Last reviewed: 24 Sep 2021
Last updated: 23 Sep 2021
03 Aug 2021

FDA echoes EMA warning on tofacitinib after trial shows increased risk of CV events, cancer, thrombosis and death

The European and US drug regulators have both now issued warnings on the use of tofacitinib after final results from a large safety trial showed an increased risk of serious cardiovascular events, malignancy, thrombosis, and death.

Tofacitinib is approved for the treatment of moderate to severely active ulcerative colitis in patients who have had an inadequate response, lost response, or are intolerant to either conventional therapy or a biological agent. In June 2021, the European Medicines Agency (EMA) advised that in patients who are current or past smokers, or who have other cardiovascular and/or malignancy risk factors, tofacitinib should only be used to treat moderate or severe ulcerative colitis if no suitable treatment alternative is available.[39] This is in addition to its previous advice to use tofacitinib with caution in patients at high risk of blood clots and that patients aged >65 years should also only be treated with tofacitinib when there is no alternative treatment.[40]

The EMA advice followed final results from the clinical safety trial, which showed an increased risk of major cardiovascular events and cancer (excluding non-melanoma skin cancer) in patients with rheumatoid arthritis treated with tofacitinib, compared with patients treated with a tumour necrosis factor (TNF)-alpha inhibitor.[41]

The EMA advises clinicians to carefully evaluate the patient’s individual benefit-risk profile when deciding to start or continue treatment with tofacitinib.[39]

In September 2021, a similar safety alert has been issued by the US Food and Drug Administration (FDA) for tofacitinib and two other Janus kinase (JAK) inhibitors (baricitinib and upadacitinib), based on results from the same study. The FDA warns about an increased risk of serious cardiovascular events, malignancy, thrombosis, and death with these agents. 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 and to 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).[42]

See Management: approach

See Management: treatment algorithm

Original source of updateexternal link opens in a new window



History and exam

Key diagnostic factors

  • presence of risk factors
  • rectal bleeding
  • diarrhoea
  • blood in stool

Other diagnostic factors

  • abdominal pain
  • arthritis and spondylitis
  • malnutrition
  • abdominal tenderness
  • fever
  • weight loss
  • constipation
  • skin rash
  • uveitis and episcleritis
  • pallor

Risk factors

  • family history of inflammatory bowel disease
  • HLA-B27
  • infection
  • non-steroidal anti-inflammatory drugs (NSAIDs)
  • not smoking or former smoker

Diagnostic investigations

1st investigations to order

  • stool studies for infective pathogens
  • faecal calprotectin
  • FBC
  • comprehensive metabolic panel (including LFTs)
  • erythrocyte sedimentation rate (ESR)
  • CRP
  • plain abdominal radiograph
  • flexible sigmoidoscopy
  • colonoscopy
  • biopsies

Treatment algorithm



Hesam A. Nooredinvand, MBBS, MRCP, BSc (Hons)

Research Fellow in Gastroenterology

St George's Hospital




HAN declares that he has no competing interests.

Andrew Poullis, BSc, MBBS, MD, FRCP

Consultant Gastroenterologist

Department of Gastroenterology

St George’s Hospital




AP is an author of a reference cited in this topic.


Dr Hesam A. Nooredinvand, and Dr Andrew Poullis would like to gratefully acknowledge Dr Ben Shandro, Dr Anet Soubieres, Dr Rhys Hewett, Dr Willem J.S. de Villiers, and Dr Houssam Mardini, previous contributors to this topic.


BS, AS, RH, WJSD, and HM declare that they have no competing interests.

Peer reviewers

Trevor Winter, MD, PhD

Associate Professor of Medicine

Division of Digestive Diseases and Nutrition

University of Kentucky




TW declares that he has no competing interests.

Sharon Stein, MD

Assistant Professor of Surgery

Division of Colon and Rectal Surgery

University Hospital Case Medical Center




SS received a fee for educational courses on laparoscopic surgery, paid for in part by Covidien, Olympus, and Applied Medical.

Use of this content is subject to our disclaimer