Safety Concerns Keep JAK Inhibitors a Second-line Treatment
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Janus kinase, or JAK, inhibitors have been used in the treatment of rheumatological disorders, including psoriatic arthritis. Their benefit in psoriatic skin disease is still being studied, however some safety concerns have kept the class of drugs as a second-line treatment option.
“JAK inhibitors are used to suppress the immune system in order to improve inflammation in the joints and in the skin,” Alexis R. Ogdie, MD, MSCE, associate professor of medicine and epidemiology at the University of Pennsylvania Perelman School of Medicine, said. “These work across multiple different cytokines and there’s a lot left to learn about exactly how they work.”
MD, MSCE
Mechanism of Action
Exactly how JAK inhibitors work is still not fully clear, but immune response and cell growth is regulated by targeting and blocking cytokine signaling mediated by the JAK signal transducer and activator of transcription pathway, according to a review published in Skin Therapy Letter earlier this year.
Unlike tumor necrosis factor (TNF) of interleukin (IL)-17 inhibitors, which each block one cytokine type, JAK inhibitors most likely work across multiple cytokines, according to Ogdie.
“There’s still a lot left to learn about exactly how they work, but we think they mainly work in the information access that involves TNF, IL-1, IL-6, interferon and other more blunt cytokines,” she said.
The cytokines bind to the cytokine receptor, transducing a signal, added Arthur Kavanaugh, MD, professor of medicine and director of the Center for Innovative Therapy at University of California, San Diego. This class of medications inhibit the four JAK enzymes — JAK1, JAK2, JAK3 and TYK2.
“There’s a large number of cytokines that use these enzymes and, relevant to psoriatic disease, are the cytokines such as IL-23, but also the dozens of cytokines and growth factors that signal through these molecules,” Kavanaugh said.
What is available
In the JAK inhibitor class, there are currently six medications available in the United States: tofacitinib (Xeljanz, Pfizer), baricitinib (Olumiant, Lilly), ruxolitinib (Jakafi, Incyte), upadacitinib (Rinvoq, AbbVie) fedratinib (Inrebic, Celgene) and abrocitinib (Cibinqo, Pfizer). A topical form of ruxolitinib (Opzelura, Incyte) is also available.
The FDA first approved tofacitinib for rheumatoid arthritis (RA), which was followed by approvals for baricitinib and upadacitinib for the same indication.
Tofacitinib, approved for psoriatic arthritis (PsA) in 2017, is most often used for this indication and is being studied for use in psoriasis as well. Ruxolitinib is also in clinical trials for plaque psoriasis, while upadacitinib is approved for PsA and dermatitis and used off-label to treat psoriasis.
“There’s a wide selection of drugs available for psoriasis and psoriatic arthritis, so we have to think about which drug suits the patient,” Laura Coates, MBChB, MRCP, PhD, National Institute for Health and Care Research clinician scientist and senior clinical research fellow at Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, said. “JAKs have shown efficacy in RA and PsA, and they’ve been investigated in other dermatological conditions. We’ve seen in the PsA trials that they do show efficacy in psoriasis, although not to the same level as some of the newer biologics used in dermatology.”
Efficacy and benefits
In PsA, tofacitinib was found to be beneficial in improving American College of Rheumatology (ACR) 20 and ACR 50 response in patients who had an inadequate response to disease-modifying antirheumatic drugs such as methotrexate.
Oral tofacitinib 10 mg twice daily has been found to show significant reduction in psoriasis in several trials and was also noninferior to etanercept 50 mg twice weekly, although a 5 mg dose was not significantly different from placebo in improving skin psoriasis in one 2017 study.
Baricitinib showed PASI 75 results in a significant number of patients in a phase 2b clinical trial compared with placebo.
In comparison with many biologic medications, the efficacy of JAK inhibitors has not been tested in head-to-head trials, but there are a few noted benefits to the drug type.
JAK inhibitors are oral medications, which can be a selling point for many patients over traditional biologics, which are injectable medications.
“Many of the therapeutic options in the psoriatic disease field are intravenous or subcutaneous,” Kavanaugh said. “I have yet to have a patient who would rather have a shot than pill, but the opposite is frequently true. Everyone would rather have a pill than take a shot.”
JAK inhibitors also have shown a rapid onset of action and some effect in reducing pain, according to Ogdie, which has added to their benefits.
Additionally, topical formulations of tofacitinib and ruxolitinib are being trialed for psoriasis. Despite poor medication adherence, topical formulations often have more favorable safety profiles, which could address the main issue with JAK inhibitors according to a review article.
