Inflammatory bowel disease (IBD) continues to become more prevalent in NZ. Current work being undertaken by Angela Forbes (PhD student at the University of Otago, Christchurch) suggests that there are more than 4,000 patients living with IBD in Canterbury alone. If these numbers were to be extrapolated to include all of New Zealand, over 40,000 people may be living with IBD in our small country.

This poses important hurdles for our health system in order to diagnose patients early and to establish effective treatments to improve quality of life. The treatment of IBD requires a range of modalities including lifestyle factors (e.g. diet, smoking cessation), medications, and, sometimes, surgery. Medications are important to induce and maintain remission.

In recent times there has been an increasing number of medications proven to be safe and effective for the treatment of IBD. What is most exciting is that some of these medications belong to new classes of drugs which work in different ways to those that are currently available. This is important because there is evidence that some drugs will be more effective for some people while other drugs will be more effective for others. One of these new classes is the Janus kinase (JAK) inhibitors.

Over the last 25 years most new drugs have been in the “biologic” category. This means that a protein is shaped in the form of an antibody which targets a specific part of the immune system. Biologic medications currently marketed throughout the world for the treatment of IBD (NZ in bold) include anti-TNF biologics (infliximab, adalimumab, golimumab, certolizumab), anti-IL-12/23 biologics (ustekinumab, risankizumab), and anti-a4b7 biologics (vedolizumab). Each of these drugs has a different target and a different safety profile, but all are given by injection under the skin or by infusion into a vein. Furthermore, because these are proteins, the body’s immune system can sometimes view biologic drugs as “foreign” and inactivate them, leading to the drug levels dropping and the effect being lost.

As with almost all medications used to treat IBD, JAK inhibitors work by reducing the activity of the immune system. However, instead of doing this by blocking a specific molecule in the inflammatory pathway, they block the signalling of receptors in immune cells leading to multiple effects on a range of cell functions. The specific receptors that a JAK inhibitor blocks (selectivity), allow one to predict the effect (beneficial and side effect) that the drug may have (Figure 1).

The JAK inhibitors that are currently licenced for the treatment of ulcerative colitis are tofacitinib, filgotinib and upadacitnib. There are also emerging data in Crohn’s disease for both filgotinib and upadacitinib. However, as can be seen in Figure 1, other JAK inhibitors, including those with gut selectivity, are currently in development.  

Herrera-deGuise C, Serra-Ruiz X, Lastiri E, Borruel N. JAK inhibitors: A new dawn for oral therapies in inflammatory bowel diseases. Front Med (Lausanne). 2023 Mar 2;10:1089099. doi: 10.3389/fmed.2023.1089099. PMID: 36936239; PMCID: PMC10017532. Copyright © 2023 Herrera-deGuise, Serra-Ruiz, Lastiri and Borruel. 

In addition to providing a new target for IBD therapy, JAK inhibitors are given as tablets rather than infusions or injections. Furthermore, they have a rapid onset of action and are not subject to inactivation by the immune system. These characteristics make them more appealing for some patients and reduce the burden on the healthcare system associated with receiving infusions at the hospital.

As with all therapies, there are side effects. Some of these are similar to other IBD drugs that work on the immune system with an increased risk of infections. This has especially been the case for Herpes Zoster (HZ) infections leading to shingles. Older patients and those who had previously not responded anti-TNF drugs (infliximab and adalimumab) were most at risk. It is advised that patients >50 years receiving JAK inhibitors receive a vaccine to prevent shingles (it is important that this not be a “live vaccine”, but an “adjuvanted recombinant herpes zoster subunit vaccine” such as “Shingrix”. Live vaccines such as “Zostavax” for shingles should not be given to patients who are immunosuppressed).

JAK inhibitors may increase cholesterol levels, and these should be monitored and treated, especially if there are other risk factors for heart disease. High dose tofacitinib has been associated with deep vein thrombosis and pulmonary thromboembolism (blood clots) in older patients who were being treated with the medication for rheumatoid arthritis. However, it is not clear if this applies to IBD patients or other JAK inhibitors. At present, using the lowest dose is recommended and considering other risk factors for blood clots before prescribing this class of drug. Blood counts may also drop slightly and temporarily and should be monitored.

At present JAK inhibitors are not recommended during conception, pregnancy, or breastfeeding.

In summary, JAK inhibitors are an exciting development for people with IBD. They work in a new way, work rapidly, and are taken orally which may be preferable for some patients. Some of the side effects may make these drugs less attractive for older patients with IBD due to the risks of shingles, raised cholesterol, and blood clots, but further studies reporting side effects are needed.

Finally, it is interesting that Pharmac decided to fund upadacitinb for rheumatoid arthritis in 2021. This occurred when it was found that another drug, tocilizumab, which was already funded for rheumatoid arthritis, was effective against COVID and supplies of that drug became limited. Given that upadacitinib is already available in NZ for rheumatoid arthritis, the NZ IBD community should advocate for access to be widened to include patients with IBD.