10.5826/dpc.1202a104
Introduction: The randomised, open-label, assessor-blinded, parallel-group SPIRIT-H2H trial (NCT03151551) demonstrated superiority of ixekizumab over adalimumab in simultaneously achieving improvement in joint symptoms (American College of Rheumatology [ACR]50) and clearance of skin lesions (Psoriasis Area and Severity Index [PASI]100) in biologic-naïve patients with active psoriatic arthritis (PsA) and plaque psoriasis (PsO) at Week 24. Additionally, this higher efficacy of ixekizumab versus adalimumab was maintained through Week 52.
Objectives: This analysis aimed to investigate the efficacy and safety of ixekizumab and adalimumab in the subgroup of patients with PsA and moderate-to-severe PsO through W52.
Methods: Efficacy and safety outcomes were analysed in patients with PsA and moderate-to-severe PsO (PASI ≥12, Body Surface Area ≥10%, static Physician Global Assessment ≥3) through W52. Categorical and continuous outcomes were analysed using logistic regression models and mixed model for repeated measures, respectively.
Results: More ixekizumab- versus adalimumab-treated patients simultaneously achieved PASI100 and ACR50 at W24 (40.8% versus 17.6%, p=0.015) and W52 (38.8% versus 17.6%, p=0.026). Likewise, more ixekizumab- versus adalimumab-treated patients achieved PASI100 (59.2% versus 25.5%, p=0.001) and PASI90 (81.6% versus 60.8%, p=0.028) through W52, and nail PsO clearance at W24. Joint symptom improvements were comparable between treatment groups. No new safety findings were reported.
Conclusions: Ixekizumab had higher efficacy than adalimumab in simultaneous achievement of ACR50 and PASI100 at W24 and W52 in patients with PsA and moderate-to-severe PsO. Ixekizumab-treated patients also showed higher response rates for nail PsO clearance and for reporting minimal or no impact on quality of life at Week 24.
text/xml
2160-9381
1936
en
Melinda Gooderham
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
psoriasis
Efficacy and safety of ixekizumab versus adalimumab in patients with active psoriatic arthritis and moderate-to-severe psoriasis: 52-week results from the randomised SPIRIT-H2H trial
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Original Article
2022-05-02
2021-08-04
2022-05-02
2022-05-24
e2022104
Dermatol Pract Concept
Introduction: The randomised, open-label, assessor-blinded, parallel-group SPIRIT-H2H trial (NCT03151551) demonstrated superiority of ixekizumab over adalimumab in simultaneously achieving improvement in joint symptoms (American College of Rheumatology [ACR]50) and clearance of skin lesions (Psoriasis Area and Severity Index [PASI]100) in biologic-naïve patients with active psoriatic arthritis (PsA) and plaque psoriasis (PsO) at Week 24. Additionally, this higher efficacy of ixekizumab versus adalimumab was maintained through Week 52.
Objectives: This analysis aimed to investigate the efficacy and safety of ixekizumab and adalimumab in the subgroup of patients with PsA and moderate-to-severe PsO through W52.
Methods: Efficacy and safety outcomes were analysed in patients with PsA and moderate-to-severe PsO (PASI ≥12, Body Surface Area ≥10%, static Physician Global Assessment ≥3) through W52. Categorical and continuous outcomes were analysed using logistic regression models and mixed model for repeated measures, respectively.
Results: More ixekizumab- versus adalimumab-treated patients simultaneously achieved PASI100 and ACR50 at W24 (40.8% versus 17.6%, p=0.015) and W52 (38.8% versus 17.6%, p=0.026). Likewise, more ixekizumab- versus adalimumab-treated patients achieved PASI100 (59.2% versus 25.5%, p=0.001) and PASI90 (81.6% versus 60.8%, p=0.028) through W52, and nail PsO clearance at W24. Joint symptom improvements were comparable between treatment groups. No new safety findings were reported.
Conclusions: Ixekizumab had higher efficacy than adalimumab in simultaneous achievement of ACR50 and PASI100 at W24 and W52 in patients with PsA and moderate-to-severe PsO. Ixekizumab-treated patients also showed higher response rates for nail PsO clearance and for reporting minimal or no impact on quality of life at Week 24.
Melinda Gooderham
2022/05/02
10.5826/dpc.1202a104
e2022104
SKiN Centre for Dermatology, Probity Medical Research and Queen's University, Peterborough, Ontario, Canada
2160-9381
psoriasis
en
e2022104
Smolen JS, Sebba A, Ruderman EM, et al. Efficacy and Safety of Ixekizumab with or Without Methotrexate in Biologic-Naïve Patients with Psoriatic Arthritis: 52-Week Results from SPIRIT-H2H Study. Rheumatol Ther. 2020;7:1021–1035. DOI: 10.1007/s40744-020-00250-3. PMID: 33200394. PMCID: PMC7695764.
Efficacy and safety of ixekizumab versus adalimumab in patients with active psoriatic arthritis and moderate-to-severe psoriasis: 52-week results from the randomised SPIRIT-H2H trial
https://dpcj.org/index.php/dpc/article/download/1936/1579
 Efficacy and Safety of Ixekizumab Versus Adalimumab
     in Biologic-naïve Patients With Active Psoriatic
  Arthritis and Moderate-to-severe Psoriasis: 52-week
     Results From the Randomized SPIRIT-H2H Trial
              Kristian Reich1, Lars Erik Kristensen2, Saxon D. Smith3, Phoebe Rich4,
          Christophe Sapin5, Soyi Liu Leage5, Robert McKenzie5, Christopher Schuster5,6,
                             Elisabeth Riedl5,6, Melinda Gooderham7


