Received: 19 November 2020 | Accepted: 24 November 2020

DOI: 10.1111/1346-8138.15727

REVIEW ARTICLE

Psoriasis: Recent progress in molecular-targeted therapies

Masaru Honma1,2 | Kei Hayashi2

1
Department of Dermatology, Asahikawa
Medical University Hospital, Asahikawa,
Japan
2
International Medical Support Center,
Asahikawa Medical University Hospital,
Asahikawa, Japan
Correspondence
Masaru Honma, Department of
Dermatology, Asahikawa Medical
University Hospital, 2-1-1-1 Midorigaoka-
Higashi, Asahikawa 078-8550, Japan.
Email: wanwan@asahikawa-med.ac.jp
Abstract
Psoriasis is a multifactorial recalcitrant inflammatory skin disease characterized by
bothersome scaly reddish plaques especially on frequently chafed body parts, such as
the extensor sites of the extremities and scalp. Nonetheless, through recent advance in
molecular-targeted therapies including biologics and small-molecule inhibitors, even the
severest symptoms of psoriasis and its comorbidities, such as psoriatic arthritis, can be
excellently treated. The superb clinical effects lead to not only remarkable alleviation of
symptoms but also a deep understanding of patients’ impaired “quality of life” caused
by this disease. Along with the development of novel treatment options targeting vari-
ous specific molecules, such as proinflammatory cytokines and signal transduction-as-
sociated molecules, clinicians have thoroughly understood the molecular mechanism of
psoriasis, and discovered that the IL-23/IL-17 axis mainly depending on Th17 cell function
is a crucial pathogenesis of this disease. Accumulation of knowledge about the working
mechanism and clinical effect of molecular-targeted therapies is indispensable for clini-
cians to establish a more refined therapeutic strategy for treating psoriasis.

KEYWORDS
biologics, cytokines, IL-17, IL-23, IL-36, JAK, molecular mechanism, PDE4, psoriasis, psoriatic
arthritis, RORγT, small-molecule inhibitors, TNF

1 | I NTRO D U C TI O N The molecular-targeted therapies can be classified into two

Psoriasis is a recurrent, persistent inflammatory skin disorder
­accompanied with various extracutaneous comorbidities, such as
psoriatic arthritis (PsA), uveitis, metabolic disorders, and cardio-
vascular diseases.1-5 While the conventional therapies have been
insufficiently effective in controlling severe psoriasis symptoms,
novel molecular-targeted therapies can generally treat such condi-
tion successfully. The successful clinical effects provide not only
remarkable mitigation of skin lesions and the related symptoms
including various comorbidities but also a deep understanding of
patients’ impaired “quality of life” and “unmet needs” on the treat-
ment for psoriasis.6-9 Psoriasis can induce and enhance systemic
inflammatory responses causing metabolic abnormality/cardiovas-
cular diseases called as “psoriatic march”10-13 and irreversible joint
destruction caused by PsA. Thus, these effective systemic thera-
pies should be considered to minimize the risk of systemic visceral
involvements and permanent functional loss at the appropriate
timing.14-17
representative groups: biologics targeting cytokines and the
receptors involved in psoriasis pathomechanism, and small-molecule
inhibitors targeting intracellular signaling molecules. Through the
development of novel therapeutic options focusing on specific mol-
ecules, the detailed molecular mechanism of psoriasis can be deeply
understood. Knowledge about the working mechanism and clinical
effect of various molecular-targeted therapies is indispensable for
establishing a more adequate refined strategy for treating psoriasis.
Hence, this review describes these systemic molecular-targeted
therapies including those agents under development highlighting
the working mechanisms and clinical effects.
2 | M O LEC U L A R M EC H A N I S M O F
PSORIASIS
Given the excellent efficacy of the molecular-targeting therapies,
the interleukin (IL)-23/IL-17 axis that mainly depends on Th17 cell

J Dermatol. 2021;48:761–777. wileyonlinelibrary.com/journal/jde

© 2021 Japanese Dermatological Association | 761
762 | HONMA and HAYASHI

function is crucial for psoriasis pathogenesis (Figure 1).1,4,18,19
In the initiation phase, plasmacytoid dendritic cells (DCs) that
are activated by a complex of antimicrobial peptide (AMP) and
self-nucleotide derived from injured keratinocytes via Toll-like
receptors (TLRs) release a large amount of interferon (IFN)-α,
which stimulates myeloid (conventional) DCs. 20,21 These acti-
vated DCs produce tumor necrosis factor (TNF) and IL-23, which
both help maintain an immune response. TNF potentiates DCs
by themselves and accelerates the inflammatory response by
1,22
various immune cells, whereas IL-23 significantly fortifies
the pathogenic potential of Th17 cells, which are differentiated
from naive CD4 + T cells in the presence of TGF-β, IL-21, and IL-
6. 23,24 Furthermore, IL-17 and IL-22 released by Th17 and other
cells that possess more innate characteristics, such as innate
lymphoid cell (ILC)-3 and γδ-T cells, induce epidermal keratino-
cyte hyperproliferation and enhance the production of inflam-
matory cytokines and chemokines, such as IL-17C, IL-8 (CXCL-8),
and vascular endothelial growth factor (VEGF) from the epider-
1,4,18,19
mis. These factors contribute to the formation of psoriatic
epidermis phenotype and vicious inflammatory loop in the psori-
atic lesion. Th17 cytokines and TNF independently and synergis-
tically induce the expression of CCL20, which is a chemokine that
recruits CCR6-expresssing lymphocytes, such as Th17 cells, into
psoriatic skin lesions. 25,26 The CCL20/CCR6 axis is also indispen-
sable for psoriasis pathomechanism. 27,28
3 | C Y TO K I N E-TA RG E TE D TH E R A PI E S
Regarding the cytokine-targeted therapy, approximately 10 mon-
oclonal antibodies are available for treating psoriasis, and these
biologics target Th17-related cytokines such as TNF, IL-23, and
IL-17. TNF inhibitors can effectively treat plaque-type psoriasis,
PsA, other inflammatory disorders including rheumatoid arthritis
(RA), inflammatory bowel disease (IBD), and Behcet’s disease. IL-23
and IL-17 inhibitors demonstrate excellent clinical effects rela-
tively specific for psoriasis and its comorbidities (Table 1). In ad-
dition to full-size immunoglobulin, several next-generation agents,
such as affibodies and nanobodies, are currently being developed
(Table 1). 29-31 These novel therapeutics are composed of consider-
ably smaller proteins, such as a single domain of antibody and non-
immunoglobulin-based protein, with high affinity and specificity
to the targeted molecules, and enabling a considerably higher
bioavailability. 29-32

