10.5826/dpc.1303a245
Introduction: Psoriasis is a common chronic, immune-mediated, inflammatory skin disease that in certain localization results difficult to treat. Psoriatic lesions in difficult-to-treat areas might be hardly managed as no standardized therapeutic approach and the application of topical treatments might have marred limitations. Systemic agents, including biologic therapies, have been proven effective in treating this subgroup of patients. In particular, current evidence has shown beneficial effects with the use of brodalumab, a fully human IgG2 monoclonal antibody antagonizing the IL-17 receptor A subunit (IL-17RA).
Objectives:  The aim of this narrative review was to collect published data about efficacy and safety of brodalumab in the treatment of psoriasis occurring in difficult-to-treat areas.  
Methods: Data on brodalumab effectiveness and safety deriving from both trials and real-world setting that had been published in the last 15 years were collected for this review, together with clinical findings issued during international meetings.
Results: In phase 3 trials, brodalumab demonstrated to be effective in promoting a rapid response in scalp psoriasis as well as in generalized pustular psoriasis and erythrodermic psoriasis. Nail psoriasis demonstrated marked clinical improvement after treatment with brodalumab. Amelioration of palmoplantar psoriasis was also described in brodalumab-treated patients. Various retrospective real-world studies reported a complete clearance of psoriatic lesions in difficult-to-treat areas, including genitalia, through short-term brodalumab treatment. 
Conclusions: Brodalumab, combining rapid and sustained efficacy with a favorable safety profile, may be a valid therapeutic option for severe variants of psoriasis as well as for psoriasis localized in difficult-to-treat areas.
text/xml
2160-9381
3688
en
Andrea Chiricozzi
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
folds
Brodalumab in the Treatment of Plaque Psoriasis Localized in Difficult-to-Treat Areas: a Narrative Review 
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Review
2023-07-31
2023-07-15
2023-07-31
2023-12-21
e2023245
Dermatol Pract Concept
Introduction: Psoriasis is a common chronic, immune-mediated, inflammatory skin disease that in certain localization results difficult to treat. Psoriatic lesions in difficult-to-treat areas might be hardly managed as no standardized therapeutic approach and the application of topical treatments might have marred limitations. Systemic agents, including biologic therapies, have been proven effective in treating this subgroup of patients. In particular, current evidence has shown beneficial effects with the use of brodalumab, a fully human IgG2 monoclonal antibody antagonizing the IL-17 receptor A subunit (IL-17RA).
Objectives:  The aim of this narrative review was to collect published data about efficacy and safety of brodalumab in the treatment of psoriasis occurring in difficult-to-treat areas.  
Methods: Data on brodalumab effectiveness and safety deriving from both trials and real-world setting that had been published in the last 15 years were collected for this review, together with clinical findings issued during international meetings.
Results: In phase 3 trials, brodalumab demonstrated to be effective in promoting a rapid response in scalp psoriasis as well as in generalized pustular psoriasis and erythrodermic psoriasis. Nail psoriasis demonstrated marked clinical improvement after treatment with brodalumab. Amelioration of palmoplantar psoriasis was also described in brodalumab-treated patients. Various retrospective real-world studies reported a complete clearance of psoriatic lesions in difficult-to-treat areas, including genitalia, through short-term brodalumab treatment. 
Conclusions: Brodalumab, combining rapid and sustained efficacy with a favorable safety profile, may be a valid therapeutic option for severe variants of psoriasis as well as for psoriasis localized in difficult-to-treat areas.
Andrea Chiricozzi
2023/07/31
10.5826/dpc.1303a245
e2023245
Dermatologia, Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore; Dermatologia, Dipartimento Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
2160-9381
folds
en
e2023245
Pinter A, Wilsmann-Theis D, Peitsch WK, Mössner R. Interleukin-17 receptor A blockade with brodalumab in palmoplantar pustular psoriasis: Report on four cases. J Dermatol. 2019;46(5):426-430. DOI: 10.1111/1346-8138.14815. PMID: 30786053.
Brodalumab in the Treatment of Plaque Psoriasis Localized in Difficult-to-Treat Areas: a Narrative Review 
https://dpcj.org/index.php/dpc/article/download/3688/2256
            Brodalumab in the Treatment of Plaque
         Psoriasis Localized in Difficult-to-Treat Areas:
                      A Narrative Review
                  Maria Vittoria Cannizzaro1, Giulia Coscarella1,2, Andrea Chiricozzi1,2


