Real-World Evidence Confirms the Benefits of JAK Inhibitors in Patients With Rheumatoid Arthritis

The real-world treatment benefit of Janus kinase (JAK) inhibitors among US patients with rheumatoid arthritis (RA) was demonstrated across various observational studies, which focused on clinical disease activity changes, patient-reported outcomes (PROs), and treatment adherence, persistence, and effectiveness.¹

The authors of the Drug, Healthcare, and Patient Safety systematic review noted that the core pharmacotherapy for RA consists of disease-modifying antirheumatic drugs (DMARDs), including conventional synthetic DMARDs (csDMARDs), targeted synthetic DMARDs (tsDMARDs), and biological DMARDs (bDMARDs). The current guidelines recommend that patients with RA use csDMARDs as the first-line therapy and then add or switch to bDMARDs or tsDMARDs.

tsDMARDs, also known as JAK inhibitors, represent this population's newest approved class of oral treatments. Tofacitinib, baricitinib, and upadacitinib are the 3 FDA-approved JAK inhibitors, receiving approval in 2012, 2018, and 2019, respectively²; tofacitinib and baricitinib nonselectively inhibit JAKs 1, 2, and 3, whereas upadacitinib selectively targets the JAK 1.³

Several randomized controlled trials (RCTs) demonstrated clinical improvement with JAK inhibitors, suggesting superior clinical efficacy of novel JAK inhibitor treatment for patients with RA vs other biologics.¹ However, patients enrolled in RCTs often differ from those seen in the routine clinical setting, meaning that the treatment efficacy outcomes demonstrated in RCTs may not reflect real-world effectiveness outcomes.

Therefore, the researchers emphasized the need to evaluate the real-world effectiveness of JAK inhibitors as they become increasingly available. To complement the efficacy data from RCTs, they conducted a systematic review to synthesize the real-world effectiveness outcomes of JAK inhibitors from real-world observational studies among patients with RA in US health care settings.

Janus kinase inhibitors are effective in improving treatment adherence, persistence, clinical outcomes, and patient-reported outcomes among US patients with rheumatoid arthritis. | Image Credit: doucefleur - stock.adobe.com

The researchers searched PubMed, CINAHL, and Embase from each database’s inception to June 2, 2023, for relevant publications using search terms like “rheumatoid arthritis,” “Janus kinase inhibitors,” and “real-world databases.” Eligible studies evaluated real-world effectiveness outcomes of JAK inhibitors among US patients with RA. The researchers extracted characteristics and effectiveness measures from each eligible study, focusing on JAK inhibitor treatment patterns, PROs, and clinical responses.

They initially identified 1236 studies, narrowing them down to 35. Of these, 23 studies (65.71%) used administrative claims data sets including claims only, claims plus electronic health records (EHRs), or claims plus registry data. Nine studies used patient registry data sets and 3 used EHRs.

Sample sizes ranged from 455 to 30,556 patients in the administrative claims databases, 252 to 4044 in the EHR databases, and 103 to 8572 in the patient registry databases. Among the studies, 10 evaluated all JAK inhibitors (28.57%), 20 (57.14%) focused on tofacitinib, and 5 (14.28%) only evaluated upadacitinib.

The JAK inhibitor treatment pattern-related measures featured in the studies included adherence, persistence, and claims-based effectiveness algorithms. Of the studies, 11 reported JAK inhibitor adherence among patients with RA, all of which used administrative claims data sets, including MarketScan, Medicare, and Optum. The researchers determined a wide range of adherence across these studies, with an adherence rate between 0.53 and 0.83 for the proportion of days covered (PDC).

Additionally, JAK inhibitor persistence was reported in 14 studies, all of which used administrative claims data sets. They found that the median time in treatment without discontinuation was between 121 and 516 days; the JAK inhibitor discontinuation rate was between 11% and 72.4%.

Also, 6 studies used effectiveness algorithms, which involved specific criteria to measure adherence, including high adherence, no biologic or tofacitinib switch or addition, and no DMARD switch or addition. The percentage of patients effectively treated ranged from 14.8% to 26%.

In terms of clinical response measures, the most common was the Clinical Disease Activity Index (CDAI). Of the 10 studies using this measurement, 9 used registry data sets, and 1 used EHRs. The researchers found that the mean change in JAKi CDAI after 6 months ranged between –4.7 and 5.1. Other reported outcomes included disease activity score, swollen joint count, and tender joint count.

Lastly, 12 studies measured PROs among those with RA using JAK inhibitors. Of these, 10 utilized registry data sets, and 2 used EHRs. The researchers noted that the most widely reported PRO was pain, with all 12 studies including it in their findings; the mean change in pain ranged from –9.3 to 8.9 across these studies. The studies evaluated several other PRO outcomes, like morning stiffness and fatigue.

Conversely, the researchers acknowledged their study’s limitations, including the heterogeneities across studies due to the differences in design and patient population. Despite their limitations, the researchers expressed confidence in their findings and identified areas for further research.

“Findings in this review complement the efficacy data observed in RCT populations and confirm the treatment benefit of [JAK inhibitors] for treatment in RA in a broader group of patients other than the RCT setting,” the authors concluded. “Future reviews focusing on the comparative effectiveness studies between [JAK inhibitors] and other biologics would help to further inform clinical practice.”

References

1. Gandy C, Bazzazzadehgan S, Bruera S, Huang Y. Evaluation of real-world evidence to assess effectiveness outcomes of Janus kinase inhibitors for rheumatoid arthritis: a systematic review of US studies. Drug Healthc Patient Saf. 2025;17:25-49. doi:10.2147/DHPS.S492887
2. Harrington R, Harkins P, Conway R. Janus kinase inhibitors in rheumatoid arthritis: an update on the efficacy and safety of tofacitinib, baricitinib and upadacitinib. J Clin Med. 2023;12(20):6690. doi:10.3390/jcm12206690
3. Yamaoka K. Janus kinase inhibitors for rheumatoid arthritis. Curr Opin Chem Biol. 2016;32:29-33. doi:10.1016/j.cbpa.2016.03.006