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Biological therapy (anti-TNF or anti-IL-17) is currently recommended in AS patients with inadequate or no responses to NSAIDs.
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Loss of response to existing bDMARDs remains to be solved.
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Increasing data showed that JAKi provides benefits for active AS.
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Up-to-date meta-analysis provides high-grade evidence supporting JAKi as a new and safe therapeutic strategy for active AS.
Abstract
Objectives
To assess the efficacy and safety of janus kinase (JAK) inhibitors in the treatment of ankylosing spondylitis (AS).
Methods
We searched the PubMed and Cochrane Central Register of Controlled Trials to Nov 1, 2021. We included all randomized controlled trials (RCTs) evaluating JAK inhibitors in the treatment of AS. Two reviewers independently selected studies, extracted data and assessed the risk of bias.
Results
Four RCT studies with 779 participants were included in the meta-analysis. Compared with placebo group, percentages of participants achieving responses of Assessment of spondyloarthritis international society(ASAS) 20, ASAS 40, ASAS 5/6, Bath AS disease activity index (BASDAI) 50 were significantly higher in JAK inhibitor group respectively; changes from baseline in AS disease activity score using C-reactive protein(ASDAS-CRP), Maastricht AS enthesitis score (MASES), AS Quality of Life (ASQoL) score, short-form-36 health survey physical component summary (SF-36 PCS) score, BASDAI, Bath AS functional index (BASFI), Bath AS metrology index (BASMI), Functional Assessment of Chronic Illness Therapy-fatigue (FACIT-F) score, SPARCC joint score and Work Productivity and Activity Impairment (WPAI) Overall Work Impairment score showed significant improvements in JAK inhibitor group. The incidence of adverse events (AEs) and severe adverse events (SAEs) showed no significant differences between the JAK inhibitor and placebo groups.
Conclusions
JAK inhibitors showed a satisfactory and promising efficacy in the treatment of active AS not only in mitigating disease activity, but also substantially improving patient's physical function, emotional well-being and social participation. The results of this meta-analysis provide solid evidence for JAK inhibitor as a novel therapeutic strategy for patients with active AS.
]. It was characterized by enthesitis involving the spine, inflammation of sacroiliac joints, and inflammatory low back pain, leading to functional impairment, irreversible structural damage and loss of quality of life and work productivity [
]. Therapy options for AS are limited because conventional synthetic disease modifying antirheumatic drugs(cDMARDs) routinely used for RA are not effective in alleviating axial symptoms of AS [
]. According to the Assessment of SpondyloArthritis international Society (ASAS) and European League Against Rheumatism (EULAR) recommendations, non-steroidal antiinflammatory drugs (NSAIDs) are recommended as first-line therapy for AS [
]. Anti-tumor necrosis factor (TNF) agents and anti-interleukin (IL)-17 are the only two kinds of bDMARD approved for AS in the recent years. Nevertheless, loss of response to existing bDMARDs remains unsolved for some refractory AS patients [
]. Therefore, additional targeted drugs are needed. Over the past decades, Janus kinases(JAK) inhibitors have been widely used in the treatment of autoinflammatory and immune-mediated diseases, including rheumatoid arthritis(RA), psoriatic arthritis(PsA), psoriasis(Pso) and inflammatory bowel diseases (IBD) [
Safety of janus kinase inhibitors in patients with inflammatory bowel diseases or other immune-mediated diseases: a systematic review and meta-analysis.
]. With the development and expanding indications of JAK inhibitors, increasing studies have demonstrated that they also provide benefits for patients with AS [
]. Thus, we performed a systematic review and meta-analysis of updated RCTs to evaluate the efficacy and safety of JAK inhibitors in the treatment of AS.
2. Materials and methods
This meta-analysis was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement for conducting and reporting a meta-analysis of RCTs.
2.1 Search strategy
We searched the PubMed and Cochrane Central Register of Controlled Trials to Nov 1, 2021. Search algorithms consisted of the following terms: ‘JAK inhibitor’, ‘Janus Kinase Inhibitor’, ‘Ankylosing spondylitis’, ‘Ankylosing Spondylarthritides’, ‘Ankylosing Spondylarthritis’. We also searched for potentially relevant publications in the reference lists.
