Last reviewed: 20 Sep 2021
Last updated: 23 Sep 2021
03 Aug 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).[42]

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 - the induction dose for ulcerative colitis) in the preliminary analysis.[43]

The FDA advises clinicians to:[42]

  • 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) for tofacitinib only in June 2021, 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.[43][44]

See Management: approach

See Management: treatment algorithm

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History and exam

Key diagnostic factors

  • rectal bleeding
  • diarrhea
  • 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
  • nonsteroidal anti-inflammatory drugs (NSAIDs)
  • not smoking or former smoker

Diagnostic investigations

1st investigations to order

  • stool studies for infective pathogens
  • fecal calprotectin
  • CBC
  • 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.

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