Association between baseline cardiovascular risk and incidence rates of major adverse cardiovascular events and malignancies in patients with psoriatic arthritis and psoriasis receiving tofacitinib

Abstract

Background: Tofacitinib is a Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA) and has been investigated for psoriasis (PsO). Objectives: This post hoc analysis examined baseline cardiovascular (CV) disease risk and its association with the occurrence of major adverse cardiovascular events (MACE) and malignancies in tofacitinib-treated patients with PsA and PsO. Design: Included three phase III/long-term extension (LTE) PsA trials and seven phase II/phase III/LTE PsO trials of patients receiving ⩾ 1 dose of tofacitinib. Methods: Incidence rates (IRs: patients with events/100 patient-years) for MACE and malignancies (excluding non-melanoma skin cancer) were determined in subgroups according to history of atherosclerotic CV disease (ASCVD), baseline 10-year risk of ASCVD (in patients without history of ASCVD), and baseline metabolic syndrome (MetS). Results: For patients with PsA ( N = 783) and PsO ( N = 3663), respectively, tofacitinib exposure was 2038 and 8950 patient-years (median duration: 3.0 and 2.4 years), and 40.9% and 32.7% had MetS. Excluding missing CV risk profile data, 51/773 (6.6%) and 144/3629 (4.0%) patients had history of ASCVD, and in patients without history of ASCVD, around 20.0% had intermediate/high baseline 10-year ASCVD risk. For PsA and PsO, IRs of MACE were greatest in those with history of ASCVD or high baseline 10-year ASCVD risk. For PsA, five of six patients with MACE had baseline MetS. Malignancy IRs in patients with PsA were greatest in those with intermediate/high baseline 10-year ASCVD risk. Of these, eight of nine patients with malignancies had baseline MetS. In the PsO cohort, IR of malignancies was notably greater with high versus low/borderline/intermediate baseline 10-year ASCVD risk. Conclusion: In tofacitinib-treated patients with PsA/PsO, increased ASCVD risk and baseline MetS were associated with higher IRs for MACE and malignancies. Our results support assessing CV risk in patients with PsA/PsO and suggest enhanced cancer monitoring in those with increased ASCVD risk. Registration (ClinicalTrials.gov): NCT01877668/NCT01882439/NCT01976364/NCT00678210/NCT01710046/NCT01241591/NCT01186744/NCT01276639/NCT01309737/NCT01163253 Plain Language Summary People who have psoriatic arthritis or psoriasis may have more heart-related problems and cancer if they have a higher risk of cardiovascular disease: A study in people with psoriatic arthritis or psoriasis receiving tofacitinib Why was this study done? • People with psoriatic arthritis (PsA) and psoriasis (PsO) are more likely than the general population to have a disease affecting the heart and blood vessels [cardiovascular (CV) disease]. • People who are more likely to have CV disease may also be more likely to have certain types of cancer. • Tofacitinib is a medicine to treat people with PsA and has been tested in people with PsO. • We wanted to know if the risk of CV disease affects the number of heart-related problems (including heart attack, stroke, or death) and cancer in people with PsA and PsO. What did the researchers do? • We used results from 10 clinical trials. • In these trials, people with PsA and PsO were taking tofacitinib 5 or 10 mg twice a day. • After the trials had ended, we measured people’s risk of CV disease using a risk calculator. This risk calculator showed if they had a low, borderline, intermediate, or high risk of CV disease over the next 10 years. We also checked if they had had CV disease before treatment. • We checked if people had a group of conditions linked to CV disease: diabetes, high blood pressure, and obesity. • We counted the cases of heart-related problems and cancer in people once they started taking tofacitinib. What did the researchers find? In people with PsA and PsO taking tofacitinib: • There were more cases of heart-related problems and cancer in people who had intermediate or high risk of CV disease. • There were more cases of heart-related problems in people who had had CV disease before. • More people with diabetes, high blood pressure, and obesity had heart-related problems and cancer than people without those conditions. What do the findings mean? • It is important to measure risk and assess history of CV disease in people with PsA and PsO, including those taking tofacitinib. • We should test for cancer in people with high risk of CV disease.

Oral Presentation Abstracts

“…Additionally, the STAR-RA study reported that RA patients on tofacitinib had no increased cardiovascular risk whilst those with a cardiovascular disease history did4 . A post-hoc analysis of PsA patients on tofacitinib had similar findings5 . Data on other JAKi also demonstrated no increased risk.…”

“…Huang W 1,11 , Luo S 2,11 , Chen D 3,11 , Tsai C 4,11 , Hsieh S 5,11 ,Lu L 6,11 , Jan Wu Y 7,11 , Chen M 4,11 , Hsieh T 1,11 , Yeh F 8,11 , Su Y 9,11 , Liao Y 1,11 , Lee T 10,11 , Sheu H Therefore, the in vitro experimental method of using inflammatory cytokines such as interleukin-1 beta (IL-1ß) to create an inflammatory environment in two-dimensional (2D) monolayer culture is certainly different from the in vivo inflammatory environment of OA. In addition, the effects of various factors affecting the survival/engraftment of administered cells can be evaluated in a 3D co-culture system composed of spheroids created from different lineage cells within the joint cavity that would better mimic the inflammatory environment of OA.…”

“…5 , Siri D 6 , Zeng X 7 , D'Silva K 8 , Cheng L 8 , Sornasse T 8 , Doan T 8 , Kruzikas D 8 , Friedman A 8…”

Risk of dyslipidemia and major adverse cardiac events with tofacitinib versus adalimumab in rheumatoid arthritis: a real-world cohort study from 7580 patients

“…The findings that women and young adults may warrant closer monitoring for tofacitinib-associated dyslipidemia could inform more tailored RA treatment approaches. No differences in lipid response to tofacitinib versus adalimumab were observed by race, contrasting with some cardiovascular studies showing higher event risks in minorities (Khosrow-Khavar et al, 2022;Kristensen et al, 2023a;Kristensen et al, 2023b;Schreiber et al, 2023). This study was limited by potential misclassification bias, lack of treatment dose-response data, and inability to make conclusions about long-term MACE risks.…”

Causes of Autoimmune Psoriasis and Associated Cardiovascular Disease: Roles of Human Endogenous Retroviruses and Antihypertensive Drugs—A Systematic Review and Meta-analysis

“…Considering this scenario, a recent post-hoc analysis of various phases of clinical trial study reported that tofacitinib exposure, a Janus kinase inhibitor used for PsA treatment, increase the incidence rate (IR, with 95% CI) of major adverse cardiovascular event/MACE in whom had a baseline history of atherosclerotic CVD (ASCVD) [0.75 (0.02-4.21)], followed by the high (≥ 20%) 10-year risk of ASCVD [1.37 (0.03-7.63)], and the high risk of malignancies [1.13 (0.45-2.33)] in a subset of PsA patients [56]. The highest IR of MACE with a history of ASCVD [1.87 (0.69-4.08)], a high 10-year risk of ASCVD [1.49 (0.55-3.24)], followed by the high risk of malignancy [3.48 (1.90-5.83)] was reported in the PsD patients 54 .…”