Janus kinase inhibitors

Janus kinase (JAK) inhibitors are generally orally administrable, occasionally also locally 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, which are often condensed. If the JAK signaling pathway is blocked at the cellular level, this blockade indirectly inhibits the cytokine pathways. The receptors in the JAK/STAT signaling pathway are proteins that interact extracellularly with ligands. The most important of these are the cytokines (glycoproteins) secreted by cells. Cytokines are categorized according to the receptors to which they bind:

• Class I cytokines(interleukin-2family/interleukin-6family and interleukins-12,-13,-23, TLP, etc.)
• and
• class II cytokines (type I, II and type III interferons, interleukin-10 family)

are subdivided.

The cytokine receptors to which they bind consist of several, usually 2 transmembrane protein chains (hetero- and homodimers) with an extracellular and a cytosolic part. The cytosolic parts consist of several structural domains, which are also referred to as "motifs" and have binding sites for JAK and STAT. In some receptor chains, binding sites for inhibitory regulatory proteins, such as the SOCS proteins, are located between the JAK and STAT binding motifs.

Since JAK/STAT signaling is very dynamic and involves rapid transmission from the cell membrane to the cell nucleus with a complexly organized response, both activating and regulating factors are required. The regulating factors include the SOCS proteins (SOCS1-7; CIS). These are induced by STAT and are the most important feedback inhibitors of the JAK/STAT signaling pathway.

Janus kinase (JAK) inhibitors can simultaneously block several inflammation-inducing cytokines, e.g. interleukin-6, interleukin-12, interleukin-13, unlike classic direct cytokine inhibitors (biologics) which only inhibit one specific cytokine, e.g. Il-13, Il-17, IL-23. Depending on which JAK receptor pair is blocked, a large number of cytokines are blocked. This leads to a wider spectrum of side effects, but also to a "wider" range of possible applications, which is relevant for their clinical use.

Biologics (e.g. TNF-alpha antagonists) prevent inflammatory messengers from docking to specific cell receptors outside the cell. Janus kinase inhibitors have a broader effect because they modulate several cytokines at the same time by inhibiting the kinase pathway.

There are four members of the JAK family:

• JAK1
• JAK2
• JAK3 and
• TYK2.

The Janus kinase inhibitors have different selectivity. The following classification can be made according to their different selectivity. The first generation (alpha group) includes small molecules such as baricitinib and tofacitinib, which act as non-selective inhibitors of JAK. They are molecularly similar to each other.

Second-generation drugs (beta group) such as filgotinib and upadacitinib, on the other hand, have a higher selective inhibitory effect against JAK. This difference in selectivity between the two generations is associated with some differences in their safety and efficacy.

Alpha group of JAK inhibitors:

• Baricitinib - ^Olumiant®
• Ruxolitinib - ^Jakavi®
• Tofacitinib - ^Xeljanz®

Beta group of JAK inhibitors:

• Abrocitinib - ^Cibinqo®
• Deucravacitinib - ^Sotyktu®
• Filgotinib - ^Jyselecta®
• Upadacitinib - ^Rinvoq®

Janus kinase signal transducer and transcriptional activator (JAK-STAT) is an important inflammatory pathway in a number of dermatologic, hematologic and rheumatologic diseases and JAK inhibitors are a new treatment option for these diseases. Baricitinib and ruxolitinib phosphate act on JAK1 and JAK2, fedratinib hydrochloride acts on JAK2, tofacitinib citrate acts on JAK1, JAK2 and JAK3, ritlecitinib acts on JAK3, upadacitinib and abrocitinib act only on JAK1 and deucravacitinib allosterically inhibits only TYK2(tyrosine kinase 2).

Note: In allosteric inhibition, the active center of the receptor is not blocked but the JAK inhibitor binds to a different site of the molecule. The result is that the kinase changes its molecular structure. The substrate no longer fits into the active center. The activity decreases!

