A systematic review with network meta-analysis of the available biologic therapies for psoriatic disease domains

SYSTEMATIC REVIEW published: 15 January 2021 doi: 10.3389/fmed.2020.618163 Frontiers in Medicine | www.frontiersin.org 1January 2021 | Volume 7 | Article 618163 Edited by: Francesco Ciccia, University of Campania Luigi Vanvitelli, Italy Reviewed by: Raffaele Scarpa, University of Naples Federico II, Italy Ennio Lubrano, University of Molise, Italy *Correspondence: Tiago Torres [email protected] †These authors have contributed equally to this work Specialty section: This article was submitted to Rheumatology, a section of the journal Frontiers in Medicine Received: 16 October 2020 Accepted: 26 November 2020 Published: 15 January 2021 Citation: Torres T, Barcelos A, Filipe P and Fonseca JE (2021) A Systematic Review With Network Meta-Analysis of the Available Biologic Therapies for Psoriatic Disease Domains. Front. Med. 7:618163. doi: 10.3389/fmed.2020.618163 A Systematic Review With Network Meta-Analysis of the Available Biologic Therapies for Psoriatic Disease Domains Tiago Torres1,2*†, Anabela Barcelos3,4,5†, Paulo Filipe6,7,8 and João Eurico Fonseca9,10 1Department of Dermatology, Centro Hospitalar Universitário do Porto, Porto, Portugal, 2Multidisciplinar Medical Research Unit, Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal, 3Rheumatology Department, Centro Hospitalar do Baixo Vouga, Aveiro, Portugal, 4NOVA National School of Public Health, Public Health Research Centre, Universidade NOVA de Lisboa – Portugal, Lisbon, Portugal, 5Comprehensive Health Research Center (CHRC), Universidade NOVA de Lisboa – Portugal, Lisbon, Portugal, 6Serviço de Dermatologia e Venereologia, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal, 7Unidade de Investigação em Dermatologia, Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal, 8Clínica Universitária de Dermatologia, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal, 9Serviço de Reumatologia e Doenças Ósseas Metabólicas, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal, 10 Unidade de Investigação em Reumatologia, Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal Introduction: Several new treatments have been developed for psoriatic disease, an inflammatory condition that involves skin and joints. Notwithstanding, few studies have made direct comparisons between treatments and therefore it is difficult to select the ideal treatment for an individual patient. The aim of this systematic review with network meta-analysis (NMA) was to analyze available and approved biologic therapies for each domain of psoriatic disease: skin, peripheral arthritis, axial arthritis, enthesitis, dactylitis, and nail involvement. Methods: Data from randomized clinical trials (RCTs) were included. A systematic review was performed using the MEDLINE database (July 2020) using PICO criteria. Bayesian NMA was conducted to compare the clinical efficacy of biological therapy in terms of the American College of Rheumatology criteria (ACR, 24 weeks) and Psoriasis Area and Severity Index (PASI, 10–16 weeks). Results: Fifty-four RCTs were included in the systematic review. Due to the design of the RCTs, namely, outcomes and time points, network meta-analysis was performed for skin and peripheral arthritis domains. For the skin domain, 30 studies reporting PASI100 were included. The peripheral arthritis domain was analyzed through ACR70 in 12 studies. From the therapies approved for both domains, secukinumab and ixekizumab were the ones with the highest probability of reaching the proposed outcomes. There is a lack of outcome uniformization in the dactylitis, enthesitis, and nail domains, and therefore, an objective comparison of the studies was not feasible. Nevertheless, secukinumab was the treatment with the best compromise between the number of studies in each domain and the results obtained in the different outcomes. Torres et al. Biologic Therapy for Psoriatic Disease Conclusion: Secukinumab and ixekizumab were the treatments with the highest probability of reaching both PASI100 