1 Dermatologia, Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
2 Dermatologia, Dipartimento Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy



Key words: brodalumab, psoriasis, pustular psoriasis, scalp, genitals
Citation: Cannizzaro MV, Coscarella G, Chiricozzi A. Brodalumab in the Treatment of Plaque Psoriasis Localized In Difficult-To-Treat
Areas: A Narrative Review. Dermatol Pract Concept. 2023;13(3):e2023245. DOI: https://doi.org/10.5826/dpc.1303a245
Accepted: July 1, 2023; Published: July 2023
Copyright: ©2023 Cannizzaro et al. This is an open-access article distributed under the terms of the Creative Commons
Attribution-NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted
noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: With the unrestricted contribution of Leo Pharma.
Competing Interests: Andrea Chiricozzi has served as advisory board member and consultant and has received fees and speaker's honoraria
or has participated in clinical trials for AbbVie, Almirall, Bristol Myers Squibb, Leo Pharma, Lilly, Janssen, Novartis, Pfizer and Sanofi
Genzyme. The other authors have no conflicts of interest to declare.
Authorship: All authors have contributed significantly to this publication.
Corresponding Author: Giulia Coscarella, MD, Dermatologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino
Gemelli 8, 00168 Rome, Italy Tel.: +39-320.6223136 Email: giuliacoscarella@gmail.com




  ABSTRACT             Introduction: Psoriasis is a common chronic, immune-mediated, inflammatory skin disease that in
                       certain localization results difficult to treat. Psoriatic lesions in difficult-to-treat areas might be hardly
                       managed as no standardized therapeutic approach and the application of topical treatments might
                       have great limitations. Systemic agents, including biologic therapies, have been proven effective in
                       treating this subgroup of patients. In particular, current evidence has shown beneficial effects with
                       the use of brodalumab, a fully human IgG2 monoclonal antibody antagonizing the IL-17 receptor A
                       subunit (IL-17RA).
                       Objectives: The aim of this narrative review was to collect published data about efficacy and safety
                       of brodalumab in the treatment of psoriasis occurring in difficult-to-treat areas.
                       Methods: Data on brodalumab effectiveness and safety deriving from both trials and real-world set-
                       ting that had been published in the last 15 years were collected for this review, together with clinical
                       findings issued during international meetings.
                       Results: In phase 3 trials, brodalumab demonstrated to be effective in promoting a rapid response in
                       scalp psoriasis as well as in generalized pustular psoriasis and erythrodermic psoriasis. Nail psoriasis
                       demonstrated marked clinical improvement after treatment with brodalumab. Amelioration of palmo-




Review | Dermatol Pract Concept. 2023;13(3):e2023245                                                                                    1
                       plantar psoriasis was also described in brodalumab-treated patients. Various retrospective real-world
                       studies reported a complete clearance of psoriatic lesions in difficult-to-treat areas, including genitalia,
                       through short-term brodalumab treatment.
                       Conclusions: Brodalumab, combining rapid and sustained efficacy with a favorable safety profile,
                       may be a valid therapeutic option for severe variants of psoriasis as well as for psoriasis localized in
                       difficult-to-treat areas.




