with RA, including 5,639 in the TCZ group and 3,986 in the comparator group. The characteristics of included studies are given in detail in the supplementary materials* (Table SI). Of the 15 studies, all except one [26] compared TCZ with placebo [26–40]. All selected studies except one trial [35] used TCZ at 4 and 8 mg/kg intravenously. Except for one study [30], they were all multicenter trials. Four studies were conducted in the USA [33, 35, 36, 39], two each in Germany [28, 29], and one each in the Nether­lands, Japan, France, Australia, South Africa, and the UK [27, 31, 32, 34, 37, 40]. A fixed dose of 8 mg/kg was the reported regimen of TCZ in nine trials [26, 27, 29–31, 33, 34, 39], fixed doses of 4 mg/kg and 8 mg/kg were given in the remaining six studies [28, 32, 36–38, 40], and a single trial used a subcutaneous regimen at a dose of 164 mg [35].

Quality of the evidence

An overview of the risk of bias per study is presented in Figure 2. In a single further study, information on random sequence generation, blinding of participants and staff, selective reporting, or allocation concealment could not be retrieved, leading to a judgment of unclear risk of bias [30]. In 14 studies, the allocation concealment was adequate and therefore led to a low risk of bias. We found a high risk of detection bias in 3 included studies [30, 31, 40]. However, by considering the dose as an important variable which may cause heterogeneity between studies, subgroup analysis was performed using doses of 4 mg and 8 mg. A total of 5 studies with 2214 patients (1117, 1097 assigned to TCZ 4 mg and comparator groups, respectively) and 14 studies in which patients were randomly assigned to TCZ 8 mg or another comparator were included in the meta-analysis. The results of Cochrane Q and I2 statistics showed that 5 and 14 studies of 4 and 8 mg of TCZ were heterogeneous, so OR as the main effect size was estimated by using the random effects model (Table II). The results of Cochrane Q and I2 statistics of clinical efficacy endpoints showed that our studies were hete­rogeneous with I2 = 78–96 and p < 0.01, so a weighted estimation of OR was obtained using a random effect model.
The summary estimation of primary and secondary endpoints showed that the significantly high proportion of patients treated by TCZ achieved ACR20/50/70, remission, and DAS28 remission. American College of Rheumatology 20 with OR = 2.33 (95% CI: [1.49; 3.66]) indicated that patients treated with TCZ who achieved ACR20 had an OR of 2.33 compared with the control group. Also, the OR of remission (OR = 4.94; 95% CI: [3.07; 7.95]) showed the significant clinical effect of TCZ versus other comparators. A total of 8 studies that reported the DAS28 (good) also indicated the significantly higher proportion of DAS28 remission in patients treated with TCZ (OR = 8.20; 95% CI: [4.99; 13.48]) (Table I). In all defined sub-groups patients treated with TCZ showed a higher proportion of improvement than comparator groups. However, assessing the pooled estimation of OR of ACR20/50/70 remission and DAS28 revealed that there was no significant clinical efficacy between the two groups of 4 mg and 8 mg dose of TCZ. So, the type of TCZ as TCZ monotherapy or combination therapy (TCZ + MTX and TCZ + DMARD) was considered with a dose of TCZ as sub-group variables and five sub-groups were defined (Fig. S1). There was a significant difference between the five subgroup in ACR20 (p = 0.02). The patient who received TCZ monotherapy at 8 mg showed a higher proportion in ACR20 than other subgroups (OR = 4.60; 95% CI: [2.35; 9.0]) (Fig. S1A).
Also, there was a significant difference in ACR50 between the five sub-groups (p = 0.02). The patients who were treated with TCZ monotherapy with 4 mg (TCZ 4 mg) showed a higher proportion of ACR50 than other sub-groups (OR = 4.78; 95% CI: [2.69; 8.51]) (Fig. S1B). Also, TCZ 4 mg had higher efficacy in RA patients to achieve ACR70 compared to other subgroups of treatment (OR = 8.0; 95% CI: [3.23; 19.80]) and there was a significant difference in the proportion of RA patients who achieved ACR70 between defined sub-groups (p = 0.01) (Fig. S1C). Assessing the remission as clinical efficacy between the defined subgroups revealed that combination thera­py of TCZ (8 mg) + DMARD had the highest proportion of remission in RA patients (OR = 23.25; 95% CI: [4.32; 125.03]). However, there was no significant difference in the proportion of remission and DAS28 remission in RA patients between the 5 subgroups (Fig. S1D–S1F). Since the follow-up time may cause the heterogeneity between the results of studies, so it was adjusted in subgroup analysis with dose and type of TCZ. It also could lead to finding the best subgroup of TCZ intervention within which patients achieved the highest improvement and clinical efficacy. Based on this definition of subgroup analysis, all studies were categorized into 7 sub-groups. There was a significant difference between the seven sub-groups in ACR20/50/70 (p < 0.001) (Table III). Patients who were treated with TCZ 8 mg and followed until 24 weeks showed the highest proportion in ACR20 compared to other sub-groups (OR = 4.60; 95% CI: [2.35; 9.0]) (Table III).
However, investigation of ACR50/70 (OR = 4.78; 95% CI: [2.69, 8.51], OR = 8.0; 95% CI: [3.23; 19.80], respectively) showed that patients with RA who were treated with TCZ 4 mg and followed until 24 weeks revealed the highest improvement proportion (Table III). These results were exactly equal to the result of sub-group analysis based on the type and dose of TCZ. Furthermore, there was a significant difference of remission between the seven sub-groups (p < 0.001), it was also found that TCZ (8 mg) + DMARD had the highest proportion of remission in patients with RA (OR = 23.25; 95% CI [4.32; 125.03]) (Fig. S2).

