Medicines Healthcare Products Regulatory Agency
Advice for healthcare professionals:
- an increased incidence of malignancy, major adverse cardiovascular events (MACE), serious infections, venous thromboembolism (VTE) and mortality, when compared to those treated with tumour necrosis factor (TNF)-alpha inhibitors, has been observed in trials of patients with rheumatoid arthritis with certain risk factors when treated with some JAK inhibitors, particularly tofacitinib see advice for tofacitinib from 2020 and 2021
- following a review, these risks are considered class effects across JAK inhibitors used for chronic inflammatory disorders and therefore it is advised to avoid prescribing these medicines unless there are no suitable alternatives in patients with the following risk factors:
- age 65 years or older
- current or past long-time smoking
- other risk factors for cardiovascular disease or malignancy
- use caution if prescribing in patients with risk factors for VTE other than those listed above (see below for more details)
- where applicable, use lower doses in patients with risk factors (see individual Summary of Product Characteristics of each medicine for further detail abrocitinib (Cibinqo), baricitinib (Olumiant), upadacitinib (Rinvoq), and filgotinib (Jyseleca)
- the incidence of non-melanoma skin cancer in the study was also higher with tofacitinib than with a TNF inhibitor therefore carry out periodic skin examinations in all patients on JAK inhibitor medicines to check for signs of skin malignancy
- inform patients of these risks and key signs and symptoms that could warrant urgent medical attention (see below)
- report suspected adverse drug reactions associated with JAK inhibitors on a Yellow Card
Advice for healthcare professionals to provide to patients and caregivers:
- JAK inhibitors are effective medicines for treating chronic inflammatory disorders such as severe arthritis, psoriatic arthritis, inflammatory bowel diseases, and atopic eczema (atopic dermatitis)
- however, these medicines can increase a patients risk of developing major cardiovascular problems (such as heart attack or stroke), cancer, blood clots in the lungs and in the deep veins of the body, serious infections, and death when compared with other treatments for these conditions called TNF-alpha inhibitors
- the risks are greater if you have risk factors, such as being age 65 years or older, have an already increased risk of major cardiovascular problems or cancer, or if you smoke or have smoked in the past for a long time
- if you have a risk factor, your doctor will consider alternative treatment options and only offer you treatment with a JAK inhibitor if nothing else is suitable for you
- your doctor may recommend a lower dose of the JAK inhibitor medicine, to minimise possible risks
- contact your doctor or seek urgent medical advice if, during treatment, you experience chest pain or tightness (which may spread to arms, jaw, neck and back), shortness of breath, cold sweats, light headedness, sudden dizziness, weakness in arms and legs or slurred speech these are signs of a medical emergency
- examine your skin periodically and let your doctor or nurse know if you notice any new growths on your skin or changes to moles (including itching, shape and discharge, which may not be as obvious on darker skin tones); these could require investigation for possible skin cancer
- always read the leaflet that accompanies your medicines and talk to your doctor, nurse, or pharmacist if you are concerned about side effects
Background
Janus kinase (JAK) inhibitors are a class of medicines that include Cibinqo (abrocitinib), Jyseleca (filgotinib), Olumiant (baricitinib), Rinvoq (upadacitinib), and Xeljanz (tofacitinib). They are used in the treatment of chronic inflammatory disorders such as rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, ulcerative colitis, Crohns disease, atopic dermatitis, and alopecia areata. See specific product information for further detail abrocitinib (Cibinqo), baricitinib (Olumiant), upadacitinib (Rinvoq), and filgotinib (Jyseleca).
This advice is not relevant for use of JAK inhibitors (ruxolitinib (Jakavi?) and fedratinib (Inrebic?) to treat myeloproliferative disorders, nor Olumiant used outside of the licence in the short-term treatment of COVID-19.
Risks previously identified for Xeljanz (tofacitinib)
In 2020, the results of a clinical safety trial in patients with rheumatoid arthritis aged 50 years or older with at least one cardiovascular risk factor (Study A3921133; the phase 3B/4 randomised safety endpoint trial)[footnote 1] found that tofacitinib was associated with an increased risk of major adverse cardiovascular events (MACE, defined as death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke), malignancies, VTE, and serious and fatal infections, compared with TNF-alpha inhibitors (etanercept or adalimumab).
Prescribers of tofacitinib were informed of the trial findings and the recommended risk minimisation measures in a letter and Drug Safety Update in 2020 and a further letter and Drug Safety Update in 2021. The tofacitinib product information and educational materials were updated at this time.
Further information on the incidence rates and hazard ratios for these events in the tofacitinib groups compared with the TNF-alpha inhibitor group can be found in the letters for healthcare professionals relating to venous thromboembolism and serious and fatal infections (2020) and major adverse cardiovascular events and malignancies (2021).
Given the findings, we advised that tofacitinib should not be used in patients older than 65 years of age, people who are current or past smokers, or individuals with other cardiovascular (such as diabetes or coronary artery disease) or malignancy risk factors unless there are no suitable treatment alternatives.
Review of the risks across the class of JAK inhibitors
Following the findings for tofacitinib, a broader review was conducted by the European Medicines Agency in 2022, looking at all JAK inhibitors indicated for inflammatory diseases.
As well as the results of study A3921133 for tofacitinib, the review considered the preliminary findings of a multi-database observational cohort study of baricitinib (Olumiant) treatment (study B023), which also suggested an increased risk of major cardiovascular events (incidence rate ratio (IRR) 1.92; 95% CI 1.27 to 2.91) and VTE (IRR 1.34; 95% CI 0.84 to 2.14) in patients with rheumatoid arthritis treated with Olumiant compared with those treated with TNF-alpha inhibitors.
The latest review looked at the available mechanistic and safety data for each of the 5 JAK inhibitors approved as treatments for inflammatory conditions. The review concluded that the effects could be considered a class effect, while acknowledging that the extent to which the findings of study A3921133 applied to all JAK inhibitors was dependent on the similarities of each treated population in terms of the presence of risk factors.
The MHRA reviewed the recommendations together with information relevant to the use of these medicines