and ACR70 outcomes. Due to the lack of a standard evaluation of outcomes of the other psoriatic disease domains, a network meta-analysis for all the domains was not possible to perform. Keywords: psoriasis, psoriatic arthritis, psoriatic disease, biologic therapy, systematic review, network meta-analysis INTRODUCTION Psoriasis (PsO) affects 1–3% of the world population. Psoriatic arthritis (PsA) occurs in a third of the patients with PsO. These two conditions share clinical, genetic, and pathogenic factors and can be considered a single entity—psoriatic disease (PsD) (1–3). PsD involves chronic inflammation of the skin, nails, and joints (arthritis, enthesitis, dactylitis, and spondylitis) (4). Autoimmune mechanisms are involved in PsA pathogenesis, and this is ultimately related with the systemic nature of the disease and raised the concept of a Systemic Psoriatic Disease. This fact highlights the heterogeneity of the disease and the need for optimizing its management (5). Optimal management of PsD requires early diagnosis, monitoring of the disease activity, and treatment with effective and safe therapies. Over the last 20 years, targeted therapies emerged in the treatment of PsD, namely, biologic agents such as tumor necrosis factor inhibitors (TNFi), IL-17 inhibitors (IL-17i), and IL-12/23 inhibitors (IL-12/23i), and small molecules, such as Janus Kinase (JAK) or phosphodiesterase 4 (PDE4) inhibitors (6). The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) is a global association of more than 500 rheumatologists, dermatologists, and patient research partners that publish treatment recommendations for PsD (2). The treatment of six domains—peripheral arthritis, axial disease, enthesitis, dactylitis, skin disease, and nail disease— are included in the recommendations directed to anyone involved in the treatment of patients with PsD (2). Based on these recommendations, we performed a systematic review and network meta-analyses assessing the main results of randomized clinical trials (RCT) including biologic therapies in the treatment of patients with PsD. METHODS Literature Search A literature search according to the Population, Intervention, Comparator, Outcomes (PICO) framework was performed establishing criteria for study eligibility. The population was defined as adult (≥18 years) patients with the PsD (PsO and/or PsA) and the intervention as any biologic therapy: adalimumab (ADA), etanercept (ETN), infliximab (IFX), golimumab (GOL), certolizumab (CZP), ustekinumab (UST), secukinumab (SEC), ixekizumab (IXE), guselkumab (GUS), brodalumab (BRD), risankizumab (RIS), and tildrakizumab (TIL), in all formulations and treatment durations. The comparator was the same drug (different dose or regimen), any different drug, or placebo. Outcomes considered were American College of Rheumatology (ACR) or Psoriasis Area Severity Index (PASI) or dactylitis assessment or enthesitis assessment or nail psoriasis assessment. The MEDLINE database search was performed on 1 July 2020, with the filters “Humans,” “Clinical Trials,” “Phase III,” and “English,” with no date limits. In line with the GRAPPA and EULAR recommendations, we did not include abatacept in this systematic review. In addition, as this systematic review was focused only on biologic treatments apremilast and tofacitinib were not analyzed. Statistics and Network Meta-Analyses Network meta-analyses (NMA) were carried out using the web application CINeMA 1.9.0 (Confidence in Network MetaAnalysis) from Cochrane (7). This application is based on a described methodological framework that considers six domains: within-study bias, reporting bias, indirectness, imprecision, heterogeneity, and incoherence (8). NMAs based on the Bayesian framework using the fixed-effects model were performed to pool all the direct and indirect evidence together. Odds ratio (OR) with 95% credible intervals (CrI) was used to evaluate comparisons. Only comparisons showing high confidence in the six domains were considered for the results. Assessment of Bias Assessment of bias was performed using the latest version