Adverse events

All studies reported 86 different side effects. How­ever, 14 of them were held in common between the studies and included in the meta-analysis. The result showed no significant difference in many adverse events between TCZ and the comparator groups. However, side effects such as skin and subcutaneous tissue disorders (OR = 1.96; 95% CI: [1.47; 2.62]) and eye abnormalities (OR = 2.37; 95% CI: [1.28; 4.41]) were significantly more frequent in the TCZ group in both 4 mg and 8 mg doses than comparator groups. Also, nervous system disorders for the 8 mg dose (OR = 1.43; 95% CI: [1.11; 1.84]) and clinical and laboratory abnormalities for 4 mg (OR = 2.40; 95% CI: [1.39; 4.14]), as other adverse events, were significantly higher in the TCZ group than comparators in doses of 8 mg and 4 mg, respectively. Nevertheless, there was no difference in all of the adverse events between 4 mg and 8 mg doses (Table IV).

Discussion

As far as the evidence may suggest, this is the first meta-analysis to show the safety and efficacy of TCZ in the clinical outcome of patients with RA. The previous limited evidence on analysis of clinical studies on TCZ could suggest benefit for the clinical outcomes of patients with moderate to severe RA not responding to at least one anti-TNF therapy [41, 42]. Although adverse events in patients with RA treated with TCZ, such as abnormal liver function tests (LFTs) and infections, were more frequent than in the comparator groups [42], this therapy was associated with significantly fewer adverse event-related withdrawals [41]. Overall, treatment with TCZ led to statistically significant lower disease activity, as well as significant disease remission, especially in monotherapy form. This finding was consistent with several well-conducted clinical studies [43–46].
The present meta-analysis showed that, although the dose of TCZ did not make a significant difference in the proportion of patient’s clinical remission [47], adding other drugs such as methotrexate had a statistically significant impact on disease remission. This finding was in agreement with other clinical evidence showing that adding methotrexate to TCZ was better than TCZ alone [42]. This meta-analysis showed that patients who received TCZ monotherapy (8 mg) had significantly higher clinical remission, a finding which was consistent with previous clinical reports [17, 48]. Moreover, a significantly higher proportion of patients achieved clinical remission at 24-week follow-up. Other prospective studies also reported that patients with RA showed a better clinical response at 24-week follow-up [49–51]. Though former meta-analyses and large prospective cohorts have pointed out serious infection among the most prevalent adverse events associated with TCZ therapy [34, 52–54], our meta-analysis also showed that this adverse event was lower in patients receiving TCZ than in the control group, but the difference did not reach statistical significance.
Interestingly, our meta-analysis revealed that clinical and laboratory abnormalities, skin and subcutaneous tissue disorders, and eye abnormalities were significantly more frequent in patients receiving TCZ than in the control group. In a single meta-analysis, Teitsma et al. [17] analyzed the efficacy and safety of TCZ as monotherapy or combination therapy reported in randomized controlled trials. They only searched three major databases, i.e. MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials (CENTRAL), as well as the dose of 8 mg/kg.
Although combination therapy was reported to be marginally superior considering treatment response, increased cost and associated adverse events make TCZ as monotherapy a suitable choice for patients who cannot tolerate conventional DMARDs. Our pooled analysis was conducted based on a comprehensive search in five major databases – PubMed, Scopus, EMBASE, Web of Sciences (ISI), and Cochrane Library – and 3 recent randomized controlled trials using a total of 2695 subjects (1505 in the intervention group and 1190 in the comparison group) found in the period 2016–2020. In this context, both previous and our meta-analysis showed a higher significant treatment response. We also compared the treatment response and adverse events considering both different doses and drugs used in combination with TCZ.

Clinical comments

Based on the evidence provided above plus our findings, we recommend the use of this drug, especially the administration of higher doses in patients with mode­rate to severe RA as quickly as possible, which may play a more effective role in the treatment and recovery of patients; principally as the European registration autho­rities recommended administration of 8 mg TCZ straight away without using the dose of 4 mg initially [55]. Also, due to serious complications and clinical and laboratory abnormalities, careful monitoring for laboratory abnormalities is recommended. We also believe that longer follow-up times, particularly after 24 weeks of therapy, are recommendable. This meta-analysis demonstrated that TCZ can be added to patients using other drugs such as methotrexate and DMARDs; while not surprising, it is worth knowing that TCZ can be used with mentioned drugs as background therapy.

Limitation of the study

The present meta-analysis has some limitations that should be addressed. Diverse treatment regimens, various TCZ dosage and frequency, as well as different comparators, were applied in the selected studies.

Conclusions

This systematic review and meta-analysis suggest that the combination therapy of TCZ with other drugs such as methotrexate and DMARDs has been studied for various clinical effects with slighthly was superior to monotherapy, therefore presented meta-analysis has been studied. Although the data are promising, long-term performance and safety data need to be fully identified, as well as the risks and benefits of TCZ, especially appro­priate timing, dosage and regimen. The authors declare no conflict of interest.

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Copyright: © 2021 Narodowy Instytut Geriatrii, Reumatologii i Rehabilitacji w Warszawie. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License (http://creativecommons.org/licenses/by-nc-sa/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.






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