Risk Stratification of Patients with Psoriatic Arthritis and Ankylosing Spondylitis for Treatment with Tofacitinib: A Review of Current Clinical Data

Abstract

In this commentary, we review clinical data which helps inform individualized benefit-risk assessment for tofacitinib in patients with psoriatic arthritis (PsA) and ankylosing spondylitis (AS). ORAL Surveillance, a safety trial of patients ≥ 50 years of age with rheumatoid arthritis (RA) and cardiovascular risk factors, found increased rates of safety outcomes (including major adverse cardiovascular events [MACE], malignancies excluding non-melanoma skin cancer, and venous thromboembolism) with tofacitinib versus tumor necrosis factor inhibitors (TNFi). Post hoc analyses of ORAL Surveillance have identified subpopulations with different relative risk versus TNFi; higher risk with tofacitinib was confined to patients ≥ 65 years of age and/or long-time current/past smokers, and specifically for MACE, patients with a history of atherosclerotic cardiovascular disease (ASCVD). In patients without these risk factors, risk differences between tofacitinib and TNFi could not be detected. Given differences in demographics, pathophysiology, and comorbidities, we sought to examine whether the risk stratification observed in RA is also appropriate for PsA and AS. Data from the PsA tofacitinib development program show low absolute risk of safety outcomes in patients < 65 years of age and never smokers, and low MACE risk in patients with no history of ASCVD, consistent with results from ORAL Surveillance. No MACE, malignancies, or venous thromboembolism were reported in the tofacitinib AS development program. The mechanism of the ORAL Surveillance safety findings is unknown, and there are no similar prospective studies of sufficient size and duration. Accordingly, it is appropriate to use a precautionary approach and extrapolate differentiating risk factors identified from ORAL Surveillance (age ≥ 65 years, long-time current/past smoking, and history of ASCVD) to PsA and AS. We recommend an individualized approach to treatment decisions based on these readily identifiable risk factors, in line with updated labeling for Janus kinase inhibitors and international guidelines for the treatment of PsA and AS.Trial Registration: NCT02092467, NCT01262118, NCT01484561, NCT00147498, NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT01164579, NCT00976599, NCT01059864, NCT01359150, NCT02147587, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT01039688, NCT02281552, NCT02187055, NCT02831855, NCT00413699, NCT00661661, NCT01877668, NCT01882439, NCT01976364, NCT00678210, NCT01710046, NCT01241591, NCT01186744, NCT01276639, NCT01309737, NCT01163253, NCT01786668, NCT03502616.

Keywords: Age; Ankylosing spondylitis; Cardiovascular disease; Psoriatic arthritis; Smoking; Tofacitinib.

Fig. 1

Risk of MACE, malignancies (excluding NMSC), and VTE in the tofacitinib PsA, AS, and RA clinical development programs and ORAL Surveillance by age and smoking history. Figure adapted from Kristensen LE, et al. Ann Rheum Dis. 2023;82:901–910. https://doi.org/10.1136/ard-2022-223715. Data from the tofacitinib AS clinical development program previously reported by Deodhar et al. [20]. Horizontal dotted line and blue shaded area represent the IR (95% CI) in tofacitinib-treated patients who were < 65 years of age and never smokers in ORAL Surveillance. IRs express the number of patients with first events per 100 patient-years. All data are for combined tofacitinib doses. ^aExcluding ORAL Surveillance. ^bIn the tofacitinib RA clinical development program, 2.7% (N = 214) of patients had unknown smoking status. Patients < 65 y/o with unknown smoking status were not included in the ‘< 65 y/o and never smoker’ group. AS ankylosing spondylitis, CI confidence interval, IR incidence rate, MACE major adverse cardiovascular events, n number of patients with events, N number of evaluable patients, NMSC non-melanoma skin cancer, PsA psoriatic arthritis, RA rheumatoid arthritis, TNFi tumor necrosis factor inhibitor, VTE venous thromboembolism, y/o years of age

Fig. 2

Incidence of MACE (per 100 patient-years) by history of ASCVD in the tofacitinib PsA, PsO, and RA clinical development programs and ORAL Surveillance. No events of MACE occurred in the AS clinical development program. ORAL Surveillance data previously published [19]. RA data previously published for individual tofacitinib doses [21]; PsA and PsO data for patients with a history of ASCVD previously published [22]. Horizontal dotted line and blue shaded area represent the IR (95% CI) in tofacitinib-treated patients who had no history of ASCVD in ORAL Surveillance. IRs express the number of patients with first events per 100 patient-years. All data are for combined tofacitinib doses. ^aExcluding ORAL Surveillance. AS ankylosing spondylitis, ASCVD atherosclerotic cardiovascular disease, CI confidence interval, IR incidence rate, MACE major adverse cardiovascular events, n number of patients with event, N number of evaluable patients, PsA psoriatic arthritis, PsO psoriasis, RA rheumatoid arthritis, TNFi tumor necrosis factor inhibitor