Introduction                                                        with psoriasis in difficult-to-treat areas. Mounting evidence
                                                                    has proven beneficial effects with the use of brodalumab, a
Psoriasis is a chronic, immune-mediated, inflammatory skin          fully human IgG2 monoclonal antibody antagonizing the IL-
disease that is associated with a wide array of comorbidities       17 receptor A subunit (IL-17RA), that has been approved for
[1,2], as well as with detrimental physical effects, disability,    the treatment of plaque psoriasis at the induction dose of 210
reduced psychological wellbeing and impaired quality of life        mg s.c. at weeks 0, 1, and 2 and at the maintenance dose of
(QoL) [3]. Silvery scales on an erythematous plaque can af-         210 mg every 2 weeks [14,15]. The administration of broda-
fect any body area, though scalp, nails, palm and soles, or         lumab provides a rapid improvement in disease severity and
genitalia may be recalcitrant to therapies, hence are defined       a favorable safety profile in moderate-to-severe psoriasis. In
difficult-to-treat areas [4,5].                                     addition, data from comparative studies show a faster onset
    Patients affected by psoriasis in difficult-to-treat areas      of action with brodalumab compared to other biologic ther-
might experience difficulties in performing topical treat-          apies, as early as after 2 weeks of treatment [16]. Efficacy
ments, stigmatization of the disease and a marked impact            of brodalumab on psoriasis is well documented from both
on QoL [5,6]. Albeit the percentage of affected body area is        RCT and real-world data showing increasing percentage
minimal, psoriasis localized in these regions may represent a       of patients achieving PASI 75, 90 and 100 response rates
challenging condition for physicians.                               through 24 weeks of treatment [17], even in patients who
    The scalp is one of the first sites to be affected, and its     failed previous biologics, including selective anti-interlukin
involvement, occurring in about 80% of patients, increases          (IL)-17 agents. As reported in comparative studies from RCT
with disease duration. Scalp psoriasis presents with erythema,      AMAGINE 1/2/3, brodalumab demonstrated to be effective
scaling, and pruritus, often resembling seborrheic dermatitis       and faster also for patients with difficult-to-treat areas, even
[7-9]. To assess disease severity and treatment response, the       compared with other biologic agents [16,18].
Psoriasis Scalp Severity Index (PSSI) is commonly used [10].
    Nail psoriasis is seen in up to 80% of psoriatic patients,
being the only psoriatic manifestation in 6% of cases. Nail         Objectives
psoriasis correlates with disease severity and its presence is
                                                                    The aim of this narrative review was to collect published
associated with higher risk of developing psoriatic arthritis.
                                                                    data about efficacy and safety of brodalumab in the treat-
Clinical manifestations of nail psoriasis may vary whether
                                                                    ment of psoriasis occurring in difficult-to-treat areas.
affecting nail matrix, nail bed, the proximal nail fold or the
hyponychium [11,12]. The NAPSI is an objective assessment
instrument that is used to assess the severity of nail psoriasis
                                                                    Methods
and the area of involvement of the nail unit [10]).
    Palmoplantar psoriasis (PPP) can appear as hyperkera-           We carried out a search of the English-language literature
