What are JAK inhibitors and how do they work?
Janus kinase (JAK) inhibitors are a class of targeted disease-modifying antirheumatic drugs (DMARDs) that modulate the immune system by inhibiting specific signaling pathways. These small-molecule inhibitors work by disrupting the JAK-signal transducer and activator of transcription (JAK-STAT) pathway inside cells. This pathway is crucial for transmitting signals from cytokines, which are proteins that play a central role in inflammation and the immune response. By blocking these signals, JAK inhibitors effectively reduce the inflammation that drives a range of autoimmune and inflammatory conditions.
Unlike traditional biologics, which are often injectable antibodies, many JAK inhibitors are small oral molecules. Their oral formulation and rapid onset of action offer a distinct advantage for many patients. However, the non-selective inhibition of multiple cytokine receptors can increase the risk of side effects, including serious infections and other significant health concerns, which is why close patient monitoring is essential.
FDA-approved oral JAK inhibitors and their uses
Tofacitinib (Xeljanz)
Tofacitinib was one of the first oral JAK inhibitors approved by the FDA, with its initial nod for rheumatoid arthritis (RA) in 2012. It primarily inhibits JAK1 and JAK3. Its indications have since expanded to include:
- Moderate to severe RA
- Active psoriatic arthritis (PsA)
- Moderate to severe ulcerative colitis (UC)
- Active polyarticular course juvenile idiopathic arthritis (pcJIA)
- Active ankylosing spondylitis (AS)
Baricitinib (Olumiant)
Approved in 2018 for RA, baricitinib is a JAK1/JAK2 inhibitor with a broader application profile. The FDA has also approved it for:
- Moderate to severe atopic dermatitis (AD)
- Severe alopecia areata (AA) in adults
Upadacitinib (Rinvoq)
As a selective JAK1 inhibitor, upadacitinib has shown strong efficacy across several inflammatory conditions. Its FDA-approved uses include:
- Moderate to severe RA
- Active PsA
- Moderate to severe AD
- Moderate to severe UC
- Active AS and non-radiographic axial spondyloarthritis
Ruxolitinib (Jakafi)
Ruxolitinib targets JAK1 and JAK2 pathways. Its FDA approvals focus on hematologic malignancies and graft-versus-host disease (GVHD):
- Intermediate or high-risk myelofibrosis (MF)
- Polycythemia vera (PV) in patients with an inadequate response to or intolerance of hydroxyurea
- Acute and chronic GVHD
Specialized JAK inhibitors for hematology
- Fedratinib (Inrebic): Approved in 2019 for adults with intermediate-2 or high-risk MF, including post-PV MF and post-essential thrombocythemia MF.
- Pacritinib (Vonjo): Approved in 2022 for patients with intermediate or high-risk MF who have severe thrombocytopenia (platelet count <50 × 109/L). It is a JAK2 inhibitor with potent activity against FLT3, improving platelet counts rather than reducing them.
- Momelotinib (Ojjaara): Approved in 2023 for intermediate or high-risk MF with anemia, as it uniquely improves hemoglobin levels.
Additional oral JAK inhibitors
- Ritlecitinib (Litfulo): Approved in 2023 for severe AA in adolescents and adults ages 12 and up.
- Deuruxolitinib (Leqselvi): Approved in 2024 for severe AA in adults 18 years and older.
- Abrocitinib (Cibinqo): Approved in 2022 for moderate to severe AD in adults.
- Deucravacitinib (Sotyktu): A selective TYK2 inhibitor approved in 2022 for moderate to severe plaque psoriasis in adults. TYK2 is a member of the JAK family.
FDA-approved topical JAK inhibitors
Ruxolitinib (Opzelura) cream was the first topical JAK inhibitor approved by the FDA in 2021. It is indicated for treating non-segmental vitiligo in patients 12 years and older, and for mild to moderate atopic dermatitis in non-immunocompromised patients 12 years and older.
Comparison of key FDA-approved JAK inhibitors
| Generic Name | Brand Name(s) | Primary Target(s) | FDA-Approved Indications |
|---|---|---|---|
| Tofacitinib | Xeljanz | JAK1, JAK3 | RA, PsA, UC, pcJIA, AS |
| Baricitinib | Olumiant | JAK1, JAK2 | RA, AD, severe AA |
| Upadacitinib | Rinvoq | JAK1 | RA, PsA, AD, UC, AS |
| Ruxolitinib | Jakafi, Opzelura | JAK1, JAK2 | MF, PV, GVHD, AD (topical), Vitiligo (topical) |
| Fedratinib | Inrebic | JAK2, FLT3 | MF |
| Pacritinib | Vonjo | JAK2, IRAK1, FLT3 | MF with severe thrombocytopenia |
| Momelotinib | Ojjaara | JAK1, JAK2, ACVR1 | MF with anemia |
| Ritlecitinib | Litfulo | JAK3, TEC | Severe AA |
| Deucravacitinib | Sotyktu | TYK2 | Moderate to severe plaque psoriasis |
Important safety information
Due to their mechanism of action, which broadly suppresses the immune system, JAK inhibitors carry significant warnings. The FDA has mandated boxed warnings for these medications, highlighting several serious risks.
- Serious Infections: Increased risk of serious bacterial, fungal, viral, and mycobacterial infections, including opportunistic infections. Before starting treatment, patients should be screened for tuberculosis and have appropriate vaccinations.
- Malignancy: An elevated risk of certain cancers, including lymphomas and other malignancies, has been observed.
- Major Adverse Cardiovascular Events (MACE): In clinical trials, an increased rate of cardiovascular events, such as heart attack and stroke, was noted, particularly with higher doses.
- Thrombosis: Increased risk of blood clots, including deep vein thrombosis (DVT) and pulmonary embolism (PE).
- Mortality: In some studies, particularly those involving higher doses in certain patient populations, an increased risk of death has been observed.
Patients should discuss their medical history and these potential risks with their healthcare provider before beginning treatment. Regular monitoring is crucial to manage and detect side effects early. For more detailed information on drug safety, refer to the FDA Drug Safety website.
Future outlook for JAK inhibitors
The field of JAK inhibition is rapidly advancing, with ongoing research into new and improved agents. Scientists are exploring more selective inhibitors, as well as novel combination therapies to improve efficacy and manage side effects. Research is also focused on determining the optimal sequencing of JAK inhibitors in patients who have failed or become intolerant to other treatments, such as biologics. The potential for JAK inhibitors to treat a broader spectrum of inflammatory and malignant diseases, while improving long-term safety, remains a key area of investigation. As research progresses, updated guidelines and new treatment options will continue to emerge, offering more personalized care for patients with chronic inflammatory conditions.
Conclusion
Janus kinase inhibitors represent a significant advancement in the treatment of a wide range of autoimmune, inflammatory, and hematologic conditions. With numerous FDA-approved options now available, both orally and topically, these targeted therapies offer new hope for patients who have not responded to conventional treatments. However, their use requires careful consideration of the associated risks, including serious infections, blood clots, and malignancy, which are highlighted by FDA boxed warnings. Ongoing research and real-world experience continue to refine our understanding of their optimal use, safety, and efficacy, further shaping the treatment landscape for these complex diseases.
