JAK Inhibitors for Treatment of Psoriasis: Focus on Selective TYK2 Inhibitors

Miguel Nogueira1 · Luis Puig2 · Tiago Torres1,3

© Springer Nature Switzerland AG 2020

Despite advances in the treatment of psoriasis, there is an unmet need for effective and safe oral treatments. The Janus Kinase– Signal Transducer and Activator of Transcription (JAK–STAT) pathway plays a significant role in intracellular signalling of cytokines of numerous cellular processes, important in both normal and pathological states of immune-mediated inflamma- tory diseases. Particularly in psoriasis, where the interleukin (IL)-23/IL-17 axis is currently considered the crucial pathogenic pathway, blocking the JAK–STAT pathway with small molecules would be expected to be clinically effective. However, relative non-specificity and low therapeutic index of the available JAK inhibitors have delayed their integration into the therapeutic armamentarium of psoriasis. Current research appears to be focused on Tyrosine kinase 2 (TYK2), the first described member of the JAK family. Data from the Phase II trial of BMS-986165—a selective TYK2 inhibitor—in psoriasis have been published and clinical results are encouraging, with a large Phase III programme ongoing. Further, the selective TYK2 inhibitor PF-06826647 is being tested in moderate-to-severe psoriasis in a Phase II clinical trial. Brepocitinib, a potent TYK2/JAK1 inhibitor, is also being evaluated, as both oral and topical treatment. Results of studies with TYK2 inhibitors will be important in assessing the clinical efficacy and safety of these drugs and their place in the therapeutic armamentarium of psoriasis. This article reviews current data on the impact of JAK inhibitors in the treatment of adult patients with moderate-to-severe psoriasis.

Key Points

Blockade of the JAK/STAT signalling pathway with small molecules (JAK inhibitors), in particular TYK2 inhibition, seems promising to fulfil an unmet need for safe and effec- tive oral treatments for psoriasis and psoriatic arthritis.
Selective (BMS-986165 and PF-06826647) and non-selec- tive (Brepocitinib) TYK2 inhibitors are showing promising efficacy and safety results in the treatment of psoriasis.
Ongoing clinical trials will be important to place this class of drugs in the therapeutic armamentarium of psoriasis.
Psoriasis is a chronic, inflammatory, immune-mediated, and debilitating skin disease, with a high impact on patients’ qual- ity of life [1]. Although its pathogenesis is complex and not yet fully understood, the interleukin (IL)-23/IL-17 axis is currently considered to be its main pathogenic pathway [2–4].
In recent years, several biologic drugs targeting this specific signalling pathway have been developed, with encouraging results [5–22]. However, the need for parenteral administra- tion (intravenous or subcutaneous), risk of immunogenicity, potential adverse effects and loss of efficacy over time, justifies the search for further therapeutic solutions.
The development of small molecules blocking intracellular signalling pathways has evolved in recent years. Compared to biologic agents, these small molecules are easier to synthesise,

[email protected]
less expensive to produce and can be administered orally or topically [23], which is associated with greater patient con-

1Department of Dermatology, Centro Hospitalar Universitário do Porto, Porto, Portugal
2Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
3Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal
venience and improved quality of life [24]. Also, oral admin- istration can potentially reduce the cost of healthcare support for outpatient and inpatient care services [24].
Conventional oral therapies (such as methotrexate, cyclo- sporine, acitretin), are associated with several side effects, drug

interactions, and long-term toxicity. Apremilast, a phospho- diesterase-4 (PDE4) inhibitor approved by the United States Food and Drug Administration (FDA) and the European Medi- cines Agency (EMA) for the treatment of moderate-to-severe psoriasis [25] has shown limited efficacy [26]. Thus, it is nec- essary to develop other orally administered therapies.
The Janus Kinase–Signal Transducer and Activator of Tran- scription (JAK–STAT) signalling pathway is an intracellular signalling system through which extracellular factors control gene expression [27, 28]. Knowledge about this pathway has increased over the years, with a growing understanding of the importance of blocking JAK–STAT pathway-specific con- stituents in several immune-mediated diseases [29, 30]. Spe- cifically, in psoriasis and psoriatic arthritis (PsA) blocking the JAK–STAT pathway with oral JAK inhibitors (JAKi) appears to result in beneficial clinical outcomes [31–48].
This article aims to review the current knowledge on the impact of JAKi in the treatment of adult patients with mod- erate-to-severe psoriasis, with particular focus on selective Tyrosine Kinase 2 (TYK2) inhibitors.

2JAK–STAT Signalling Pathway

The JAK–STAT pathways play a role in intracellular signal- ling of cytokines in a variety of cellular processes, and are important in both normal and pathological states such as immune-mediated inflammatory diseases, including psoria- sis and PsA.
The coupling of a circulating cytokine, such as a specific interferon (IFN) or interleukin (IL), to its receptor on the cell surface triggers a conformational change of the recep- tor, activating and recruiting a combination of two JAKs [27, 49, 50]. Consequently, JAKs phosphorylate the receptor, allowing STAT proteins to attach, become phosphorylated and dimerised [51]. When dimerised, STAT proteins can translocate to the cell nucleus and alter gene expression [51]
(see Fig. 1).
There are four different types of JAK proteins (JAK1, JAK2, JAK3, and TYK2) and seven different STAT proteins (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6). Each STAT protein can bind to various members of the JAK family [27, 52, 53].
All JAK proteins play an important role in mammals. Studies in mice with JAK1-deficiency revealed severely compromised lymphopoiesis and insufficiency to respond to both type I and II IFNs, with lethal outcome [54]. There are no reports of human beings with JAK1-deficiency [54]. JAK1 pairs either with JAK2, JAK3 or Tyk2, and it mainly transduces signals from IFN-α, IFN-γ, IL-6, and IL-10 receptors.
JAK2 is mainly associated with the critical functions of induction and regulation of erythropoiesis [55]. JAK2 pairs

with itself, JAK1 or TYK2, and is crucial to transmit sig- nals for receptors of cytokines such as erythropoietin, throm- bopoietin and haemopoietic cell development cytokines as well as IL-12 and IL-23 receptors. Even though primitive erythrocytes were found in JAK2-deficient mice, the cell count was severely reduced, affecting effective erythropoie- sis [55]. Postnatal or adult JAK2 deletion in mice has been noted to result in thrombocytopenia and anaemia, suggest- ing the role of JAK2 in the development of not only the erythroid but also the megakaryocytic components of bone marrow [56, 57]. There are no reports of humans with a loss of function of the JAK2 protein. On the other hand, gain of function of the JAK2 gene is associated with several myeloproliferative diseases, such as polycythaemia vera and essential thrombocythemia [58, 59].
JAK3 is expressed mainly in lymphoid and hematopoi- etic tissues, in contrast with the ubiquitous expression of the other members of the JAK family [52, 60]. JAK3 only pairs with JAK1 and binds to the common γ-chain cytokine receptor family, which is shared by IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 receptors and is essential for lymphocyte development [60–62]. In humans, JAK3 gene deficiency results in a lack of activity of T, NK, and functional B cells, consequently leading to the development of severe combined immunodeficiency and life-threatening infections [61–63].
TYK2 is involved in intracellular signalling initiated by different cytokines, such as type I IFN, IL-6, IL-12, or IL-23 [52, 62, 64]. Loss of activity of TYK2 results in increased risk for severe cutaneous infections by agents such as herpesviridae, staphylococci, and mycobacte- ria [65]. Conversely, TYK2 deletion in mice leads to increased resistance to autoimmune, allergic, and inflam- matory diseases [66–68].
Following ligand (interferons, interleukins, growth fac- tors, hormones) binding and JAK-mediated phosphoryla- tion of their specific receptors, STATs become phospho- rylated by JAKs to form homo- and heterodimers. Their complex role in genetic and epigenetic control of tran- scription [51, 69, 70], is beyond the scope of this review.
The JAK–STAT signalling pathway is involved in the pathogenesis of several inflammatory and autoim- mune diseases including rheumatoid arthritis (RA), pso- riasis, PsA and inflammatory bowel disease, since many cytokines involved in the pathogenesis of these immune- mediated conditions use JAK–STAT pathways for signal transduction. Several JAKi have been approved for the treatment of RA and PsA, while others are being devel- oped for the treatment of psoriasis.