totic, pustular, or with mixed morphologies; itching, pain,         regarding difficult-to-treat psoriasis and treatment, with spe-
and fissuring are the most complained symptoms [13]. Pal-           cial focus on brodalumab effectiveness in both trial and real-
moplantar Psoriasis and palmoplantar pustolosis are mon-            world setting. We used the following databases: PubMed,
itored using the Palmoplantar Psoriasis Area and Severity           Embase, Google Scholar, ResearchGate, and Scopus. Key-
Index (PPASI) and the Palmoplantar Pustulosis Psoriasis             words used were: “psoriasis”, “difficult-to-treat psoriasis”,
Area and Severity Index (PPPASI), respectively [10].                “psoriasis treatment”, “IL-17 inhibitors”, “Anti-IL-17RA”,
    Though no standardized treatment approach exists, bio-          “brodalumab”. All articles published in the last 15 years and
logic therapies have been proven effective in treating patients     data from recent international meetings were reviewed.




2                                                                               Review | Dermatol Pract Concept. 2023;13(3):e2023245
Results                                                                heterodimer with IL-17RA and is also important in mediat-
                                                                       ing IL-17A signaling [24-25] (Figure 1).
Psoriasis Pathogenesis and Druggable Targets                               The expression of IL-17A, IL-17C, and IL-17F is in-
Psoriasis pathogenesis is multifaceted, being characterized            creased up to eightfold in psoriatic lesions compared to
by the involvement of a wide array of both immune and tis-             non-lesional skin with the greatest increase being detected
sue cells and by the increased signals of different cytokines          for IL-17C and IL-17F, though IL-17A results the most bi-
(TNF-α, IL-23, IL-17A, IL-22, IFN -γ) [19]. Though, multiple           ologically active (up to 30-fold more active than IL-17F)
immune pathways contribute to the inflammatory process,                [22,26,27].
the IL-23/Th17/IL-17A molecular axis is considered crucial                 Mounting evidence supporting the central role of IL-17A
in the pathogenesis of psoriasis and IL-17A is the pivotal             in psoriasis includes the upregulation of both IL-17A and
effector cytokines in this pathogenic model [20-21].                   its related genes in lesional and non-lesional skin of patients
    IL-17A belongs to the IL-17 cytokine family, consisting            with psoriasis. The increased expression of IL-17A derives
of six members (IL-17A-F) which signal through dimeric                 from immune cells involved in psoriasis pathogenesis such as
receptors that included five receptor subunits (IL-17RA to             T helper (h) cells, T cytotoxic (c) 17, innate lymphoid cells
IL-17RE) [22,23]. The receptor complex binding to both IL-17A          (ILC)3, mast cells, and neutrophils, that infiltrate lesional
and IL-17F, consists of two subunits: IL-17RA and IL-17RC,             skin and contribute to its abundant expression [27]. In vitro,
while IL-17C acts through a receptor composed by the sub-              IL-17 affects the expression of a large set of genes (more
units IL-17RA and IL-17RE. IL-17E (also called IL-25) acts             than 600 up- or down-regulated gene probes) in a recon-
through a receptor composed of the subunits IL-17RA and                stituted human epidermis model, and its effects are ampli-
IL- 17RB, whereas IL-17B and IL-17D have a ligand-receptor             fied by the synergism with other cytokines, including IL-22
interaction not well-defined. IL-17RD acts as an alternative           and TNF-α, strengthening the production of chemokines,