1 Center for Translational Research in Inflammatory Skin Diseases, Institute for Health Services Research in Dermatology and Nursing,
  University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
2 Musculoskeletal Statistics Unit, The Parker Institute, Copenhagen University Hospital, Bispebjerg and Frederiksberg Hospital,
  Copenhagen, Denmark;
3 The Dermatology and Skin Cancer Centre, St Leonards, and Discipline of Dermatology, Sydney Medical School, University of Sydney,
  Sydney, Australia;
4 Oregon Dermatology and Research, Portland, Oregon, USA;
5 Eli Lilly and Company, Indianapolis, Indiana, USA;
6 Department of Dermatology, Medical University of Vienna, Vienna, Austria;
7 SKiN Centre for Dermatology, Probity Medical Research and Queen’s University, Peterborough, Ontario, Canada.



Key words: ixekizumab, adalimumab, SPIRIT-H2H, nail psoriasis, psoriasis,
Citation: Reich K, Kristensen LE, Smith SD et al. Efficacy and safety of ixekizumab versus adalimumab in biologic-naïve patients with
active psoriatic arthritis and moderate-to-severe psoriasis: 52-week results from the randomized SPIRIT-H2H trial. Dermatol Pract
Concept. 2022;12(2):e2022104. DOI: https://doi.org/10.5826/dpc.1202a104
Accepted: October 25, 2021; Published: April 2022
Copyright: ©2022 Reich 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: This work was supported by Eli Lilly and Company, which contributed to study design, data collection, data analysis, data
interpretation, manuscript preparation, and publication decisions.
Competing interests: K. Reich reports conflicts of interest from Abbvie, Affibody, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly
and Company, Forward Pharma, Janssen, Kyowa Kirin, Leo, and UCB. L.E. Kristensen reports conflicts of interest from AbbVie, Amgen, Biogen,
Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Forward Pharma, Janssen, Merck, and Co., Novartis, Pfizer, and UCB. S.D. Smith has
been an advisor for and/or received speaking fees and/or served as an investigator in clinical trials for AbbVie, Amgen, Biogen, Bristol Myers
Squibb, Eli Lilly and Company, Janssen Cilag, Leo Pharma, Novartis, Pfizer, Sanofi Genzyme, and UCB. P. Rich has been a principal investigator
for AbbVie, Amgen, Arcutis, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Dermavant, Eli Lilly and Company, Merck, Novartis, Pfizer
and Sandoz, Sun Pharma, and UCB; a consultant for AbbVie, Novartis and Polichem; and an advisory board participant for AbbVie, Eli Lilly and
Company, Leo, Novartis, and Sandoz. C. Sapin, S. Liu Leage, R. McKenzie, C. Schuster, and E. Riedl are employees and minor shareholders of Eli
Lilly and Company. M. Gooderham has received grant/research support from: AbbVie, Actelion Pharmaceuticals, Akros Pharma, Amgen, Arcutis
Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Dermira, Dermavant, Eli Lilly and Company, Galderma SA, Incyte, Kyowa
Kirin, Janssen, LEO Pharma, MedImmune, Merck and Co., Novartis, Pfizer, Regeneron Pharmaceuticals, Roche Laboratories, Sanofi Genzyme,
UCB, and Bausch/Valeant Pharmaceuticals. Consultant for: Akros Pharma, Amgen, Boehringer Ingelheim, Celgene, Eli Lilly and Company, Janssen,
Novartis, Sanofi Genzyme, Valeant Pharmaceuticals. Speakers bureau for: AbbVie, Amgen, Arcutis, Boehringer Ingelheim International GmbH,
Celgene, Eli Lilly and Company, Galderma SA, Janssen, LEO Pharma, Novartis, Pfizer, Regeneron Pharmaceuticals, Sanofi Genzyme, and UCB.
Authorship: All authors have contributed significantly to this publication
Corresponding author: Elisabeth Riedl, MD, Eli Lilly Regional Operations GmbH, Erdberger Lände 26, 1030 Vienna, Austria.
E-mail: riedl_elisabeth@lilly.com