2.1JAK–STAT Pathway in Psoriasis

Psoriasis is a skin-related autoimmune disease in which mul- tiple cytokines (e.g. IFN-α, IFN-γ, TNF-α, IL-1, IL-2, IL-6,

Fig. 1 Schematic representation of Janus Kinase–Signal Transducer and Activator of Transcription (JAK/STAT) pathway and the mech- anism of action of JAK inhibitors (JAKi). The JAK–STAT pathway begins with the coupling of a circulating cytokine to its receptor pre- sent in the cell membrane. This connection triggers a conformational change of the receptor, which then activates and recruits a combina- tion of autophosphorylated JAKs. JAKs are then responsible for phos- phorylating the receptor and create conditions to phosphorylate the STAT proteins, causing their dimerisation. When dimerized, STAT

proteins are capable of translocating to the cell nucleus and altering gene transcription. JAKi binds to the Adenosine Triphosphate (ATP)- binding site on JAK, inhibiting the phosphorylation and activation of JAKs. The STAT proteins are not activated, and the remaining cascade is then compromised, resulting in less transcription of pro- inflammatory and pathological genes. Psoriasis-associated cytokines and members of the JAK and STAT families to which they relate are summarised in Table 1

IL-8, IL-12, IL-13, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-36) and inflammatory cell populations, including T cells, neutrophils, DCs and others, have been pathogeneti- cally implicated [2–4, 71]. The identification of the IL-23/
IL-17 axis as the main pathogenic pathway in psoriasis pathogenesis has had a major impact in our understanding of this disease and changed its therapeutic paradigm [2–4, 71]. Many of the critical pathogenic mediators of psoriasis, including several cytokines of the IL-23/IL-17 signalling pathway, are linked to the JAK–STAT signalling pathway and its upregulation with increased expression of STAT1 and STAT3 has been demonstrated in psoriatic lesional skin compared to normal skin [2, 3, 71–76]. Psoriasis-associated cytokines and members of the JAK and STAT families to which they relate are summarised in Table 1 [77–91].
STAT1 is responsible for signal transduction of both type I (i.e. IFN-α/β) and type II (also known as IFN-γ) IFNs mainly through a JAK1/JAK2-dependent mechanism. IFN-γ has an important role on sensitising keratinocytes

and promoting influx of different types of inflammatory cells into lesional psoriatic skin [3]. Its production is also stimulated by IL-12 through a TYK2-dependent mecha- nism [3]. The increased production of STAT1 leads to the production of multiple pro-inflammatory mediators and the activation and maturation of dendritic cells with sub- sequent stimulation of Th1 and Th17 cells [73, 74, 92].
STAT3, primarily activated by JAK1, JAK2, and TYK2, is involved in key steps of psoriasis pathogenesis. Through the activation of the JAK2/TYK2 pair induced by IL-23, STAT3 is involved in the induction and differentiation of Th17 cells [72, 93]. STAT3 is also associated with dif- ferentiation of Th17 cells and keratinocyte proliferation through a JAK1/JAK2 or JAK1/TYK2 signalling induced by IL-6 [72, 75, 93]. IL-17 plays an indirect activation of STAT3 through the process of inducing the production of IL-19 and IL-36 by keratinocytes, leading to epider- mal hyperplasia [3]. Additionally, Th17 cells can produce IL-22, which is also responsible for epidermal hyperplasia

and anti-microbial peptides production through the activa- tion of STAT3 [30, 93–95].
Although IL-23 is closely associated with the activity of TYK2 and JAK2 for downstream signalling events, and IL-12 primarily with TYK2 activity, TNF-α, IL-1, and IL-17 do not activate the JAK–STAT pathway. However, their activity can be indirectly suppressed by the inhibition of the JAK–STAT pathway [30, 94, 95].
Regarding PsA, despite the importance of TNF-α in its pathogenesis, the JAK/STAT pathway seems to play a major role in the development of the disease. The activation and performance of STAT1 and STAT3 appear to play an impor- tant role in the onset of a pathological synovial response [96]. This response results from the action of IFN-γ, IL-6, as well as the cytokines enrolled in the IL-23/IL-17 axis, through the activity of JAK1, JAK2 and TYK2 mainly [96].
Therefore, the JAK/STAT pathway regulates several steps in psoriasis pathogenesis, which makes it an interesting tar- get for a new class of small-molecule agents.

3JAKi Studied in Psoriatic Disease

Several oral JAKi have been studied in psoriasis in recent years [31–48]. Their mechanism of action is illustrated in Fig. 1 and their main characteristics are summarised in Table 2.

3.1JAK 1/3 Inhibitor: Tofacitinib

Tofacitinib (Xeljanz®) is an oral JAKi that acts primarily on JAK1 and JAK3, and its clinical efficacy and safety in mod- erate-to-severe psoriasis have been studied in phase II and phase III clinical trials [33, 38–42]. Phase III trials evaluated tofacitinib at 5 mg twice-daily (BID) and 10 mg BID doses. Short term (week 12 or week 16) Psoriasis Area and Severity Index (PASI) improvement of 75% or higher compared to baseline (PASI75) was achieved in approximately 40–64% of patients in the active treatment groups. Greater efficacy was observed with higher doses of tofacitinib, and 10 mg BID regimen was shown to be non-inferior to etanercept. Treatment response was maintained over 2 years of treat- ment for most patients, with no unexpected adverse events (AEs) [38]. In a study that evaluated treatment withdrawal and retreatment, patients were randomised to receive either tofacitinib 5 mg BID or 10 mg BID for 24 weeks [42]. At week 24, patients who achieved both PASI 75 and Physi- cian’s Global Assessment (PGA) of ‘clear’ or ‘almost clear’ (PGA response) were re-randomised to receive placebo (withdrawal) or the previous dose of tofacitinib [42]. After 16 weeks, PASI75 response was maintained in a greater proportion of patients receiving either 5 mg BID (56.2%) or 10 mg BID (62.3%) of tofacinib than placebo (23.3% and 26.1%, depending on previous treatment dose, p < 0.05 for both comparisons) [42]. After 16 weeks of re-treatment with the previous dosing regimen among patients receiving placebo who relapsed (more than 50% reduction in PASI response compared to week 24) during the treatment-with- drawal period, PASI75 response was achieved in 61% of

Table 1 Psoriasis-associated cytokines and members of the JAK and STAT families to which they relate
1. Cytokines 2. Main JAKs activated 3. Main STATs activated
TNF-α Does not directly activate JAK/STAT
IL-1 Does not directly activate JAK/STAT
IL-8 Does not directly activate JAK/STAT
IL-17 Does not directly activate JAK/STAT
IL-18 Does not directly activate JAK/STAT
IL-36 Does not directly activate JAK/STAT

Table 2 Characteristics of oral JAKi and their position in psoriatic disease

Drug, company
Main selectivity
Approved indications
Phase of clinical trials in plaque psoriasis
Phase of clinical trials in psoriatic arthritis

Tofacitinib (Xeljanz®), Pfizer
JAK1 and JAK3
Rheumatoid arthritis Psoriatic arthritis Ulcerative colitis
Phase III (completed)—not approved for psoriasis and no ongoing clinical trials
Already approved

Baricitinib (Olumiant®), Eli Lilly and Company
JAK1 and JAK2
Rheumatoid arthritis
Phase II (completed)—no
ongoing clinical trials
No clinical trials

Itacitinib, Incyte Corpora- tion
Phase II (completed)—no
ongoing clinical trials
No clinical trials

Solcitinibb, GlaxoSmith- Kline
Phase II (completed)—dis- continued investigation in psoriasis
No clinical trials

Abrocitinib, Pfizer
Phase II (completed)—dis- continued investigation in psoriasis
No clinical trials