F I G U R E 1 Molecular mechanism of psoriasis. Plasmacytoid dendritic cells (DCs) activated by a complex of antimicrobial peptide (AMP)
and self-nucleotide release a large amount of interferon (IFN)-α, which stimulates myeloid DCs. Tumor necrosis factor (TNF) potentiates
DCs by themselves and accelerates the inflammatory response of various immune cells. Interleukin (IL)-23 is a key factor fortifying the
pathogenic potential of Th17 cells differentiated depending on transforming growth factor (TGF)-β, IL-21, and IL-6. IL-17 and IL-22 released
by Th17 and the other cells possessing more innate characteristics (e.g. innate lymphoid cell [ILC]-3 and γδ-T cells) induce epidermal
keratinocyte hyperproliferation. IL-17 also enhances the production of inflammatory cytokines and chemokines from the epidermis
synergistically with TNF. The accelerated inflammatory response hardens the vicious loop in the molecular mechanism of psoriasis [Color
figure can be viewed at wileyonlinelibrary.com]
TA B L E 1 Molecular-targeted therapies for the treatment of psoriasis and other inflammatory disorders (approved agent in the US and in Japan)

FDA approval (approval in Japan)

Target Behcet
HONMA and HAYASHI

Classification molecule Agent Structure Psoriasis PsA AS RA CD UC uveitis D HS PG PPP

TNF-inhibitor TNF Infliximab chimeric IgG1 + (+) + (+) + (+) + (+) + (+) + (+) + (+) + (+) - - -
Adalimumab human IgG1 + (+) + (+) + (+) + (+) + (+) + (+) + (+) - (+) + (+) applied -
certolizumab PEGylated, humanized + (+) + (+) + (-) + (+) + (-) - - - - - -
pegol Fab fragment
Etanercept fusion protein of + (-) + (-) + (-) + (+) - - - - - - -
TNFR and IgG1
IL-17 inhibitor IL-17A Secukinumab human IgG1κ + (+) + (+) + (+) - - - - - Phase 3 - -
Ixekizumab humanized IgG4 + (+) + (+) + (+) - - - - - - - -
ABY-035 affibody Phase 2 - - - - - - - - - -
netakimab humanized IgG1 Phase 3 Phase 3 Phase - - - - - - - -
(BCD-085) 3
vunakizumab humanized IgG1k Phase 2 - - - - - - - - - -
(SHR-1314)
IL-17A/F bimekizumab humanized IgG1 Phase 3 Phase 3 Phase - - - - - Phase 3 - -
(UCB4940) 3
sonelokinab bispecific nanobody Phase 2b - - - - - - - - - -
(M1095)
IL-17RA Brodalumab human IgG2 + (+) - (+) - (+) - - - - - - - Phase 3
IL-12/23 inhibitor IL-12/23 p40 Ustekinumab human IgG1 + (+) + (+) - - + (+) + (+) - - - - -
subunit
IL-23 p19 inhibitor IL-23 p19 Guselkumab human IgG1 + (+) + (+) - - Phase 2/3 Phase - - - - - (+)
subunit 2/3
Risankizumab humanized IgG1 + (+) - (+) - - Phase 3 Phase 3 - - Phase 2 - Phase 3
Tildrakizumab humanized IgG1 + (+) - - - - - - - - - -
mirikizumab humanized IgG4 Phase 3 - - - Phase 3 Phase 3 - - - - -
(LY3074828)
IL-36 inhibitor IL-36 spesolimab (BI humanized IgG1 - - - - - Phase - - - - Phase 2
receptor 655130)b 2/3
imsidolimab humanized Ig - - - - - - - - - - Phase 2
(ANB019)b
|
763

(Continues)
 764
|

TA B L E 1 (Continued)

FDA approval (approval in Japan)

Target Behcet
Classification molecule Agent Structure Psoriasis PsA AS RA CD UC uveitis D HS PG PPP
a
PDE4 inhibitor PDE4 Apremilast small molecule + (+) + (+) - - - - - + (+) - - -
Roflumilast small molecule Phase 2 - - - - - - - - - -
Hemay005 small molecule Phase 2 - - - - - - - - - -
JAK inhibitor JAK1/3 Tofacitinib small molecule - + (-) - + (+) - + (+) - - - -
JAK1/2 Baricitinib small molecule - - - + (+) - - - - - - -
JAK1 upadacitinib small molecule - applied Phase + (+) Phase 3 Phase 3 - - Phase 2 - -
(ABT-494) 3
JAK1 Filgotinib small molecule - Phase 3 Phase applied Phase 3 Phase 3 - - - - -
3
TYK2 BMS-986165 small molecule Phase 3 - - - Phase 3 Phase 3 - - - - -
TYK2 PF-06826647 small molecule Phase 2 - - - - - - - - - -
TYK2/JAK1 brepocitinib small molecule Phase 2 - - - - - - - - - -
(PF-
06700841-
00)
Other inhibitors RORgT AUR101 small molecule Phase 2 - - - - - - - - - -
RORgT BI 730357 small molecule Phase 2 - - - - - - - - - -
IRAK-4 CF101 small molecule Phase 3 - Phase Phase - - Phase - - - -
3 3 2

