Rheumatoid arthritis

Last reviewed: 24 Apr 2022
Last updated: 14 Dec 2021
14 Dec 2021

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).[48]

This follows final results from a large randomised safety clinical trial comparing tofacitinib with tumour 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.[49]

The FDA advises clinicians to:[48]

  • 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 non-melanoma 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 aged >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.[49][50][51]

See Management: approach

See Management: treatment algorithm

Original source of update



History and exam

Key diagnostic factors

  • active symmetrical arthritis lasting >6 weeks
  • age 50 to 55 years
  • female sex
  • joint pain
  • joint swelling
More key diagnostic factors

Other diagnostic factors

  • morning stiffness
  • swan neck deformity
  • Boutonniere's deformity
  • ulnar deviation
  • rheumatoid nodules
  • vasculitic lesions
  • pleuritic chest pain
  • scleritis and/or uveitis
Other diagnostic factors

Risk factors

  • genetic predisposition
  • smoking
More risk factors

Diagnostic investigations

1st investigations to order

  • rheumatoid factor (RF)
  • anti-cyclic citrullinated peptide (anti-CCP) antibody
  • radiographs
  • ultrasonography
More 1st investigations to order

Investigations to consider

  • disease activity score(s)
More investigations to consider

Treatment algorithm


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
Yusuf Yazici

Clinical Associate Professor of Medicine

New York University School of Medicine

New York



YY receives research support from BMS and Genentech; he has consulted for Amgen, BMS, and Sanofi.

Peer reviewers

Chris Deighton, BMedSc, MD, FRCP

Consultant Rheumatologist

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)

Consultant Rheumatologist

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




Not disclosed.

Prabha Ranganathan, MD, MS

Associate Professor of Medicine

Division of Rheumatology

Washington University School of Medicine

St Louis



PR declares that she has no competing interests.

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