Patients with rheumatoid arthritis receiving tofacitinib had greater improvement in selected efficacy outcomes compared with those receiving adalimumab in a systematic review and meta-analysis published in Frontiers in Pharmacology, although the findings require cautious interpretation because of substantial heterogeneity, dose-related concerns, and limited long-term safety assessment.
Both tofacitinib and adalimumab are used in patients with inadequate response to conventional disease-modifying antirheumatic drugs. However, current American College of Rheumatology and European Alliance of Associations for Rheumatology recommendations generally favor biologic agents over Janus kinase inhibitors in patients with cardiovascular disease, thromboembolic risk, or prior malignancy because of safety concerns associated with the JAK inhibitor class.
The review included nine studies with 24,643 patients, comprising six randomized controlled trials and three cohort studies. However, the patient count was heavily influenced by observational data; one retrospective cohort study contributed 14,891 patients, representing more than half of the pooled population.
The primary outcome was American College of Rheumatology 20% response criteria. Secondary outcomes included changes in visual analog scale scores, Disease Activity Score 28-C-reactive protein, Health Assessment Questionnaire–Disability Index, and adverse events.
Across seven comparison groups including 1,982 patients, tofacitinib was associated with a higher ACR20 response rate than adalimumab. Tofacitinib also was associated with greater improvement in HAQ-DI scores across nine comparison groups and greater improvement in VAS scores across six comparison groups, although the VAS analysis was derived from only two underlying studies.
No statistically significant difference was observed between therapies in DAS28-CRP improvement, a finding that was also less stable in sensitivity analyses.
The apparent efficacy advantage was strongly influenced by dose. In subgroup analysis, tofacitinib doses greater than 5 mg twice daily were associated with higher ACR20 response rates compared with adalimumab, whereas doses of 5 mg twice daily or lower showed no statistically significant difference. The study discussion noted that the overall ACR20 advantage was largely driven by inclusion of a 2012 dose-ranging trial.
That distinction may limit the applicability of the findings to current practice. The standard approved maintenance dose of tofacitinib for rheumatoid arthritis is 5 mg twice daily (or the bioequivalent 11 mg once-daily extended-release formulation), whereas higher doses now carry additional regulatory restrictions following safety findings from the ORAL Surveillance trial.
The safety findings also should not be interpreted as reassurance about long-term comparative safety. Although overall adverse-event rates did not differ statistically between groups, the analysis was not designed or powered to evaluate major adverse cardiovascular events, malignancy, thrombosis, serious infection, or death. The US Food and Drug Administration requires boxed warnings for several JAK inhibitors, including tofacitinib, for serious heart-related events, cancer, blood clots, and death.
Heterogeneity across several efficacy analyses further complicates interpretation. The ACR20 analysis showed substantial heterogeneity, with an I² of 74%, suggesting the studies were not measuring a homogeneous treatment effect. Sensitivity analyses indicated that the ACR20 finding was directionally stable when individual studies were removed, but the high heterogeneity still limits confidence in the pooled estimate. VAS findings were similarly unstable in sensitivity analyses.
The researchers cited several limitations, including retrospective cohort data, variation in patient populations and follow-up duration, limited subgroup data, and insufficient data for outcomes such as ACR50. They also noted that combining randomized and observational studies may have introduced confounding and mixed treatment effects.
"This meta-analysis found tofacitinib significantly superior to adalimumab in improving ACR20, VAS, and HAQ-DI, with no significant difference in adverse event rates or DAS28-CRP improvement between the two," wrote Chunyan Zhu, of Dongying People's Hospital in China, and colleagues.
The study's headline conclusion, however, should be interpreted alongside the dose-dependent findings, substantial heterogeneity, and unresolved long-term safety concerns associated with JAK inhibitors.
The researchers concluded that larger multicenter prospective studies are needed to clarify the comparative benefits and risks of tofacitinib and adalimumab in patients with rheumatoid arthritis.
The study reported no funding and no conflicts of interest.
Source: Frontiers in Pharmacology