Notes: Indication of each agent is described according to the label information in the US (https://daily​med.nlm.nih.gov/daily​med/) and Japan (https://www.info.pmda.go.jp/psear​ch/html/menu_tenpu_base.
html). Information of clinical trials (phase 2 or 3) is described according to the data at the site of database (https://clini​c altr​ials.gov/).
Green: agents approved in both the US and Japan. Light blue: agents approved in the US but not in Japan. Yellow: agents approved in Japan but not in the US. Orange: agents in clinical trials.
Abbreviations: PsA, psoriatic arthritis; AS, ankylosing spondylitis; RA, rheumatoid arthritis; CD, Crohn’s disease; UC, ulcerative colitis; Behcet D, Behcet’s disease; HS, hidradenitis suppurativa; PG,
pyoderma gangrenosum; PPP, palmoplantar pustulosis; applied, applied for approval.
a
Indication for recalcitrant oral ulcers in Behcet D.
b
Phase 2 studies evaluating efficacy and safety for GPP treatment are ongoing.
HONMA and HAYASHI
HONMA and HAYASHI
3.1 | TNF and the inhibitors
While TNF is mainly produced by DCs, it is also manufactured by
other cells, such as Th1, Th17, macrophages, mast cells, neutrophils,
keratinocytes, and endothelial cells. 2,21,33,34 TNF acts as a proin-
flammatory cytokine via NF-κB signaling activation through TNF
receptors, which are broadly expressed on various cell types. 22
The TNF-mediated response is shared by inflammatory diseases
and several conditions, such as RA, spondyloarthritis, IBD, uveitis,
22
Behcet’s disease, and severe drug eruption (Table 1). TNF is also
indispensable for granuloma-formation and the maintenance against
Mycobacterium tuberculosis infection.35-37 The reactivation risk of
tuberculosis is possibly lower during IL-17 or IL-23 inhibitor therapy
than during TNF inhibitor therapy.38
3.1.1 | Etanercept
Etanercept, which is a fusion protein of TNF-receptor and the Fc
region of IgG1, can bind to soluble and membrane-bound TNF and
neutralize the function.39 Although the Fc region has a complement-
binding domain, etanercept does not display antibody-dependent
cellular cytotoxicity.39 The United States (US) and European Union
have approved the use of etanercept for treating RA, juvenile RA,
ankylosing spondylitis (AS), psoriasis, and PsA; however, Japan has
not yet approved this drug for treating psoriasis and PsA (Table 1).
Etanercept alone (50 mg/week) has shown preferable efficacy
against plaque-type psoriasis, and the improvement ratios in the pso-
riasis-area and severity index (PASI) by 50%, 70%, and 90% (PASI50,
PASI70, and PASI90) were 58% (placebo 14%), 34% (placebo 4%),
and 12% (placebo 1%), respectively.40 Etanercept monotherapy is
comparative with the combination therapy of etanercept and meth-
otrexate (MTX), but it is more effective in treating PsA than MTX
monotherapy. The American College of Rheumatology improvement
ratio by 20%, 50%, and 70% (ACR20, ACR50, and ACR70) is 60.9%,
44.4%, and 29.2%, respectively.41 Regardless of MTX coadministra-
tion, the reproducible effect of etanercept reflects considerably
42
lower immunogenicity than that of other TNF inhibitors.
3.1.2 | Infliximab
Infliximab is a chimeric anti-TNF-α monoclonal antibody composed
of a constant region of human IgGlκ and the murine variable anti-
gen-binding region of high-affinity anti-human TNF-α antibody.43
It specifically binds to both soluble and membrane-bound TNF,
and a complex of membrane-associated TNF can induce apoptosis
of activated T cells and macrophages.44,45 Intravenous infliximab is
broadly approved for treating RA, psoriasis, PsA, AS, IBD, uveitis,
and Behcet’s disease. In a multicenter, double-blind, and placebo-
controlled phase 3 trial, infliximab administration (5 mg/kg at weeks
0, 2, and 6, then every 8 weeks) was excellently effective against
moderate-to-severe plaque-type psoriasis, and the PASI50, PASI75,
| 765
and PASI90 were 91% (placebo 23%), 80% (placebo 7%), and 57%
(placebo 1%) at week 10, respectively.46 In the IMPACT2 study, in-
fliximab was also highly effective for treating PsA; at week 24, the
ACR20, ACR50, and ACR70 were 54% (placebo 16%), 41% (placebo
4%), and 27% (placebo 2%), respectively.47 After infliximab therapy,
the modified Sharp/van der Heijde score (modified total Sharp score
[mTSS]) including the evaluation of radiographic progression is sig-
nificantly reduced.48 Given the chimeric structure, antidrug antibody
(ADA) against infliximab can be more frequently detected and affect
the clinical efficacy than that against other biologics.49 Nevertheless,
MTX coadministration can diminish ADA frequency, and contribute
a higher drug survival rate of infliximab.50,51 Considering that the
trough level of infliximab with the clinical effect against RA52 and
psoriasis,53 the dose increment of infliximab of up to 6 mg/kg every
4 weeks or 10 mg/kg every 8 weeks (approved only in Japan) can
be used for psoriasis cases with the loss of treatment efficacy.54
Monitoring of the trough level of infliximab and ADA may contrib-
ute to making proper decisions for further therapeutic options.55
Unfortunately, the mechanism of the infusion reaction, which refers
to the relatively infliximab-specific adverse reaction among various
biologics used for psoriasis treatment, remains insufficiently under-
stood; however, it may possibly involve an immunological reaction
via the ADA and cytokine-release syndrome.56,57
3.1.3 | Adalimumab
Adalimumab is a human IgG1-type monoclonal antibody neutralizing
human TNF.58 Similar to infliximab, adalimumab specifically binds
to both soluble and membrane-bound TNF-α, inducing apoptosis of
activated T cells and macrophages.44,45 It is broadly used for treat-
ing RA, plaque-type psoriasis, PsA, AS, IBD, uveitis, and Behcet’s
disease. In a randomized, double-blinded, placebo-controlled, and
multicenter phase 3 study, adalimumab monotherapy (80, 40, and
40 mg at week 0, 1, and then every other week [eow], respectively)
was highly effective against moderate-to-severe plaque-type pso-
riasis; the ratios of PASI75, PASI90, and PASI100 at week 12 were
68% (placebo 5%), 37% (placebo 2%), and 14% (placebo < 1%), re-
spectively.58 In a double-blind and placebo-controlled phase 2/3
trial focusing on the treatment of adult Japanese psoriatic cases,
the PASI50, PASI75, and PASI90 ratios at week 16 were 81.4% (pla-
cebo 19.6%), 62.8% (placebo 4.3%), and 39.5% (placebo 0%) in the
group treated with 40 mg eow of adalimumab subcutaneously, and
90.5%, 81.0%, and 61.9% in the group treated with 80 mg eow of
adalimumab, respectively.59 Adalimumab effectively treats PsA,
and the ratios achieving ACR20, ACR50, and ACR70 at week 24
are 57% (placebo 15%), 39% (placebo 6%), and 23% (placebo 1%),
respectively.60 In addition, adalimumab could inhibit radiographic
progression evaluated by mTSS.60 During adalimumab therapy, ADA
frequency is relatively increased, affecting the clinical efficacy of
this drug61 similar to infliximab. Therefore, for cases with secondary
loss of treatment efficacy, increasing dose to 80 mg eow or applying
MTX coadministration can be the therapeutic options.50,62
766 | HONMA and HAYASHI