Filgotinib, Galapagos NV JAK1 None No clinical trials Phase III—2 clinical trials set
to start soon

Upadacitinib (Rinvoq®), AbbVie
Rheumatoid arthritis
No clinical trials
Phase III—2 ongoing clinical

Peficitinib (Smyraf®), Astel- las Pharma Inc.
Pan-JAK (moder- ate selectivity for JAK3)
Rheumatoid arthritis (Japan) Phase II (completed)—dis- continued investigation in psoriasis
No clinical trials

BMS-986165, Bristol-Myers Squibb
Phase III—4 ongoing clini-
cal trials
Phase II—1 ongoing clinical

PF-06826647, Pfizer
Phase II—1 ongoing clini-
cal trial
No clinical trials

Brepocitinib, Pfizer
TYK2 and JAK1 None
Phase II (completed)—no
ongoing clinical trials
Phase IIb—1 ongoing clinical

Ongoing clinical studies of TYK2 inhibitors in psoriatic disease are detailed in Table 3

patients receiving tofacitinib 10 mg BID and 36.8% in the group receiving tofacitinib 5 mg BID [42]. In another Phase III trial, 74.1% of patients who reached PASI75 response at short term (week 16) and received 5 mg BID and 79.4% of those who received 10 mg BID maintained their response through week 52 [33].
Regarding safety, clinical trials in psoriasis have shown that tofacitinib was generally well tolerated; the rate of AEs was similar with 5 mg and 10 mg BID, with cytopenia and infections being the most common AEs [33, 38–42].
Regarding PsA, the efficacy and safety of tofacitinib have been evaluated in two randomised, multinational, double- blind, placebo-controlled phase III trials (OPAL Broaden and OPAL Beyond) [44, 45]. Patients received either 5 or 10 mg tofacitinib BID, placebo, or adalimumab in OPAL Broaden only. Patients also received one background con- ventional synthetic disease-modifying antirheumatic drug (csDMARD). Primary endpoints [i.e. improvement of 20% in the American College Rheumatology score (ACR20) and change from baseline in Health Assessment Questionnaire- Disability Index (HAQ-DI) at month 3] showed significant improvements in patients receiving tofacitinib 5 or 10 mg BID versus placebo, and efficacy was maintained at month
6. Significant differences in ACR20 rates were observed as early as week 2. Although none of these studies was designed or had the statistical power to compare the effi- cacy of tofacitinib with adalimumab, there was no substan- tial numerical difference in their impact on the primary out- comes. The safety profile was similar to those in previous trials in psoriasis and RA [44, 45, 97].
A topical formulation of tofacitinib has also been tested in chronic plaque psoriasis in three distinct randomised clinical trials (NCT01831466, NCT00678561 and NCT01246583), with a total of 628 participants enrolled in the studies [98]. The results showed only a modest improvement in the dis- ease with this type of formulation, despite the relatively favourable safety profile [98].
There are some special safety concerns related to the drug. A dose-dependent risk of developing herpes zoster was noted, with higher rates of infection occurring in patients receiving tofacitinib compared to those receiving placebo [99]. Gastric perforation was also a complication observed in the group of patients receiving tofacitinib, and further studies are needed to confirm this association [100]. Despite the fact that current evidence on the usage of tofacitinib in RA and PsA in the approved therapeutic dosages (5 mg

BID) seem to indicate that no significantly increased risk of thromboembolic events exists [101–103], the provisional results of an ongoing trial in RA comparing tofacitinib 5 mg BID and 10 mg BID with a TNF-blocker identified an increased occurrence of blood clots and death in the group of patients receiving tofacitinib 10 mg BID, compared to the other two groups. For that reason, patients from this group were allowed to switch and continue treatment with tofaci- tinib 5 mg BID [104]. Since RA may be associated with increased risk of thromboembolic events [101, 105], long- term studies with a larger number of patients treated with tofacitinib are needed to better understand the development of this complication.
In 2015 the FDA declined to approve tofacitinib for mod- erate-to-severe psoriasis, indicating that additional safety analyses were required. Tofacitinib is no longer being devel- oped for psoriasis according to Pfizer’s drug development pipeline. Currently, oral tofacitinib is both FDA and EMA approved for the treatment of PsA, RA, and ulcerative colitis [106–109].

3.2JAK1/2 Inhibitor: Baricitinib and Ruxolitinib

Baricitinib (Olumiant®) is an oral JAKi with higher selec- tivity for JAK1 and JAK2, which has also been studied in patients with moderate-to-severe psoriasis in Phase II trials [43]. At week 12, significantly higher PASI75 response rates were observed in the 8 mg and 10 mg dose groups com- pared with placebo (42.9%, 54.1%, and 16.7%, respectively, p < 0.05) [43].
Although baricitinib was well tolerated in all dosing regi- mens over 24 weeks, dose-dependent changes in laboratory values [decrease in haemoglobin levels and neutrophil count, increased serum creatinine and high- and low-density lipo- proteins, and increased creatine phosphokinase (CPK) lev- els] have been observed [43].
Baricitinib has also been associated with development of herpes zoster, gastric perforation, and thrombotic events [110, 111]. This association was not significant in studies including patients with RA or psoriasis compared with pla- cebo [102, 112]. However, these AEs should be assessed in more detail in clinical trials with larger numbers of patients. So far, FDA and EMA have approved baricitinib only for the treatment of RA [113]. No clinical studies are evaluating its use in psoriasis or PsA at this time.
Ruxolitinib (Jakafi ®/Jakavi®), a JAK1/JAK2 inhibitor, was approved by both FDA and EMA for the treatment of myelofibrosis and polycythemia vera in its oral formulation. However, in psoriasis, its use has only been tested in its topi- cal cream formulation. Three clinical trials (NCT00617994, NCT00820950 and NCT00778700) that enrolled a total of 253 participants evaluated the clinical efficacy and safety of the drug in psoriasis [98]. The published results showed

that all treatment groups had a statistically significant improvement in total lesion score compared to vehicle, and that the drug was non-inferior when compared to calcipot- riene and betamethasone dipropionate [98]. The studies did not demonstrate any significant AE [98]. Although topical application of the drug is currently being tested for other immune-mediated diseases, such as atopic dermatitis and vitiligo, there are no studies ongoing in psoriasis and it is not approved for psoriatic disease.

3.3Selective JAK1 Inhibitors: Itacitinib, Abrocitinib, Solcitinib, Filgotinib and Upadacitinib

The clinical efficacy of the JAK1 selective inhibitor itaci- tinib (INCB039110) in moderate-to-severe psoriasis was studied in a 12-week Phase II trial with 50 patients [34]. Several dosing regimens (100 mg once daily, 200 mg once daily, 200 mg BID or 600 mg once daily) were evaluated and an α = 0.1 significance level was used. The mean percentage change from baseline in the static PGA at week 4 (primary endpoint) was statistically superior with itacitinib 200 mg BID and 600 mg once daily compared to placebo [34]. At week 4, PASI75 response rates were 0%, 11.1%, 0%, 22.2% and 27.7% in the placebo, itacitinib 100 mg once-daily, 200 mg once-daily, 200 mg BID, and 600 mg once-daily groups, respectively [34]. A statistically significant differ- ence versus placebo (p = 0.093) was observed solely for itac- itinib 600 mg once daily [34]. Across all groups, the drug was usually well tolerated, with nasopharyngitis being the most common treatment-related AE [34]. There are currently no ongoing clinical trials involving this drug in psoriasis.
JAK1 inhibitors abrocitinib (PF-04965842) and solcitinib (GSK2586184) have also been evaluated in 12-week phase II clinical trials in patients with moderate-to-severe psoriasis with positive results [36, 37], but they are no longer being tested for psoriasis because solcitinib was discontinued due to AEs, whereas development priorities changed for abroci- tinib, with phase III trials for atopic dermatitis currently ongoing.
Filgotinib is being developed and currently tested for PsA, but not for psoriasis. In a Phase II trial, including 131 patients (65 receiving filgotinib and 66 placebo), 80% of patients in the filgotinib group and 33% in the placebo group achieved ACR20 at week 16 (treatment difference 47% [95% CI 30.2–59.6], p < 0.0001) [46]. The onset of action of fil- gotinib was rapid, with measurable improvements in disease activity after 1 week of treatment [46]. Filgotinib was well tolerated and associated with mostly mild-to-moderate AEs. The most common events were nasopharyngitis and head- ache, occurring at similar proportions in each group [46]. Rates of treatment-emergent AEs and treatment discontinu- ations due to such events were similar to those of placebo. One case of serious infection (pneumonia) that led to death