Figure 1. IL-17 cytokines family. The IL-17 cytokine family members signal through different dimeric receptor complexes that include five
subunits (IL-17RA to IL-17RE).
Binding to receptor complex, IL-17 cytokines are able to induce the expression of specific downstream genes, mostly transducing for pro-in-
flammatory mediators.
CCL, CXCL Chemokine ligand; IL Interleukin; TNF-α = Tumor necrosis factor alpha.




Review | Dermatol Pract Concept. 2023;13(3):e2023245                                                                                     3
pro-inflammatory cytokines, and antimicrobial peptides                   of its receptor on TH17 cells, especially when pooled with
(AMPs). They key psoriasis-signature genes are mostly in-                IL-6, TGF-β, IL-1, and IL-23 [36-38]. There is an import-
duced by IL-17 stimulation on keratinocytes and, conversely              ant bidirectional relationship between IL-17A and IL-17C,
to signals mediated by other pivotal cytokines, IL-17A signal            because IL-17A is a strong inducer of IL-17C in keratino-
greatly characterizes the psoriasis lesional skin transcrip-             cytes and IL-17C can induce high-level synthesis of IL-17A
tome [28-30].                                                            in T lymphocytes. Because IL-17C is produced in massive
    Similarly to IL-17A, IL‐17F and IL‐17C act in synergy                quantities by keratinocytes (eg, production in psoriasis is
with other cytokines, such as TNF-α or IL‐1, inducing ex-                100-fold higher than IL-17 A [35], the actions of this cy-
pression of antimicrobial peptides (AMPs), chemokines and                tokine may come to lead the IL-17 response axis in chronic
proinflammatory cytokines, which promote innate immune                   inflammatory conditions. IL‐17C may thereby amplify the
responses, the recruitment of inflammatory cells, and ke-                inflammatory response by further enhancing the production
ratinocyte activation and proliferation [31]. Furthermore,               of inflammatory mediators, including C‐C motif chemokine
an interplay between IL‐17A, IL‐17F and IL‐17C has been                  ligand 20 (CCL20), which attracts IL‐17‐producing T cells.
described, and both IL‐17A and IL‐17F, as well as IL‐17C,                Additionally, IL‐17C was shown directly to induce expres-
acting in autocrine manner, are able to induce the expres-               sion of IL‐17A and IL‐17F in mouse Th17 cells [36].
sion of IL‐17C in keratinocytes [32]. IL‐17A, IL‐17A/F and
IL‐17F exert their effects on a range of tissue cells, of which          Therapeutic Agents Used in the Management
keratinocytes and fibroblasts are the main target cells in the           of Moderate-to-Severe Plaque Psoriasis
skin [33] (Figure 2). Keratinocyte response to either IL-17C             Treatment of patients affected by hard-to-treat psoriasis is
or IL-17A stimulation are very similar, with strong induction            often challenging. The anatomical structure of affected sites
of S100A7/A9 proteins and antimicrobial proteins and cyto-               may hamper the application and reduce the absorption of
kines or chemokines including CXCL1, IL-1, IL-8, CCL20,                  topical treatments [39,40]. Physical therapies may be effec-
and IL-36. IL-17C also stimulates Th17 T cells to increase               tive for palmoplantar areas, but time consuming. Traditional
synthesis of IL-17A/F and IL-22 promoting an autoimmune                  therapies (cyclosporine, methotrexate, acitretin, dimethyl
activation [34,35]. Indeed the IL-17RA/RE receptor com-                  fumarate) can provide some benefits, but often not well tol-
plex is expressed on both epithelial and TH17 cells, with                erated or aggravated by side effects. A new small molecule,
IL-17C that amplifies its own signal, inducing the expression            apremilast, demonstrated to be effective on PSA and PSO,




