The landscape of high quality treatments is improving every year, providing doctors with more options for treating people. They are also able to limit side effects and roadblocks that would previously have derailed treatment or made recovery difficult. Today, another drug type has found its way into the toolbox of possible treatments for ankylosing spondylitis (AS): Janus kinase (JAK) inhibitors.

The field of autoimmune and chronic inflammatory diseases is a good example of the progress that has occurred. Just 4 decades ago, the standard treatment was nonsteroidal anti-inflammatory drugs (NSAIDs). People with various conditions, including rheumatoid arthritis (RA) and AS, would take high dosages of drugs such as aspirin. The side effects were plentiful, and the results were mixed.

Then, newer NSAIDs became available, and the landscape improved a bit.

The early 2000s saw the first breakthrough in treatment for these conditions, as anti-TNF inhibitors became available to people with AS or other autoimmune conditions.

Today, JAK inhibitors are also available. Although doctors have used these drugs for about a decade to treat RA and several other inflammatory conditions, the Food and Drug Administration (FDA) only approved them for use in people with AS in 2021.

Now, doctors are turning to JAK inhibitors as the possible next step for treating people who have found other treatment options ineffective.

This article provides a deeper look at JAK inhibitors, including how experts think they may fit into the treatment landscape for AS and what those black box warnings mean.

JAK inhibitors are not new to rheumatologists. Tofacitinib (Xeljanz) has been an approved RA treatment since 2012. In 2017, the FDA approved it to treat people with psoriatic arthritis who did not respond well to other treatments. The next year, in 2018, the drug got approval to treat ulcerative colitis, an inflammatory condition that affects the intestine. However, it was not until 2021 that the FDA approved this drug to treat AS.

Today, three approved JAK inhibitors are available to treat various inflammatory conditions. These are:

  • baricitinib (Olumiant)
  • tofacitinib (Xeljanz)
  • upadacitinib (Rinvoq)

The FDA has approved all three to treat RA but only upadacitinib and tofacitinib to treat AS.

It is not uncommon that a drug is available for some conditions and not others, says Dr. Orrin Troum, a rheumatologist at Providence Saint John’s Health Center in Santa Monica, California. It takes years, sometimes decades, to conduct the proper reviews and studies to show that medications can be effective for specific conditions.

“These medicines have opened up a whole arena for looking at the different proteins that are overexpressed in people who have these autoimmune or inflammatory conditions. It has really been a tremendous breakthrough to have these options,” Troum told Medical News Today.

AS is a type of inflammatory arthritis. It primarily affects the spine and large joints of the body, but Dr. Troum says that it tends to affect males and females differently. Females may have more symptoms in the neck and cervical spine, whereas males more commonly experience symptoms in the buttocks, mid-back, or thoracic spine.

AS causes inflammation in the joints and ligaments of the spine. In a typical spine and back, these joints and ligaments move freely, helping a person bend or flex. But in people with AS, these joints begin to stiffen with time and prolonged inflammation. The joints and tissues may even fuse, which can make the spine rigid and inflexible.

It remains unclear what causes AS. However, researchers do know that certain proteins are responsible for the inflammation that causes the symptoms. These inflammatory proteins lock into the immune cells that would typically work to reduce inflammation. Instead of fighting the inflammation, these proteins signal the cells to make more inflammatory proteins.

Treatments such as JAK inhibitors work to block this messaging pathway and slow or stop the production of the inflammatory proteins entirely.

JAK inhibitors belong to a group of medications called disease-modifying antirheumatic drugs, or DMARDs. DMARDs, which include methotrexate and sulfasalazine, work by suppressing the immune system broadly. This suppression prevents the immune system from producing the proteins that damage joints.

Biologics are a more targeted treatment option. These drugs block a specific type of inflammatory protein called cytokines. People will receive these medications in the form of an injection or infusion.

JAK inhibitors combine elements of classic DMARDs and biologics into one treatment. They interfere with a signaling cascade that triggers several inflammatory molecules. These drugs work inside immune cells to block the messaging path. They are also available as a pill, which generally makes the treatment process more straightforward.

However, biologic medication is more expensive than other medications to manufacture, leading to higher costs. In addition, many of these medicines come with more side effects and health risks.

When the FDA approved the first JAK inhibitor for AS treatment, it did so with a black box warning. This is a warning that the medication carries serious safety risks and may be life threatening for some people.

In the case of Xeljanz, the federal agency noted that the drug may present an “increased risk of serious heart-related events such as heart attack or stroke, cancer, blood clots, and death.”

“Patients treated with JAK inhibitors are at increased risk for developing serious infections. An infection is considered serious when it results in hospitalization or, even worse, death,” said Dr. Stella Bard, an ABMS board certified rheumatologist. “Since most patients who developed such infections were also additionally taking other immunosuppressants, such as methotrexate and or corticosteroids, it’s difficult to tell if the risk of infection is from JAK inhibitors or these particular immunosuppressants.”

Bard noted that these infections include bacterial and viral infections, such as herpes zoster (shingles) and tuberculosis (TB). Invasive fungal infections, such as cryptococcosis and pneumocystis, are also possible.

Secondly, JAK inhibitors can increase a person’s total cholesterol levels. This puts them at risk of major adverse cardiovascular events (MACE), such as heart attack or stroke.

A 2022 study compared JAK inhibitors with TNF blockers in people with RA who were aged 50 years and over and had at least one cardiovascular risk factor. The researchers found a higher rate of these major adverse cardiovascular events with the use of JAK inhibitors.

For that reason, doctors may decide not to prescribe JAK inhibitors to people who currently smoke, individuals who previously smoked, and those with a history of heart attack or stroke.

The study also showed that some people taking JAK inhibitors had a higher rate of lymphoma and other cancers, including lung cancer. People with a history of smoking were at increased risk. The same mechanisms that block immune system response may prevent the body from fighting certain tumors.

Only 51.3% of patients with axial spondyloarthritis — of which AS is a specific subset — respond to TNF inhibitors. Some of those people lose their response to the medication over time or develop undesirable side effects, while others are not eligible to take it at all. For these reasons, there is always a need for new treatment options for conditions such as AS.

However, Troum believes that the array of treatments available now gives doctors more ways to approach the condition than they have had in his entire career.

“JAK inhibitors are quite remarkable. They’re being looked at for other disease states, such as Still’s disease, a form of juvenile rheumatoid arthritis,” he said.

As with any medical advancements, though, there is a need to weigh the benefits of the new drugs with the risks.

“These drugs, I believe, are typically safe,” said Troum. “They absolutely have a place in the armament of treating these conditions. The majority of the [severe side effects] were in people at high risk: men over 65 with cardiovascular risks.”

“But the data showed what they showed, so there has to be caution. The FDA is cautious, and rightfully so. But it’s a very important addition. It’s another bullet in our belt to treat patients.”