was observed in the filgotinib group. Increased haemoglobin and high-density lipoprotein (HDL) levels, stable natural killer cell and lymphocyte counts, and decreased platelet numbers were also reported. No malignancies, thromboem- bolic events, or cases of opportunistic infections, including tuberculosis, were reported in this study [46].
Upadacitinib (Rinvoq®), an oral JAK1 inhibitor recently approved for the treatment of moderate-to-severe RA [114], is also being tested in patients with PsA, with two ongoing Phase III studies (NCT03104374 and NCT03104400). No clinical trials have been developed to assess its efficacy and safety in psoriasis.

3.4JAK3 Inhibitor: Peficitinib

A 6-week Phase IIa randomised, placebo-controlled study to evaluate the clinical efficacy and safety of different drug regimens (10 mg BID, 25 mg BID, 60 mg BID, 100 mg BID, 50 mg once daily) of peficitinib (Smyraf®), an oral pan-JAK inhibitor with moderate selectivity for JAK3 over JAK1, JAK2 and TYK2, enrolled 124 patients with moderate-to- severe plaque psoriasis [48]. The mean change in PASI score from baseline to the end of the treatment period (42 days)— primary endpoint—was significantly higher in all the dif- ferent groups of treatment compared to the placebo group (p < 0.001 in all treatment groups) [48]. The proportion of patients who achieved PASI75 at the end of the treatment period was significantly higher only in the groups receiving 10 mg BID, 60 mg BID and 100 mg BID (31.6%, 26.3% and 58.8%, respectively), compared to placebo (3.4%) [48]. No serious AEs were registered [48]. The drug is approved in Japan for the treatment of RA. However, there are no further completed or ongoing clinical trials in psoriatic disease.

3.5TYK2 Inhibitors: BMS‑986165, PF‑06826647 and Brepocitinib

The TYK2 gene was first associated with psoriasis sus- ceptibility in a genome-wide association study (GWAS) in 2010 [115]. TYK2 loss-of-function mutation is associated with defects in several cytokine signalling pathways, which are important in the pathogenesis of psoriasis, such as type
IIFN, IL-6, IL-10, IL-12, and IL-23 [116]. Even though individuals with deactivating genetic variants of TYK2 are highly protected from some immune-mediated diseases, they do not show an increased risk of hospitalisation due to mycobacterial, viral, or fungal infections, suggesting that inhibiting TYK2 activation may be associated with an opti- mal balance between efficacy and safety [117].
As knowledge about psoriasis has evolved, the focus on JAK inhibition has shifted, and now seems to be moving toward the JAK family member TYK2.

BMS-986165 is an oral selective TYK2 inhibitor that is being studied for psoriasis, PsA, Crohn’s disease, ulcerative colitis, and systemic lupus erythematosus. BMS-986165 showed high selectivity in vitro for the TYK2 pseudoki- nase domain. In primary human peripheral blood mononu- clear cells stimulated with IFN-α and IL-23, BMS-986165 inhibited TYK2-mediated phosphorylation of STAT1 and STAT3, respectively. By contrast, it was considerably less potent (> 100-fold) against receptor-mediated pathways that depended on other JAKs [118].
In a phase I trial involving 108 healthy subjects, BMS- 986165 was shown to be safe and well tolerated [31]. Simi- lar non-serious AEs were found in the active and placebo groups (75% and 76%, respectively) and no serious AEs were reported. The most common AEs were headache, nau- sea, rash and upper respiratory tract infection. BMS-986165 was also evaluated in a 12-week phase II double-blind trial, in which 267 adults with moderate-to-severe psoriasis were randomised to receive the drug (3 mg every other day, 3 mg once daily, 3 mg BID, 6 mg BID, or 12 mg once daily) or placebo [32]. Dosing regimens of 3 mg once daily, 3 mg BID, 6 mg BID and 12 mg once daily proved their efficacy and showed statistical superiority versus placebo regarding PASI75 response rates (39%, 69%, 67%, and 75%, respec- tively, compared to 7% in the placebo group, p < 0.05) [32]. Three serious AEs were reported in three different patients from different active groups—gastroenteritis due to rotavi- rus, accidental eye injury, and dizziness in a patient with a history of vestibular dysfunction—compared to two serious AEs in one patient in the placebo group [32]. From 55 to 80% of patients in the active treatment groups developed AEs (compared to 51% in the placebo group); nasophar- yngitis, diarrhoea, headache, nausea, and upper respiratory tract infection were the most common [32]. No significant changes from baseline in mean values of blood counts or serum levels of lipids, creatinine, liver enzymes or immu- noglobulins—IgE, IgM, IgA or IgG—were reported [32]. No cases of herpes zoster infection or cardiovascular events were reported [32].
Three large phase III trials on plaque psoriasis (NCT03624127, NCT03611751, and NCT04036435) comparing BMS-986165 to placebo or apremilast are now ongoing. A smaller phase III clinical trial with 80 Japanese patients with moderate-to-severe psoriasis (NCT03924427) is also under development. In addition to those, one Phase
IItrial (NCT03881059) to assess the clinical effect of the drug in PsA is in progress (see Table 3). These trials will provide more data about the impact of BMS-986165 in dif- ferent patients with psoriatic disease.
Another selective TYK2 inhibitor, PF-06826647, is also being tested in moderate-to-severe psoriasis in an ongoing phase II clinical trial (NCT03895372). The results from a

Table 3 Clinical trials in progress with selective (BMS986165 and PF-06826647) and non-selective (Brepocitinib) TYK2 inhibitors in psoriatic disease

Drug, company Route of administra- tion
Clinical trial Condition Phase Estimated enrol- ment (number of participants)
Status Estimated study completion date

BMS-986165, Bristol-Myers
NCT03624127 Psoriasis
Active, not recruit-
July 19, 2020

Squibb Oral NCT03611751 Psoriasis III 1000 Recruiting July 8, 2020
Oral NCT03924427 Psoriasis III 80 Recruiting November 10, 2020
Oral NCT04036435 Psoriasis III 1680 Recruiting September 1, 2022
Oral NCT03881059 Psoriatic arthritis II 180 Recruiting December 31, 2020
PF-06826647, Pfizer Oral NCT03895372 Psoriasis II 160 Recruiting December 27, 2020
Brepocitinib, Pfizer Topical NCT03850483 Psoriasis IIb 240 Recruiting May 13, 2020
Oral NCT03963401 Psoriatic arthritis IIb 196 Recruiting April 27, 2021

