Clin Rheumatol (2014) 33:165–173 DOI 10.1007/s10067-013-2452-7
REVIEW ARTICLE
Tofacitinib for acute rheumatoid arthritis patients who have had an inadequate response to disease-modifying antirheumatic drug (DMARD): a systematic review and meta-analysis Xingming Zhang & Fuxiang Liang & Xiaoxue Yin & Xiaojuan Xiao & Peiyu Shi & Dang Wei & Liang Yao & Qi Wang & Yaolong Chen
Received: 22 November 2013 / Accepted: 24 November 2013 / Published online: 4 January 2014 # Clinical Rheumatology 2014
Abstract The aim of this systematic review and metaanalysis is to assess the efficacy and safety of tofacitinib for the treatment of patients with acute rheumatoid arthritis (RA) who have had an inadequate response to disease-modifying antirheumatic drug (DMARD). Randomized controlled trials were searched in MEDLINE (1966–2013), Embase (1947– 2013), the Cochrane Central Register of Controlled Trials (1948–2013), WHO International Clinical Trial Registration Platform (2004–2013), Clinical Trial.gov (1999–2013), and China Biology Medicine disc (1978–2013). The review included 10 studies involving 4,929 patients. A pooled analysis of six studies showed that tofacitinib had a superior effect over placebo (both with background therapy) at weeks 12 and 24. Also, the pooled results of three studies showed that tofacitinib monotherapy had a significantly greater effect over placebo. Compared to adalimumab, tofacitinib was found to be more efficacious as well. For safety, tofacitinib monotherapy had less serious adverse events (sAE) than placebo but not other adverse effects (oAE). In the comparison of tofacitinib and placebo both with background therapy, no difference in Electronic supplementary material The online version of this article (doi:10.1007/s10067-013-2452-7) contains supplementary material, which is available to authorized users. X. Zhang : F. Liang : D. Wei : L. Yao : Q. Wang : Y. Chen (*) Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, China e-mail: [email protected] X. Yin : P. Shi The Second Clinical Medical School, Lanzhou University, Lanzhou, Gansu 730000, China X. Xiao Department of Radiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
sAE and oAE were found. However, the quality of the evidence was quite low when evaluated using GRADE. Tofacitinib alone, or together with non-biologic DMARDs, was associated with more favorable remission in the signs and symptoms of RA than adalimumab or placebo. Also, tofacitinib monotherapy was safer than placebo with regards to reported sAE, but not oAE. However, the quality of evidence is exceedingly low; long-term, large-scale, and highquality post-marketing research is suggested to further verify the conclusion. Keywords Rheumatoid treatment outcome meta-analysis . Tofacitinib arthritis
Introduction Rheumatoid arthritis (RA) is an acute and chronic autoimmune inflammatory disease characterized as a destructive damage process in joint tissues, which is associated with disability and premature mortality. The treatment of RA mainly focuses upon patients' remission of symptoms. The use of disease-modifying antirheumatic drugs (DMARDs), such as methotrexate (MTX) and leflunomide, has been the optimal treatment of RA since the past decade. DMARDs work mainly by reducing disease activity, slowing the progression of disease and improving patients' quality of life. However, a proportion of patients cannot tolerate these agents in longterm therapy or only have inadequate response to the traditional DMARDs. Targeting this group of patients, the US Food and Drug Administration approved tofacitinib in December 2012. Since then, tofacitinib, namely Xeljanz or CP690550, a pill taken twice a day that acts on blocking Janus
166
kinases, which are important molecules in the joint inflammation in patients with RA [1], has been prescribed to treat active acute RA with an inadequate response or intolerability to methotrexate. Tofacitinib may be used as monotherapy or in combination with MTX or other non-biologic DMARDs, and is available as a 5-mg tablet to be administered orally, twice daily. Higher doses have not been approved. There are no studies investigating the use of tofacitinib with biologic DMARDs and it is not recommended [2]. As a novel medication, tofacitinib has been investigated for its efficacy and safety in some clinical trials; however, those trials are all pre-market studies and there is no systematic review or meta-analysis which assessed the evidence for tofacitinib in the treatment of RA. The aim of this systematic review and meta-analysis is to assess the efficacy and safety of tofacitinib, compared to placebo or other medications, for the treatment of patients with acute rheumatoid arthritis who have had an inadequate response to at least one DMARD.