Original Article | Dermatol Pract Concept. 2022;12(2):e2022104                                                                               1
    ABSTRACT         Introduction: The randomized, open-label, assessor-blinded, parallel-group SPIRIT-H2H trial
                     (NCT03151551) demonstrated superiority of ixekizumab over adalimumab in simultaneously achiev-
                     ing improvement in joint symptoms (American College of Rheumatology [ACR]50) and skin clearance
                     (Psoriasis Area and Severity Index [PASI]100) in biologic-naïve patients with active psoriatic arthritis
                     (PsA) and plaque psoriasis (PsO) at Week (W) 24. Higher efficacy of ixekizumab versus adalimumab
                     was maintained through W52.
                     Objectives: This analysis investigated efficacy and safety of ixekizumab and adalimumab in the sub-
                     group of patients with PsA and moderate-to-severe PsO through W52.
                     Methods: Efficacy and safety outcomes were analyzed in patients with PsA and moderate-to-severe
                     PsO (PASI ≥ 12, Body Surface Area ≥ 10%, static Physician Global Assessment ≥ 3) through W52. Cat-
                     egorical and continuous outcomes were analyzed using logistic regression models and mixed model for
                     repeated measures, respectively.
                     Results: More ixekizumab- versus adalimumab-treated patients simultaneously achieved PASI100
                     and ACR50 at W24 (40.8% versus 17.6%, P = 0.015) and W52 (38.8% versus 17.6%, P = 0.026).
                     Likewise, more ixekizumab- versus adalimumab-treated patients achieved PASI100 (59.2% versus
                     25.5%, P = 0.001) and PASI90 (81.6% versus 60.8%, P = 0.028) through W52, and nail PsO clearance
                     at W24. Joint symptom improvements were comparable between groups. No new safety findings were
                     reported.
                     Conclusions: Ixekizumab had higher efficacy than adalimumab in simultaneous achievement of
                     ACR50 and PASI100 at W24 and W52 in patients with PsA and moderate-to-severe PsO. Ixekizum-
                     ab-treated patients showed higher response rates for nail PsO clearance and for reporting minimal or
                     no impact on quality of life at W24.




Introduction                                                      use of biologics targeting inflammatory cytokines, such as
                                                                  interleukin (IL)-17A and tumor necrosis factor (TNF) [9,10].
Plaque psoriasis (PsO) is a chronic, inflammatory skin con-       Biologics inhibiting either IL-17 or TNF (such as adalim-
dition that has a high disease burden and significantly im-       umab [ADA]) signaling pathways have demonstrated high
pacts patients’ quality of life (QoL), especially in those with   efficacy in improving joint symptoms in patients with PsA
moderate-to-severe disease and involvement of difficult to        in randomized clinical trials [11–19]. As higher rates of skin
treat areas, such as the nails. Psoriatic arthritis (PsA) is a    clearance have been observed for anti-IL-17 versus anti-TNF
chronic, immune-mediated, seronegative spondylarthritis           biologics, the comparative efficacy of these biologics in
associated with musculoskeletal and non-skeletal manifes-         patients with concurrent PsA and moderate-to-severe PsO
tations. A personal or familial history of PsO is one of the      should be investigated [15,18–22].
diagnostic criteria for PsA, as PsO commonly precedes the
development of PsA [1]. Up to 30% of patients with PsO
                                                                  Objectives
will develop PsA, in particular those with scalp, intergluteal/
perianal and nail involvement, further increasing the disease     Ixekizumab (IXE), a high-affinity monoclonal antibody that
burden and reducing QoL [1-4]. The prevalence of nail PsO,        selectively targets IL-17A, is efficacious in patients with PsO
a painful and burdensome manifestation, is higher in PsA          and/or PsA [15,17,21,23]. The SPIRIT-H2H trial, the first di-
than PsO [5,6]. One possible explanation of this is the an-       rect comparison of IXE and ADA in biologic-naïve patients
atomical connection between the nail matrix and structures        with active PsA and PsO, reported that significantly more
of the distal interphalangeal joint [7]. Therefore, successful    IXE- versus ADA-treated patients simultaneously achieved
treatment of both joint and skin symptoms is important in         American College of Rheumatology (ACR)50 and complete
achieving optimal improvements to health-related QoL in           clearance of PsO at Week (W) 24 and W52 [18,19]. This anal-
patients with PsO and PsA, with clearance of co-existing nail     ysis aims to compare the efficacy of IXE versus ADA through
PsO providing additional benefits [8]. First-line treatments      W52 in the subgroup of patients with active PsA and mod-
for PsO and PsA include conventional systemic therapies           erate-to-severe PsO in the SPIRIT-H2H trial, who received
and conventional systemic disease modifying anti-rheumatic        dosage regimens per approved label for moderate-to-severe
drugs (csDMARDS), respectively. For patients with inade-          PsO. As this subgroup is reflective of the patients eligible for
quate responses to these, the European Dermatology Forum          biologic treatment in routine dermatological clinical practice,
and European League Against Rheumatism recommend the              this analysis will inform treatment decisions in these settings.