phase I clinical trial that also enrolled psoriatic patients have not yet been published.
Even though brepocitinib (formerly known as PF-06700841) is not a selective TYK2 inhibitor (rather a potent TYK2/JAK1 inhibitor), it has been shown to be safe and well tolerated at doses up to 200 mg once daily in a Phase I clinical trial [35]. Thirty patients with psoria- sis received PF-06700841 30 or 100 mg or placebo once daily for 28 days; PGA response of clear/almost clear was achieved in 57.1%, 100%, and 0% of patients, respectively [35]. All the AEs were considered to be mild-to-moderate both in healthy subjects and patients with psoriasis [35]. However, a reduction in platelets and reticulocytes count occurred, indicating an inhibition of the EPO-JAK2 pathway by the drug [35].
In a phase IIa trial, 212 patients with moderate-to-severe psoriasis were randomised to receive placebo for 12 weeks or brepocitinib (30 mg once daily or 60 mg once daily) for an induction period of 4 weeks. Then, the group that received the drug switched to either placebo or brepocitinib (10 mg once daily, 30 mg once daily, 100 mg once per week) for a maintenance period of 8 weeks [47]. The primary endpoint was change from baseline in PASI score at week 12, and five treatment arms (brepocitinib 60 mg and then 100 mg once a week; 60 mg and then 30 mg once daily; 30 mg and then 100 mg once a week; 30 mg and then 30 mg once daily; and 30 mg and then 10 mg once daily) achieved significant responses (p <0.05) compared to placebo [47]. The group of patients receiving brepocitinib 30 mg for both induction and maintenance period had the highest PASI75 response rate (86.2%; 90% CI 71.16, 95.15), whereas the group receiving placebo for 12 weeks had the lowest (13.0%; 90% CI 3.65, 30.36) [47]. A total of 149 patients developed AEs, with 6 serious AEs recorded in 5 patients. One patient died during the study (gunshot wound). No herpes zoster events occurred during this study [47].
No other clinical trials with oral brepocitinib in pso- riasis are now ongoing. However, a Phase IIb study (NCT03963401) is now recruiting to evaluate the drug effi- cacy and safety profile in patients with active PsA. Topical application of brepocitinib cream is also being tested in a phase IIb clinical trial involving patients with mild-to-mod- erate psoriasis (NCT03850483).


Treatment of psoriasis has evolved rapidly and favourably in recent years, with several biologic drugs acting on dif- ferent cytokine pathways and achieving promising results. However, there is still an unmet need for effective and safe oral treatments.
Small molecules may have some advantages over bio- logic agents, particularly the possibility of oral administra- tion, lack of immunogenicity and potentially reduced costs, placing these drugs in a very attractive position for future research in the management of psoriasis.
From the results published so far, inhibition of the JAK–STAT pathway appears to be effective in psoriasis and psoriatic arthritis. However, although several JAK1/2/3 (JAK1/2, pan-JAK with moderate selectivity to JAK3, and selective JAK1 inhibitors) inhibitors are being developed for immune-mediated diseases, their clinical development in psoriasis has been abandoned, mostly due to their efficacy/
safety ratio, and only filgotinib and upadacitinib are still being studied in PsA. While tofacitinib has completed a large phase III psoriasis clinical programme, the FDA declined its approval and additional safety analyses were required. Nevertheless, tofacitinib was later approved for treatment of PsA, demonstrating the importance of the JAK–STAT pathway in psoriatic disease and suggesting that JAKi may eventually join the expanding numbers of drugs approved for the treatment of moderate-to-severe psoriasis and PsA, when

additional data on their long-term clinical efficacy, safety, and durability of response become available.
The inhibition of JAK family members may directly and indirectly suppress the activity of multiple cytokines that play a role in the pathogenesis of psoriasis. Thus, differ- ences may be found between wide-ranging inhibition that suppresses the signalling of multiple psoriasis mediators, and selective inhibition that may spare other members of the JAK family and thereby avoid corresponding safety concerns. Indeed, inhibition of JAK1, 2, and 3 has been associated with an increased risk of serious infections and opportunistic infections. Also, dose-dependent changes in laboratory parameters, including lipids, levels of haemo- globin, decreased numbers of lymphocytes, NK cells, neu- trophils, and platelets have been observed, as well as cases of venous thromboembolism and gastrointestinal perfora- tion. On the other hand, selective TYK2 inhibitors, that can prevent IL-23/IL-17 axis signalling, have raised significant expectations regarding oral treatment of moderate-to-severe psoriasis. The reported results on clinical efficacy and safety, including those from the phase II clinical trial with BMS- 986165, are highly promising. This selective TYK2 inhibitor did not increase the incidence of herpes zoster and thrombo- embolic events, and the same happened with dyslipidaemia, a common effect of JAK1 inhibitors mediated through IL-6 signalling impairment; thus, BMS-986165 might be consid- ered to belong to a different therapeutic class compared to nonselective JAKi. Data from ongoing studies will clarify whether TYK2 selective inhibitor(s) can be included among the approved drugs for treatment of psoriasis.


Oral JAK inhibitors are showing promising efficacy and safety results in the treatment of psoriasis, particularly recent data regarding selective TYK2 inhibitors. Future studies with oral JAKi will be important to place this class of drugs in the therapeutic armamentarium of psoriasis.

Compliance with Ethical Standards

Funding No sources of funding were used to conduct this study or prepare this manuscript.

Conflict of interest Miguel Nogueira has no conflicts of interest. Luis Puig has received consultancy and/or speaker’s honoraria from and/
or participated in clinical trials sponsored by AbbVie, Almirall, Am- gen, Baxalta, Biogen, Boehringer Ingelheim, Celgene, Gebro, Janssen, LEO Pharma, Eli Lilly and Company, Merck-Serono, MSD, Mylan, Novartis, Pfizer, Regeneron, Roche, Sandoz, Samsung-Bioepis, Sa- nofi, and UCB. Tiago Torres has received consultancy and/or speak- er’s honoraria from and/or participated in clinical trials sponsored by AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, Bris- tol Myers Squibb, Celgene, Janssen, Biocad, LEO Pharma, Eli Lilly,

MSD, Novartis, Pfizer, Samsung-Bioepis, Sanofi-Genzyme and San- doz.


1.Langley RGB, Krueger GG, Griffiths CEM. Psoriasis: epide- miology, clinical features, and quality of life. Ann Rheum Dis. 2005;64(Suppl 2):ii18–23.
2.Hawkes JE, Yan BY, Chan TC, Krueger JG. Discovery of the IL-23/IL-17 signaling pathway and the treatment of psoriasis. J Immunol. 2018;201(6):1605–13.
3.Hawkes JE, Chan TC, Krueger JG. Psoriasis pathogenesis and the development of novel targeted immune therapies. J Allergy Clin Immunol. 2017;140(3):645–53.
4.Di Cesare A, Di Meglio P, Nestle FO. The IL-23/Th17 axis in the immunopathogenesis of psoriasis. J Investig Dermatol. 2009;129(6):1339–50.
5.Papp KA, Griffiths CEM, Gordon K, et al. Long-term safety of ustekinumab in patients with moderate-to-severe pso- riasis: final results from 5 years of follow-up. Br J Dermatol. 2013;168(4):844–54.
6.Thaçi D, Blauvelt A, Reich K, et al. Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate to severe plaque psoriasis: CLEAR, a randomized controlled trial. J Am Acad Dermatol. 2015;73(3):400–9.
7.Reich K, Pinter A, Lacour JP, et al. Comparison of ixekizumab with ustekinumab in moderate-to-severe psoriasis: 24-week results from IXORA-S, a phase III study. Br J Dermatol. 2017;177(4):1014–23.
8.Papp KA, Reich K, Paul C, et al. A prospective phase III, rand- omized, double-blind, placebo-controlled study of brodalumab in patients with moderate-to-severe plaque psoriasis. Br J Dermatol. 2016;175(2):273–86.
9.Langley RG, Elewski BE, Lebwohl M, et al. Secukinumab in plaque psoriasis—results of two phase 3 trials. N Engl J Med. 2014;371(4):326–38.
10.Griffiths CEM, Strober BE, van de Kerkhof P, et al. Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis. N Engl J Med. 2010;362(2):118–28.
11.Gordon KB, Blauvelt A, Papp KA, et al. Phase 3 trials of ixeki- zumab in moderate-to-severe plaque psoriasis. N Engl J Med. 2016;375(4):345–56.
12.Leonardi CL, Kimball AB, Papp KA, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet. 2008;371(9625):1665–74.
13.Papp KA, Langley RG, Lebwohl M, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet. 2008;371(9625):1675–84.
14.Reich K, Papp KA, Armstrong AW, et al. Safety of guselkumab in patients with moderate-to-severe psoriasis treated through 100 weeks: a pooled analysis from the randomised VOYAGE 1 and VOYAGE 2 studies. Br J Dermatol. 2019;180(5):1039–49.
15.Griffiths CEM, Reich K, Lebwohl M, et al. Comparison of ixeki- zumab with etanercept or placebo in moderate-to-severe psoria- sis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials. Lancet. 2015;386(9993):541–51.
16.Papp K, Leonardi C, Menter MA, et al. Safety and efficacy of brodalumab for psoriasis after 120 weeks of treatment. J Am Acad Dermatol. 2014;71(6):1183–90 (e3).

