JAK inhibitors in GCA? Save

It’s been eight years, and here we are again. The ACR annual meeting was last in Washington DC in 2016, and there’s probably a lot about ACR 2024 in DC that seems familiar. Maybe for some, it’s the half-smoke hot dogs that DC is famous for, maybe for others it’s something else (as an Australian, who am I to say). Sometimes ACR Convergence can have little overtones of Groundhog Day, living the same story over and over.

For others again, it’s the fact that we have a phase 3 trial in giant cell arteritis back on the opening day plenary stage. The SELECT-GCA study, looking at upadacitinib in GCA, was scheduled to anchor the ACR 2024 opening plenary for a reason - it is highly notable and badly needed.

That might surprise the audience from eight years ago. Certainly, many people felt that when GiACTA was presented at the opening plenary at ACR 2016, looking at tocilizumab in GCA, that it would signal a whole new treatment indication and diverse therapeutic armamentarium. At a time when we had seemingly solved inflammatory arthritis and biosimilars were going to end pharmaceutical innovation, this seemed like the new frontier for drug development.

Well, here we are in 2024, and we still only have one registered therapy for GCA, the very same one presented in 2016. It has taken us some time to build up the courage to use it in place of the high doses of glucocorticoids that we were used to pouring into our GCA patients, and even longer to understand some of the difficulties with its use. Not all patients respond initially, not all patients tolerate it, we still don’t know how long to treat for, and questions remain about whether tocilizumab truly modifies the disease, or just spares steroid.

So, as it happens, one therapy is not sufficient to solve a disease, even as it comes off patent in different jurisdictions. Clearly, we need other options, and ideally ones which can influence interferon gamma to influence vascular sequelae. Even before considering rapid time-to-effect, or the ease of administration, JAK inhibitors hold substantial appeal.

SELECT-GCA shows that there is substance behind the appeal. 

Both from the top-line results in the plenary and the subgroup analysis in the oral abstract sessions, we see that upadacitinib works in GCA in a substantial way: keeps patients in remission, reduces steroid exposure, and improves fatigue, with benefit right across the board. We will wait to see how many of the holes in tocilizumab’s therapeutic offering are plugged by upadacitinib, but clearly many patients could benefit.

Will rheumatologists prescribe it, though? 

We are still collectively reeling as a speciality from ACR 2021, when the ORAL Surveillance results came thick and fast, and surprised many - even if the warning signs had been there. Undoubtedly, it raises questions about incremental cardiovascular and cancer risk from tofacitinib compared to TNF inhibitors in rheumatoid arthritis. There are no doubt questions in the detail, but in scenarios adjacent to the above, some concern might be caveated but justifiable.

In a different disease with a different treatment paradigm, with far fewer choices and a dependence on steroids we just can’t seem to shake yet, our thinking should not be the same. It might be a disease of older people, and there might be inherent cardiovascular involvement, but the therapeutic context is dramatically different - and we are simply not in a place to reflexively dismiss a therapy that might be right for many.

Of course, JAK inhibitors are not universally good or bad - very few of our therapies are. They might be slightly but palpably riskier than other therapies in some of our diseases, but we need to fight the mental heuristic that JAK inhibitors are always a safety risk.

We sometimes live with the illusion that things are either bad or good, because that can be the easiest way for us to explain it to others. We cannot not fall for that thinking ourselves, especially in situations where we are not blessed with options.