2                                                                     Original Article | Dermatol Pract Concept. 2022;12(2):e2022104
Methods                                                          fingernails score and proportion of patients achieving com-
                                                                 plete clearance of nail psoriasis (NAPSI = 0) in the subgroup
Participants and Study Design                                    of patients with NAPSI ≥ 1 at baseline.
SPIRIT-H2H (Clinicaltrials.gov: NCT03151551) is a 52-
week, multicenter, randomized, open-label, assessor-blinded,
                                                                 Safety
parallel-group study evaluating the efficacy and safety
of IXE versus ADA in biologic-naïve, csDMARD-inade-              Treatment-emergent adverse events (TEAEs) were defined as
quate-responder patients with active PsA and PsO. The study      events that initially occurred or worsened in severity after
population and study design have been previously published       the first dose of the study treatment and on or before the
[18]. Briefly, patients were aged ≥ 18 years, had a confirmed    date of the final visit within the treatment period. Adverse
diagnosis of PsA of ≥ 6 months, had active PsA (≥ 3/66           events (AEs) of special interest included infections, injection
swollen joints and ≥ 3/68 tender joints) and PsO (≥ 3% of        site reactions, malignancies, major adverse cardiovascu-
the Body Surface Area [BSA] affected), fulfilled the Classi-     lar events, allergic reactions/hypersensitivity, inflammatory
fication for Psoriatic Arthritis (CASPAR) criteria and were      bowel disease, depression, hepatic laboratory changes, cyto-
not previously treated with biologics or Janus kinase inhib-     penia, and neutropenia. Cerebrocardiovascular events were
itors. Patients on csDMARDs at screening were permitted          adjudicated by external clinical events committees. Safety
to continue at a stable dose. Randomization was stratified       results for the total study population have been published
by concomitant csDMARD use and moderate-to-severe PsO            previously [18,19].
involvement (PASI ≥ 12, BSA ≥ 10%, and static Physician
Global Assessment [sPGA] ≥ 3) at baseline.                       Statistical Analysis
    Patients were randomized at a 1:1 ratio to receive IXE or    Efficacy
ADA. Patients with active PsA and moderate-to-severe PsO         In this post hoc analysis, efficacy analyses were performed
were treated as per approved label for moderate-to-severe        on the intent-to-treat population, consisting of all random-
PsO and received a 160 mg IXE starting dose at W0, fol-          ized patients according to the treatment assigned at W0.
lowed by 80 mg IXE every 2 weeks (Q2W) from W2 to W12            Categorical variables were assessed using logistic regression
and every 4 weeks thereafter, or an 80 mg ADA starting dose,     models with treatment and concomitant csDMARD use
followed by 40 mg ADA Q2W starting at W1.                        at baseline as factors, as well as Fisher’s exact tests when-
    In this post hoc analysis, only patients with active PsA     ever relevant. The non-responder imputation (NRI) method
and moderate-to-severe PsO at baseline were included.            was used in case of missing data: patients were considered
    SPIRIT-H2H was conducted in accordance with the              non-responders if they did not meet the clinical response
ethical principles of the Declaration of Helsinki. The study     criteria or had missing clinical response data at a particular
protocol was approved by the ethical review boards of all        time point of analysis. Continuous variables were analyzed
participating sites prior to the start of study-related proce-   using a mixed effects model of repeated measures analysis,
dures. Informed consent was obtained from all participants.      which included treatment group, concomitant csDMARD
                                                                 use at baseline, and visit as fixed factors, baseline value as
Efficacy Endpoints                                               a covariate, and baseline-by-visit and treatment-by-visit in-
                                                                 teraction terms.
Endpoints were assessed in all patients with active PsA and
                                                                 Safety
moderate-to-severe PsO at baseline. The primary endpoint
of SPIRIT-H2H was the proportion of patients who simul-          Descriptive statistics were performed on the safety popu-
taneously achieved ACR50 and PASI100 responses at W24.           lation, defined as all randomized patients who received ≥
Major secondary endpoints were the proportion of patients        1 dose of the study treatment.
achieving ACR50 and the proportion of patients achieving
PASI100 at W24.                                                  Results
    Endpoints at W52 included the proportion of patients
simultaneously achieving ACR50 and PASI100 responses,            Baseline Characteristics
PASI100, PASI90 or PASI75 responses, change from base-           Of the 566 biologic-naïve patients included in the SPIR-
line in Dermatology Life Quality Index (DLQI) total score,       IT-H2H study, 49 (17.3%) of the IXE-treated patients and
proportion of patients achieving DLQI (0,1), change from         51 (18.0%) of the ADA-treated patients had moderate-
baseline in the Itch Numeric Rating Scale (NRS) score, pro-      to-­severe PsO (PASI ≥ 12, sPGA ≥ 3, and BSA ≥ 10%) at
portion of patients achieving Itch NRS score = 0, and change     baseline. The frequency of moderate-to-severe PsO and
from baseline in the Nail Psoriasis Severity Index (NAPSI)       nail PsO in the overall SPIRIT-H2H population is visually


Original Article | Dermatol Pract Concept. 2022;12(2):e2022104                                                                3
Figure 1. Schematic representation of moderate-to-severe psoriasis and nail psoriasis frequency in the SPIRIT-H2H patient population. Venn
diagrams show the proportion of patients with moderate-to-severe PsO and nail PsO (NAPSI ≥ 1) in the IXE (n = 283) and ADA (n = 283)
groups of the entire SPIRIT-H2H population at baseline.

ADA = Adalimumab; IXE = Ixekizumab; Mod-sev = Moderate-to-severe; NAPSI = Nail Psoriasis Severity Index; PsA = Psoriatic arthritis;
PsO = Plaque psoriasis.