17.Ohtsuki M, Kubo H, Morishima H, Goto R, Zheng R, Nakagawa H. Guselkumab, an anti-interleukin-23 monoclonal antibody, for the treatment of moderate to severe plaque-type psoriasis in Japanese patients: efficacy and safety results from a phase 3, randomized, double-blind, placebo-controlled study. J Dermatol. 2018;45(9):1053–62.
18.Gordon KB, Blauvelt A, Foley P, et al. Efficacy of guselkumab in subpopulations of patients with moderate-to-severe plaque psoriasis: a pooled analysis of the phase III VOYAGE 1 and VOYAGE 2 studies. Br J Dermatol. 2018;178(1):132–9.
19.Reich K, Armstrong AW, Foley P, et al. Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the treatment of patients with moderate to severe psoriasis with randomized withdrawal and retreatment: results from the phase III, double-blind, placebo- and active comparator-controlled VOYAGE 2 trial. J Am Acad Dermatol. 2017;76(3):418–31.
20.Griffiths CEM, Papp KA, Kimball AB, et al. Long-term efficacy of guselkumab for the treatment of moderate-to-severe psoria- sis: results from the phase 3 VOYAGE 1 trial through 2 years. J Drugs Dermatol. 2018;17(8):826–32.
21.Langley RG, Tsai T-F, Flavin S, et al. Efficacy and safety of guselkumab in patients with psoriasis who have an inad- equate response to ustekinumab: results of the randomized, double-blind, phase III NAVIGATE trial. Br J Dermatol. 2018;178(1):114–23.
22.Blauvelt A, Papp KA, Griffiths CEM, et al. Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, com- pared with adalimumab for the continuous treatment of patients with moderate to severe psoriasis: results from the phase III, double-blinded, placebo- and active comparator-. J Am Acad Dermatol. 2017;76(3):405–17.
23.Torres T, Filipe P. Small molecules in the treatment of psoriasis. Drug Dev Res. 2015;76(5):215–27.
24.Bhattacharyya GS. Oral systemic therapy: not all “win-win”. Indian J Med Paediatr Oncol. 2010;31(1):1–3.
25.Fala L. Otezla (Apremilast), an oral PDE-4 inhibitor, receives FDA approval for the treatment of patients with active psori- atic arthritis and plaque psoriasis. Am Health Drug Benefits. 2015;8(Spec Feature):105–10.
26.Vangipuram R, Alikhan A. Apremilast for the management of moderate to severe plaque psoriasis. Expert Rev Clin Pharmacol. 2017;10(4):349–60.
27.Harrison DA. The JAK/STAT pathway. Cold Spring Harb Per- spect Biol. 2012;4(3):a011205.
28.Stark GR, Darnell JE Jr. The JAK–STAT pathway at twenty. Immunity. 2012;36(4):503–14.
29.O’Shea JJ, Schwartz DM, Villarino AV, Gadina M, McI- nnes IB, Laurence A. The JAK–STAT pathway: impact on human disease and therapeutic intervention. Annu Rev Med. 2015;66:311–28.
30.Villarino AV, Kanno Y, Ferdinand JR, O’Shea JJ. Mechanisms of JAK/STAT signaling in immunity and disease. J Immunol. 2015;194(1):21–7.
31.Catlett I, Aras U, Liu Y, Bei D, Girgis I, Murthy B, Hon- czarenko M, Rose S. SAT0226 A first-in-human study of BMS-986165, a selective, potent, allosteric small molecule inhibitor of tyrosine kinase 2 [abstract]. Ann Rheum Dis. 2017;76(Suppl_2):859.
32.Papp KA, Gordon K, Thaçi D, Morita A, Gooderham M, Foley P, et al. Phase 2 trial of selective tyrosine kinase 2 inhibition in psoriasis. N Engl J Med. 2018;379(14):1313–21.
33.Papp KA, Krueger JG, Feldman SR, Langley RG, Thaci D, Torii H, et al. Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: long-term efficacy and safety results from 2 randomized phase-III studies and 1

open-label long-term extension study. J Am Acad Dermatol. 2016;74(5):841–50.
34.Bissonnette R, Luchi M, Fidelus-Gort R, Jackson S, Zhang H, Flores R, et al. A randomized, double-blind, placebo-controlled, dose-escalation study of the safety and efficacy of INCB039110, an oral janus kinase 1 inhibitor, in patients with stable, chronic plaque psoriasis. J Dermatol Treat. 2016;27(4):332–8.
35.Banfield C, Scaramozza M, Zhang W, Kieras E, Page KM, Fen- some A, et al. The safety, tolerability, pharmacokinetics, and pharmacodynamics of a TYK2/JAK1 inhibitor (PF-06700841) in healthy subjects and patients with plaque psoriasis. J Clin Pharmacol. 2018;58(4):434–47.
36.Schmieder GJ, Draelos ZD, Pariser DM, Banfield C, Cox L, Hodge M, et al. Efficacy and safety of the Janus kinase 1 inhibi- tor PF-04965842 in patients with moderate-to-severe psoriasis: phase II, randomized, double-blind, placebo-controlled study. Br J Dermatol. 2018;179(1):54–62.
37.Ludbrook VJ, Hicks KJ, Hanrott KE, Patel JS, Binks MH, Wyres MR, et al. Investigation of selective JAK1 inhibitor GSK2586184 for the treatment of psoriasis in a randomized placebo-controlled phase IIa study. Br J Dermatol. 2016;174(5):985–95.
38.Papp KA, Menter MA, Abe M, Elewski B, Feldman SR, Got- tlieb AB, et al. Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: results from two ran- domized, placebo-controlled, phase III trials. Br J Dermatol. 2015;173(4):949–61.
39.Bachelez H, van de Kerkhof PCM, Strohal R, Kubanov A, Valen- zuela F, Lee J-H, et al. Tofacitinib versus etanercept or placebo in moderate-to-severe chronic plaque psoriasis: a phase 3 ran- domised non-inferiority trial. Lancet. 2015;386(9993):552–61.
40.Krueger J, Clark JD, Suárez-Fariñas M, Fuentes-Duculan J, Cueto I, Wang CQ, et al. Tofacitinib attenuates pathologic immune pathways in patients with psoriasis: a randomized phase 2 study. J Allergy Clin Immunol. 2016;137(4):1079–90.
41.Papp KA, Menter MA, Strober B, Langley RG, Buonanno M, Wolk R, et al. Efficacy and safety of tofacitinib, an oral Janus kinase inhibitor, in the treatment of psoriasis: a phase 2b rand- omized placebo-controlled dose-ranging study. Br J Dermatol. 2012;167(3):668–77.
42.Bissonnette R, Iversen L, Sofen H, Griffiths CEM, Foley P, Romiti R, et al. Tofacitinib withdrawal and retreatment in mod- erate-to-severe chronic plaque psoriasis: a randomized controlled trial. Br J Dermatol. 2015;172(5):1395–406.
43.Papp KA, Menter MA, Raman M, Disch D, Schlichting DE, Gaich C, et al. A randomized phase 2b trial of baricitinib, an oral Janus kinase (JAK) 1/JAK2 inhibitor, in patients with moderate- to-severe psoriasis. Br J Dermatol. 2016;174(6):1266–76.
44.Mease PJ, Hall S, FitzGerald O, van der Heijde D, Merola JF, Avila-Zapata F, et al. Tofacitinib or adalimumab versus placebo for psoriatic arthritis. N Engl J Med. 2017;377(16):1537–50.
45.Gladman D, Rigby W, Azevedo VF, Behrens F, Blanco R, Kaszuba A, et al. Tofacitinib for psoriatic arthritis in patients with an inadequate response to TNF inahibitors. N Engl J Med. 2017;377(16):1525–36.
46.Mease P, Coates LC, Helliwell PS, Stanislavchuk M, Rychlewska- Hanczewska A, Dudek A, et al. Efficacy and safety of filgotinib, a selective Janus Kinase 1 inhibitor, in patients with active psori- atic arthritis (EQUATOR): results from a randomised, placebo- controlled, phase 2 trial. Lancet. 2018;392(10162):2367–77.
47.Forman S, Pariser DM, Poulin Y, Vincent MS, Gilbert SA, Kieras EM, et al. Phase 2A, randomised, double-blind, placebo-con- trolled study to evaluate efficacy and safety of PF-06700841 in patients with moderate-to- severe plaque psoriasis [abstract]. Exp Dermatol. 2018.
48.Papp K, Pariser D, Catlin M, Wierz G, Ball G, Akinlade B, et al. A phase 2a randomized, double-blind, placebo-controlled,

