FDA issues warning about increased risk of serious cardiovascular events, malignancy, thrombosis, and death with tofacitinib and other JAK inhibitors
The US Food and Drug Administration (FDA) has issued a warning about an increased risk of serious cardiovascular events, malignancy, thrombosis, and death with tofacitinib and two other Janus kinase (JAK) inhibitors (baricitinib and upadacitinib).
This follows final results from a large randomized safety clinical trial comparing tofacitinib with tumor necrosis factor (TNF)-alpha inhibitors in patients with rheumatoid arthritis. The study found an increased risk of blood clots and death with the lower dose of tofacitinib (5 mg twice daily); this serious event had previously been reported only with the higher dose (10 mg twice daily) in the preliminary analysis.
The FDA advises clinicians to:
Reserve tofacitinib, baricitinib, and upadacitinib for patients who have had an inadequate response or are intolerant to one or more TNF-alpha inhibitors
Consider the patient's individual benefit-risk profile when deciding to prescribe or continue treatment with these medications, particularly in patients who are current or past smokers, patients with other cardiovascular risk factors, those who develop a malignancy, and those with a known malignancy (other than a successfully treated nonmelanoma skin cancer).
Two other JAK inhibitors, ruxolitinib and fedratinib, are not indicated for the treatment of arthritis and other inflammatory conditions and so are not affected by this warning.
A similar safety alert was issued by the European Medicines Agency (EMA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA) for tofacitinib, based on results from the same study. The EMA advice relates to patients ages >65 years, those who are current or past smokers, patients with other cardiovascular risk factors, and patients with other malignancy risk factors. In these patient groups, tofacitinib should only be used to treat moderate or severe ulcerative colitis, if no suitable treatment alternative is available.
Rheumatoid arthritis (RA) is a chronic, erosive arthritis that requires early and aggressive treatment.
Diagnosed clinically. Laboratory and radiographic testing provide prognostic information more often than diagnostic information.
Early and aggressive treatment with disease-modifying antirheumatic drugs (DMARDs), potentially combined with a biologic agent or a targeted synthetic DMARD, is recommended.
Disease activity scores (e.g., 28-joint count version of disease activity score [DAS28], clinical disease activity index [CDAI], simplified disease activity index [SDAI], routine assessment patient index data [RAPID3]) are used routinely to provide optimum care for RA patients.
Rheumatoid arthritis (RA) is a chronic inflammatory condition affecting around 1% of the population, making it the most common inflammatory arthritis seen by physicians. It primarily affects the small joints of the hands and feet and, if not treated aggressively, can be a major cause of work loss, decreased quality of life, need for joint replacement surgery, and mortality. RA is a clinical diagnosis; laboratory and radiographic tests help to confirm the diagnosis and provide useful prognostic information.
History and exam
Key diagnostic factors
- active symmetric arthritis lasting >6 weeks
- age 50 to 55 years
- female sex
- joint pain
- joint swelling
Other diagnostic factors
- morning stiffness
- swan neck deformity
- Boutonniere deformity
- ulnar deviation
- rheumatoid nodules
- vasculitic lesions
- pleuritic chest pain
- scleritis and/or uveitis
- genetic predisposition
1st investigations to order
- rheumatoid factor (RF)
- anticyclic citrullinated peptide (anti-CCP) antibody
Investigations to consider
- disease activity score(s)
mild disease activity at initial presentation: not pregnant or planning pregnancy
moderate-to-severe disease activity at initial presentation: not pregnant or planning pregnancy
pregnant or planning pregnancy
failure to reach low disease activity after 3 months of therapy: not pregnant or planning pregnancy
Yusuf Yazici, MD
Clinical Associate Professor of Medicine
New York University School of Medicine
YY receives research support from BMS and Genentech; he has consulted for Amgen, BMS, and Sanofi.
Chris Deighton, BMedSc, MD, FRCP
Department of Rheumatology
Royal Derby Hospital
CD has received honoraria for talks at symposia sponsored by Wyeth and Abbott.
Raashid Luqmani, DM FRCP, FRCP(E)
Nuffield Orthopaedic Centre
Senior Lecturer in Rheumatology
Botnar Research Centre
University of Oxford
RL declares that he has no competing interests.
Alan Bridges, MD
Professor of Medicine
Section of Rheumatology
University of Wisconsin
AB has received fees for speaking and consulting from Abbott, BMS, UCB, and Genentech.
John Kirwan, BSc, MB, BS, MD
Emeritus Professor of Rheumatic Diseases
School of Clinical Sciences
University of Bristol
JK declares that he has no competing interests.
Paul Emery, MA, MD, FMedSci
Professor of Rheumatology
Arthritis Research UK
Leeds Institute of Rheumatic and Musculoskeletal Medicine
University of Leeds
Leeds Musculoskeletal Biomedical Research Unit
Leeds Teaching Hospitals NHS Trust
Prabha Ranganathan, MD, MS
Associate Professor of Medicine
Division of Rheumatology
Washington University School of Medicine
PR declares that she has no competing interests.
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- American College of Rheumatology guideline for the treatment of rheumatoid arthritis
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