Figure 2. Key psoriasis pathogenic circuits mediated by IL-17 cytokines.
IL‐17A strongly induces IL-17C expression in keratinocytes. IL-17C amplifies its own signal through the induction of IL-17C receptor on
Th17 cells and the increase of IL-17A synthesis. IL-17A and IL-17F exert their effects on other tissue cells, such as fibroblasts, inducing the
production of several proinflammatory mediators. Other inflammatory loops result in the induction of IL-17C on Th17 cells.
IL = Interleukin.


4                                                                                     Review | Dermatol Pract Concept. 2023;13(3):e2023245
                                                                           Table 1. Results from clinical trials and real-world experiences related to brodalumab efficacy in difficult-to-treat psoriasis.
                                                                                                                                                                                    specific outcomes        Baseline severity
                                                                                                                                                                                   for diffcult-to-treat    in diffcult-to-treat
                                                        Author                     Drug            Trial/NCT          Endpoints        Design       Regimen/dose            N              areas                   areas                   Follow-up
                                                        Elewski,               Brodalumab,        Amagine-1        W12 (induction        RCT        BDL210 Q2W            222         PSSI75 PSSI100          PSSI>15 (out of        W12 PASI75 in 89%
                                                        J Dermatolog           Placebo                                period)                       Placebo Q2W           219                                    PASI72)            W12 PASI100 by 63.4%
                                                        Treat 2022                                                                                                                                                                   W12 PASI75 by 9.5%
                                                                                                                                                                                                                                     W12 PASI100 by 3.2
                                                        Nakagawa,              Brodalumab       NCT01748539              W12             RCT        BDL 210 Q2W             37           PSSI                    PSSI 43.7            W12 PSSI -94.5%
                                                        J Dermatol Sci.        Placebo                                                                Placebo               38        NAPSI (22pts)              NAPSI 6.3            W12 NAPSI-47.6%
                                                        2016                                                                                                                             DLQI                    DLQI10.7               W12 DLQI -9
                                                                                                                                                                                                                 PSSI 26.2            W12 PSSI -12.6%
                                                                                                                                                                                                                 NAPSI7.2             W12 NAPSI -7.6%
                                                                                                                                                                                                                 DLQI9.4               W12 NAPSI -2.2




Review | Dermatol Pract Concept. 2023;13(3):e2023245
                                                        Elewski,               Brodalumab,      AMAGINE-2/3         W12/24/36/52         RCT        BDL210 at W0,         104         NAPSI (target)           NAPSI 9.6 (4)            W52 NAPSI 1.6
                                                        J Dermatolog           Ustekinumab                                                           W1, W2, then         179                                 NAPSI 9.9 (3.6)           W52 NAPSI 2.5
                                                        Treat 2022                                                                                      Q2W
                                                                                                                                                   UST45/90 at W0/
                                                                                                                                                   W4 then Q12W
                                                        Yamasaki, Br Jd,       Brodalumab       NCT01782937              W52            Open       BDL 210mg GPP            12             PSS                    PSS 4.4              W52 PSS 0 in 91%
                                                        2017                                                                            Label                                              PSSI                  PSSI 16.7              W52 PSSI -82
                                                                                                                                                                                          NAPSI                 NAPSI 10.8             W52 NAPSI -67.5
                                                                                                                                                                                          DLQI                   DQLI 7.9               W52 DLQI -5.5
                                                        Gregoriu, JEADV        Brodalumab               -            Prosp-open,                  BDL 210 at W0,            30        NAPSI (finger)            NAPSI 19.6              W24 NAPSI 2.3
                                                        2021                                                            W24                       W1, W2, W3 then                                               DLQI 22.8               W24 DLQI 3.7
                                                                                                                                                       Q2W
                                                        Politou, Am Acad       Brodalumab         ABSTRACT               W12             Case          BDL 210               4            PPPGA                                           W12 PPGA 0
                                                        Dermatol. 2020                                                                  report
                                                        Nakao, Ejd, 2018       Brodalumab               -                                Case        BDL 210 mg              1            PPPASI                PPPASI 13.2             W24 PPPASI 4.0
                                                                                                                                        report
                                                        Pinter,          Brodalumab                     -                               Case         BDL 210 mg              4             PPGA                    Mean 8                  ET mean 8
                                                        Journal f                                                                       Series
                                                        Dermatology 2019
                                                        Okubo, Jeadv           Brodalumab         ABSTRACT               W16                           BDL 210            126             PPPASI             Mean change in                   13.73
                                                        Poster 2022                                                                                     Placebo                                              PPASI total score                 8.45