The distribution of the individual JAK inhibitors is influenced in different ways by the plasma protein binding rate once biochemical bioavailability has been achieved. It varies depending on the agent. However, in order to reach the site of action, the JAK inhibitors must be unbound. They therefore interact in different ways with various drug transporters. Drug transporters (carrier proteins). These increase the concentration gradient (solute carriers/SLC) or actively transport with ATP consumption (ATP-binding cassette/ABC). SLCs are preferentially used for uptake, ABCs for efflux of drugs (as with JAK inhibitors) into and out of the cell. For baricitinib and upadacitinib, for example, the BCRP (breast cancer resistance protein) acts as a transporter. The organic anionic transporters 1 and 3 (OAT1/3) transport tofacitinib. However, individual transport proteins can also be inhibited by JAK inhibitors (OCT1/2 by abrocitinib) (Veeravilli V et al. 2020). Ruxolitinib also inhibits both transporter proteins (OAT1/3) in the intestine, which can inhibit the transport capacity for other drugs (e.g. ciclosporin). JAK inhibitors can also regulate the expression of transport proteins in a function-dependent manner. Examples of this are ruxolitinib and PXR (pregnance X receptor) (Alim K et al. 2021). It is important to note that the effect of JAK inhibitors is largely dependent on their adhesion to the binding pocket of their receptors. This time window is referred to as "resident time".

The metabolization of JAK inhibitors takes place to varying degrees in the endoplasmic reticulum in hepatocytes and, after epicutaneous application, also in keratinocytes. The determining reaction partners are the monooxygenases of the cytochrome P450 system (CYP). In a second reaction step, the oxidation products are combined with water-soluble molecules, e.g. glucuronic acid, via the functional groups introduced and can thus be excreted renally or fecally. The cytochome P450 systems have numerous subtypes. The CYP3A4 subtype is most frequently involved in metabolization, and less frequently the CYP2C19 subtype. The representatives of the beta group of Janus kinases are mainly metabolized via CYP3A4, partly also via CYP2D6 (upadicinib). The biotransformation of JAK inhibitors can also be altered by pharmacokinetic interactions with certain co-applied drugs. The representatives of the JAK alpha group are less sensitive to this. The representatives of the beta group, on the other hand, compete with CYP2C19 inhibitors such as fluvoxamine or fluconazole. The use of abrocitinib is considered contraindicated with simultaneous administration of rifampicin (CYP3A4 inducer). A dose reduction is recommended for upadacitinib with concomitant administration of CYP3A4 inhibitors (e.g. ketoconazole).

The most extensive studies are available for the following indications: atopic dermatitis, psoriasis and psoriatic arthritis, alopecia areata, chronic hand eczema, vitiligo. The indications in detail:

Dermatological indications:

• Upadacitinib (atopic dermatitis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis)
• Abrocitinib (atopic dermatitis)
• Baricitinib (atopic dermatitis, alopecia areata)
• Ritlecitinib (alopecia areata)
• Delgocitinib (atopic dermatitis, chronic hand eczema)
• Ruxolitinib (systemic for myelofibrosis (MF) and polycythaemia vera; topical for non-segmental vitiligo and atopic dermatitis)
• Deucravacitinib (psoriasis vulgaris)
• Note: Due to their physicochemical properties, JAK inhibitors are used both systemically and topically. The molecular weight range of 300-400g/mol suggests cutaneous bioavailability, although topical efficacy also depends on the galenic formulation and significant differences in solubility.

Rheumatologic indications:

• Tofacitinib (rheumatoid arthritis; ulcerative colitis; psoriatic arthritis)
• Filgotinib (rheumatoid arthritis)

Hematologic indications:

• Fedratinib (splenomegaly and primary and secondary myelofibrosis)

The use of JAK inhibitors is not permitted according to the current state of knowledge.