2.2 Inclusion criteria
Only randomized placebo-controlled trials involving adult patients with AS were included. At least one experimental group was treated with any of the JAK inhibitors potentially under development for AS. Among a series of articles reporting the same RCT, only the most comprehensive and updated was included. Only studies published in english are considered.
2.3 Study selection and data extraction
The studies were screened and data were extracted by two authors (Shu Li and Ni Mao) independently, and disagreements were settled by the third author (Xi Xie). Clearly irrelevant studies were identified and excluded by reviewing titles or abstracts. The full text of the selected articles was analysed to identify whether it contained information of interest. And we also checked the results posted on ClinicalTrials.gov or EU Clinical Trials Register through the NCT number of each RCT to refine data collection. The following essential information was collected from the included trials: last name of first author, publication year, study design, number of patients, patient characteristics, intervention, and the outcomes of therapeutical effects. Adverse events(AEs) and severe adverse events(SAEs) were further documented. If the data reported formats cannot be used directly, they will be converted into the appropriate format applicable for meta-analysis according to the Cochrane Handbook recommendations.
2.4 Quality assessment
The methodological quality of the included studies were assessed by two authors independently according to the items of the Cochrane quality assessment tool: random sequence generation, allocation concealment, blinding of the participants and personnel, blinding of the outcome assessment, incomplete outcome data, selection reporting, and other bias.
2.5 Statistical analysis
Statistical analyses were performed using Review Manager software(RevMan 5.3, the Cochrane Collaboration, Copenhagen, Denmark). Dichotomous data were described as risk ratios (RRs) with corresponding 95% confidence intervals(CIs), and continuous data were expressed as mean differences (MDs) with 95% CIs. The heterogeneity among studies was evaluated by the I2 test; I2>50% indicates significant heterogeneity. Random-effects model was used to cover any heterogeneity among studies, allowing for a more conservative estimate of the effect of individual intervention. Statistical significance was defined as P <0:05. Sensitivity analysis was performed by removing one single study at a time to assess the impact of the removed study.
3. Results
3.1 Study selection
The diagram of study selection flow were demonstrated in Fig. 1. 150 articles were initially identified at the beginning, 51 of which were removed due to duplication. And then, 75 studies were ruled out after going through the titles and abstracts. A total of 24 articles were assessed through reading the full texts for further eligibility; and 20 articles were excluded with the following reasons: not meeting the inclusion criteria, duplicate data reporting, or not RCT study. At last 4 RCTs were included in the meta-analysis [
Efficacy and safety of upadacitinib in patients with active ankylosing spondylitis (SELECT-AXIS 1): a multicentre, randomised, double-blind, placebo-controlled, phase 2/3 trial.
Efficacy and safety of filgotinib, a selective Janus kinase 1 inhibitor, in patients with active ankylosing spondylitis (TORTUGA): results from a randomised, placebo-controlled, phase 2 trial.
Characteristics of the included RCT studies were shown in Table 1. The inclusion criteria included an established diagnosis of adult AS based on the 1984 Modified New York Criteria and active disease despite NSAIDs therapy or intolerant to NSAIDs. Stable dose of cDMARD therapy for at least 4 weeks prior to baseline was allowed. The outcome measures included percentage of participants achieving responses of ASAS 20, ASAS 40, ASAS 5/6, Bath AS disease activity index (BASDAI) 50, ASAS Partial Remission, ASDAS Clinically Important Improvement, ASDAS Major Improvement, ASDAS inactive disease, and changes from baseline in AS disease activity score using C-reactive protein (ASDAS-CRP), Bath AS functional index (BASFI), Bath AS metrology index (BASMI), Maastricht AS enthesitis score (MASES), AS Quality of Life (ASQoL) Score, Short-Form-36 health survey (SF-36) including physical and mental component summary (SF-36 PCS and MCS) scores, Functional Assessment of Chronic Illness Therapy-fatigue (FACIT-F) score and Work Productivity and Activity Impairment (WPAI) Overall Work Impairment score.
Table 1Characteristic of studies included in the meta-analysis.