                Table 1. Baseline demographics and disease characteristics of patients with PsA
                                        and moderate-to-severe PsO
                            Category                                         IXE (n = 49)                       ADA (n = 51)
 Age (years)                                                                  45.3 ± 11.5                         46.3 ± 11.3
 Male, n (%)                                                                    30 (61.2)                          33 (64.7)
            2
 BMI (kg/m )                                                                   29.5 ± 7.3                          30.2 ± 8.7
 Duration of symptoms since PsO diagnosis (years)                             17.0 ± 10.5                         15.0 ± 11.3
 Duration of symptoms since PsA diagnosis (years)                               7.0 ± 7.4                          5.7 ± 6.2
 PASI                                                                         22.9 ± 10.5                          20.5 ± 7.3
 sPGA                                                                           3.6 ± 0.7                          3.6 ± 0.7
 Percentage BSA                                                               41.2 ± 24.1                         32.5 ± 19.3
 Fingernail NAPSI ≥ 1, n (%)                                                    37 (75.5)                          41 (80.4)
 Fingernail NAPSI                                                             26.1 ± 21.6                         23.3 ± 18.5
 Fingernail NAPSI > 16, n (%)                                                   21 (42.9)                          24 (47.1)
 Fingernail NAPSI > 40, n (%)                                                   10 (20.4)                           7 (13.7)
 Itch NRS                                                                       6.5 ± 2.5                          7.6 ± 1.8
 DLQI                                                                          16.9 ± 7.3                          16.7 ± 6.4
 Tender joint count                                                           24.2 ± 15.7                         23.9 ± 15.5
 Swollen joint count                                                           12.4 ± 9.7                         13.0 ± 11.0
 CRP level (mg/L)                                                             14.5 ± 21.7                         17.6 ± 28.9
 Concomitant MTX use, n (%)                                                     25 (51.0)                          28 (54.9)

Unless indicated otherwise, data are presented as mean ± SD.

ADA = Adalimumab; BMI = Body Mass Index; BSA = Body surface area; CRP = C reactive protein; DLQI = Dermatology Life Quality
­Index; MTX = Methotrexate; NAPSI = Nail Psoriasis Severity Index; NRS = Numeric Rating Scale; PASI = Psoriasis Area and Severity Index;
 PsA = Psoriatic arthritis; PsO = Plaque psoriasis; SD = Standard deviation; sPGA = Static Physician Global Assessment.



represented in Figure 1. Baseline demographics and dis-                IXE- and ADA-treated patients, respectively, had concomi-
ease characteristics were mostly balanced between the IXE              tant methotrexate (MTX) use at baseline, which was permit-
and ADA groups (­Table 1). Totals of 51.0% and 54.9% of                ted throughout the study.



4                                                                           Original Article | Dermatol Pract Concept. 2022;12(2):e2022104
Efficacy on Skin, Nails, and Joints                                 IXE- versus ADA-treated patients had a NAPSI = 0 response
                                                                    at all time points through W52 (Figure 4A). The mean change
In the subgroup of patients with active PsA and moder-              from baseline in fingernail NAPSI score indicated a more
ate-to-severe PsO at baseline, a significantly higher propor-       rapid decrease overall and a statistically larger difference for
tion of patients treated with IXE versus ADA simultaneously         IXE- versus ADA-treated patients at W40, and numerically
achieved the primary endpoint, ACR50 and PASI100, at                greater for all other time points through W52 (-21.9 versus
W24 (40.8% versus 17.6%, P = 0.015) and W52 (38.8%                  -20.9, P = 0.583) (Figure 4B).
versus 17.6%, P = 0.026); statistically significant differences
were observed as early as W8 (Figure 2).
    Complete skin clearance (PASI100 response) was                  Patient-reported Outcomes
achieved by a significantly higher proportion in the
                                                                    The baseline DLQI scores for the subgroup of patients with
IXE versus ADA group at W24 (59.2% versus 27.5%,
                                                                    active PsA and moderate-to-severe PsO were 16.9 (standard
P = 0.002) and W52 (59.2% versus 25.5%, P = 0.001); sig-
                                                                    deviation [SD] ± 7.3) and 16.7 (SD ± 6.4) for IXE- and ADA-
nificant differences were observed as early as W4 (the first
                                                                    treated patients, respectively, which was reflective of the high
PASI assessment) and maintained throughout the study
                                                                    disease burden of this subgroup (Table 1). In the IXE versus
(­
 Figure 3A). Likewise, PASI90 response was significantly
                                                                    ADA group, significantly more patients reported no or only
greater in IXE- versus ADA-treated patients at all time points
                                                                    minimal impact of skin disease on their QoL (DLQI 0,1) at
starting at W4, except at W32 (Figure 3B). IXE- versus ADA-
                                                                    W24 (59.2% versus 33.3%, P = 0.016) and numerically more
treated patients had more rapid PASI75 responses with a sig-
                                                                    at W52 (55.1% versus 37.3%, P = 0.108) (Figure 5A). IXE-
nificantly higher proportion achieving PASI75 from W4 to
                                                                    versus ADA-treated patients had a more rapid mean reduction
W16, and numerically, but not significantly (except for W40),
                                                                    in DLQI score from baseline. The mean change in DLQI was
more patients achieving PASI75 through W52 (Figure 3C).
                                                                    consistently greater in the IXE- versus ADA-treated patients
    With regard to joint outcomes, no significant differences
                                                                    and was statistically greater at W4 through W16 (Figure 5B).
were observed in ACR50 at W24 and in ACR20, ACR50, or
                                                                       The mean change in Itch NRS score from baseline and
ACR70 responses between IXE- and ADA-treated patients
                                                                    complete resolution of itch (Itch NRS = 0) were numerically
through W52 (Table 2).
                                                                    higher (except for the mean change in Itch NRS score from
    Nail PsO was prevalent in patients with active PsA and
                                                                    baseline at W52, which was numerically equal) but not sig-
moderate-to-severe PsO, affecting 75.5% (n = 37) and 80.4%
                                                                    nificantly different in the IXE versus ADA group at all time-
(n = 41) of IXE- and ADA-treated patients, respectively, at
                                                                    points through W52 (Figure 5C and D).
baseline (fingernail NAPSI ≥ 1). Baseline demographics and
disease characteristics of patients with nail PsO were bal-
anced between the IXE and ADA groups (data not shown).              Safety
Complete clearance of fingernail PsO occurred in 75.7%
of IXE- versus 51.2% of ADA-treated patients at W24                 The frequency of TEAEs was similar in patients receiving
(P = 0.035), and a numerically higher proportion of                 IXE versus ADA (59.2% versus 58.8%) (Table 3); all TEAEs




