Baricitinib
Oral JAK 1 and JAK 2 inhibitor for rheumatoid arthritis and alopecia areata
Baricitinib is an oral, selective Janus kinase inhibitor (JAK 1 and JAK 2) developed by Eli Lilly and Incyte. The EMA granted marketing authorisation in 2017 under the trade name Olumiant for the treatment of moderate to severe active rheumatoid arthritis in adults. Since 2020 baricitinib has also been approved for the treatment of moderate to severe atopic dermatitis, and since 2022 for severe alopecia areata. During the pandemic baricitinib gained temporary prominence as an adjunctive therapy in hospitalised Covid 19 patients.
As a JAK inhibitor baricitinib belongs to the so called targeted synthetic DMARDs. The mechanism differs fundamentally from classical DMARDs (methotrexate, sulfasalazine) and from biologics (TNF α inhibitors, IL 6 inhibitors). Oral availability and an intracellular mode of action offer a convenience advantage over injected biologics. At the same time the European authorities issued a warning in 2023 on cardiovascular and malignancy risks in at risk patients, which has made the indication more conservative.
Mechanism of Action
Janus kinases (JAK 1, JAK 2, JAK 3, TYK2) are intracellular tyrosine kinases that couple cytokine receptors to the STAT signalling pathway (Signal Transducers and Activators of Transcription). Cytokines such as interferons, interleukins and growth factors activate JAKs, which in turn phosphorylate STATs; these translocate to the nucleus and regulate gene expression. Many inflammatory and immune processes are controlled through this pathway.
Baricitinib preferentially inhibits JAK 1 and JAK 2, with lower affinity for JAK 3 and TYK2. Blockade attenuates the signalling of interleukin 6, interleukin 12, interleukin 23, interferon α, interferon γ, granulocyte macrophage colony stimulating factor and other cytokines. The consequence is a dampening of the inflammatory cascade, which is clinically effective especially in rheumatoid arthritis, atopic dermatitis and autoimmune dermatoses.
Oral bioavailability is approximately 80 percent, and the half life is around 12 hours. The compound is eliminated predominantly unchanged by the renal route, so the dose must be adjusted in renal impairment. The effect on clinical parameters usually develops within two to four weeks.
Indications
- Moderate to severe active rheumatoid arthritis in adults after inadequate response to or intolerance of conventional DMARDs or biologics
- Moderate to severe atopic dermatitis in adults who are candidates for systemic therapy
- Severe alopecia areata in adults with more than 50 percent scalp hair loss
- Juvenile idiopathic arthritis in patients from the age of two years (approved in 2023)
In patients with cardiovascular risk factors, in smokers over 50 years of age or with a history of malignancy baricitinib should be used more cautiously according to the 2023 Dear Doctor letter. TNF α inhibitors are preferred in these groups.
Dosage and Administration
Standard dose: 4 mg once daily. For patients over 75 years of age, with an increased risk of infection or for long term maintenance: 2 mg once daily. Combination with methotrexate in rheumatoid arthritis: possible and often useful.
The medicine is taken orally with or without food at the same time of day. Tablets should be swallowed whole with fluid. Treatment is reviewed after 12 to 16 weeks; if there is no response the indication must be reconsidered.
Renal impairment: eGFR 30 to 60 ml/min, 2 mg once daily; eGFR below 30 ml/min, not recommended. Hepatic impairment: no dose adjustment in mild to moderate impairment; use is not recommended in severe impairment. OAT3 inhibitors (probenecid): choose 2 mg once daily. Lymphocyte count below 0.5 × 10⁹/l: interrupt therapy until recovery.
Side Effects
Very common and common: upper respiratory tract infections, herpes zoster reactivation (an increased risk compared with TNF inhibitors), urinary tract infections, headache, nausea, acne, elevated cholesterol, raised creatine kinase, elevated liver enzymes.
Uncommon: venous thromboembolism including deep vein thrombosis and pulmonary embolism, serious infections such as pneumonia, tuberculosis reactivation, sepsis and opportunistic infections.
Rare but important risks: lymphoma and other malignancies (especially in smokers over 65 years of age), cardiovascular events such as myocardial infarction and stroke, gastrointestinal perforations, leukopenia, neutropenia and anaemia.