Efficacy and safety of upadacitinib in patients with active ankylosing spondylitis (SELECT-AXIS 1): a multicentre, randomised, double-blind, placebo-controlled, phase 2/3 trial.
Efficacy and safety of filgotinib, a selective Janus kinase 1 inhibitor, in patients with active ankylosing spondylitis (TORTUGA): results from a randomised, placebo-controlled, phase 2 trial.
* Calculated from the extracted data given according to the Cochrane Handbook recommendations.
ASAS 20: defined as an improvement of ≥ 20% and an absolute improvement of ≥ 1 unit from Baseline in at least 3 of the 4 domains(PGA, total back pain, BASFI, BASDAI), with no deterioration (defined as a worsening of ≥ 20% and a net worsening of ≥ 1 units) in the remaining domain; ASAS 40: defined as improvement of ≥ 40% relative to Baseline and absolute improvement of ≥ 2 units in ≥ 3 of the 4 domains(PGA, total back pain, BASFI, BASDAI) with no deterioration (defined as a net worsening of > 0 units) in the potential remaining domain; ASAS 5/6: defined as ≥20% improvement in at least 5 of 6 domains (PGA, total back pain, BASFI, BASDAI, CRP and spinal mobility) ; ASAS partial remission: defined as a score of 2 or less in each of the 4 domains in ASAS (PGA, total back pain, BASFI, BASDAI); BASDAI50: defined as decrease of ≥50% from Baseline in BASDAI score at specified time points; ASDAS clinically important improvement; defined as change (decrease) from baseline of ≥1.1 units; ASDAS major improvement: defined as a response if improvement (decrease) from baseline in ASDAS-CRP of ≥2.0 units; ASDAS inactive disease: defined as a response if actual ASDAS-CRP was <1.3 units.
Risk of bias summary for each included study was presented in Fig. 2. All of the studies were RCT trials. The patients were randomized to receive either placebo or JAK inhibitor. All trials performed quadruple blinding (participant, care provider, investigator, outcomes assessor).
Fig. 2Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4.1 Efficacy of JAK inhibitor versus placebo in treating AS
All of the four RCTs with 779 participants reported the significantly better response rates of ASAS 20, ASAS 40, BASDAI 50, ASDAS Clinically Important Improvement, ASDAS Major Improvement, and ASDAS inactive disease in JAK inhibitor group, and the estimated RRs and 95%CIs were listed in Table 2 and Fig. 3. The response rates of ASAS 5/6 and ASAS Partial Remission were also significantly higher in the JAK inhibitor group than in the placebo group (Table 2, Fig. 3). Except for ∆SF-36 MCS, other efficacy outcomes, including ∆ASDAS-CRP, ∆MASES, ∆ASQoL, ∆SF-36 PCS, ∆BASDAI, ∆BASFI, ∆BASMI, ∆FACIT-F total score, ∆SPARCC SI joint score, ∆SPARCC Spine score and ∆WPAI Overall Work Impairment, demonstrated significant differences between the two groups, indicating better efficacy in JAK inhibitor group (Table 2).
Table 2Meta-analysis of effects of JAK inhibitor versus placebo in treating AS.
Significant heterogeneity (I2>50%) was found in the meta-analysis of efficacy outcomes including ASAS 5/6 (59%), ASDAS Major Improvement(63%), ASDAS inactive disease(55%), and ∆WPAI Overall Work Impairment(51%). Sensitivity analysis was conducted by removing one single trial each time, and the results showed the source of heterogeneity attributed to the study of Deodhar 2021 in assessing ASAS5/6[
Efficacy and safety of upadacitinib in patients with active ankylosing spondylitis (SELECT-AXIS 1): a multicentre, randomised, double-blind, placebo-controlled, phase 2/3 trial.
], the cause of heterogeneity presumably came from the difference between the magnitude of the effect size.
