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Upadacitinib Outcomes in High Risk RA Patients

A safety analysis of six phase III SELECT trials showed that higher-risk rheumatoid arthritis (RA) patients had an increased risk of MACE, malignancy (excluding NMSC) and venous thromboembolic events (VTE) regardless of being treated with either upadacitinib (UPA) or adalimumab (ADA).

This analysis ensued after publication of the tofacitinib ORAL Surveillance study that showed an increased risk of MACE, malignancy, VTE and serious infectious events (SIEs) in high risk RA patients treated with tofacitinib (compared to those treated wtih tumour necrosis factor inhibitor [TNFi]. The FDA applied boxed warnings from this tofacitinib trial to other JAK inhibitors. This post hoc study examined the potential risk of UPA in a similar higher-risk RA population.

A post hoc safety analysis used data in 6 phase III SELECT trials with updadacitinib (versus ADA and MTX) and looked at CV, malignancy, VTE and SIE outcomes in RA patients treated with either UPA 15 mg per day (n = 3209), adalimumab 40 mg every other week (n=579) or MTX (n=314). The analysis compared treatment groups among all patients, higher risk RA patients and (aged ≥50 years, ≥1 CV risk factor), and from higher-risk patients in the SELECT-COMPARE study (a head-to-head UPA versus ADA trial) in RA patients.

Higher risk RA patients had increased rates of MACE, malignancy (excluding non-melanoma skin cancer (NMSC)) and VTE compared to the overall population, but no difference was seen between treatment groups.

UPA use in higher-risk populations were more likely to have SIE (than comparators) and in all populations, UPA patients had more herpes zoster (HZ) and NMSC events. 

At odds with the ORAL surveillance results, both UPA and ADA yielded similar increased rates of MACE, malignancy (excluding NMSC) and VTE when used in higher-risk RA patients. UPA did associate with higher rates of HZ and NMSC (all patients) and more SIE (higher risk RA patients) reports. 

While this, and many other, post hoc analyses have attempted to "match' the inclusion criteria used for the ORAL Surveillance study, such subsetting is a coarse demographic match that does not account for baseline disease activity, the number of comorbidities or the history of prior failed DMARDs or biologic therapies.

Hence, while there may be some reassurance from this analysis, the results of the ORAL surveillance trial would best be studied against another large, randomized prospective trial - one that could answer whether JAK inhibitors are not as protective as TNF inhibitors in these serious adverse event outcomes or whether JAK inhibitors augment these risks relative to TNF inhibitors.


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