General Information: A review by the EMA has shown that Janus kinase (JAK) inhibitors for the treatment of chronic inflammatory diseases (rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata and vitiligo) are associated with a higher risk of serious cardiovascular events, venous thromboembolism (VTE), malignant diseases, serious infections and higher overall mortality compared to TNF-alpha inhibitors(BfArM risk information)! In principle, the risk of side effects is similar to that of all JAK inhibitors and biologics: first and foremost is the increased risk of infection.

In contrast to established biologics such as TNF-alpha antagonists, there is an increased rate of varicella-zoster reactivation during treatment with Janus kinase inhibitors - especially when higher doses are used. A recent meta-analysis of almost 6,000 patients revealed a general risk of 3.2 herpes zoster infections per 100 patient-years. The relative risks for the individual Janus kinase inhibitors are approximately 2.0 for tofacitinib, 3.2 for baricitinib and 3.0 for upadacitinib.

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

Acne: Acne has been associated with JAK inhibitor therapy as an ADR in numerous clinical studies. There are no reliable data on the overall incidence of acne with JAK inhibitors. The data from a meta-analysis show a significant increase in the incidence of acne when using combined JAK1 and JAK2 inhibitors and with the TYK2 inhibitor deucravacitinib (Martinez J et al. 2023).

Skin cancer: An additional risk of developing skin cancer in connection with JAKi therapy cannot be ruled out. An increased risk of Merkel cell carcinoma is being discussed (Jalles C et al. 2022).

Long-term effects: Versch. Authors report that the need for chemotherapy was significantly increased in patients who had previously taken JAK inibitors (Harada T et al. 2021)!

Many Janus kinase inhibitors are substrates of CYP450 isoenzymes and interactions with CYP inhibitors and inducers are possible. Immunosuppressants can increase the adverse effects of JAK inhibitors.

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

Other agents:

• Oclacitinib - Apoquel® - veterinary drugs

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.

1. Alim K et al. (2021) Interactions of janus kinase inhibitors with drug transporters and consequences for pharmacokinetics and toxicity. Expert Opin Drug Metab Toxicol 17:259-271
2. Fleischmann R et al. (2012) Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med 367:495-507.
3. Harada T et al. (2021) Outcomes of methotrexate-associated lymphoproliferative disorders in rheumatoid arthritis patients treated with disease-modifying anti-rheumatic drugs. Br J Haematol 194:101-110.
4. Jalles C et al. (2022) Skin cancers under Janus kinase inhibitors: A World Health Organization drug safety database analysis. Therapy 77:649-656.
5. Martinez J et al. (2023) Janus Kinase Inhibitors and Adverse Events of Acne: A Systematic Review and Meta-Analysis. JAMA Dermatol 159:1339-1345.
6. O'Shea JJ et al. (2013) Janus kinase inhibitors in autoimmune diseases. Ann Rheum Dis 72 Suppl 2: ii111-115
7. Pavithran K et al. (2012) Janus kinase inhibitors: jackpot or potluck? Oncol Rev 6: e13
8. Prechter F et al. (2019) Janus kinase inhibitors: therapy with a drop of bitterness: reactivation of herpes zoster. Dtsch Arztebl 116: A-1540 / B-1271 / C-1251.
9. Triyangkulsri K et al. (2018) Role of janus kinase inhibitors in the treatment of alopecia areata. Drug Des Devel Ther 12: 2323-2335
10. Tsai SY et al. (2024) Comparative safety of oral Janus kinase inhibitors versus dupilumab in patients with atopic dermatitis: A population-based cohort study. J Allergy Clin Immunol 154:1195-1203.e3.
11. van Vollenhoven RF et al. (2012) Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med 367:508-519.
12. Veeravalli V et al. (2020) Critical Assessment of Pharmacokinetic Drug-Drug Interaction Potential of Tofacitinib, Baricitinib and Upadacitinib, the Three Approved Janus Kinase Inhibitors for Rheumatoid Arthritis Treatment. Drug Saf 43:711-725.