Figure 2. Percentage of patients with PsA and moderate-to-severe PsO simultaneously achieving ACR50 and PASI100 through Week 52. IXE
versus ADA: * P ≤ 0.05.

ACR = American College of Rheumatology; ADA = Adalimumab; IXE = Ixekizumab; PASI = Psoriasis Area and Severity Index; PsA =
­Psoriatic arthritis; PsO = Plaque psoriasis.



Original Article | Dermatol Pract Concept. 2022;12(2):e2022104                                                                    5
                    A




                    B




                    C




Figure 3. Skin outcomes through Week 52. Percentage of patients with PsA and moderate-to-severe PsO achieving (A) PASI100, (B) PASI90,
and (C) PASI75. IXE versus ADA: * P ≤ 0.05, ** P ≤ 0.01, *** P ≤ 0.001.

ADA = Adalimumab; IXE = Ixekizumab; PASI = Psoriasis Area and Severity Index; PsA = Psoriatic arthritis; PsO = Plaque psoriasis.



6                                                                         Original Article | Dermatol Pract Concept. 2022;12(2):e2022104
                                      Table 2. Joint outcomes at Weeks 24 and 52
                                     Week 24                                                       Week 52
                                          Treatment                                                      Treatment
                                           difference                                                     difference
               IXE          ADA         IXE versus ADA                      IXE           ADA          IXE versus ADA
             (n = 49)     (n = 51)          (95% CI)              Pa      (n = 49)      (n = 51)           (95% CI)                Pa
 ACR70      21 (42.9) 17 (33.3)          9.5 (-9.4, 28.5)        0.411    21 (42.9)    20 (39.2)       3.6 (-15.6, 22.9)        0.839
 ACR50      29 (59.2) 28 (54.9)          4.3 (-15.1, 23.7)       0.691    27 (55.1)    32 (62.7)       -7.6 (-26.9, 11.6)       0.542
 ACR20      37 (75.5) 40 (78.4)         -2.9 (-19.4, 13.6)       0.814    36 (73.5)    41 (80.4)       -6.9 (-23.4, 9.6)        0.480

Unless otherwise indicated, values are presented as n (%).
a
  P value: IXE versus ADA
ACR = American College of Rheumatology; ADA = Adalimumab; CI = Confidence intervals; IXE = Ixekizumab.




                A




                B




Figure 4. Clinical response rate for Fingernail PsO endpoints through Week 52. Graphs depict results for patients with moderate-to-severe
PsO, PsA and a fingernail NAPSI ≥ 1 score at baseline. (A) Percentage of patients achieving fingernail NAPSI = 0 through Week 52. (B) Mean
change in fingernail NAPSI score from baseline through Week 52. IXE versus ADA: * P ≤ 0.05, **P ≤ 0.01.

ADA = Adalimumab; IXE = Ixekizumab; NAPSI = Nail Psoriasis Severity Index; PsA = Psoriatic arthritis; PsO = Plaque psoriasis.



Original Article | Dermatol Pract Concept. 2022;12(2):e2022104                                                                          7
    A                                                                  B




    C                                                                  D




Figure 5. Clinical response rate for quality-of-life endpoints through Week 52. Graphs depict results for patients with PsA and moder-
ate-to-severe PsO at baseline. (A) Percentage of patients achieving DLQI (0,1) through Week 52. (B) Mean change from baseline in DLQI
score through Week 52. (C) Percentage of patients achieving Itch NRS = 0 through Week 52. (D) Mean change from baseline in Itch NRS
score through Week 52. IXE versus ADA: * P ≤ 0.05, **P ≤ 0.01.

