Rheumatoid arthritis (RA) is a chronic, autoimmune inflammatory disease that can be challenging to treat. Without effective treatment, it can lead to irreversible joint damage.
To address the needs of people with difficult-to-treat cases of RA, researchers have been developing and testing a new class of medications known as JAK inhibitors.
JAK inhibitors are a form of disease-modifying antirheumatic drug (DMARD).
With RA, a person’s immune system attacks healthy cells in the lining of the joints and other parts of the body. DMARDs work by suppressing this immune response.
All DMARDs can potentially help reduce disease activity in people with RA. However, for some individuals, sustained remission remains an elusive goal.
The Food and Drug Administration (FDA) have so far approved three JAK inhibitors to treat RA, and researchers have identified other JAK inhibitors that show promise in clinical trials.
These medications carry a risk of adverse events and side effects. However, they also have the potential to reduce symptoms and disease activity in people who do not respond to other treatments.
So, what are JAK inhibitors, and how do they compare with other treatment options for RA?
What are the potential benefits and risks of trying a JAK inhibitor, and how can people work with their doctors to determine which treatment approach might be best for them?
RA is usually a progressive condition, meaning that without treatment, it gets worse over time.
If RA is not treated effectively, it can destroy bone and cartilage, and lead to disability.
RA causes chronic inflammation in the joints and other parts of the body. People with RA also have an increased risk of develop cardiovascular disease.
“Treating active rheumatoid arthritis is very important,” Dr. Diane Horowitz, the director of The Rheumatoid Arthritis Center at Northwell Health in Manhasset, NY, told Medical News Today.
“It’s not about treating just the pain or treating just the swelling, it’s also about preventing damage [to the joints] and preventing nonjoint manifestations,” she added.
For people with RA in the early stages, methotrexate is the most common DMARD that doctors prescribe initially. It is also the first-line treatment that the American College of Rheumatology recommend.
However, a review of randomized controlled trials found that among people with RA who took methotrexate alone, no more than 50% experienced remission.
In those with the condition for more than 1 year, remission rates fluctuated around just 30%.
In general, the longer people have lived with RA, the more difficult it can be to treat.
In cases when treatment with methotrexate alone is not enough to control disease activity, doctors may advise a person to add another DMARD to their treatment plan.
This second-line treatment often involves a biologic DMARD, such as adalimumab (Humira), etanercept (Enbrel), infliximab (Remicade), or rituximab (Rituxan).
In recent years, however, doctors have also added JAK inhibitors to the roster of options they may prescribe.
The authors of a review in the journal EMJ say the development of JAK inhibitors is “a major breakthrough since the advent of biologics.”
Biologic DMARDs first appeared in the 1990s, with manufacturers designing them to interact with other components of the immune system.
Specifically, biologic DMARDS work by targeting cytokines and immune cells involved in the development of RA.
Cytokines are proteins that are important for cell signaling and allow communication between immune cells.
Biologic DMARDs interfere with the production or action of specific cytokines or immune cells. This action interrupts signaling pathways that drive inflammation in RA.
Biologic DMARDs can be highly effective for some individuals with RA, but they do not help everyone.
Scientists writing in the journal Drugs say that targeting a single cytokine does not work for all individuals.
Unlike biologic DMARDs, JAK inhibitors target a group of small signaling molecules that help transmit signals from multiple types of cytokines.
The small signaling molecules are known as Janus kinases, or JAKs.
JAK inhibitors block the JAK signaling pathway and appear to limit some cellular processes that cause RA progression.
“I think most rheumatologists felt when we entered the biologic era, that was it,” Herbert S. B. Baraf, a clinical professor of medicine at George Washington University and managing partner emeritus at Arthritis and Rheumatism Associates, told MNT.
“But the discovery of the JAK and related pathways has made tremendous inroads, both in rheumatology and oncology, and I’m sure other fields,” he said.
To date, the FDA have approved three JAK inhibitors for the treatment of RA. These are:
Studies have found that these drugs are effective and relatively safe for treating moderate to severe RA.
Some studies suggest that certain JAK inhibitors may be slightly more effective than adalimumab (Humira) or other biologic DMARDs alone.
For example, a 2017 study found that 70% of people that researchers treated with a combination of Olumiant and methotrexate experienced 20% improvements in key symptom criteria.
This result was in comparison with 61% they treated with Humira and methotrexate.
However, people receiving Olumiant experienced a higher rate of serious adverse events.
A clinical trial from 2019 found that combination therapy with Rinvoq and methotrexate was slightly more effective for achieving “low disease activity or remission,” in comparison with treatment with Humira and methotrexate.
The rate of adverse events in this study was similar across both treatment groups.
As well as the JAK inhibitors that the FDA have already sactioned for RA, clinical trials have also assessed the experimental drugs filgotinib and peficitinib.
A phase III clinical trial found that peficitinb was more effective than a placebo for reducing symptoms of RA.
In November 2019, the manufacturer of filgotinib announced that the results from phase III clinical trials showed the drug was effective and tolerably safe for treating RA.
These findings suggest that JAK inhibitors may have an important role to play in the treatment of RA, especially for those who have not responded well to other treatments.
However, more studies are needed to understand how safe these drugs are, and how well they work.
Also, researchers say they need to do more trials to compare different JAK inhibitors and evaluate them against biologic DMARDs.
JAK inhibitors are the newest addition to the market, and so less long-term safety data is available about them than other DMARDs.
So far, studies suggest that JAK inhibitors pose risks that are similar to those of biologic DMARDs.
A review study from January 2020 concludes, “The overall safety profile of [JAK inhibitors] seems to be consistent with that of biological drugs in terms of both the type of adverse events and their incidence.”
JAK inhibitors and biologic DMARDs are both immunosuppressant drugs that can have an increased risk of serious and opportunistic infections.
Certain infections may be more common in people who are taking JAK inhibitors, including herpes zoster infection, which is the shingles virus.
But a recent phase III clinical trial on filgotinib found the rate of herpes zoster infections was low in people who took the medication and similar to those who took a placebo.
It is possible that this JAK inhibitor may pose a similar or lower risk of infection than other DMARDS, but scientists need to do more research still.
Again, researchers need more studies to understand how the risks of different DMARDs compare.
In time, Baraf expects that JAK inhibitors may take on a larger role in the treatment of RA.
“Although most of us use these as second-line treatments, I can see a day when these will be used prior to a biologic and, because most of them are effective even in the absence of methotrexate, possibly even as a first-line agent for patients with this disease,” Baraf said.
In the meantime, Horowitz encourages people to talk to their rheumatologists about the different treatment approaches.
“I think they should ask their doctors about the risks and the benefits of drugs,” Horowitz said, “and they should ask their doctors why they think one drug is better than another drug.”
Doctors who prescribe JAK inhibitors or other DMARDs can help manage the risk of adverse events by monitoring people for signs and symptoms of infection.
Doctors will do tests to check for conditions, such as tuberculosis, hepatitis B, and hepatitis C before prescribing the medication.
They will also likely do ongoing blood testing to check for low blood cell counts and other issues that may be important.
Although DMARDs carry a risk of adverse events, they can also have substantial benefits for reducing RA disease activity and symptoms. For people who have active RA, forgoing treatment with DMARDs is itself a risky choice, Horowitz said.
“If someone has very active rheumatoid arthritis, and they’re saying, ‘oh, I’m worried about the drugs,’ I will tell them that there’s risk from not taking drugs, too,” she explained.
“It’s really important to have that good therapeutic relationship with your doctor, where you can discuss all these different risks and then make the right choice,” she added.