                                                       BDL = brodalumab; DLQI = Dermatology Life Quality Index; NAPSI = Nail Psoriasis Severity Index; PGA = Physician Global Assessment; PSS = Psoriasis Symptoms Scale; PSSI = Psoriasis Scalp Severity Index;
                                                       PPPASI = Palmoplantar Pustulosis Psoriasis Area and Severity Index; Q2W = every other week; RCT = randomized clinical trials.




5
including difficult areas including nails and scalp [41]. Dif-   (92.8% versus 14.4%; P value <0.001). At week 12, PSSI75
ferent classes of biologic agents have been also approved for    was achieved by 89% of patients receiving brodalumab,
the treatment of moderate-severe psoriasis, and anti-TNFs        compared with 9.5% of patients receiving placebo, while
represented the first approved biologic class. Patients may      PSSI100 was observed in 63.4% of brodalumab-treated pa-
experience beneficial effects through p40IL-12/23 inhibition     tients versus 3.2% of the placebo group [48,52].
(ustekinumab) or through IL-23 blockade (guselkumab, ri-            Brodalumab effectiveness was also confirmed in a sub-
sankizumab, tildrakizumab). Comparative studies demon-           analysis of a phase 2, randomized, placebo-controlled trial
strated superiority of anti-IL-17 agents compared with           (NCT01748539) reporting a mean PSSI improvement rate
ustekinumab in treating difficult areas [42-48]. Nowadays,       of 94.5% after 12 weeks of therapy with brodalumab 210
four anti-IL-17 agents are approved for the treatment of         mg Q2W from baseline, versus 12.6% of placebo-treated pa-
plaque psoriasis: secukinumab and ixekizumab are directed        tients (P = 0.001) [53].
against IL-17A, bimekizumab neutralizes both IL-17A and             Data deriving from another study conducted on patients
IL-17F, while brodalumab antagonizes IL-17RA. Substan-           affected by severe forms of psoriasis, namely generalized
tial clinical efficacy was achieved in patients treated with     pustular (GPP) and erythrodermic (PsE), also revealed great
secukinumab and ixekizumab. Recently, elevated efficacy,         efficacy of brodalumab therapy in reducing skin manifesta-
with even higher response rates compared to secukinumab          tions, including scalp psoriasis lesions, with improvements in
or ixekizumab, was demonstrated in phase III studies test-       PSSI score occurring in 80.9% of all treated patients (includ-
ing bimekizumab, indicating that IL‐17F also contributes to      ing GPP and PsE) at week 12 and in 90% of all patients after
drive skin inflammation in psoriasis [46,47]. Moreover, the      52 weeks of treatment, concurrently with Dermatology Life
simultaneous inhibition of several IL‐17 family cytokines in-    Quality Index (DLQI) ameliorations throughout the obser-
duced by brodalumab, has been shown to be efficacious in         vation period (DLQI scoring 0 or 1 was achieved by 80% of
the treatment of psoriasis [48-49].                              patients at week 52) [54].
    Brodalumab extensively suppresses tissue response to IL-
17 cytokine impulse, normalizing the expression of IL-17-        Nail Psoriasis
dependent genes, in tissue cells, particularly keratinocytes.    Brodalumab effects on psoriatic nails were assessed in two
This modulation is dose dependent and after 12 weeks of          trials. Head-to-head trials, AMAGINE-2 and AMAGINE 3
treatment a profound molecular response, with >95%-im-           trials, comparing brodalumab with ustekinumab, included
provement in differentially expressed psoriasis genes was        283 patients with nail involvement [52]. Patients random-
obtained [43]. This effect is rapidly detected with greater      ized to brodalumab 210 mg every two weeks (BLD210 q2w)
magnitude than with other biological agents, resulting in a      had a greater reduction in mean nail-target NAPSI score
lower residual alteration of gene expression compared with       compared with those randomized to ustekinumab 45/90 mg
ustekinumab and etanercept [50].                                 every 12 weeks (UST45/90 q12w), at week 12 (43.7% ver-
    The distinctive mechanism of blocking multiple IL-17         sus 31.8%, P < 0.05), with further improvements at week
family cytokines (IL-17A, E, F, C) may account for the effec-    24 (76.9% versus 58.9%, P < 0.05), and at week 36 (82.4%
tiveness of brodalumab in achieving skin clearance in psori-     versus 69.0%, P < 0.05). A greater amelioration was also
asis patients, comprising those with inadequate response to      seen at week 52 in the brodalumab arm (83.1% versus
other biologics, in particular the anti-IL-17 [51].              75.0%), although statistical significance was not reported.
    Data from RCT and real-world experiences showed effi-        At week 24, 31.6% of patients achieved a complete reso-
cacy of brodalumab also in treating difficult areas and severe   lution of nail psoriasis (NAPSI100) in the brodalumab arm
variants of psoriasis, such as generalized pustular and erhy-    compared with 18.8% in ustekinumab subcohort (P < 0.05).
trodermic psoriasis.                                             At week 52, 63.8% of brodalumab-treated and 39.1% of
                                                                 ustekinumab-treated patients achieved NAPSI100 (P <
Data From Randomized Controlled Trials                           0.05), respectively. Safety was comparable between broda-
Scalp Psoriasis                                                  lumab and ustekinumab treatment groups (adverse events:
Brodalumab showed to be effective and rapid on scalp pso-        57.3% versus 56.3%; severe adverse events 1.2% versus
riasis as reported in a post-hoc analysis from the phase 3       1.0%) [52].
AMAGINE 1 study (a randomized, placebo-controlled,                  Improvement of nail psoriasis has also been reported
phase 3 study, NCT01708590) which detected improvement           in the Japanese trial (NCT01748539) on 22 patients (out
rates from baseline in mean PSSI seen as early as at week        of 38) treated using 210mg brodalumab with total NAPSI
2 in patients receiving brodalumab versus placebo (PSSI:         score reduction of 47.6% after 12 weeks (mean NAPSI
67.6% versus 6.7% at week 2). Treatment response was             change from baseline in the placebo group was 9.6% at
maintained with further reduction in PSSI through week 12        week12) [53].