3.1.4 | Certolizumab pegol
Certolizumab pegol (CZP), which is a PEGylated, humanized Fab fragment
neutralizing human TNF,63 lacks the Fc portion of immunoglobulin, which
64
plays an essential role in transplacental translocation. In contrast to inf-
liximab and adalimumab, it does not induce apoptosis of activated T cells
and macrophages.44 According to CIMPASI-1 and CIMPASI-2 studies fo-
cusing on CZP efficacy in treating plaque-type psoriasis, the PASI75 and
PASI90 ratios at week 16 were 76.7% (placebo 9.9%) and 45.9% (placebo
4.3%) in the group treated with 200 mg eow of CZP subcutaneously, while
82.0% and 52.2% in the group treated by 400 mg eow of CZP, respec-
63
tively. The clinical response of the CZP-treated group against PsA was
significantly higher than that of the placebo group at week 24 (RAPID-
PsA study).65 Additionally, the response ratios of groups treated with 200
and 400 mg eow of CZP are were 63.8% and 56.3% (placebo 23.5%) in
ACR20, 44.2% and 40.0% (placebo 12.5%) in ACR50, and 28.3 and 23.7%
(placebo 4.4%) in ACR70, respectively.65 As observed in other TNF inhibi-
tors, ADA can frequently be detected in CZP-treated cases, but the exist-
66,67
ence of ADA is usually not associated with the trough level of CZP.
3.2 | IL-17 and the inhibitors
The IL-17 family consists of six subunits (IL-17A, IL-17B, IL-17C,
IL-17D, IL-17E, and IL-17F). Functional IL-17 is composed of
homodimers of each subtype or a heterodimer of IL-17A and IL-
17F; the IL-17-signaling is transmitted via ligand-specific IL-17
receptors (IL-17R) (Figure 2a), whereas IL-17A signaling can be
transmitted via IL-17RA, IL-17RC, and IL-17RD. 68-71
IL-17 recep-
tors share a similar expression of fibroblast growth factor and
IL-17R (SEFIR) domain, which is an intracellular domain recruiting
Act-1; Act-1 activates NF-κB and mitogen-activated protein kinase
(MAPK) pathways (Figure 2b). 68-70 IL-17 is important for prevent-
ing the cutaneous and mucosal infection of Candida albicans and
Staphylococcus aureus, 68-70,72 and maintaining the epithelial bar-
rier formation of the intestine.73,74 Among the subtypes, IL-17A
is the most essentially implicated in healthy and disease condi-
tions including psoriasis69 and is produced by Th17, Tc17, tissue-
resident memory T (T RM), ILC3, invariant natural killer T (iNKT),
γδ-T, and mucosal associated invariant T (MAIT) cells.75 Fatty acid-
dependent, long-lived CD8-positive T RM is present even in healed
epidermis, and IL-17-production from TRM is closely related to skin
lesion recurrence.76,77 In the synovial fluid of spondyloarthritis in-
cluding PsA, adaptive immunocytes, such as Th17 and Tc17 cells
can IL-23-dependently produce IL-17.75 Conversely, MAIT, iNKT,
and γδ-T cells can possibly produce IL-17 IL-23-independently.78,79
IL-17A is involved in the progression of atherosclerosis, 80 liver cir-
rhosis, 81-83 and the mechanism of insulin resistance. 84 Generally,
IL-17 inhibitors have lower immunogenicity than that of TNF in-
hibitors, and the re-initiation of IL-17 inhibitor therapy shows a