ADA = Adalimumab; DLQI = Dermatology Life Quality Index; IXE = Ixekizumab; NRS = Numeric Rating Scale; PsA = Psoriatic arthritis;
PsO = Plaque psoriasis.




in the IXE group and 86.7% in the ADA group were mild or             Overall, IXE-treated patients demonstrated higher re-
moderate, while 13.3% in the ADA group were severe. The              sponses for resolution of skin and nail manifestations of
TEAEs are consistent with the known safety profiles of both          PsO versus ADA-treated patients and comparable response
drugs. The frequency of serious AEs (SAEs) was lower in              rates regarding improvement in joint symptoms. Impor-
IXE- versus ADA-treated patients (0.0% versus 9.8%) and              tantly, while anti-TNF biologics have previously been rec-
a lower proportion of patients in the IXE group discontin-           ommended as the first-line biologic to treat patients with
ued due to an AE compared with ADA group (2.0% versus                PsA and PsO, these results indicate that IXE is as good as,
7.8%). No deaths occurred during the study.                          if not better than, ADA in treating patients with active PsA
                                                                     and moderate-to-severe PsO [24].

Conclusions                                                                Moderate-to-severe PsO can have considerable negative
                                                                     effects on patients QoL, and the burden of disease can be
This subgroup analysis focused on the biologic-naïve pa-             further compounded by the presence of nail PsO and co-
tients with active PsA and moderate-to-severe PsO at                 morbid PsA. The IXE group had significantly more patients
baseline in the SPIRIT-H2H trial, which demonstrated                 achieving DLQI (0,1) at W24 and numerically more through
higher efficacy of IXE versus ADA in patients with active            W52 compared with the ADA group, indicating that rapid
PsA and PsO, and determined that IXE is also more ef-                and sustained skin clearance had important and clinically
ficacious than ADA for simultaneously achieving ACR50                meaningful effects on QoL for patients with active PsA and
and PASI100 at W24 and W52 in this subgroup [18,19].                 moderate-to-severe PsO.



8                                                                          Original Article | Dermatol Pract Concept. 2022;12(2):e2022104
                                                      Table 3. Safety outcomes
                               Category                                           IXE (N = 49)                        ADA (N = 51)
 TEAE                                                                               29 (59.2)                            30 (58.8)
 TEAE by severity
          Mild                                                                      17 (34.7)                            15 (29.4)
          Moderate                                                                  12 (24.5)                            11 (21.6)
          Severe                                                                        0                                  4 (7.8)
 Death                                                                                  0                                     0
 SAEa                                                                                   0                                  5 (9.8)
 Treatment discontinuation due to AE                                                 1 (2.0)                               4 (7.8)
 AE of special interest
 Infections                                                                         13 (26.5)                            18 (35.3)
 Serious infectionsb                                                                    0                                  1 (2.0)
                           c
 Injection site reactions                                                            2 (4.1)                                  0
                                        d
 Allergic/hypersensitivity reactions                                                 2 (4.1)                               2 (3.9)
 Cerebrocardiovascular eventse                                                          0                                  1 (2.0)
 Depression                                                                          1 (2.0)                                  0

Data are presented as n (%).
a
  SAEs were acute abdomen disorder (n = 1), pyrexia (n = 1), cellulitis (n = 1), polyneuropathy (n = 1), and peripheral artery occlusion and
necrosis ischemic vascular disorder (n = 1).
b
  Serious infection was cellulitis.
c
  Defined by High Level Term (HLT).
d
  No confirmed anaphylaxis reported after medical review.
e
  Cerebro-cardiovascular events are defined using terms from the following subcategories: cardiovascular death, myocardial infarction,
­hospitalization for unstable angina, hospitalization for heart failure, hospitalization for serious arrhythmia, hospitalization for hypertension,
 resuscitated sudden death, cardiogenic shock due to myocardial infarction, coronary revascularization procedure, neurologic-stroke, and
 peripheral vascular events.
 ADA = Adalimumab; AE = Adverse event; IXE = Ixekizumab; SAE = Serious adverse event; TEAE = Treatment-emergent adverse event.