sequential dose-escalation study to evaluate the efficacy and safety of ASP015K, a novel Janus kinase inhibitor, in patients with moderate-to-severe psoriasis. Br J Dermatol. 2015;173(3):767–76.
49.Darnell JE Jr, Kerr IM, Stark GR. JAK–STAT pathways and tran- scriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994;264(5164):1415–21.
50.Beadling C, Guschin D, Witthuhn BA, Ziemiecki A, Ihle JN, Kerr IM, et al. Activation of JAK kinases and STAT proteins by inter- leukin-2 and interferon alpha, but not the T cell antigen receptor, in human T lymphocytes. EMBO J. 1994;13(23):5605–15.
51.Lim CP, Cao X. Structure, function, and regulation of STAT proteins. Mol Biosyst. 2006;2(11):536–50.
52.Ghoreschi K, Laurence A, O’Shea JJ. Janus kinases in immune cell signaling. Immunol Rev. 2009;228(1):273–87.
53.Leonard WJ, O’Shea JJ. Jaks and STATs: biological implications. Annu Rev Immunol. 1998;16:293–322.
54.Müller M, Briscoe J, Laxton C, Guschin D, Ziemiecki A, Silven- noinen O, et al. The protein tyrosine kinase JAK1 complements defects in interferon-alpha/beta and -gamma signal transduction. Nature. 1993;366(6451):129–35.
55.Witthuhn BA, Quelle FW, Silvennoinen O, Yi T, Tang B, Miura O, et al. JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin. Cell. 1993;74(2):227–36.
56.Akada H, Akada S, Hutchison RE, Sakamoto K, Wagner KU, Mohi G. Critical role of Jak2 in the maintenance and function of adult hematopoietic stem cells. Stem Cells. 2014;32(7):1878–89.
57.Park SO, Wamsley HL, Bae K, Hu Z, Li X, Choe SW, et al. Con- ditional deletion of Jak2 reveals an essential role in hematopoie- sis throughout mouse ontogeny: implications for Jak2 inhibition in humans. PLoS One. 2013;8(3):e59675.
58.James C, Ugo V, Le Couédic JP, Staerk J, Delhommeau F, Lacout C, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005;434(7037):1144–8.
59.Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, et al. A gain-of-function mutation of JAK2 in myeloprolifera- tive disorders. N Engl J Med. 2005;352(17):1779–90.
60.Thomis DC, Berg LJ. The role of Jak3 in lymphoid development, activation, and signaling. Curr Opin Immunol. 1997;9(4):541–7.
61.Cornejo MG, Boggon TJ, Mercher T. JAK3: a two-faced player in hematological disorders. Int J Biochem Cell Biol. 2009;41(12):2376–9.
62.Welsch K, Holstein J, Laurence A, Ghoreschi K. Targeting JAK/
STAT signalling in inflammatory skin diseases with small mol- ecule inhibitors. Eur J Immunol. 2017;47(7):1096–107.
63.Russell SM, Tayebi N, Nakajima H, Riedy MC, Roberts JL, Aman MJ, et al. Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development. Science. 1995;270(5237):797–800.
64.Velazquez L, Fellous M, Stark GR, Pellegrini S. A protein tyros- ine kinase in the interferon alpha/beta signaling pathway. Cell. 1992;70(2):313–22.
65.Kreins AY, Ciancanelli MJ, Okada S, Kong XF, Ramírez-Alejo N, Kilic SS, et al. Human TYK2 deficiency: mycobacterial and viral infections without hyper-IgE syndrome. J Exp Med. 2015;212(10):1641–62.
66.Strobl B, Stoiber D, Sexl V, Mueller M. Tyrosine kinase 2 (TYK2) in cytokine signalling and host immunity. Front Biosci (Landmark Ed). 2011;16:3214–32.
67.Seto Y, Nakajima H, Suto A, Shimoda K, Saito Y, Nakayama KI, et al. Enhanced Th2 cell-mediated allergic inflammation in Tyk2-deficient mice. J Immunol. 2003;170(2):1077–83.
68.Spach KM, Noubade R, McElvany B, Hickey WF, Blankenhorn EP, Teuscher C. A single nucleotide polymorphism in Tyk2

controls susceptibility to experimental allergic encephalomyeli- tis. J Immunol. 2009;182(12):7776–83.
69.Bromberg JF. Activation of STAT proteins and growth control. Bioessays. 2001;23(2):161–9.
70.Delgoffe GM, Vignali DAA. STAT heterodimers in immu- nity: a mixed message or a unique signal? JAK STAT. 2013;2(1):e23060.
71.Kim J, Krueger JG. The immunopathogenesis of psoriasis. Der- matol Clin. 2015;33(1):13–23.
72.Sano S, Chan KS, Carbajal S, Clifford J, Peavey M, Kiguchi K, et al. Stat3 links activated keratinocytes and immunocytes required for development of psoriasis in a novel transgenic mouse model. Nat Med. 2005;11(1):43–9.
73.Van der Fits L, Van der Wel LI, Laman JD, Prens EP, Verschuren MCM. In psoriasis lesional skin the type I interferon signaling pathway is activated, whereas interferon-α sensitivity is unal- tered. J Investig Dermatol. 2004;122(1):51–60.
74.Hald A, Andrés RM, Salskov-Iversen ML, Kjellerup RB, Iversen L, Johansen C. STAT1 expression and activation is increased in lesional psoriatic skin. Br J Dermatol. 2013;168(2):302–10.
75.Banerjee S, Biehl A, Gadina M, Hasni S, Schwartz DM. JAK– STAT signaling as a target for inflammatory and autoimmune dis- eases: current and future prospects. Drugs. 2017;77(5):521–46.
76.Lowes MA, Suárez-Fariñas M, Krueger JG. Immunology of pso- riasis. Annu Rev Immunol. 2014;32:227–55.
77.Monin L, Gaffen SL. Interleukin 17 family cytokines: signaling mechanisms, biological activities, and therapeutic implications. Cold Spring Harb Perspect Biol. 2018;10(4):a028522.
78.Waugh DJJ, Wilson C. The interleukin-8 pathway in cancer. Clin Cancer Res. 2008;14(21):6735–41.
79.Wang X, Lupardus P, LaPorte SL, Garcia KC. Structural biology of shared cytokine receptors. Annu Rev Immunol. 2009;27:29–60.
80.Garlanda C, Dinarello CA, Mantovani A. The interleukin-1 fam- ily: back to the future. Immunity. 2013;39(6):1003–18.
81.Commins S, Steinke JW, Borish L. The extended IL-10 super- family: IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, and IL-29. J Allergy Clin Immunol. 2008;121(5):1108–11.
82.Baker SJ, Rane SG, Reddy EP. Hematopoietic cytokine receptor signaling. Oncogene. 2007;26(47):6724–37.
83.Russell SM, Johnston JA, Noguchi M, Kawamura M, Bacon CM, Friedmann M, et al. Interaction of IL-2R beta and gamma c chains with Jak1 and Jak3: implications for XSCID and XCID. Science. 1994;266(5187):1042–5.
84.Rutz S, Wang X, Ouyang W. The IL-20 subfamily of cytokines— from host defence to tissue homeostasis. Nat Rev Immunol. 2014;14(12):783–95.
85.Schindler C, Plumlee C. Inteferons pen the JAK–STAT pathway. Semin Cell Dev Biol. 2008;19(4):311–8.
86.Vignali DAA, Kuchroo VK. IL-12 family cytokines: immuno- logical playmakers. Nat Immunol. 2012;13(8):722–8.
87.Renauld JC. Class II cytokine receptors and their ligands: key antiviral and inflammatory modulators. Nat Rev Immunol. 2003;3(8):667–76.
88.Lejeune D, Dumoutier L, Constantinescu S, Kruijer W, Schuringa JJ, Renauld JC. Interleukin-22 (IL-22) activates the JAK/STAT, ERK, JNK, and p38 MAP kinase pathways in a rat hepatoma cell line: pathways that are shared with and distinct from IL-10. J Biol Chem. 2002;277(37):33676–82.
89.Heinrich PC, Behrmann I, Müller-Newen G, Schaper F, Graeve L. Interleukin-6-type cytokine signalling through the gp130/Jak/
STAT pathway. Biochem J. 1998;334(Pt 2):297–314.
90.Hershey GKK. IL-13 receptors and signaling pathways: an evolv- ing web. J Allergy Clin Immunol. 2003;111(4):677–90.