Dear Doctor letter 2023: The EMA issued a reinforced warning for the entire JAK inhibitor class concerning malignancies, cardiovascular events and thromboembolism. In patients over 65 years of age, smokers, those with a history of malignancy or atherosclerotic vascular disease, JAK inhibitors should only be used if no alternative therapy is available.
Interactions
- Strong OAT3 inhibitors (probenecid): marked rise in plasma concentrations, dose reduction to 2 mg
- Live vaccines (MMR, varicella, yellow fever, zoster live vaccine): avoid during and for at least four weeks after the end of therapy
- Inactivated vaccines: possible, with a partially reduced immune response; influenza and pneumococcal vaccination are recommended
- Other immunosuppressive or immunomodulatory therapies (biologics, ciclosporin, tacrolimus): combination is not recommended because of additive infection risk
- Methotrexate, sulfasalazine, hydroxychloroquine: combination is possible and often useful in rheumatoid arthritis
- Hormonal contraceptives, digoxin, simvastatin: no clinically relevant interactions documented
Special Notes
Screening before treatment starts: tuberculosis (IGRA test), hepatitis B and C serology, HIV status where risk factors are present, vaccination status, full blood count with differential, renal and hepatic function, lipids. Live vaccinations should be refreshed at least four weeks before starting therapy.
Monitoring during therapy: full blood count at four and 12 weeks, then every three months. Lymphocytes below 0.5, neutrophils below 1.0 or haemoglobin below 8.0 require interruption of therapy. Lipids at 12 weeks and then annually. Liver values regularly. Annual skin cancer screening in UV exposed patients.
Herpes zoster: the risk under JAK inhibitors is about twice as high as under TNF inhibitors. Patients should be informed of early signs (burning pain, dermatomal rash); the zoster inactivated vaccine (Shingrix) is recommended and is permitted during JAK therapy.
Pregnancy: baricitinib is contraindicated, and women of childbearing potential must use reliable contraception. Breastfeeding: transfer into breast milk cannot be excluded, breastfeeding during therapy is not recommended.
Covid 19: baricitinib received emergency authorisation for severely ill hospitalised Covid 19 patients and was used in combination with dexamethasone. With the easing of severe pandemic courses the importance of this indication has declined.
You might also be interested in
- Methotrexate, the classical DMARD in rheumatoid arthritis
- Dupilumab, an IL 4 and IL 13 antibody for atopic dermatitis
- Ustekinumab, an IL 12 and IL 23 blocker for psoriasis and Crohn's disease
- Ruxolitinib, a JAK inhibitor in haematological oncology
- Etanercept, a TNF receptor fusion protein
Frequently Asked Questions
How does a JAK inhibitor differ from a biologic?
Biologics such as TNF antibodies or IL 6 blockers bind large extracellular proteins and are given by injection or infusion. JAK inhibitors are small molecules taken orally that act intracellularly on several cytokine signalling pathways. Their action is therefore broader, but the side effect profile also differs, particularly regarding infection risk and laboratory parameters.
Why the EMA warning in 2023?
A large comparative study (ORAL Surveillance with tofacitinib) showed an increased risk of myocardial infarction, malignancy and thromboembolism in smokers and cardiovascular preexisting patients over 50 years of age. The EMA extended the warning as a precaution to the whole class of JAK inhibitors including baricitinib. The indication has therefore become more conservative in risk groups.
When does the effect start?
In rheumatoid arthritis joint pain and morning stiffness often improve as early as one to two weeks, with the full effect at 12 weeks. In atopic dermatitis improvement of pruritus also begins rapidly. In alopecia areata it can take months until visible hair regrowth, with the first results assessed after six to nine months.
Can I interrupt therapy when I have an infection?
During acute severe infections baricitinib is paused in consultation with the treating physician until the infection has resolved. For mild viral colds a pause is usually not necessary. Fever, severe cough, dyspnoea, a herpes zoster eruption or severe diarrhoea should always be evaluated medically before the tablet is resumed.
Sources
- EMA, Olumiant (Baricitinib) EPAR
- AWMF, S2e Guideline on Rheumatoid Arthritis and Atopic Dermatitis
- Gelbe Liste, Baricitinib active substance profile
- BfArM, Federal Institute for Drugs and Medical Devices
Legal Notice and Disclaimer
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