6                                                                           Review | Dermatol Pract Concept. 2023;13(3):e2023245
   In a prospective open-label trial with 30 patients af-         Real-World Data on Brodalumab Effectiveness and
fected by nail psoriasis treated with brodalumab 210 mg           Safety for Hard-to-treat Psoriasis Areas
q2w, a significant improvement was observed after 12 and          Real-world data reported in a retrospective longitudinal
24 weeks of treatment compared with baseline (P < 0.001:          study on 90 patients with moderate-to-severe plaque pso-
mean finger absolute NAPSI score at the BL: 19.6, W12: 9.6,       riasis treated for 12 months, demonstrated complete clear-
W24: 2.63; mean toes absolute NAPSI at the BL 24.9; W12:          ance of scalp, nails, palmo-plantar areas and genitalia [58].
16.1; W24: 7.2)54. NAPSI improvement was also associated          Efficacy of brodalumab on palmoplantar psoriasis was also
with a decrease of DLQI, from a mean value of 22.8, to            described in case reports or case series [59].
a mean value of 3.7, after 24 weeks of treatment. Adverse            Politou et al reported successfully response to broda-
events (AE) incidence (10.0%) was low, and no seriousAEs          lumab in 4 patients, obtaining PPPGA score 0 at week 16,
occurred.                                                         after secukinumab failure [60].
   A recent network meta-analysis of head-to-head tri-               In a case report, a patient suffering from PSO and PPP,
als investigating the complete resolution of nail psoriasis       who previously failed adalimumab and secukinumab, was
identified ixekizumab as the biologic agent with the high-        successfully treated with brodalumab, with clinical improve-
est response rate (RR: 1.4, 95%CI= 0.73-3.1) resulting            ment observed after 2 weeks and the complete clearance af-
superior to brodalumab (RR: 0.92, 95%CI= 0.14-7.4),               ter 6 months [61].
guselkumab (RR: 0.81, 95%CI= 0.40-1.8), infliximab                   Contrasting findings were described in a case series con-
(RR: 0.90,95%CI= 0.19-4.6) and ustekinumab (RR: 0.33,95%          sisting of four patients treated for PPP, obtaining partial
CI= 0.083-1.6), using adalimumab as reference [55].               response only in one patient, while the three other patients
                                                                  had no response or worsening of PPP. One patient had a
Palmoplantar Psoriasis                                            partial response and after 7 months, due to worsening of
Preliminary results of a multicenter, randomized, double-         arthralgia and bad tongue symptoms, brodalumab was
blind, placebo-controlled phase 3, Japanese study on              stopped [62].
126 patients affected by palmoplantar pustulosis showed
great improvement in the brodalumab-treated group. After          Conclusions
16 weeks of treatment, total PPPASI score change from base-
line was significantly higher with brodalumab: 13.73 versus       The successful management of patients affected by psoriasis
placebo 8.45% (P = 0,0049) with 16.0% of patients treated         in difficult-to-treat areas still represents an unmet therapeu-
with brodalumab who achieved PPPASI-90 response com-              tic need that has been partially covered by currently avail-
pared with versus 0.0% of placebo [56].                           able therapeutic options. Brodalumab, combining rapid and
   Results from a Phase 4 clinical trial investigating efficacy   sustained efficacy with a favorable safety profile, may be a
of brodalumab in the treatment of palmoplantar psoriasis          valid therapeutic option not only for plaque psoriasis but
have not been published yet (NCT04622033).                        also for severe variants of psoriasis as well as for psoriasis
                                                                  localized in difficult-to-treat areas.
Rare and Severe Forms of Psoriasis                                   An expert panel recently sought to define the best areas
An open-label, multicenter, long-term phase III study in Jap-     of action for brodalumab, clarifying the optimal place-in-
anese patients affected by rare and severe form of psoriasis      therapy for this drug. Through a Delphi methodology, the
has been conducted [57]. Out of 30 patients treated with          expert panel agreed in considering brodalumab an appropri-
210 mg brodalumab, 12 were affected by GPP and 18 pa-             ate therapeutic choice when there is involvement of difficult-
tients by erythrodermic psoriasis. The primary endpoint was       to-treat areas, such as scalp/nails or palmo-plantar area [17].
the Clinical Global Impression of Improvement (CGI). Ten          Moreover, the expert panel highlighted the benefits of broda-
patients with GPP and 16 with erythrodermic psoriasis com-        lumab in treating psoriasis in difficult-to-treat areas, includ-
pleted the study and CGI was achieved in 11 patients with         ing the amelioration obtained on pruritus. In addition, the
GPP and 18 with erythrodermic psoriasis after a 52-week           expert panel noted that the scalp tends to be the first site to
treatment (last observation carried forward). The most com-       clear from psoriasis as well as the first site where the disease
monly reported adverse event was nasopharyngitis (33.3%)          recurs whether brodalumab fails.
and five serious adverse events occurred during the study;           The advantage of brodalumab in inhibiting multiple patho-
none of the serious adverse events was considered related to      genic IL-17 cytokines through 17RA blockade, is clinically
treatment. Overall brodalumab demonstrated to be safe and         reflected by a rapid response and high rate of skin clearance,
significantly improved symptoms of patients with either GPP       even in the treatment of psoriasis localized in difficult-
or erythrodermic psoriasis throughout the 52-week observa-        to-treat areas. Nevertheless, having limited data deriving
tion period [57].                                                 from both trials and real-world studies, further evidence is



Review | Dermatol Pract Concept. 2023;13(3):e2023245                                                                            7
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these peculiar forms of psoriasis.                                           solution for injection in pre-filled syringe: Summary of Prod-
                                                                             uct Characteristics. Date of first authorisation:17 July 2017
                                                                             Availabre from from:https://www.ema.europa.eu/en/documents
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