91.Malek TR, Castro I. Interleukin-2 receptor signaling: at the interface between tolerance and immunity. Immunity. 2010;33(2):153–65.
92.Yao Y, Richman L, Morehouse C, de los Reyes M, Higgs BW, Boutrin A, et al. Type I interferon: potential therapeutic target for psoriasis? PLoS One. 2008;3(7):e2737.
93.Calautti E, Avalle L, Poli V. Psoriasis: A STAT3-centric view. Int J Mol Sci. 2018;19(1):E171.
94.Schwartz DM, Bonelli M, Gadina M, O’Shea JJ. Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases. Nat Rev Rheumatol. 2016;12(1):25–36.
95.Damsky W, King BA. JAK inhibitors in dermatology: the promise of a new drug class. J Am Acad Dermatol. 2017;76(4):736–44.
96.Gao W, McGarry T, Orr C, McCormick J, Veale DJ, Fearon U. Tofacitinib regulates synovial inflammation in psoriatic arthritis, inhibiting STAT activation and induction of negative feedback inhibitors. Ann Rheum Dis. 2016;75(1):311–5.
97.Paik J, Deeks ED. Tofacitinib: a review in psoriatic arthritis. Drugs. 2019;79(6):655–63.
98.Hosking AM, Juhasz M, Mesinkovska NA. Topical Janus kinase inhibitors: a review of applications in dermatology. J Am Acad Dermatol. 2018;79(3):535–44.
99.Winthrop KL, Lebwohl M, Cohen AD, Weinberg JM, Tyring SK, Rottinghaus ST, et al. Herpes zoster in psoriasis patients treated with tofacitinib. J Am Acad Dermatol. 2017;77(2):302–9.
100.Xie F, Yun H, Bernatsky S, Curtis JR. Brief report: risk of gas- trointestinal perforation among rheumatoid arthritis patients receiving tofacitinib, tocilizumab, or other biologic treatments. Arthritis Rheumatol. 2016;68(11):2612–7.
101.Scott IC, Hider SL, Scott DL. Thromboembolism with janus kinase (JAK) inhibitors for rheumatoid arthritis: how real is the risk? Drug Saf. 2018;41(7):645–53.
102.Harigai M. Growing evidence of the safety of JAK inhibitors in patients with rheumatoid arthritis. Rheumatology (Oxford). 2019;58(Supplement_1):i34–42.
103.Mease PJ, Kremer J, Cohen S, Curtis JR, Charles-Schoeman C, Loftus EV, et al. Incidence of thromboembolic events in the tofacitinib rheumatoid arthritis, psoriasis, psoriatic arthritis and ulcerative colitis development programs [abstract]. Arthritis Rheumatol. 2017; 69(Suppl 10).
incidence-of-thromboembolic-events-in-the-tofacitinib-rheum atoid-arthritis-psoriasis-psoriatic-arthritis-and-ulcerative-colit is-development-programs/. Accessed 2 Oct 2019.
104.Food and Drug Administration. FDA approves Boxed Warning about increased risk of blood clots and death with higher dose of arthritis and ulcerative colitis medicine tofacitinib (Xeljanz, Xel- janz XR). 2019. ability/fda-approves-boxed-warning-about-increased-risk-blood
-clots-and-death-higher-dose-arthritis-and. Accessed 2 Oct 2019.
105.Kim SC, Schneeweiss S, Liu J, Solomon DH. Risk of venous thromboembolism in patients with rheumatoid arthritis. Arthritis Care Res (Hoboken). 2013;65(10):1600–7.

106.Berekmeri A, Mahmood F, Wittmann M, Helliwell P. Tofacitinib for the treatment of psoriasis and psoriatic arthritis. Expert Rev Clin Immunol. 2018;14(9):719–30.
107.European Medicines Agency. Xeljanz: product information]. 2017.
xeljanz. Accessed 2 Oct 2019.
108.Food and Drug Administration. Xeljanz: FDA approves new treatment for moderately to severely active ulcerative colitis. 2018.
fda-approves-new-treatment-moderately-severely-active-ulcer ative-colitis. Accessed 2 Oct 2019.
109.Traynor K. FDA approves tofacitinib for rheumatoid arthritis. Am J Health Syst Pharm. 2012;69(24):2120.
110.European Medicines Agency. European Medicines Agency Assessment report: baricitinib. 2016 https://www.ema.europ sment-report_en.pdf. Accessed 2 Oct 2019.
111.Eli Lilly and Company. Update on Baricitinib. 2017 https://inves e-provide-update-baricitinib?releaseid=1034247. Accessed 2 Oct 2019.
112.Taylor PC, Weinblatt ME, Burmester GR, Rooney TP, Witt S, Walls CD, et al. Cardiovascular safety during treatment with baricitinib in rheumatoid arthritis. Arthritis Rheumatol. 2019;71(7):1042–55.
113.Mogul A, Corsi K, McAuliffe L. Baricitinib: the second FDA- approved JAK inhibitor for the treatment of rheumatoid arthritis. Ann Pharmacother. 2019;53(9):947–53.
114.Food and Drug Administration. Novel Drug Approvals for 2019. entities-and-new-therapeutic-biological-products/novel-drug- approvals-2019. Accessed 18 Oct 2019.
115.Genetic Analysis of Psoriasis Consortium & the Wellcome Trust Case Control Consortium 2, Strange A, Capon F, Spencer CCA, Knight J, Weale ME, et al. A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nat Genet. 2010;42(11):985–90.
116.Minegishi Y, Saito M, Morio T, Watanabe K, Agematsu K, Tsuchiya S, et al. Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity. 2006;25(5):745–55.
117.Dendrou CA, Cortes A, Shipman L, Evans HG, Attfield KE, Jostins L, et al. Resolving TYK2 locus genotype-to- phenotype differences in autoimmunity. Sci Transl Med. 2016;8(363):363ra149.
118.Burke JR, Cheng L, Gillooly KM, Strnad J, Zupa-Fernandez A, Catlett IM, et al. Autoimmune pathways in mice and humans are blocked by pharmacological stabilization of the TYK2 pseudoki- nase domain. Sci Transl Med. 2019;11(502):eaaw1736.

Leave a Reply

Your email address will not be published. Required fields are marked *


You may use these HTML tags and attributes: <a href="" title=""> <abbr title=""> <acronym title=""> <b> <blockquote cite=""> <cite> <code> <del datetime=""> <em> <i> <q cite=""> <strike> <strong>