F I G U R E 2 (a) Interleukin (IL)-17 family and the receptors. Signaling of IL-17 families are transmitted via specific receptor pairs. IL-17A-
signaling is transmitted via IL-17RA, IL-17RC, and IL-17RD. IL-17RA is shared by IL-17A, IL-17F, IL-17C, and IL-17E-signaling. (b) Molecular
structure of an IL-17 receptor (IL-17R). Two fibronectin III (FN)-like domains constitute the extracellular position, which is necessary for the
specific binding between ligands and receptors. A similar expression of fibroblast growth factor and IL-17R (SEFIR) domain is shared as an
intracytoplasmic region of the IL-17R family, recruiting Act1 which is an adaptor protein required to activate the IL-17-dependent signaling
pathways. Act1 also possesses the SEFIR-domain, which is required for the homophilic interaction with that of IL-17R. The cytoplasmic tail is
composed of the C/EBP-β activation domain (CBAD) [Color figure can be viewed at wileyonlinelibrary.com]
HONMA and HAYASHI
reproducible effect in cases that had once achieved treatment
success. 85-88
3.2.1 | Secukinumab
Secukinumab, which is a human IgG1κ-type monoclonal antibody against
human IL-17A, has excellent clinical efficacy and the lowest immuno-
genicity among the biologics used for treating psoriasis, and other inflam-
89,90
matory disorders. While secukinumab shows an excellent effect on
psoriasis, PsA and AS, it can possibly worsen IBD including Crohn’s dis-
91
ease. In randomized phase 3 studies, the ratios of PASI75, PASI90, and
PASI100 at week 12 were 81.6% (placebo 4.5%), 59.2% (placebo 1.2%),
and 28.6% (placebo 0.8%) in ERASURE study and 77.1% (placebo 4.9%),
54.2% (placebo 1.5%), and 24.1% (placebo 0%) in FIXTURE study, respec-
tively.92 Head-to-head trials versus adalimumab in PsA revealed that the
clinical responses of secukimumab and adalimumab are comparable at
week 52 (response rates in the secukinumab- and adalimumab-treated
93
groups: ACR20, 67% and 62%; ACR50, 49% and 42%, respectively).
In the combined evaluation of PASI90 and ACR50, the secukinumab-
treated group showed a superior response rate to the adalimumab-
treated group.93 Secukinumab presents an excellent clinical effect in AS
treatment; the effect is evident even by administering a lower dose of
secukinumab compared with that in PsA treatment.94
3.2.2 | Ixekizumab
Ixekizumab is a humanized IgG4 antibody that lacks binding capacity
to complement, and the amino acid in the hinge region is replaced to
prevent forming semi-antibodies and inadequate heterodimerized an-
tibodies.95 Its binding affinity to IL-17A is considerably stronger than
that of secukinumab.95 In randomized phase 3 studies, the PASI75,
PASI90, and PASI100 ratios at week 12 in the ixekizumab-treated
group (160 and 80 mg at week 0 and then eow, respectively) were
89.1% (placebo 3.9%), 70.9% (placebo 0.5%), and 35.3% (placebo 0.0%)
in UNCOVER-1 study and 87%, 68%, and 38% in UNCOVER-3 study.96
Skin lesions improved earlier in the ixekizumab-treated group than in
the guselkumab-treated group in a head-to-head study (IXORA-R
study).97 In a head-to-head trial comparing the clinical effects between
ixekizumab and adalimumab against PsA, these drugs demonstrated
similar efficacy at week 24 (response rates: ACR20 68.9% and 72.1%;
ACR50 50.5% and 46.6%, respectively).98 In the combined evalua-
tion of PASI100 and ACR50, the ixekizumab-treated group showed
a superior response rate to the adalimumab-treated group.98 Similar
to secukinumab, ixekizumab has excellent clinical efficacy against AS
symptoms, and its effect is comparable with that of adalimumab.99
3.2.3 | Brodalumab
Brodalumab, which is a monoclonal human IgG2 antibody against IL-17
receptor A (IL-17RA),100 interrupts the signal of IL-17A, F, C, and E by
| 767
inhibiting IL-17RA (Figure 2).68-71 In randomized phase 3 studies, the
PASI75, PASI90, and PASI100 ratios at week 12 in the brodalumab-
treated group (210 mg eow) were 86% (placebo 8%), 70% (placebo
3%), and 44% (placebo 1%) in AMAGINE-2 study and 85% (placebo
6%), 52% (placebo 2%), and 37% (placebo 0.3%) in AMAGINE-3 study,
respectively.101 In a randomized phase 3 studies evaluating drug effi-
cacy against PsA (AMVISION-1 and AMVISION-2 trials), brodalumab
showed comparable clinical effects with other IL-17A inhibitors.102
The ACR20, ACR50, and ACR70 response rates in the brodalumab-
treated group at week 24 were 53.6% (placebo 23.8%), 36.4% (pla-
cebo 10.4%), and 20.9% (placebo 4.7%), respectively.102
3.2.4 | Bimekizumab (under development)
Bimekizumab is a monoclonal humanized IgG1 antibody that is still
currently being developed; this drug specifically neutralizes both
IL-17A and IL-17F.103 While IL-17A and IL-17F present similar bioac-
tivity, the affinity of IL-17A to IL-17RA is considerably higher than
that of IL-17F.104 IL-17F is produced by lymphocytes as well as by
the colonic epithelium.105 In a randomized, double-blinded and pla-
cebo-controlled phase 2b study (BE ABLE 1), the PASI75, PASI90,
and PASI100 ratios at week 12 in the bimekizumab-treated (320 mg
every 4 weeks) group reached 93.0% (placebo 4.8%), 79.1% (placebo
0%), and 55.8% (placebo 0%), respectively.106 Bimekizumab was also
highly effective for active PsA in a phase 2b study (BE ACTIVE), and
the response rates of ACR20, ACR50, and ACR70 at week 24 in the
bimekizumab-treated (160 mg every 4 week with 320 mg loading
dose at baseline) group were 78%, 62%, and 41%, respectively.107
3.3 | IL-12/23 p40, IL-23 p19 and the inhibitors
The IL-12 cytokine family consists of IL-12, IL-23, IL-27, and IL-35
108
. These cytokines share subunits and the specific receptors
(Figure 3).108,109 For instance, p40 subunit is shared by IL-12 and IL-23,
and p19 subunit is specifically used by IL-23 (Figure 3). In the psoriatic
skin, the expression of both p40 and p19 subunits is increased but
not that of p35 subunit, which is another component of IL-12, sug-
gesting that IL-23 has a more specific effect in psoriatic skin.110 IL-12
and IL-23 a show distinct function in the T cell diversity. IL-12 mainly
works by inducing Th1 cells, whereas IL-23 mainly induces the patho-
genic potential of Th17 cells (Figure 3).108,109 Under IL-23 stimulation,
FoxP3-positive regulatory T cells (Treg) are potentiated to produce
IL-17.111,112 Similar to IL-17 inhibitors, IL-23 inhibitors have lower im-
munogenicity than TNF-inhibitors, and the reproducible effect can be
observed on cases that had once achieved treatment success. 88,113
3.3.1 | Ustekinumab
Ustekinumab is a human IgG1 antibody neutralizing human IL-12/23
p40 subunit.114,115 Thus, it inhibits both IL-12 and IL-23-dependent
768 | HONMA and HAYASHI

