JAK inhibitors

Question 1

What are the major risk factors associated with JAK inhibitors?

Answer 1

Increased risk of severe and possibly fatal infection
Increased risk of venous thromboembolism
Increased risk of cardiovascular disease
Increased risk of malignancy

Question 2

What does the evidence state about the risk between use of Tofacitinib and CVD and malignancies?

Answer 2

From a clinical trial of patients aged 50 years or older with rheumatoid arthritis with at least one cardiovascular risk factor:

Showed an increase incidence of major adverse cardiovascular event and
Increased incidence of malignancies particularly lung cancer and lymphoma (except non-melanoma skin cancer)

This is in comparison to use of TNF-a inhibitors

Question 3

By assessing the risk of CVD and malignancy associated with Tofacitinib which patients would be contra-indicated or cautioned for its use?

Answer 3

Over 65 (also associated with infection risk)
Current smokers or past smoker
CVD disease

Cautioned:
Those with CVD or malignancy risk factors that there is no suitable alternative

Question 4

What does the evidence state about the risk between use of Tofacitinib and incidence of infection?

Answer 4

Tofacitinib is found to increase the risk of serious and fatal infections, with higher rates of infections in the elderly.

Question 5

What are the consequences of JAK inhibitors on the immune system?

Answer 5

Lead to viral reactivation
Increases the risk of serious and fatal infections

Hence are contra-indicated in serious infections and active TB

Question 6

What does the evidence state about the risk between use of Tofacitinib and VTE?

Answer 6

There is a dose-dependent increased risk between Tofacitinib and severe VTE.

Question 7

How would you manage the risk of VTE in patients prescribed Tofacitinib (and other JAK inhibitors) ?

Answer 7

Use with caution in patients that have a known risk factor for VTE
Educate patients of the warning signs and symptoms of a VTE and prompt them to seek medical treatment immediately if it does occur
Discontinue Tofacitinib permanently if VTE does occur
Does not exceed recommended prescribing dose

Question 8

By assessment of the potential adverse effects of Tofacitinib, in which patients is the drug contra-indicated?

Answer 8

Patients over 65
Current or past long-term smokers
Patients with other cardiovascular disease
Patients with malignancy risk factors

All should be avoided unless there are no other alternatives

Question 9

By assessment of the potential adverse effects of Tofacitinib, in which patients is the drug cautioned?

Answer 9

Patients with risk factors, use lower doses
In patients with VTE risk factors

Question 10

What advise should be given to patients before starting Tofacitinib?

Answer 10

Inform patients and their carers of these risks, and the signs and symptoms that warrant urgent medical attention

Receive all recommended vaccines including prophylactic varicella zooster vaccine. Live vaccines should be at least 2 weeks if not 4 weeks before treatment starts.

Question 11

What monitoring should a patient receive whilst having Tofacitinib?

Answer 11

Measure D dimer levels after 12 months of treatment (assessment of risk for VTE), if the D dimer level is 2 times the upper limit of normal or more, consider treatment discontinuation unless potential benefit outweighs risk.

Skin examinations due to increased risk of malignancy

Question 12

What other therapy may have to be initiated alongside Tofacitinib?

Answer 12

Anti-tuberculosis therapy should be initiated in patients with untreated latent tuberculosis, active tuberculosis or at risk of tuberculosis before starting Tofacitinib therapy.

Question 13

What are the key interactions between Tofacitinib and CYP3A4 and CYP2C19?

Answer 13

Adjust the dose (normally reduce by a half) if the patient is also taking CYP3A4 inhibitors and/or CYP2C19 inhibitors.

Question 14

What are some of the risk factors for developing VTE?

Answer 14

Major surgery
Immobilisation
Myocardial infarction in the last 3 months
Previous VTE
Malignancy
HRT and contraception
Coagulation disorders

Additional risk factors:
Increasing age
Obesity
Diabetes
HTN
Smoking

Question 15

What are some of the risk factors for infection?

Answer 15

Chronic or recurrent infection
Exposure to TB
History of serious opportunistic infection
Conditions that predispose infection (Diabetes, Chronic lung disease)
Recurrent infections
Elderly

Question 16

Is CV risk dose dependent or not dose dependent?

Answer 16

Baricitinib, Filgotinib and Upadacitinib therapy is associated with a dose dependent rise in lipids.

Question 17

Which JAK inhibitors are known to increase the risk between Diverticulitis and Gastro-intestinal perforation?

Answer 17

It has been reported in:
Baricitinib
Tofacitinib
Upadacitinib

Question 18

When did most cases of Diverticulitis occur with JAK inhibitors?

Answer 18

When patients were concomitantly taking medicines associated with an increased risk of Diverticulitis.

Question 19

How should the risk of Diverticulitis be managed in patients taking JAK inhibitors?

Answer 19

It should be used in caution in patients with pre-existing diverticular disease and in patients on long-term concomitant medications associated with an increased risk of Diverticulitis such as NSAIDs, corticosteroids and opioids.
Advise patients on JAK inhibitors to seek medical attention if they experience severe abdominal pain with fever, nausea and vomiting or other symptoms of Diverticulitis.
Must be a prompt evaluation of patients presenting with new onset abdominal signs and symptoms to identify Diverticulitis early and GI perforation.

Question 20

What are the cautions for use regarding Diverticular disease?

Answer 20

Cautioned in patients with diverticular disease or those with the known risk factors.

Question 21

What other monitoring is required for JAK inhibitors?

Answer 21

Full blood count- withhold treatment in low absolute neutrophil and lymphocyte count and haemoglobin (can further decrease it).

In Baricitinib, Tofacitinib, Upadacitinib can cause an increase in LFT.

Question 22

How effective is Upadacitinib?

Answer 22

Limited data for effectiveness in patients with RA over 75 years.
There is an increased risk of adverse effects in patients over 65.

Question 23

What are the key drug interactions of Upadacitinib?

Answer 23

The drug is metabolised by CYP3A4 and therefore if taken with drugs that are inducers or inhibitors or this enzyme this can result in a change in exposure of the drug.