Safety concerns
A number of adverse cardiovascular (CV) events and cancers were found in patients who had taken tofacitinib in one PsA trial, especially in older patients.
The ORAL Surveillance trial found an increased risk for blood clots and death in the 10 mg dose, as well as risks for major CV events and cancers in both doses.
“There are a lot of side effects there that we don’t have to necessarily talk about as much for our other therapies, which are raising concern for patients,” Ogdie said.
The study found a cumulative risk for cancers of 6.1% over 5.5 years, compared with 3.8% for those taking a TNF inhibitor.
Major adverse CV events were found to occur in 3.4% of patients taking tofacitinib, compared with 2.5% of those taking the TNF inhibitor, with the incidence rate of these events being higher in those aged older than 65 years.
Infections and infestations were the most common and serious events found, which included upper respiratory tract infections, bronchitis and urinary tract infections, as well as pneumonia.
While this trial focused specifically on patients with RA aged older than 50 years who already had at least one CV risk factor, its data was enough to warrant a warning from the FDA.
The black box warning includes a risk for blood clots, stroke, malignancy, venous thromboembolism, herpes zoster and death.
“If you look at the overall increased risk, it was relatively small, but it did seem to be that there was a slight increased risk “in certain subgroups of patients, such as those over 65 years of age and smokers,” Kavanaugh said.
Screening and monitoring
With this warning in mind, prescribing a JAK inhibitor to patients should come after baseline testing and include regular monitoring, much like what is done for patients on biologics, according to Coates.
“Similar to other conditions and other medications, we do intermittent monitoring blood tests and keep an eye on them in the clinic,” she said. “I don’t think there’s a big need for additional monitoring, although obviously anyone with hypertension, diabetes and other risk factors is someone you want to make sure is being looked after and monitored, and you would want to optimize any treatment for those comorbidities.”
In addition to CV baseline tests, regular liver function and creatinine level tests should also be completed, similar to what is done before other medications, and a shingles or herpes zoster vaccine is recommended, Ogdie added.
Future of JAKs
JAK inhibitors may very well be approved for psoriasis in the near future and will continue to be used as a treatment option for PsA. While they are most likely not the first line treatment option due to safety concerns, they remain effective.
“We’ve had a JAK inhibitor available in the clinic for a decade now,” Kavanaugh said. “They have some limitations, but I think we can use them well.”
For some patients with psoriatic disease, JAK inhibitors may very well be the best option, and as future studies are completed and more data analyzed, it is possible they will become more popular.
“It’s an oral medication with effectiveness across multiple domains,” Coates said. “They are much more likely to be used second- or third-line, but they definitely fill a gap. I think there’s definitely a subgroup of patients where they are still the right drug, or the best option to balance up those benefits and risks.”
- References:
- Shalabi MMK, et al. Skin Therapy Lett. 2022;27(1):4-9.
- Funk PJ, et al. Expert Rev Clin Immunol. 2022;doi:10.1080/1744666X.2022.2039121.
- Kvist-Hansen A, et al. Dermatol Ther (Heidelb). 2020;doi:10.1007/s13555-019-00347-w.
- FDA approves boxed warning about increased risk of blood clots and death with higher dose of arthritis and ulcerative colitis medicine tofacitinib (Xeljanz, Xeljanz XR). https://www.fda.gov/drugs/drug-safety-and-availability/fda-approves-boxed-warning-about-increased-risk-blood-clots-and-death-higher-dose-arthritis-and. Published July 26, 2019. Accessed July 25, 2022.
- Furumoto Y, et al. BioDrugs. 2013;doi:10.1007/s40259-013-0040-7.
- Colbert RA, et al. N Engl J Med. 2017;doi:10.1056/NEJMe1709907.
- Gladman D, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1615977.
- Mease P, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1615975.
- For more information:
- Laura Coates, MBChB, MRCP, PhD, can be reached at Nuffield Department of Orthapaedics, Rheumatology and Musculoskeletal Sciences, B4495, Headington, Oxford OX3 7LD, United Kingdom; email: laura.coates@ndorms.ox.ac.uk.
- Arthur Kavanaugh, MD, can be reached at 9350 Campus Point Drive, La Jolla, CA 92037; email: akavanaugh@health.ucsd.edu.
- Alexis R. Ogdie, MD, MSCE, can be reached at Penn Medicine, Perelman Center for Advanced Medicine, South Pavilion, 1st floor, 3400 Civic Center Blvd., Philadelphia, PA 19104; email: OgdieA@pennmedicine.upenn.edu.