Tofacitinib: First Oral JAK1/3 Inhibitor for Rheumatoid Arthritis, Psoriatic Arthritis, and Ulcerative Colitis
Tofacitinib (brand name Xeljanz, Pfizer) is the first orally available Janus kinase inhibitor and was approved in the European Union in 2017 for the treatment of moderate to severe active rheumatoid arthritis. Approvals have since been obtained for psoriatic arthritis, ulcerative colitis, ankylosing spondylitis, and juvenile idiopathic arthritis. Oral availability represented a paradigm shift in a therapeutic field previously dominated by biologics administered via subcutaneous or intravenous routes.
Tofacitinib is the focus of the ORAL Surveillance study (NCT02092467), a post-authorization safety study whose results in 2021 led to an EMA and FDA wide safety warning for the entire class of JAK inhibitors. The study demonstrated in patients aged 50 years and older with cardiovascular risk factors an increased risk of myocardial infarction, stroke, cancer (particularly lung and lymphoid malignancies), thromboembolism, and mortality compared to TNF inhibitors. These data have changed therapeutic approaches and must be communicated transparently to patients.
Mechanism of Action
Tofacitinib inhibits predominantly JAK1 and JAK3, to a lesser extent JAK2 and TYK2. JAK1 and JAK3 are central to signal transduction of numerous proinflammatory cytokines, including interleukin 2, interleukin 6, interleukin 15, interleukin 21, and interferon gamma. When a cytokine binds to its receptor, JAKs phosphorylate downstream STAT signaling molecules, which migrate to the cell nucleus and activate pro-inflammatory genes.
By blocking JAK activity, intracellular signal transduction of pro-inflammatory cytokines decreases, reducing T and B cell activation, acute phase proteins, and tissue-damaging effects. In rheumatoid arthritis, this results in reduction of synovial inflammation and bone erosion. In ulcerative colitis, JAK inhibition leads to improvement in stool frequency, mucosal inflammation, and quality of life.
Tofacitinib is metabolized via CYP3A4 (primary pathway) and CYP2C19. Half-life approximately three hours, necessitating twice-daily administration. An extended-release formulation (Xeljanz XR) permits once-daily dosing.
Indications
- Moderate to severe active rheumatoid arthritis (RA): in case of inadequate response to conventional DMARDs or biologics
- Active psoriatic arthritis (PsA): in case of failure or intolerance of DMARDs
- Moderate to severe active ulcerative colitis: in case of inadequate response to conventional therapy or biologics
- Active ankylosing spondylitis (Bechterew disease): in case of inadequate response to NSAIDs and biologics
- Juvenile idiopathic arthritis (JIA) from 2 years: in polyarticular presentation
Dosage and Administration
Rheumatoid arthritis and psoriatic arthritis: 5 mg twice daily orally or 11 mg extended-release once daily. Ulcerative colitis: Induction 10 mg twice daily for 8 weeks, then maintenance 5 mg twice daily. If inadequate response, maintenance dose can be increased to 10 mg twice daily.
Moderate to severe renal impairment and moderate hepatic impairment: halve dose. Severe hepatic impairment (Child Pugh C): contraindicated.
In patients aged 65 years and over or with cardiovascular risk factors: Tofacitinib should only be used when no suitable therapeutic alternatives are available, according to EMA recommendation 2023.
Adverse Effects
Common: upper respiratory tract infections, urinary tract infections, nasopharyngitis, diarrhea, nausea, headache, elevated liver transaminases, hyperlipidemia (LDL and HDL), anemia, neutropenia, lymphopenia.
Serious: herpes zoster reactivation (in some studies significantly more frequent than placebo), severe infections including opportunistic infections such as tuberculosis, invasive fungal infections, Pneumocystis jirovecii pneumonia. Venous thromboembolism (pulmonary embolism, deep vein thrombosis) and arterial events (myocardial infarction, stroke) increased in risk patients. Malignancies including lymphoma, non-melanoma skin cancer, lung cancer (especially in smokers). Gastrointestinal perforations.
Important: Patients must be informed about signs of thrombosis (unilaterally swollen warm leg, shortness of breath, chest pain) and unusual infections and should seek immediate medical attention if suspected.
Drug Interactions
- Strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, HIV protease inhibitors): elevated tofacitinib levels; halve tofacitinib dose or avoid combination
- Strong CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, St. John's wort): reduced tofacitinib levels, possible loss of efficacy
- Other immunosuppressive agents (biologics, cyclosporine, azathioprine): additive infection and tumor risk, avoid combination
- Live vaccines: contraindicated during therapy
- Hormonal contraceptives: moderate level increase possible, but clinically less relevant
- Methotrexate: combination possible, note additive hepatotoxicity
Special Precautions
Pregnancy and lactation: contraindicated. Ensure safe contraception during therapy and for at least four weeks thereafter.
Before starting therapy: tuberculosis screening, hepatitis B/C/HIV serology, check current vaccinations, lipid status, blood count. Patients should have received all recommended vaccinations including herpes zoster protection vaccination with Shingrix before starting therapy.
Monitoring: blood count and liver transaminases at 4 and 12 weeks, then individually. Lipid status 12 weeks after initiation. If lymphopenia below 500/microliter or neutropenia below 1000/microliter, interrupt therapy.
EMA Recommendation 2023: in patients with the following risk factors, use only if no therapeutic alternative exists: age 65 years and over, current or former smokers, cardiovascular risk factors, previous malignancies (except treated non-melanoma skin cancer).
You May Also Be Interested In
- Filgotinib, preferential JAK1 inhibitor
- Baricitinib, JAK1/2 inhibitor
- Upadacitinib, another preferential JAK1 inhibitor
- Methotrexate, classic DMARD
- Adalimumab, TNF alpha antibody
Frequently Asked Questions
What did the ORAL Surveillance study show?
In this large comparative study between tofacitinib and TNF inhibitors in rheumatoid arthritis patients aged 50 years and over with cardiovascular risk factors, more serious cardiovascular events, more cancer diagnoses, and more thromboembolism were observed under tofacitinib. The results were published in 2021 and led to a safety warning for the entire JAK inhibitor class.
Why should I receive a shingles vaccination before therapy?
Tofacitinib significantly increases the risk of herpes zoster reactivation, in some studies by a factor of two to four compared to placebo. The recombinant protective vaccination Shingrix is effective (efficacy over 90 percent) and can be given under tofacitinib, but is ideally administered before starting therapy. Live vaccines against herpes zoster are contraindicated under tofacitinib.
How quickly does tofacitinib work?
First improvements are usually visible in rheumatoid arthritis after 2 to 4 weeks, with full response developing over 3 to 6 months. In ulcerative colitis, the induction phase is evaluated after 8 weeks.
Can I combine tofacitinib with methotrexate?
Yes, the combination has been tested in studies and is possible in rheumatoid arthritis. Combination with biologics or other JAK inhibitors is contraindicated due to additive infection and tumor risk.
Sources
- EMA, Xeljanz (Tofacitinib) EPAR
- DGRh Guideline Rheumatoid Arthritis and DGVS Guideline Ulcerative Colitis
- Gelbe Liste, Tofacitinib Substance Profile
- BfArM, Dear Healthcare Professional Letter JAK Inhibitors 2023
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