F I G U R E 3 Interleukin (IL)-12 family cytokines and the signaling via specific receptors. IL-12 family cytokines, such as IL-12, IL-23, and IL-
35, share the subcomponents with each other. While a p40 subunit is shared by IL-12 and IL-23, a p19 subunit is specific for IL-23. The signal
is intracellularly transmitted via the receptor-specific activation of the JAK/STAT pathways. IL-12 and IL-23 utilize the receptor pairs of IL-12
receptor β1 (IL-12Rβ1)/IL-12Rβ2 and IL-23R/ IL-12Rβ1, respectively. IL-35 can bind to the homodimer or heterodimer of IL-12Rβ2 and gp130.
IL-12, IL-23, and IL-35 mainly activate STAT4, STAT3, and STAT1/4, respectively. In terms of T cell differentiation, IL-12, IL-23, and IL-35-
signaling are closely related to the induction of Th1, Th17, and Treg, respectively [Color figure can be viewed at wileyonlinelibrary.com]

signaling. Ustekinumab presents a high clinical effect in treating 3.3.2 | Guselkumab

not only psoriasis and PsA but also IBD. Hence, IL-23-independent
IL-17A production can contribute to maintaining an intestinal epi-
73
thelial barrier. In randomized phase 3 studies evaluating the effi-
cacy of ustekinumab in treating plaque-type psoriasis, the PASI75,
PASI90, and PASI100 ratios at week 12 in the ustekinumab-treated
(45 mg at week 0 and 4) group were 67.1% (placebo 3.1%), 41.6%
(placebo 2.0%), and 12.5% (placebo 0.0%) in PHOENIX-1 study
and 66.7% (placebo 3.7%), 42.3% (placebo 0.7%), and 18.1% (pla-
cebo 0.0%) in PHOENIX-2 study, respectively.114,115 In a real-world
setting, ustekinumab tends to present a longer survival rate than
116-118
TNF inhibitors. Ustekinumab also shows favorable efficacy
in treating PsA, and the response ratios of ACR20, ACR50, and
ACR70 at week 24 in the ustekinumab-treated (45 mg at weeks
0 and 4, then 45 mg every 12 weeks) group were 42.4% (pla-
cebo 22.8%), 24.9% (placebo 8.7%), and 12.2% (placebo 2.2%) in
PHOENIX-1 study115 and 43.7% (placebo 20.2%), 17.5% (placebo
6.7%), and 6.8% (placebo 2.9%) in PHOENIX-2 study, respec-
tively.119 While increasing the dose up to 90 mg every 12 weeks
can be an effective therapeutic option for cases with insufficient
clinical effect or high body weight (≥100 kg), the approved condi-
tion is different by country.
Guselukumab, which is a monoclonal human IgG1 antibody
specifically neutralizing IL-23 p19 subunit, specifically in-
hibits IL-23 signaling.113,120 It can effectively treat psoriasis,
PsA, and palmoplantar pustulosis.121 In addition, clinical tri-
als evaluating its efficacy in treating Crohn’s disease are still
ongoing (Table 1). In randomized phase 3 studies evaluating
the efficacy of guselkumab in treating moderate-to-severe
plaque-type psoriasis, the PASI75, PASI90, and PASI100 ratios
at week 16 in the guselkumab-treated (100 mg at weeks 0 and
4) group were 91.2% (placebo 5.7%), 73.3% (placebo 2.9%), and
37.4% (placebo 0.6%) in VOYAGE-1 study 120 and 86.3% (pla-
cebo 8.1%), 70.0% (placebo 2.4%), and 34.1% (placebo 0.8%)
in VOYAGE-2 study, respectively.113 Guselkumab is also effec-
tive in treating PsA, and the response ratios of ACR20, ACR50,
and ACR70 at week 24 in the guselkumab-treated (100 mg at
weeks 0 and 4, then 100 mg every 8 weeks) group were 52%
(placebo 22.8%), 30% (placebo 9%), and 12% (placebo 6%) in
DISCOVER-1 study.122 The clinical effect of guselkumab can
be reproduced independent of the previous treatment using
biologics.122,123
HONMA and HAYASHI | 769

3.3.3 | Risankizumab weeks 0 and 8) group were 78% (placebo 4%), 59% (placebo 0%),
and 31% (placebo 0%) in the 100-mg mirikizumab-treated group
Risankizumab is a monoclonal humanized IgG1 antibody and 75%, 67%, and 31% in the 300-mg mirikizumab-treated group,
neutralizing IL-23 p19 subunit.124 In randomized, double-blind, respectively.130 According to a phase 2 study, mirikizumab can also
and placebo-controlled phase 3 studies evaluating the efficacy effectively treat ulcerative colitis.131
of risankizumab in treating plaque-type psoriasis, the response
rates of PASI90 and PAI100 in the risankizumab-treated (150 mg
at weeks 0 and week 4) group at week 16 were 75.3% (placebo 3.4 | IL-36 and the inhibitors
4.9%) and 35.9% (placebo 0%) in UltIMMA-1 study and 74.8%
(placebo 2.0%) and 50.9% (placebo 2.0%) in UltIMMA-2 study, Interleukin-36, which is a proinflammatory cytokine in the IL-1 fam-
respectively.124 Furthermore, risankizumab has a significantly ily, consists of three subtypes, namely, IL-36α, IL-36β, and IL-36 γ.
higher response rate than ustekinumab and adalimumab.124,125 In The IL-36 signal is transmitted through a heterodimer of IL-36 re-
another phase 3 study, risankizumab-treated cases maintained a ceptor (IL-36R)/IL-1RAcP, and activates MAPK and NF-κB pathways
sufficient effect on skin lesions even after withdrawing risanki- by recruiting MyD88 to the intracellular Toll/interleukine-1 resist-
zumab administration.126 In this study, the risankizumab-treated ance (TIR) domain, causing the inflammatory response of various
group (subcutaneous injection of 150 mg of risankizumab at tissues (Figure 4).132-135 In addition to the agonistic cytokines, IL-36
weeks 0, 4, and 16), which achieved static physician global as-
sessment score (sPGA) of 0/1 at week 28, was randomized into
a group regularly treated with risankizumab (150 mg every
12 weeks) or a group receiving placebo. The median time to loss
of PASI90 in the risankizumab-withdrawal group was 210 days
(interquartile range 113–296 days).126 Despite its excellent ef-
ficacy in treating psoriatic skin lesions, risankizumab failed to
show significant improvement of symptoms in AS cases.127 Thus,
IL-23-independent IL-17A production has a crucial role in axial
spondylitis pathomechanism.78,79

3.3.4 | Tildrakizumab

Tildrakizumab is a monoclonal humanized IgG1 antibody against

128
IL-23 p19 subunit. It is the most recently approved agent for
psoriasis treatment with relatively abundant data about its efficacy
and safety on long-term use.128 In randomized, double-blind, and
placebo-controlled phase 3 studies evaluating the efficacy of tild-
rakizumab in treating plaque-type psoriasis, the response rates of
PASI75, PASI90, and PASI100 in the tildrakizumab-treated (100 mg
at weeks 0 and 4) group at week 12 were 64% (placebo 6%), 35%
(placebo 3%), and 14% (placebo 1%) in reSURFACE-1 study and 61%
(placebo 6%), 39% (placebo 1%), and 12% (placebo 0%) in resurface-2
study, respectively.129 In most of cases, tildrakizumab efficacy was
maintained for 142 weeks.128

