TOFACITINIB - BOON OR A BANE?

Abstract

TOPIC: Pulmonary Vascular Disease TYPE: Medical Student/Resident Case Reports INTRODUCTION: Tofacitinib (Xeljanz) is common and popular Disease Modifying Anti-Rheumatic Drug used in the treatment of moderate to severe Rheumatoid Arthritis (RA) that was approved by US FDA in 2012. It now comes with a new black-box warning for venous thromboembolism (VTE). We present a patient taking Tofacitinib as well as an oral anticoagulant that developed pulmonary embolism (PE) after receiving his first COVID-19 vaccine. CASE PRESENTATION: An 80-year-old white male with severe RA on Tofacitinib (previously failed treatment with Methotrexate and Infliximab), mild interstitial lung disease likely related to occupational silica exposure, severe Chronic Obstructive Pulmonary Disease (COPD) with oxygen dependency, 50 pack-year smoking history (quit in 2016), coronary artery disease, atrial flutter on Rivaroxaban presents to ED for worsening shortness of breath. He had just received his first COVID-19 vaccine manufactured by Moderna two weeks prior. Vital signs include; heart rate 127 bpm, respirations 40 per minute, SpO2 84% on 6 LPM oxygen and fever of 101.2 F. Pertinent labs include WBC 12.4, Lactic Acid 3, BNP 175, Troponin 0.02. Chest X-ray revealed edema and/ or atypical pneumonia, but COVID-19 screen was negative. He received IV Solumedrol and Cefepime, before being admitted. Overnight he developed new onset chest pain with increased O2 requirements up to 15 LPM. CT Chest was immediately pursued revealing right upper lobe and bilateral lower lobe segmental pulmonary emboli without right ventricular strain. He was started on a heparin drip. Tofacitinib was stopped on the recommendation of his Rheumatologist and he was discharged on Apixaban. DISCUSSION: Tofacitinib is a JAK 1-3 inhibitor causing inhibition of the CD 16/56+ natural killer cells, serum IgG-IgM-IgA and CRP. Higher doses of Tofacitinib are associated with an increased incidence of DVT/PE in elderly population, with at least one cardiovascular risk factor [1]. In study A3921133, a higher frequency of PE and all-cause mortality was seen in higher dose of Tofacitinib (10 Mg BID) when compared to TNF inhibitors [2]. In another Long-term Extension (LTE) study involving 7061 patients taking Tofacitinib, VTE was reported in 59 (0.8%) patients with an IR (95% CI) of 0.3 (0.2 to 0.3), DVT was reported in 36 (0.5%) patients (IR 0.2 [95% CI 0.1 to 0.2]) and PE in 28 (0.4%), [2]. FDA has issued a 'Boxed warning’ regarding the risk of thrombosis with 10 mg BID dose of Tofacitinib [3]. CONCLUSIONS: Clinicians are strongly urged to evaluate the risk of DVT/PE before initiating higher dose of Tofacitinib in patients greater than 50 years old with at least one cardiovascular risk factor. In our case, another confounding aspect is the incidence of PE despite treatment with an oral anticoagulant. The thrombogenic potential of Tofacitinib should strongly be explored as an independent risk factor for PE by clinicians. REFERENCE #1: [1] Mease, Philip, et. Al; Incidence of Venous and Arterial Thromboembolic Events Reported in Tofacitinib rheumatoid arthritis, psoriasis and psoriatic arthritis Development Programs and from Real-World Data, 2020, Annals of Rheumatic Disease, 79(11): 1400-1413, DOI: 10.1136/annrheumdis-2019-216761 REFERENCE #2: [2] Cohen, Stanley; et Al; Long-term Safety of Tofacitinib up to 9.5 years: A Comprehensive Integrated Analysis of the Rheumatoid Arthritis Clinical Development Programme, 2020, Rheumatic and Musculoskeletal Disease, 6(3):e001395, DOI: 10.1136/rmdopen-2020-001395 REFERENCE #3: [3] U.S. Food and Drug Administration (FDA), Initial safety trial results find increased risk of serious heart-related problems and cancer with arthritis and ulcerative colitis medicine Xeljanz, Xeljanz XR (tofacitinib), 2021, Drug Safety Communication, Retrieved from; https://www.fda.gov/drugs/drug-safety-and-availability/initial-safety-trial-results-find-increased-risk-serious-heart-related-problems-and-cancer-arthritis DISCLOSURES: No relevant relationships by Mahmoud Amarna, source=Web Response No relevant relationships by Camelia Chirculescu, source=Web Response No relevant relationships by Johnston Hospital, source=Web Response No relevant relationships by Rakesh Patel, source=Web Response No relevant relationships by Mallika Velichety, source=Web Response