This analysis provides new information about cycling JAKi or switching to a bDMARD after JAKi failure

Introduction
Rheumatoid arthritis is a chronic inflammatory disease that mainly affects a person’s joints, causing pain and disability. Rheumatoid arthritis can affect people of all ages, but it most often starts between the ages of 40 and 60. It is more common in women than men.  

There are many treatments available for rheumatoid arthritis, including disease-modifying antirheumatic drugs (often shortened to DMARDs). The term DMARD includes traditional drugs such as methotrexate, as well as newer biologic and targeted synthetic therapies (b/tsDMARDs). These work by targeting specific molecules that cause inflammation. By doing so, they reduce inflammation in the joints and decrease pain and disease worsening. The Janus kinase inhibitors (JAKi) are a class of new tsDMARDs. This includes baricitinib, filgotinib, tofacitinib, and upadacitinib. In patients being treated in everyday practice outside clinical trials, JAKi are most commonly being used in situations where they have already been shown to work. This is mainly where treatment with bDMARDs has failed and, therefore these patients have a difficult-to-treat profile.

Importantly – as has already been seen for bDMARDs – not everyone will respond to or tolerate a JAKi. As their use increases, the number of people that fail treatment with JAKi also increases, and it is important to find a solution for these patients to best help treat their rheumatoid arthritis. 

What did the authors hope to find?
At present there are two options after JAKi failure: either to cycle to a different JAKi, or to switch back to a bDMARD. The authors of this study wanted to work out which would be the best option in this scenario.

Who was studied?
The study looked at 2,000 patients with rheumatoid arthritis who were being treated in normal clinical practice. Everyone taking part had experienced failure with their first JAKi and was subsequently being treated with either a second JAKi or with a bDMARD. 

How was the study conducted?
This study used data from a group of registry databases in 17 countries. This collaboration is called the JAK-pot study, and the idea was to collect information about the use of JAKi in everyday practice. Patients in a registry are not randomised to receive any particular drug, but instead are simply observed and their data recorded as they are treated in normal everyday practice. 

Data were collected for patients with rheumatoid arthritis who had JAKi treatment failure and who were subsequently treated with either a second JAKi or with a bDMARD. Overall, 365 people received a second JAKi (the cyclers), and 1,635 moved to a bDMARD (the switchers).

The authors used these two groups to compare differences in how long people stayed on treatment with the new JAKi or bDMARD – their so-called drug retention rate. Drug retention is often thought of as being a good marker of effectiveness, safety, and tolerability, because patients usually tend to stop taking drugs that either do not work, or which have side effects. They also estimated how their disease activity changed over time using a measure called the Clinical Disease Activity Index (CDAI).

What were the main findings of the study?
The main finding was that after JAKi failure, there was not much difference between cycling to a new JAKi or switching to a bDMARD: both approaches seemed to have similar effectiveness. Improvement in disease activity as measured by the CDAI score over time was similar with both strategies. 

The authors say that they did detect an interesting trend. When side effects were the reason for stopping the first JAKi, there was a high chance that side effects would also be reported with a second JAKi. This will need to be investigated, but if it is confirmed as being relevant, it could mean that it would be wise to switch to a different type of treatment for people who get side effects on JAKi, rather than cycling. 

Are these findings new?
Yes. Before now there has been little clinical evidence to support current recommendations for managing patients with rheumatoid arthritis after failure of JAKi treatment. Only a few studies with small numbers of patients taking part have looked at the use of a second JAKi after discontinuation of a first. This study addresses this important question and gives new evidence about the best strategy to try after JAKi failure.

What are the limitations of the study?
The major limitation was that the authors had to combine data from different national registries. They point out that each country has important differences in how drugs are used. This includes issues such as access, availability, and affordability, and could affect how comparable the data are. There were also some data missing, and some treatment groups were unbalanced. This is reflective of normal clinical practice, and a common limitation of observational studies like this. Also, since upadacitinib and filgotinib have been approved only recently, most of the patients received tofacitinib and baricitinib as their first JAKi. 

Another limitation was that the primary outcome that was measured was drug retention, but this can be influenced by factors such as the number of options available and people’s individual characteristics. 

What do the authors plan on doing with this information?
The authors are working on some new data to see if the order in which different JAKi and bDMARDs are used influences patients’ response to treatment.

What does this mean for me?
If you have rheumatoid arthritis, this study could help you and your healthcare team to make decisions about when and how to use JAKi and other targeted treatments. If you are taking a JAKi and need to swap treatments, you are likely to do as well on either a second JAKi or a bDMARD, but this might depend on why the first JAKi did not work for you. 

If you have any questions or concerns about your disease or its treatment, you should speak to your doctor. 

Date prepared: November 2023
Summary based on research article published on: December 2022
From: Summary from Pombo-Suarez M, et al. After JAK inhibitor failure: to cycle or to switch, that is the question – data from the JAK-pot collaboration of registries. Ann Rheum Dis 2023;82(2):175–81. doi:10.1136/annrheumdis-2022-222835

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