Dr Ali discusses his presentation from the Advances in Inflammatory Bowel Diseases virtual regional meeting on June 19 on the present use and future promise of JAK inhibitors in management of IBD.

Tauseef Ali, MD, is an assistant clinical professor at the University of Oklahoma and gastroenterologist with SSM Health. 

TRANSCRIPT:

Dr. Tauseef Ali:  My name is Dr. Tauseef Ali. I'm a consultant physician at SSM Health, Oklahoma and clinical assistant professor at University of Oklahoma. On June 19th, at Advances in Inflammatory Bowel Disease regional conference, I made a presentation on optimal use of JAK inhibitors for the management of inflammatory bowel disease. Here are some key points that I shared with the audience.

As we know, inflammatory bowel disease is a chronic progressive disease, and with time, we get bowel damage that leads to complications such as surgeries and even increased risk of cancer. Our goal is to minimize these complications by using highly effective medical therapy.

Unfortunately, the therapies that are available to us, such as biologic therapy, we do have some challenges that we face when using these therapies. For example, in about 30% of the patients, these therapies don't work. They are called primary nonresponders. About half of the patients, with time, lose response for many reasons, such as they develop antibodies, they may develop intolerance to the drug, or they may have a mechanistic escape where now, their inflammatory pathways are different.

There are other challenges such as route of administration, whether they are given intravenously or through subcutaneous injection, or cost could be an issue with some patients.

What we have learned recently that the inflammatory pathway, when all these inflammatory proteins cause the damage, they actually attach to their receptors on the lymphocytes, and then they let the release of more inflammatory proteins through a pathway that is present inside these cells. One of the very fascinating pathways is the JAK/STAT pathway.

JAK proteins are intracellular proteins that become activated when your inflammatory proteins attach to their respective receptors. These JAK proteins then activate STAT proteins which go to the DNA and increase the transcription of the genes that produce more inflammatory proteins.

What scientists have done recently have discovered a drug that can actually inhibit this intracellular pathway of inflammation. JAK inhibitors block the JAK pathway. We know that there are different JAK proteins, different types and classes of JAK proteins from JAK1, JAK2, JAK3, and TYK2 protein.

Different inflammatory proteins activate all these different types of JAK proteins. Then that leads to the production of more inflammatory cytokines. Currently, in inflammatory bowel disease, we have tofacitinib, that is an approved JAK inhibitor for use in moderate to severe ulcerative colitis. It is a pan-JAK inhibitor, meaning it inhibits different JAK proteins.

Its use in ulcerative colitis has been studied in different trials. OCTAVE trial discovered that this drug has a very good remission rate, as well as it also help improve mucosal inflammation. In fact, it works both in patients who are anti-TNF- naïve or if they have been exposed to anti-TNF drug in the past.

One other fascinating thing that we learned about tofacitinib was the rapidity by which it works. Within a few days, you see improvement in the stool frequency, as well as rectal bleeding scores.

There was another study that I shared with my colleagues looking at the fact about the dose reduction of tofacitinib. Currently, tofacitinib is approved at 10 mg BID dose as an induction and a maintenance dose of 5 mg BID. This study looked at which patients would benefit from dose reduction and which patients would benefit from continuing the same dose.

What we discovered in that study, that patients who are in deep remission and patients who are anti-TNF-naïve are the ones who benefited from dose reduction. Patients who have inflammation, even an endoscopic score of 1, or patients who have used prior anti-TNF therapy, although they still did well, didn't do so well as compared to those when they were reduced to a lower dose.

These are the patients that you might want to continue at a higher dose if they are unable to sustain a remission. We also shared some data in Crohn's disease. We looked at different JAK inhibitors that are in development. We also discussed different types of JAK inhibitors.

As I discussed, tofacitinib is a pan-JAK inhibitor, so it blocks different types of JAK pathways; there are some specific JAK inhibitors that I call second-generation JAK inhibitors that block some very specific JAK molecules. For example, JAK1 that has been found had a very good data for inflammatory bowel disease. There is a gut-specific JAK inhibitor that is also being studied. In the end, I also discussed the safety issues with JAK inhibitors, such as risk of serious infections including herpes zoster, lipid abnormalities, cancer risk, and the risk of blood clots.

There was a recent post-marketing safety study that was done in rheumatoid arthritis patients revealing that patients who are 50 years of age and have at least one cardiovascular risk factor, these patients tend to have a higher risk of developing myocardial infarction, as well as an increased risk of malignancies such as lung cancers.

In clinical practice, when you are using JAK inhibitors, you may want to screen and vaccinate patients for herpes zoster. You may want to make sure that you screen them for any active malignancies. Risk of thromboembolism, you need to screen for that. Currently, tofacitinib is not approved to be used in pregnant females. You may need to monitor these patients for lipid abnormalities for cytopenias and such.

The other challenge using tofacitinib or any JAK inhibitors in ulcerative colitis is how do you position them or where do you position them in your current treatment algorithm? Do you use it after you fail first anti-TNF or you use 2 biologics first? Do you use it upfront? How do you use them in biologic-naïve patients or in patients who have been exposed to biologics in the past?

In conclusion, tofacitinib, which is in a category of small molecule drug therapies in inflammatory bowel disease, does represent one of the most interesting novelties in IBD therapeutic pipeline. The main advantage of this drug over biologics are its short half-life, unlikely risk of immunogenicity, so these drugs don't develop antibodies, and oral administration along with a faster onset of action. Second-generation JAK inhibitors may be associated with better efficacy and better safety profile.

What we still need is better understanding how to incorporate these drugs in treatment algorithm and how to predict response, and whether in future, we can combine these drugs with biologics to get better outcomes.

I hope you enjoyed AIBD Regional. We'll be looking forward to see you in our annual conference in December. Thank you.