Methods Protocol and registration We developed a protocol defining the search strategy and a systematic review was performed to identify those randomized controlled trials (RCTs) investigating the efficacy and safety of tofacitinib approved to treat RA with inadequate response to at least one DMARD. The review was registered on PROSPERO of the Centre for Reviews and Dissemination (CRD42013003696). The data searching, study selection, quality assessment of included studies, and data extraction were performed independently by two researchers (Z. X. M. and L. F. X.). Disagreements were resolved by discussion or with the help of a third investigator. Eligibility and exclusion criteria We assessed the studies for inclusion according to the following eligibility criteria: (1) patients had a diagnosis of RA based on the American College of Rheumatology (ACR) 1987 revised criteria and had active disease. In addition, patients had an inadequate response to at least one DMARD, and without restriction of age or gender of the patients; (2) RCTs comparing tofacitinib of any dose, either alone or in combination with any kind of medication, with placebo, or other medication, for the treatment of patients with acute rheumatoid arthritis. The following items were considered as exclusion criteria: (1) evidence of hematopoietic disorders: hemoglobin
REVIEW ARTICLE
Tofacitinib for acute rheumatoid arthritis patients who have had an inadequate response to disease-modifying antirheumatic drug (DMARD): a systematic review and meta-analysis Xingming Zhang & Fuxiang Liang & Xiaoxue Yin & Xiaojuan Xiao & Peiyu Shi & Dang Wei & Liang Yao & Qi Wang & Yaolong Chen
Received: 22 November 2013 / Accepted: 24 November 2013 / Published online: 4 January 2014 # Clinical Rheumatology 2014
Abstract The aim of this systematic review and metaanalysis is to assess the efficacy and safety of tofacitinib for the treatment of patients with acute rheumatoid arthritis (RA) who have had an inadequate response to disease-modifying antirheumatic drug (DMARD). Randomized controlled trials were searched in MEDLINE (1966–2013), Embase (1947– 2013), the Cochrane Central Register of Controlled Trials (1948–2013), WHO International Clinical Trial Registration Platform (2004–2013), Clinical Trial.gov (1999–2013), and China Biology Medicine disc (1978–2013). The review included 10 studies involving 4,929 patients. A pooled analysis of six studies showed that tofacitinib had a superior effect over placebo (both with background therapy) at weeks 12 and 24. Also, the pooled results of three studies showed that tofacitinib monotherapy had a significantly greater effect over placebo. Compared to adalimumab, tofacitinib was found to be more efficacious as well. For safety, tofacitinib monotherapy had less serious adverse events (sAE) than placebo but not other adverse effects (oAE). In the comparison of tofacitinib and placebo both with background therapy, no difference in Electronic supplementary material The online version of this article (doi:10.1007/s10067-013-2452-7) contains supplementary material, which is available to authorized users. X. Zhang : F. Liang : D. Wei : L. Yao : Q. Wang : Y. Chen (*) Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, China e-mail: [email protected] X. Yin : P. Shi The Second Clinical Medical School, Lanzhou University, Lanzhou, Gansu 730000, China X. Xiao Department of Radiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
sAE and oAE were found. However, the quality of the evidence was quite low when evaluated using GRADE. Tofacitinib alone, or together with non-biologic DMARDs, was associated with more favorable remission in the signs and symptoms of RA than adalimumab or placebo. Also, tofacitinib monotherapy was safer than placebo with regards to reported sAE, but not oAE. However, the quality of evidence is exceedingly low; long-term, large-scale, and highquality post-marketing research is suggested to further verify the conclusion. Keywords Rheumatoid treatment outcome meta-analysis . Tofacitinib arthritis
Introduction Rheumatoid arthritis (RA) is an acute and chronic autoimmune inflammatory disease characterized as a destructive damage process in joint tissues, which is associated with disability and premature mortality. The treatment of RA mainly focuses upon patients' remission of symptoms. The use of disease-modifying antirheumatic drugs (DMARDs), such as methotrexate (MTX) and leflunomide, has been the optimal treatment of RA since the past decade. DMARDs work mainly by reducing disease activity, slowing the progression of disease and improving patients' quality of life. However, a proportion of patients cannot tolerate these agents in longterm therapy or only have inadequate response to the traditional DMARDs. Targeting this group of patients, the US Food and Drug Administration approved tofacitinib in December 2012. Since then, tofacitinib, namely Xeljanz or CP690550, a pill taken twice a day that acts on blocking Janus
166
kinases, which are important molecules in the joint inflammation in patients with RA [1], has been prescribed to treat active acute RA with an inadequate response or intolerability to methotrexate. Tofacitinib may be used as monotherapy or in combination with MTX or other non-biologic DMARDs, and is available as a 5-mg tablet to be administered orally, twice daily. Higher doses have not been approved. There are no studies investigating the use of tofacitinib with biologic DMARDs and it is not recommended [2]. As a novel medication, tofacitinib has been investigated for its efficacy and safety in some clinical trials; however, those trials are all pre-market studies and there is no systematic review or meta-analysis which assessed the evidence for tofacitinib in the treatment of RA. The aim of this systematic review and meta-analysis is to assess the efficacy and safety of tofacitinib, compared to placebo or other medications, for the treatment of patients with acute rheumatoid arthritis who have had an inadequate response to at least one DMARD.
Methods Protocol and registration We developed a protocol defining the search strategy and a systematic review was performed to identify those randomized controlled trials (RCTs) investigating the efficacy and safety of tofacitinib approved to treat RA with inadequate response to at least one DMARD. The review was registered on PROSPERO of the Centre for Reviews and Dissemination (CRD42013003696). The data searching, study selection, quality assessment of included studies, and data extraction were performed independently by two researchers (Z. X. M. and L. F. X.). Disagreements were resolved by discussion or with the help of a third investigator. Eligibility and exclusion criteria We assessed the studies for inclusion according to the following eligibility criteria: (1) patients had a diagnosis of RA based on the American College of Rheumatology (ACR) 1987 revised criteria and had active disease. In addition, patients had an inadequate response to at least one DMARD, and without restriction of age or gender of the patients; (2) RCTs comparing tofacitinib of any dose, either alone or in combination with any kind of medication, with placebo, or other medication, for the treatment of patients with acute rheumatoid arthritis. The following items were considered as exclusion criteria: (1) evidence of hematopoietic disorders: hemoglobin
