Tofacitinib

Active substance from the group of Janus kinase inhibitors (JAK inhibitors) with immunomodulating properties with the molecular formula: C16H20N6O. Tofacitinib is a pyrrolopyrimidine and is present as tofacitinib citrate, a white, easily water-soluble powder.

Tofacitinib is metabolised by CYP3A4 and to a lesser extent by CYP2C19. Corresponding drug interactions must be taken into account. Tofacitinib was primarily developed for the treatment of moderately severe to severe active rheumatoid arthritis.

Tofacitinib has an immunomodulating / immunosuppressive effect. The effects are based on the inhibition of Janus kinases (JAK) and thus of the JAK-STAT signaling pathway.

Tofacitinib has been approved in the EU since March 2017 for the treatment of moderate to severe active rheumatoid arthritis. It is also approved for the treatment of ulcerative colitis. However, the active ingredient may only be prescribed if treatment with other long-acting anti-rheumatic drugs (DMARDs) has not been sufficiently successful or has not been tolerated. In addition, tofacitinib may only be given as monotherapy if treatment with methotrexate is not possible. The recommended dose is 5 mg twice daily.

Ulcerative colitis: The recommended dose for initiating therapy is 2x 10 mg/day orally over a period of 8 weeks. Maintenance dose 2x 5 mg/day p.o.

Psoriatic arthritis (PsA): Tofacitinib is indicated in adult patients in combination with methotrexate for the treatment of active psoriatic arthritis (PsA) who have had an inadequate response or intolerance to previous disease-modifying antirheumatic drug (DMARD) therapy (dosage as for rheumatoid arthritis).

Alopecia areata: Liu LY et al. were able to demonstrate in a larger study (n=90) that 77% of patients treated with tofacitinib responded clinically to the treatment. 50% achieved at least 50% improvement in the SALT (Severity of Alopecia Tool); treatment duration 4-18 months.

Prurigo nodularis: There is one study with positive results that requires further confirmation (Molloy OE et al. 2020).

Vitiligo: Several studies show a positive effect of tofacitinib on vitiligo. However, initiating phototherapy appears to be necessary for repigmentation (Craiglow BG et all. 2015).

Morbihan's disease: A casuistic contribution demonstrates positive effects in this disease (Li ZY et al. 2023).

In July 2021, the manufacturer provided information about an increased risk of serious adverse cardiovascular events and malignancies with the use of tofacitinib compared with TNF-alpha inhibitors. In the completed clinical trial (Mease P et al (2020) in patients with rheumatoid arthritis (RA) who were 50 years of age or older and had at least one additional cardiovascular risk factor, an increased incidence of myocardial infarction was observed with Xeljanz (tofacitinib) compared with tumor necrosis factor-alpha inhibitors (TNFα inhibitors). The study also showed an increased incidence of malignancies, particularly lung cancer and lymphoma, with the exception of non-melanocytic skin cancer(NMSC), under tofacitinib compared to TNFα inhibitors. As a result, tofacitinib (according to the manufacturer) should only be used in patients over 65 years of age, in patients who currently smoke or have previously smoked, in patients with other cardiovascular risk factors, and in patients with other risk factors for malignancies when no suitable treatment alternatives are available.

Strong immunosuppressive drugs such as tofacitinib generally increase the risk of serious life-threatening infections, lymphomas and tumor diseases. The most common side effects of tofacitinib include respiratory infections, headaches and digestive problems such as diarrhoea.

Xeljanz® (5/10mg film coated tablets)

Tofacitinib (and etanercept) reduces levels of interleukin-6, CCL20, CXCL10, and in therapy responders, interleukin-17A. Furthermore, in therapy responders TNF receptor 1, E-selectin, histidine kinase11, chitinase-3-like protein-1, interleukin-16, and metalloproteinase 12. The latter were found to be cardiovascular proteins (Kim et al. 2018).

Tofacitinib has been approved across Europe since 2017.

1. Ciechanowicz P et al (2018) JAK-inhibitors in dermatology. Current evidence and future applications. J Dermatolog Treat 15:1-22.
2. Craiglow BG et all. (2015) Tofacitinib Citrate for the Treatment of Vitiligo: A Pathogenesis-Directed Therapy. JAMA Dermatol 151:1110-1112.
3. Di Lernia V et al. (2016) Profile of tofacitinib citrate and its potential in the treatment of moderate-to-severe chronic plaque psoriasis. Drug Des Devel Ther 10:533-539.
4. Kim J et al. (2018) Reduction of Inflammatory and Cardiovascular Proteins in the Blood of Patients with Psoriasis: Differential Responses between Tofacitinib and Etanercept after 4 Weeks of Treatment. J Invest Dermatol 138:273-281.
5. Kostovic K et al. (2017) Tofacitinib, an Oral Janus Kinase Inhibitor: Perspectives in Dermatology. Curr Med Chem 24:1158-1167.
6. Liu LY et al. (2017) Repigmentation in vitiligo using the Janus kinase inhibitor tofacitinib may require concomitant light exposure. J Am Acad Dermatol 77:675-682.
7. Li ZY et al. (2023) Case Report: Morbihan disease treated with tofacitinib successfully. Front Immunol 14:1177316.
8. Mease P et al. (2020) Incidence of venous and arterial thromboembolic events reported in the tofacitinib rheumatoid arthritis, psoriasis and psoriatic arthritis development programs and from real-world data. Ann Rheum Dis 79:1400-1413.
9. Molloy OE et al. (2020) Successful treatment of recalcitrant nodular prurigo with tofacitinib. Clin Exp Dermatol 45: 918-920.