JAK inhibitors: risks and safety principles

Introduction

The Janus kinases (JAKs) are protein tyrosine kinases that mediate cellular responses to several cytokines and growth factors, which play a role in immune defence and immune-mediated disease^​1​. By inhibiting JAKs, JAK inhibitors (JAKi) disrupt the inflammatory signalling pathway, dampening the overactive immune response.

In the UK, the National Institute for Health and Care Excellence (NICE) has approved the use of JAKis via technology appraisals, with established and investigational uses in the management of inflammatory and haematologic disorders, such as rheumatoid arthritis^​2–5​, juvenile idiopathic arthritis^​6​, psoriatic arthritis^​7,8​, ankylosing spondylitis^​9,10​, axial spondyloarthritis^​11​, atopic dermatitis^​12,13​, Crohn’s disease^​14​, ulcerative colitis^{​15–17​}, alopecia areata^​18​, vitiligo^​19​, splenomegaly^​20,21​, myelofibrosis^​20,21​, polycythaemia vera^​22​ and graft-versus-host disease^​23​.

The evolving safety profile of JAKis makes the role of the pharmacist indispensable in safeguarding patient care, optimising patient outcomes through expert knowledge, vigilant monitoring, patient education and shared decision-making to ensure the safe and effective use of these medicines. JAKi can cause significant adverse effects and carry important safety considerations, of which pharmacists should be aware.

Mechanism of action 

There are four receptor-associated tyrosine kinases: JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2)^​24​. They transfer phosphate from adenosine triphosphate (ATP) to tyrosine residues on other proteins, including cytokine receptors, JAKs and downstream signalling molecules, triggering their enzymatic activity^​25​. One critical class of signalling molecules for type I/II cytokine receptors is the signal transducer and activator of transcription (STAT) family of DNA binding proteins — phosphorylated STATs then translocate to the nucleus, bind DNA and drive gene transcription^​25​, which drives immune responses, inflammation and haematopoiesis and makes them suitable for treating inflammatory and haematological disorders (see Figure 1^​24​).

Figure 1: The JAK-STAT Pathway (reproduced with permission)

Indications

There are many JAKis approved for different indications in the UK (see Table 1^​2–23​).

Table 1: JAKis and their indications in the UK

Contraindications and safety warnings

JAKis carry important safety considerations. A European Medicines Agency (EMA) safety alert, published in 2022, reported that tofacitinib, abrocitinib, baricitinib, upadacitinib and filgotinib are linked to a higher risk of major adverse cardiovascular events (MACE), venous thromboembolism (VTE), malignancy, serious infections and all-cause mortality^​26​. The recommendations regarding contraindications and risk versus benefit assessment for JAKi use can be seen in Box 1^{​26–34​} and 2^​26,35​. The alert resulted from the ORAL Surveillance study of tofacitinib and preliminary findings from an observational study involving baricitinib in rheumatoid arthritis where increased cardiovascular and VTE risk were observed. It is important to note that this review did not include ruxolitinib or fedratinib, which are used to treat myeloproliferative disorders, nor the use of baricitinib in the short-term treatment of COVID-19^​26​.
 
Box 1 lists the patient cohorts in which JAKis are contraindicated. Box 2 lists the patient cohorts in which JAKis should only be used if no suitable treatment alternatives are available^​26,35​.

If there are no suitable alternatives and a JAKi is needed in a patient with these risk factors, the following steps should be taken:

• Discuss the risks associated with patients; 
• A lower dose may be recommended, depending on the medicine, indication and specific risk factor;
• Carry out periodic examinations of the patients’ skin to check for skin cancer, particularly for those at risk and educate patients to do this, which is risk-dependent on choice of JAKi;
• Inform patients to seek medical attention immediately if, at any stage during treatment, chest pain or tightness — which may spread to arms, jaw, neck and back — shortness of breath, cold sweat, lightheadedness, sudden dizziness, weakness in arms and legs or slurred speech is experienced;
• Report suspected reactions to the Medicines and Healthcare products Regulatory Agency Yellow Card scheme^{​26,35,36​}.

Initiation of therapy and monitoring

JAKis should be initiated by specialist clinicians who are aware of the patient’s disease and underlying comorbidities. Treatment is generally long term; however, duration varies depending on the condition being managed.

Serious infections should be ruled out prior to starting JAKi therapy, including tuberculosis and varicella zoster. Baseline blood monitoring should also be undertaken prior to starting therapy, including full blood count, liver function tests, bilirubin, urine and electrolytes, and lipid monitoring. This should be reviewed at three-to-six monthly intervals or more frequently in accordance with local protocols or if patients are at a high risk of side effects.

Depending on baseline blood monitoring, doses may be initiated at a lower dose — refer to the summary of product characteristics for the relevant JAKi for further information.

Overview of side effects

Frequency of side effects differs slightly with different JAKi and the condition being managed. Figure 2 shows the wide-ranging side effects that JAKis can cause and how these side effects can be managed^​28,34​. JAKis are non-specific targets, inhibition of this pathway reduces inflammation, autoimmunity and cytokine-driven symptoms and may result in a wide range of adverse effects.

Figure 2: Overview of side effects of Janus kinases inhibitors

Patients on JAKis should seek immediate medical attention if they experience the symptoms of the serious conditions shown in Table 2^​26,35​.

Table 2: Serious conditions where immediate medical attention must be sought

Drug interactions and considerations for medicine switching

In general, JAKi are metabolised by the CYP450 enzymes, namely CYP3A4, CYP219, CYP29^{​27–34​}.

While some JAKis act as CYP3A4/219/29 inhibitors and inducers, the interactions are not significant for all JAKis. Healthcare professionals should refer to the British National Formulary (BNF)/British National Formulary for Children (BNFc) for each drug monograph for further details relating to drug interactions.

Common JAKi drug interactions are shown in Table 3 (list not exhaustive)^​37​.

Table 3: Examples of common drug interactions and potential management

Considerations for vaccination 

Wherever possible, immunisation or boosting of immunosuppressed individuals should either be carried out before initiation of JAKis or deferred until an improvement in immunity has been seen. The optimal timing for any vaccination should be based upon a judgement about the need for rapid protection and the likely response^​38​.

For individuals due to commence JAKi therapy, inactivated vaccines should ideally be administered at least two weeks before commencement. In some cases, this will not be possible and, therefore, vaccination may be carried out at any time and re-immunisation considered after treatment is finished and recovery has occured^​38​.

Live vaccines include influenza vaccine (nasal), measles, mumps and rubella vaccine, rotavirus vaccine, shingles vaccine, BCG vaccine, oral typhoid vaccine, varicella vaccine and yellow fever vaccine. 

Individuals who are on or have recently received high doses of certain immunosuppressive or biological therapies, including JAKis, should not be given live vaccines, owing to the risk of severe or fatal infections. As live vaccines replicate after administration, individuals should ideally wait until their immune response has been established before commencing immunosuppressive therapy. 

For most viral live vaccines, a period of up to four weeks should be sufficient prior to initiating immunosuppressive therapy and can be resumed at least three months after stopping JAKi therapy^​38​.