Infections in patients with rheumatoid arthritis receiving tofacitinib versus tumour necrosis factor inhibitors: results from the open-label, randomised controlled ORAL Surveillance trial

Abstract

ObjectivesTo characterise infections in patients with rheumatoid arthritis (RA) in ORAL Surveillance.MethodsIn this open-label, randomised controlled trial, patients with RA aged≥50 years with ≥1 additional cardiovascular risk factor received tofacitinib 5 or 10 mg two times per day or a tumour necrosis factor inhibitor (TNFi). Incidence rates (IRs; patients with first events/100 patient-years) and hazard ratios (HRs) were calculated for infections, overall and by age (50–<65 years; ≥65 years). Probabilities of infections were obtained (Kaplan-Meier estimates). Cox modelling identified infection risk factors.ResultsIRs/HRs for all infections, serious infection events (SIEs) and non-serious infections (NSIs) were higher with tofacitinib (10>5 mg two times per day) versus TNFi. For SIEs, HR (95% CI) for tofacitinib 5 and 10 mg two times per day versus TNFi, respectively, were 1.17 (0.92 to 1.50) and 1.48 (1.17 to 1.87). Increased IRs/HRs for all infections and SIEs with tofacitinib 10 mg two times per day versus TNFi were more pronounced in patients aged≥65 vs 50–<65 years. SIE probability increased from month 18 and before month 6 with tofacitinib 5 and 10 mg two times per day versus TNFi, respectively. NSI probability increased before month 6 with both tofacitinib doses versus TNFi. Across treatments, the most predictive risk factors for SIEs were increasing age, baseline opioid use, history of chronic lung disease and time-dependent oral corticosteroid use, and, for NSIs, female sex, history of chronic lung disease/infections, past smoking and time-dependent Disease Activity Score in 28 joints, C-reactive protein.ConclusionsInfections were higher with tofacitinib versus TNFi. Findings may inform future treatment decisions.Trial registration numberNCT02092467.

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update

“…Of note, the focus on CV and malignancy risk here is a consequence of the recently published data, but it is evident since the introduction of bDMARDs more than 20 years ago that infection risks, especially risks of tuberculosis reactivation or Herpes zoster, has to be taken into account and respective precautious measures initiated as needed. Moreover, in a substudy of ORAL-Surveillance, published several months after the Task Force meeting, an increased infection rate beyond Herpes Zoster was seen for tofacitinib compared with TNF-inhibition 52…”

“…Moreover, in a substudy of ORAL-Surveillance, published several months after the Task Force meeting, an increased infection rate beyond Herpes Zoster was seen for tofacitinib compared with TNF-inhibition. 52 Regarding dosing of b/ts DMARDs, the Task Force refers to previous versions of this manuscript and various consensus statements, such as starting with 8 mg/kg of tocilizumab rather than 4 mg/kg, if intravenous dosing is preferred, or the use of 2×500 mg or 1×1000 mg rituximab rather than 2×1000 mg. Further, in the absence of contraindications (see above), for baricitinib, the 4 mg daily dose, as approved in Europe, has some efficacy advantages especially in patients with long-standing RA compared with the 2 mg daily dose as approved in the USA. Finally, the use of loading doses for certolizumab pegol or sc abatacept may have to be revisited.…”

Risk of major adverse cardiovascular events with tofacitinib versus tumour necrosis factor inhibitors in patients with rheumatoid arthritis with or without a history of atherosclerotic cardiovascular disease: a post hoc analysis from ORAL Surveillance

“…Risk of malignancies (excluding non-melanoma skin cancer) and infections was also higher with tofacitinib versus TNFi in ORAL Surveillance 8 26…”

Neutrophil-lymphocyte ratio: an independent predictor of the herpes zoster risk in rheumatoid arthritis patients treated with tofacitinib

“…Herpes zoster (HZ) is a common and occasionally crippling condition that disproportionately affects elderly people and those with impaired immune systems [7]. When compared to healthy adults, patients with RA have a 1.5-2 fold higher chance of acquiring HZ [8], and various disease-modifying antirheumatic medications (DMARD) have been demonstrated to significantly raise this risk [9,10]. Tofacitinib is an oral JAK inhibitor used to treat RA.…”