3.3.5 | Mirikizumab (under development)
Mirikizumab is a monoclonal humanized IgG4 antibody against
human IL-23 p19 subunit; however, the clinical trials evaluating its
efficacy and safety in treating psoriasis and IBD are still ongoing
(Table 1).130 In a randomized, double-blind, and placebo-controlled
phase 2 study evaluating the efficacy of mirikizumab in treating
plaque-type psoriasis, the response rates of PASI75, PASI90, and
PAI100 at week 16 in the mirikizumab-treated (100 or 300 mg at
F I G U R E 4 Interleukin (IL)-36 and the receptors. IL-36 signaling
is transmitted by the receptor pair of IL-36R and IL-1Acp. The
extracellular region of the receptor consists of three Ig-like domains
necessary for the ligand-specific binding. The Toll/interleukine-1
resistance (TIR) domain recruits the adaptor protein MyD88, which
interacts with the signaling molecules associated with downward
pathways, such as NF-κB and MAP kinase via the activation of
the interleukin-1 receptor associated kinases (IRAKs).138,194 IL-36a
works as a physiological competitive inhibitor against IL-36-
signaling [Color figure can be viewed at wileyonlinelibrary.com]
770 | HONMA and HAYASHI

receptor antagonist (IL-36 Ra) is an intrinsic antagonistic cytokine

IFN-αR2
receptor

IFN-αR1/
that can bind to IL-36R. IL-36 family cytokines are produced not only

TYK-2
IFN-α

JAK-1
IFN-α
by immune cells such as macrophages, DCs, and T lymphocytes but
also epithelial tissues including the epidermis.132,136-138 Functional
deletion of IL-36Ra is one of the essential causes in generalized

receptor

IFN-γR2
IFN-γR1/
pustular psoriasis (GPP) (deficiency of interleukin thirty six receptor

IFN- γ

JAK-2
JAK-1
IFN-γ
antagonist, DITRA), and the uncontrolled IL-36 signaling causes an
139-141
accelerated inflammatory reaction in GPP. IL-17A can induce

homodimeric
IL-36-expression, and these cytokines synergistically amplify a vi-
cious circle of the inflammatory response. 136,137,142

CR

EPOR

JAK-2
EPO
3.4.1 | Spesolimab (BI 655130) (under development)

IL-6Rα/gp130
CR sharing
gp130

TYK-2
JAK-2
JAK-1
Spesolimab is a humanized monoclonal antibody against IL-36 recep-

IL-6
tor.143 In a phase 1 proof-of-concept study on seven GPP cases, a
single intravenous administration of spesolimab (10 mg/kg) signifi-

IL-4Rα/γ-
chain
cantly reduced the GPP severity score and maintained the status up
to week 20.144

IL-4

CR sharing γ-chain

β/γ-chain
IL-2Rα/IL-2R
4 | S M A LL M O LEC U LE S

JAK-3
JAK-1
IL-2
4.1 | Phosphodiesterase-4 (PDE-4) and the
inhibitors

IL-12Rβ1
TA B L E 2 Receptors and required JAKs in the signaling of representative cytokines and interferons

IL-23R/
Phosphodiesterases, which are hydrolytic enzymes of the cyclic CR sharing IL-12R β1
IL-23

nucleotides, cAMP and cGMP, consists of at least 11 subfamilies

based on the biochemical functions and homologies.145-147 In par-

IL-12Rβ2
ticular, the PDE-4 family works specifically on cAMP degradation
IL-12Rβ1/

TYK-2
and is expressed in the brain, cardiac muscle, smooth muscles, ke-

JAK-2
IL-12

ratinocytes, and immunocytes such as T lymphocytes, monocytes,

macrophages, neutrophils, DCs, and eosinophils.147 Protein kinase
IL22R1

A (PKA) activated by intracellular cAMP accumulation inhibits the

IL-10R2/

MAPK pathway associated with proinflammatory cytokine pro-

IL-22

duction and cell proliferation via Raf-1 inhibition.145-147 PKA also

suppresses transcriptional activity of NF-κB by regulating the in-
20R1 or
IL-22R1/IL-

teraction between NF-κB and CREB-binding protein (CBP)/p300

related to proinflammatory response (Figure 5).147 Conversely, PKA
R2
IL-20

accelerates the transcriptional activity of CREB/ATF-1 working on

anti-inflammatory-cytokine production by increasing CREB phos-
IL-20R2

phorylation (Figure 5).147 A competitive mechanism between CREB

IL-20R1/

IL, interleukin; JAK, Janus-activated kinase.

and NF-κB for CBP can be involved in transcriptional regulation.148

IL-19

IL-10 family receptor

EPACs, which are guanine nucleotide exchange factors specific for

Rap1/2, are activated by cAMP and can reduce the IL-6-dependent
inflammatory response via SOCS3 induction.149 EPAC1 is also indis-
IL-10R2
IL-10R1/

pensable for the adequate response of effector T cells against inhibi-

TYK-2
JAK-2
JAK-1
IL-10

tory cytokines derived from Treg.150 In addition to Treg-mediated

inhibitory mechanism via CD25-dependent IL-2 deprivation, inhibi-
tory cytokine production, and immune-checkpoint molecules,151,152
receptors

receptor pair
Cytokines

cAMP transfer can be an alternative suppression-mechanism of ef-

cytokine

(CR)