5. Discussion
This is the most up-to-date meta-analysis which assessed the efficacy and safety of JAK inhibitor treatment in patients with active AS. Our meta-analysis has a different strength as compared with the previous meta-analysis of the similar topic [
]. Firstly, we included the most recent and up-to-date literature in our meta-analysis. We collected data from four eligible RCTs that provided outcomes of JAK inhibitor treatment in active AS compared with placebo. And also, we were trying to do a perfect and precise data collection by checking the results posted on ClinicalTrials.gov or EU Clinical Trials Register. Among four RCTs, three kinds of JAK inhibitors were evaluated; a phaseⅢ and a phase Ⅱ study assessed tofacitinib [
Efficacy and safety of upadacitinib in patients with active ankylosing spondylitis (SELECT-AXIS 1): a multicentre, randomised, double-blind, placebo-controlled, phase 2/3 trial.
Efficacy and safety of filgotinib, a selective Janus kinase 1 inhibitor, in patients with active ankylosing spondylitis (TORTUGA): results from a randomised, placebo-controlled, phase 2 trial.
]. The selectivity of JAK inhibitor can be influenced by multiple factors and is dose-dependent. Among the JAK inhibitors currently under study for inflammatory diseases, it was generally accepted that clinically used doses of tofacitinib is preferentially a JAK 1, 3 inhibitor over JAK2, upadacitinib is a selective JAK1 inhibitor with effects on JAK2, and filgotinib is a highly selective JAK1 inhibitor [
Selectivity of janus kinase inhibitors in rheumatoid arthritis and other immune-mediated inflammatory diseases: is expectation the root of all headache?.
], we combined the effect indicators of different dosage groups according to the Cochrane Handbook recommendations, which were trying to minimize the selection bias and information bias. Thirdly, we included as much outcome measures as possible. In this meta-analysis, most of the comparisons showed satisfactory and significant improvements in JAK inhibitor group, including percentage of participants achieving response of ASAS20, ASAS40, ASAS 5/6, BASDAI50, and changes from baseline in ASDAS-CRP, MASES, ASQoL, SF-36 PCS, BASDAI, BASFI, BASMI, FACIT-F total score, SPARCC joint score and WPAI Overall Work Impairment, which indicated a promising efficacy of JAK inhibitor in the treatment of active AS not only in mitigating disease activity, but also substantially improving patient's physical function, emotional well-being and social participation. And also, we do not find significant differences regarding the number of participants with AEs or SAEs between JAK inhibitors and placebo.
However, there were some disadvantages in the current study. Firstly, the number of studies included in this meta-analysis was relatively small, which led to inevitable publication bias and selection bias, although no evidence of publication bias was detected in the present meta-analysis. Secondly, due to limited studies we could not do detailed subgroup analysis according to the kind of JAK inhibitor, dosage or JAK selectivity. And therefore, whether one JAK inhibitor is more effective or safer than another remains to be further investigated. Similarly, we could not rule out the bias caused by sex, age, ethnicity, disease duration, heterogenous spectrum of clinical manifestations and the time frame of studies.
Despite these disadvantages and that further researches are needed to assess the long-term efficacy and safety of JAK inhibitors, the evidences reported in our meta-analysis are currently the most updated and high-grade in this field, which provides solid evidence for JAK inhibitor as a new direction and novel therapeutic strategy for the patients with active AS.
Funding source
This research was supported by the National Natural Science Foundation of China (81873882).
Data sharing
All data will be available upon request for academic researchers.
CRediT authorship contribution statement
Shu Li: Conceptualization, Investigation, Data curation, Formal analysis, Writing – original draft. Fen Li: Investigation, Data curation. Ni Mao: Investigation, Data curation. Jia Wang: Supervision. Xi Xie: Conceptualization, Investigation, Methodology, Supervision, Writing – original draft.
Safety of janus kinase inhibitors in patients with inflammatory bowel diseases or other immune-mediated diseases: a systematic review and meta-analysis.
Efficacy and safety of upadacitinib in patients with active ankylosing spondylitis (SELECT-AXIS 1): a multicentre, randomised, double-blind, placebo-controlled, phase 2/3 trial.
Efficacy and safety of filgotinib, a selective Janus kinase 1 inhibitor, in patients with active ankylosing spondylitis (TORTUGA): results from a randomised, placebo-controlled, phase 2 trial.
Selectivity of janus kinase inhibitors in rheumatoid arthritis and other immune-mediated inflammatory diseases: is expectation the root of all headache?.
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