    Nail PsO can substantially compromise patients’ daily                  in nail PsO from baseline were higher for ADA versus GUS
activities by causing pain and impairing hand mobility and                 at W16, which suggests that the different methods of action
is a particularly difficult to treat manifestation of PsO [8].             of biologics may result in differing effects on specific PsO
Improvement and clearance of nail PsO is a long process,                   disease domains, such as nail PsO [29–31]. Importantly, our
partially due to the slow growth rate of nails, and conse-                 analysis of the SPIRIT-H2H subgroup with active PsA and
quently, efficacy cannot be evaluated before 12 weeks of                   moderate-to-severe PsO demonstrates that IXE has higher
treatment [25]. In our subgroup analysis, the proportion                   efficacy than ADA in achieving complete clearance of the
of patients experiencing nail PsO was higher than in other                 skin and nails at W24. Overall, these and previously pub-
­moderate-to-severe PsO clinical trial populations as all pa-              lished results demonstrate the consistent high efficacy of
tients had concomitant active PsA, which is associated with                IXE in achieving clearance of nail PsO. This is supported
higher rates of nail PsO than PsO [26,27]. Notably, IXE                    by multiple recent network meta-analyses, which report that
treatment resulted in a more rapid increase overall in clear-              IXE had the highest ranking among approved biologics (and
ance of nail PsO than ADA, with significantly more IXE- ver-               small molecules in one network meta-analysis) for the treat-
sus ADA-treated patients demonstrating complete clearance                  ment and/or clearance of nail PsO [32–34].
of nail PsO at W24.                                                            Of note, > 50% of patients in our subgroup analysis
    Previously published results from the IXORA-S trial                    had concomitant MTX use at baseline. Previously published
have demonstrated that IXE is superior to ustekinumab,                     studies have indicated that concomitant MTX treatment
an anti-IL-12/23 biologic, in clearance of nail PsO at W24                 improves the efficacy of ADA and other anti-TNF biolog-
[26]. Similarly, in the IXORA-R head-to-head trial compar-                 ics in treating rheumatoid arthritis, but the results regarding
ing IXE with guselkumab (GUS), an anti-IL-23p19 biologic,                  the effect of this combined therapy for PsA have been in-
IXE was superior to GUS in clearance of nail PsO at W24                    conclusive [35–38]. It has been suggested that in the over-
[28]. The VOYAGE-1 and -2 trials demonstrated superiority                  all SPIRIT-H2H study population, concomitant treatment
of GUS to ADA in achieving clear/almost clear skin at W16;                 with MTX increases the proportion of ADA-treated patients
however, post hoc analysis demonstrated that improvements                  achieving simultaneous ACR50 and PASI100, or NAPSI =



Original Article | Dermatol Pract Concept. 2022;12(2):e2022104                                                                                  9
0 at W52 but does not have a response-modifying effect in            4. Gelfand JM, Gladman DD, Mease PJ, et al. Epidemiology of pso-
IXE-treated patients [39]. Therefore, it is possible that the           riatic arthritis in the population of the United States. J Am Acad
                                                                        Dermatol. 2005;53(4):573.e571–573.e513. DOI: 10.1016/j.
proportion of ADA-treated patients achieving simultaneous
                                                                        jaad.2005.03.046. PMID: 16198775.
ACR50 and PASI100, or clearance of nail PsO in our sub-
                                                                     5. Reich K, Krüger K, Mössner R, Augustin M. Epidemiology and
group analysis is higher than would be observed in patients             clinical pattern of psoriatic arthritis in Germany: a prospec-
receiving ADA monotherapy.                                              tive interdisciplinary epidemiological study of 1511 patients
     The safety profiles of both IXE and ADA were consistent            with plaque-type psoriasis. Br J Dermatol. 2009;160(5):1040–
with previous clinical trials and the prescriber information            1047. DOI: 10.1111/j.1365-2133.2008.09023.x. PMID:
                                                                        19210498.
for both drugs. The ADA group had numerically more SAEs
                                                                     6. Rigopoulos D, Baran R, Chiheb S, et al. Recommendations for
(there were no SAEs in the IXE group) and treatment discon-
                                                                        the definition, evaluation, and treatment of nail psoriasis in adult
tinuations due to AEs, which is consistent with previously              patients with no or mild skin psoriasis: A dermatologist and nail
published safety data from the overall SPIRIT-H2H trial                 expert group consensus. J Am Acad Dermatol. 2019;81(1):228–
[18,19].                                                                240. DOI: 10.1016/j.jaad.2019.01.072. PMID: 30731172.
     The limitations of this study include the open-label de-        7. McGonagle D, Tan AL, Benjamin M. The nail as a mus-
                                                                        culoskeletal appendage--implications for an improved
sign, which may have biased the outcome assessments.
                                                                        understanding of the link between psoriasis and arthritis. Der-
Another limitation is that while the data show clinically
                                                                        matology. 2009;218(2):97–102. DOI: 10.1159/000182250.
meaningful differences, the sample size was small and this              PMID: 19060455.
post hoc analysis was not powered to demonstrate statistical         8. Jiaravuthisan MM, Sasseville D, Vender RB, Murphy F, Muhn
differences between these subgroups.                                    CY. Psoriasis of the nail: anatomy, pathology, clinical presen-
     In conclusion, this subgroup analysis demonstrated                 tation, and a review of the literature on therapy. J Am Acad
                                                                           Dermatol. 2007;57(1):1–27. DOI: 10.1016/j.jaad.2005.07.073.
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                                                                           PMID: 17572277.
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                                                                      9.   Nast A, Smith C, Spuls P, et al. EuroGuiDerm Guideline for
through W52 and confirmed IXE as an efficacious and safe                   the systemic treatment of Psoriasis Vulgaris. Available from:
treatment for patients with active PsA and moderate-to-­                   https://www.edf.one/home/Guidelines/EuroGuiDerm-psoriasis-­
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                                                                     10.   Gossec L, Baraliakos X, Kerschbaumer A, et al. EULAR rec-
IXE in treating nail PsO in patients with moderate-to-severe
                                                                           ommendations for the management of psoriatic arthritis with
PsO, irrespective of concomitant active PsA [26-28]. These
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medical writer and employee of Eli Lilly and Company, for                  four weeks as a subcutaneous injection in psoriatic arthritis:
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