fector T cells by Tregs. As FoxP3, which is the master transcriptional

JAKs

factor of Treg, inhibits the expression of PDE3b to degrade cAMP,

HONMA and HAYASHI | 771

a high intracellular concentration of cAMP is maintained in Treg
compared with other effector T cells.153,154 Treg transfers the ac-
cumulated cAMP into the target cells through gap junctions, and the
153,154
elevated cAMP can inhibit activity of the target cells. PDE-4
inhibition reduces proinflammatory-cytokine production from vari-
ous cell types including DCs, monocytes, neutrophiles, T-cells, and
147,155
synovial macrophages. In contrast, PDE-4 inhibition induces
the production of the anti-inflammatory cytokine IL-10 in mono-
cytes and increases the function of Tregs.147,155,156 During apremi-
last administration for the treatment of plaque-type psoriasis, the
157,158
plasma levels of IL-17A, IL-17F, and IL-22 significantly declined.
Moreover, clinical trials evaluating the efficacy of the topical or sys-
temic PDE-4 inhibitors, crisaborole and roflumilast, are currently
159,160
ongoing.
4.1.1 | Apremilast
Apremilast is an oral, small-molecule, selective PDE-4 inhibitor.161 In
randomized, double-blind, and placebo-controlled phase 3 studies
evaluating the efficacy of apremilast in treating moderate-to-severe
plaque-type psoriasis, the response rates of PASI75 and PASI90 in
the apremilast-treated (30 mg twice daily) group at week 16 were
33.1% (placebo 5.3%) and 9.8% (placebo 0.4%) in ESTEEM-1 study161
and 28.8% (placebo 5.8%) and 8.8% (1.5%) in ESTEEM-2 study, re-
spectively.162 In these clinical studies, apremilast displayed a favora-
ble clinical effect on nail and scalp psoriasis.163 In a retrospective
observational study, apremilast was more effective in cases with
small-plaque psoriasis than in those with large-plaque psoriasis.164
Apremilast is also effective in treating PsA; the response ratios of
ACR20, ACR50, and ACR70 at week 16 in the apremilast-treated
(30 mg twice daily) group were 32.1% (placebo 18.9%), 10.5% (pla-
cebo 5%), and 1.2% (placebo 0.6%) in PALACE-2 study165 and 41%
(placebo 18%), 15% (placebo 8%), and 4% (placebo 2%) in PALACE-3
study, respectively.166 Further, apremilast is considerably safe.
However, it is contraindicated for pregnant women. Nevertheless,
this drug does not always require regular screening for infectious
disorders, such as tuberculosis and hepatitis B virus infection.147
Headache and secretory diarrhea are the most common adverse
reactions of apremilast leading to discontinuation.167 Diarrhea is
induced by the pharmacological effect of PDE-4 inhibition, activat-
ing chloride channel of mucosal epithelia depending on cAMP accu-
mulation.168 Apremilast also presents a favorable effect on the oral
ulcer of Behcet’s disease,169 and clinical trials on several inflamma-
tory skin diseases including atopic dermatitis and hidradenitis sup-
purativa, are ongoing (Table 1).

F I G U R E 5 Function of cAMP in an inflammatory response. Adenylate cyclase (AC) activated in the downstream of G-protein-coupled
receptors (GPCRs), such as β-adrenergic receptor and prostaglandin E2 receptors, increases intracellular cAMP specifically hydrolyzed
by phosphodiesterase 4 (PDE4). Accumulation of cAMP activates protein kinase A (PKA), resulting in anti-inflammatory-cytokine
production by increasing the transcriptional activity through CREB/ATF-1. Activated PKA inhibits the MAP-kinase pathway associated with
proinflammatory-cytokine production via Raf-1 inhibition, and it also suppresses the transcriptional activity of neuclear factor-kappa B (NF-
κB) by regulating the interaction between NF-κB and CBP/p300 related to the proinflammatory response in a competitive mechanism with
phosphorylated CREB by activated PKA. EPACs can reduce interleukin (IL)-6-dependent inflammatory response, and they are indispensable
for the adequate response of effector T cells against inhibitory cytokines derived from regulatory T cells [Color figure can be viewed at
wileyonlinelibrary.com]
772 | HONMA and HAYASHI
4.2 | Janus-activated kinase
(JAK) and the inhibitors
Most of cytokines and interferons transmit their signal via type I
and II cytokine receptors lacking an enzymatic activity and JAKs,
which are nonreceptor tyrosine kinases.170-179. JAK subsequently
phosphorylates and activates signal transducer and activators of
transcription (STATs). The JAK family consists of JAK1, JAK2, JAK3,
and TYK2; inhibition of each subtype can interrupt specific STAT-
dependent signaling pathways (Table 2).180-182 Tofacitinib, which
is an oral JAK1/3-selective inhibitor, has been approved for treat-
ing plaque-type psoriasis and psoriatic arthritis in the US but not
in Japan. Although tofacitinib shows a favorable clinical effect on
plaque-type psoriasis and PsA symptoms,183-185 herpes zoster can
occur during tafacitinib treatment, especially in Asian populations
including the Japanese.186,187 Baricitinib, an oral JAK1/2-selective
inhibitor, is effective for treating moderate-to-severe psoriasis,
and the response ratio of PASI75 in a phase 2b trial was 42.9% and
54.1% (placebo 16.7%) in 8 and 10 mg of baricitinib-treated groups,
respectively.188
4.3 | Others
Oral small molecule inhibitors targeting Tyk2,189 which is one of
JAK families related to IL-23-signaling, and ROR γT,190 which is
a master transcriptional factor of Th17 cells, is currently under
development, especially for plaque-type psoriasis treatment.
In addition, nuclear receptors, such as NURR1 (NR4a), which is
a transcriptional factor associated with Treg differentiation,191
and interleukin-1 receptor associated kinase 4 (IRAK-4), which
is a kinase mediating cytokine signaling via MyD88 associa-
tion, are focused as therapeutic targets of plaque-type psoriasis
(Table 1).192,193
5 | CO N C LU S I O N
The recent progress of highly potent therapeutic options for pso-
riasis treatment brings the era of “introducing and maintaining re-
mission” in psoriasis cases. Simultaneously, the excellent effect of
these molecular-targeted therapies explains the detailed molecular
mechanism of psoriatic diseases. However, further basic research
and refinement of the therapeutic strategy are required to clarify
unmet needs on psoriasis treatment.
C O N FL I C T O F I N T E R E S T
None declared.
ORCID
Masaru Honma https://orcid.org/0000-0003-1566-5331
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How to cite this article: Honma M, Hayashi K. Psoriasis:
Recent progress in molecular-targeted therapies. J Dermatol.
2021;48:761–777. https://doi.org/10.1111/1346-8138.15727