A systematic review and meta-analysis to determine the efficacy and safety of tacrolimus in patients with rheumatoid arthritis

Tacrolimus found to be effective and safe for the treatment of rheumatoid arthritis (RA)

The latest therapeutic advancements and the understanding of the pathogenesis of RA over the last few decades have transformed the management of RA. Methotrexate and biological disease-modifying antirheumatic drugs (DMARDs) now play an integral role in RA treatment, but other conventional synthetic DMARDs are also considered for the treatment of RA patients who are contraindicated to methotrexate or without poor prognostic factors. Guidelines on RA management have also focused on achieving remission as the primary aim of treatment to minimize the structural and functional burden of disease. This goal is achieved by utilizing a range of therapies with a different mode of action such as immunomodulators. 

Tacrolimus is one such immunomodulator that acts by inhibiting calcineurin phosphatase. Inhibition of calcineurin prevents the activation of the nuclear factor of activated T cells, a transcription factor required for interleukin 2 and γ interferon production. It has been approved for preventing allograft rejection after organ transplantation worldwide but in few countries it has been approved for the treatment of RA.

Rationale behind research

Several clinical studies have reported the safety and efficacy of tacrolimus in RA management but only meta-analysis and systematic review have been published for tacrolimus, supporting its use in RA. Therefore, this study was conducted to describe the process of the literature search, evaluation of evidence quality, and the results of meta-analysis related to the efficacy and safety of tacrolimus.

Objective

The present systematic review and meta-analysis was conducted to determine the efficacy and safety of tacrolimus for the management of RA. 

Literature search

Electronic databases including PubMed, Japana Centra Revuo Medicina Web (Ichu-shi web), and the Cochrane Database of Systematic Reviews were searched from January 1998 to August 2012 for English or Japanese articles. The keywords or terms used for the search were:

#1 arthritis rheumatoid [MeSH Major Topic]

#2 tacrolimus [MeSH Major Topic]

#3 #1 AND #2

#4 #1 AND #2 Filters: Humans

Inclusion criteria

Studies were included in this meta-analysis if:

• they were randomized controlled trials
• they included adult patients with RA according to the 1987 or 2010 classification criteria
• they included the use of tacrolimus in the intervention group
• they included both safety and efficacy outcomes and the comparison with other DMARDs or placebo

Exclusion criteria

• Single-arm studies, case reports, and comments or letters to the editor were excluded

Study selection and Data extraction

Two review authors (YukK and YutK) were enrolled to assess the eligibility of titles and abstracts. Articles meeting the inclusion criteria were retrieved, and all full-text articles were screened for the inclusion and exclusion criteria. Data related to participant demographics (age, sex, diagnosis, duration of disease), medications for RA, sample size, assignment to groups, follow-up period, CRP, ACR20, ACR50, ACR70, modified total Sharp score (mTSS), modified Health Assessment Questionnaire Disability Index (mHAQ-DI), gastrointestinal disorders, renal function, infections,  metabolic and nutritional disorders were retrieved for every RCT.

Risk of Bias and Quality assessment

The review process was done according to the GRADE system. Cochrane Handbook for Systematic Reviews of Interventions (version 5.1.0) was used to determine the risk of bias in each study. The presence of random sequence generation and allocation concealment (selection bias), selective outcome reporting (reporting bias), blinding of participants and personnel (performance bias and detection bias), blinding of outcome assessment, incomplete outcome data (attrition bias), and other sources of bias were examined. The quality of evidence for each outcome was graded with the assessment of bias risk.  I2 statistics were used to determine inconsistency. Funnel plots were used to assess indirectness, imprecision, and publication bias.

Data and Statistical analysis

The relative risk or mean difference with 95% confidence interval (CI) were estimated depending on the outcomes, after collecting frequency and values. Review Manager 5.3. the software was used to conduct all statistical analysis. The evidence profiles and "Summary of findings" tables were formed using GRADEPro GDT software.

Study outcomes

• The primary outcomes were the American College of Rheumatology 20 (ACR20) and serum creatinine elevation
• Other study outcomes included ACR50, ACR70, changes in C-reactive protein (CRP), modified Health Assessment Questionnaire Disability Index, gastrointestinal disorders, metabolic and nutritional disorders, and infections and infestations

Outcomes

Study characteristics: 

• A total of five randomized controlled studies, four of which compared tacrolimus to placebo were included in the meta-analysis

Study quality:

• The certainty of the evidence was moderate for ACR20, ACR50, ACR70, changes in CRP and mHAQ-DI, creatinine elevation risk, and gastrointestinal disorders; moderate for metabolic and nutritional disorders; and low for infections and infestations

Effect of intervention on the outcome:

• ACR20, ACR 50 and ACR 70 achievement was significantly better with tacrolimus administered at a dose of 1–2 mg/day, 3 mg/day
• Changes in CRP levels show a favorable effect in patients treated with tacrolimus administered at a dose of 1–2 mg/day, 3 mg/day
• The occurrence of serum creatinine elevation ≥40% or ≥0.3 mg/dL was significantly higher in tacrolimus at both doses (1–2 mg/day and 3 mg/day) compared to placebo
• The incidence rates of gastrointestinal disorders, metabolic and nutritional disorders, infections and infestations were higher in patients treated with tacrolimus at both doses compared to placebo
  

Tacrolimus has been approved for the management of RA in Japan. Its effectiveness and safety profile makes it an ideal option for RA treatment, especially in those patients who are contraindicated to methotrexate or had a poor prognosis in combination with other DMARDs. The findings of this systematic review and meta-analysis reported the efficacy and safety of tacrolimus in patients with RA.

Both doses of tacrolimus (1–2 mg/day and 3 mg/day) revealed similar efficacy but 3 mg/day shows slightly superior efficacy and lower doses showing better safety and lower incidence of adverse events.

Also, 3 mg/day or lower doses of tacrolimus had a double chance of achieving ACR20 as compared to placebo. It is also effective in improving other objective and patient-reported outcomes such as CRP levels and mHAQ-DI scores. However, this study did not provide enough evidence for the effectiveness of tacrolimus in preventing joint destruction as compared to placebo.

The efficacy and safety of doses of tacrolimus (1–2 mg/day and 3 mg/day) were also consistent with the efficacy and safety of 5mg/day tacrolimus. This can be caused due to relationship between the concentration of blood and drug effects. Renal transplant studies have indicated a close association between tacrolimus blood concentrations and adverse events, showing that a ≥10 ng/mL dose of tacrolimus can lead to a higher risk of adverse events. A median or mean concentrations of tacrolimus of 2–3 ng/mL is effective in at least a part of RA patients.

But, the studies included in this meta-analysis lacks in reporting the association between the concentration of blood in drug and their effects. A comparative trial of tacrolimus versus mizoribine, conducted by Kawai et al. found a concentration of >10 ng/mL in 1/10^th of patients treated with 3 mg/day tacrolimus, but the association between drug concentration and efficacy are still not clear.

Safety data of tacrolimus estimated from PMS studies reported that the most frequent adverse events were infections and infestations (including upper tract infection) and gastrointestinal symptoms irrespective of the use of biologic agents. These were the well known adverse events to tacrolimus and no new adverse events were identified in PMS reports. Serious adverse effects were reported in about 2.0%, including serious infection in approximately 1.0%. Therefore, caution is required while using tacrolimus in clinical practice.