Januskinase-Inhibitors

Last updated on: 11.07.2021

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Definition
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Janus kinase (JAK) inhibitors are orally administrable, anti-inflammatory, selectively immunomodulating and antiproliferative agents. They inhibit intracellular signaling pathways that are of central importance in the network of inflammatory cytokines. Structurally, Janus kinase inhibitors are characterized by nitrogen heterocycles that are often fused.

If the JAK signalling pathway is blocked, inflammation-inducing cytokines such as interleukin-6 and interleukin-12 can no longer be produced.

Biologics (e.g. TNF-alpha antagonists) prevent the docking of inflammatory messenger substances to specific cell receptors outside the cell. Janus kinase inhibitors have a broader effect because they modulate several cytokines simultaneously by inhibiting the kinase pathway.

Classification
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Four members of the JAK family are distinguished:

The Janus kinase inhibitors-have different selectivity.

The following compounds are currently available:

Other agents:

  • Oclacitinib (Apoquel®) - veterinary medicinal product

Tofacitinib: First in its class, tofacitinib has been used for some time in the treatment of rheumatoid arthritis and psoriatic arthritis. Tofacitinib inhibits JAK1, JAK2, JAK3 and to a lesser extent TYK2 in vitro. It exhibits functional specificity for JAK1 and JAK3 over JAK2. Regarding the mechanism of action, tofacitinib is known to reversibly and competitively inhibit the ATP-binding site of JAKs. Without ATP, JAKs cannot phosphorylate other proteins.

Baricitinib: blocks JAK1 and JAK2 kinases in an enhanced manner.

Fedratinib is a JAK2-selective inhibitor that has a higher potency for JAK2 than towards the other members of the JAK family (JAK1, JAK3 and TYK2). Abnormal activation of JAK2 is associated with myeloproliferative neoplasms, including myelofibrosis and polycythaemia-vera. Fedratinib is indicated for the treatment of disease-related splenomegaly (splenomegaly) or symptomatology in adult patients with primary myelofibrosis (MF), post-polycythaemia vera myelofibrosis (post-PV-MF), or post-essential thrombocythemia myelofibrosis (post-ET-MF) who have not yet received a janus kinase (JAK) inhibitor or who are previously treated with ruxolitinib.

Ruxolitinib: JAK inhibitor for the treatment of myelofibrosis.

Upadacitinib and filgotinib primarily block the JAK1 kinase. Upadacitinib has been approved for rheumatoid arthritis since 03 2021. In the future, it will also be used in patients with psoriatic arthritis. The indication is adult patients who have responded inadequately to one or more DMARDs or are unable to tolerate them. Upadacitinib can be used as monotherapy or in combination with methotrexate. Another indication is active ankylosing spondylitis in adult patients who have responded inadequately to conventional therapy.

Pharmacodynamics (Effect)
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The active ingredients have selective immunosuppressive, anti-inflammatory and antiproliferative properties. The effects are based on the inhibition of Janus kinases (JAK). These are intracellular enzymes that belong to the group of tyrosine kinases and transfer phosphate groups. They are involved in signal transduction from the cell membrane to the cell nucleus and have an influence on gene expression.

Indication
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The best-known indication for Janus kinase inhibitors is currently rheumatoid arthritis. Other indications exist:

  • Psoriatic arthritis
  • Inflammatory intestinal diseases, ulcerative colitis
  • Myelofibrosis, polycythaemia vera
  • Allergic dermatitis, atopic dermatitis (veterinary drugs)

Further approvals in the field of autoimmune diseases are expected.

Pregnancy/nursing period
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The use of JAK inhibitors is not permitted according to the current state of knowledge.

Undesirable effects
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The risk of side effects is similar to all JAK inhibitors and the biologics: first and foremost is the increased risk of infection. In contrast to the established biologics such as the TNF-alpha antagonists, an increased rate of varicella-zoster reactivations occurs under the therapy with Janus kinase inhibitors - especially when using higher dosages. In a recent meta-analysis of nearly 6,000 patients, the overall risk was 3.2 herpes zoster infections per 100 patient-years; the relative risks for the individual janus kinase inhibitors were approximately 2.0 for tofacitinib, 3.2 for baricitinib, and 3.0 for upadacitinib. Even if the exact mechanism of varicella-zoster reactivation is not yet known, interferon-α- and interferon-γ-mediated immune processes seem to play an important role in the control of the disease. Despite the often self-limiting course, therapeutic options for herpes zoster are limited. Even though many diseases remain uncomplicated, a proportion of affected individuals continue to experience distressing symptoms for a prolonged period of time, as well as an increase in risk towards myocardial infarction and stroke (Prechter F et al. 2019) .

Risk of thrombosis: For tofacitinib (Xeljanz), there is a warning for the higher dose of 2 x 10 mg/day. For the other JAK inhibitors, this risk seems to be less.

Prevention: Currently, there are several options for vaccination against varicella zoster virus. Vaccination with a live attenuated vaccine (Varilix® or Varivax®) from 11 months of age has been recommended by the RKI since 2004, and since 2009 there has been a recommendation for a second vaccination at 15-23 months of age. In 2016, the rate of fully vaccinated children was 78 % . Since 2006, a live vaccine, Zostavax®, has been approved for vaccination from the age of 50. This vaccine can reduce the rate of reactivation after initial infection and has been shown in randomised trials to be more than 50% effective in protecting against herpes reactivation and 67% effective in protecting against post-herpetic neuralgia (Prechter F et al. 2019).

Interactions
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Many Janus kinase inhibitors are substrates of CYP450 isozymes and interactions with CYP inhibitors and inducers are possible. Immunosuppressants may increase the adverse effects.

Preparations
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  • Baricitinib - Olumiant®
  • Fedratinib - Inrebic®
  • Ruxolitinib - Jakavi®
  • Tofacitinib - Xeljanz®
  • Upadacitinib - Rinvoq®

Other agents:

  • Oclacitinib - Apoquel® - Veterinary Drugs

Note(s)
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As with all long-term therapies that impair the immune system, regular control tests must be carried out in the laboratory (blood count, lipid metabolism, liver, kidney) and any abnormalities must be clarified. Janus kinase inhibitors should be used with caution if there are far too few red blood cells (severe anaemia), as JAK inhibitors can intensify this effect.

Literature
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  1. Fleischmann R et al (2012) Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med 367:495-507.
  2. O'Shea JJ et al (2013) Janus kinase inhibitors in autoimmune diseases. Ann Rheum Dis 72 Suppl 2: ii111-115.
  3. Pavithran K et al (2012) Janus kinase inhibitors: jackpot or potluck? Oncol Rev 6: e13
  4. Prechter F et al. (2019) Janus kinase inhibitors: therapy with a downer: reactivation of herpes zoster. Dtsch Arztebl 116: A-1540 / B-1271 / C-1251.
  5. Triyangkulsri K et al. (2018) Role of janus kinase inhibitors in th treatment of alopecia areata. Drug Des Devel Ther 12: 2323-2335
  6. van Vollenhoven RF et al (2012) Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med 367:508-519.

Last updated on: 11.07.2021