of RoB2—Cochrane (9). RESULTS A detailed flowchart with the results of the literature review is shown in Figure 1. Out of the 232 references retrieved, 82 studies were selected for data (1,11–57). For NMAs, only studies reporting ACR20, ACR50, ACR70 (peripheral arthritis domain), PASI75, PASI90, or PASI100 (skin domain) were included. For the peripheral arthritis domain, only 24 weeks were included. For the skin domain, results between 10 and 16 weeks were considered. Moreover, the doses of the drugs for the systematic review and NMAs, for the peripheral arthritis and skin domains, were the ones approved by the regulatory authorities. The studies included in the NMAs are identified in Table 1. Extension studies are specified in Table 2 (48,58–84). In Figure 2 the drugs that have been studied specifically for each domain of PsD were included. Peripheral Arthritis The peripheral arthritis domain is predominantly assessed by instruments, such as ACR20, ACR50, and ACR70 criteria, which Frontiers in Medicine | www.frontiersin.org 2January 2021 | Volume 7 | Article 618163 Torres et al. Biologic Therapy for Psoriatic Disease FIGURE 1 | PRIMA flow diagram. Adapted from (10). specify the improvement of 20, 50, or 70% in the number of tender and swollen joints, respectively, and a 20, 50, or 70% improvement in three of the following five criteria: patient global assessment, physician global assessment, functional ability measure (most often Health Assessment Questionnaire—HAQ), visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein (85). The main results of the ACR response in RCTs, at 24 weeks, are included in Table 3 (1,11,18, 24,26,28,31,32,37,38,47,51,55). The head-to-head comparison of the ACR responses of SEC vs. ADA at week Frontiers in Medicine | www.frontiersin.org 3January 2021 | Volume 7 | Article 618163 Torres et al. Biologic Therapy for Psoriatic Disease TABLE 1 | RCT included in the systematic review and NMA, focusing on the outcomes of GRAPPA domains. Study Enrolled patients NMA Author Year NDrug Dosage Outcomes IMPACT 2 (1) Antoni 2005 200 IFX 5 mg/kg ①②③④ ⑤⑥⑦⑧ YES PLB ADEPT (11) Mease 2005 313 ADA 40 mg ①②③ ④⑤⑥ YES PLB (12) Reich 2005 378 IFX 5 mg/kg ④⑤ ⑥⑩ YES PLB (13) Genovese 2007 100 ADA 40 mg ①②③ ⑦⑨ NO PLB (14) Tyring 2007 618 ETN 50 mg ④⑤⑥ YES PLB PHOENIX 1 (15) Leonardi 2008 766 UST 45 mg ④⑤⑥ YES UST 90 mg PLB PHOENIX 1 (16) Papp 2008 1,230 UST 45 mg ④⑤⑥ YES UST 90 mg PLB (17) Rich 2008 378 IFX 5 mg/kg ⑩NO PLB (18) Kavanaugh 2009 405 GOL 50 mg ①②③ ④⑤⑥ ⑧⑨⑩ YES GOL 100 mg PLB (19) Barker 2011 868 IFX 5 mg/kg ④⑤⑥ YES MTX 15 mg (20) Gottlieb 2011 347 BRK 200 mg ⑤⑥⑦ YES ETN 50 mg PLB (21) Strober 2011 350 BRK 200 mg ⑤⑥⑦ YES ETN 50 mg PLB RESPOND (22) Baranauskaite 2012 115 IFX +MTX 5 mg/kg ①②③ ⑤⑧⑨ NO MTX 15 mg (23) Gottlieb 2012 478 MTX +ETN 15 mg +50 mg ④⑤⑥ NO PSUMMIT 1 (24) McInnes 2013 615 UST 45 mg ①②③ ⑥⑧⑨ YES UST 90 mg PLB ERASURE (25) Langley 2014 738 SEC 150 mg ⑤⑥⑦ YES SEC 300 mg PLB FIXTURE (25) Langley 2014 1,306 SEC 150 mg ⑤⑥⑦ YES SEC 300 mg ETN 50 mg PLB RAPID-PsA (26) Mease 2014 409 CZP 200 mg ①②③ ④⑤⑥ ⑧⑨⑩ YES CZP 400 mg PLB PHOENIX 1 (27) Rich 2014 766 UST 45 mg ④⑤ ⑥⑩ YES UST 90 mg PLB (Continued) Frontiers in Medicine | www.frontiersin.org 4January 2021 | Volume 7 | Article 618163 Torres et al. Biologic Therapy for Psoriatic Disease TABLE 1 | Continued Study Enrolled patients NMA Author Year NDrug Dosage Outcomes PSUMMIT 2 (28) Ritchlin 2014 312 UST 45 mg ①②③ ⑤⑧⑨ YES UST 90 mg PLB UNOCOVER 2 (29) Griffiths 2015 1,224 IXE 80 mg 2 w ⑤⑥⑦ YES IXE 80 mg 4 w ETN 50 mg PLB UNOCOVER 3 (29) Griffiths 2015 1,346 IXE 80 mg 2 w YES IXE 80 mg 4 w ⑤⑥⑦ ETN 50 mg PLB AMAGINE-2 (30) Lebwohl 2015 1,831 BRD 140 mg ⑤⑦ YES BRD 210 mg UST 45/95 mg PLB AMAGINE-3 (30) Lebwohl 2015 1,881 BRD 140 mg ⑤⑦ YES BRD 210 mg UST 45/95 mg PLB FUTURE 2 (31) McInnes 2015 397 SEC 75 mg ①②③ ⑤⑥⑧ YES SEC 150 mg SEC 300 mg PLB (32) Mease 2015 606 SEC 10 mg/kg ①②⑤ ⑥⑧⑨ YES SEC 75 mg SEC 150 mg PLB CLEAR (33) Thaçi 2015 676 SEC 300 mg ⑤⑥⑦ YES UST 45/90 mg BELIEVE (34) Thaçi 2015 730 ADA 40 mg ⑩NO PLB AMAGINE-1 (35) Papp 2016 661 BRD 140 mg ⑤⑥⑦ YES BRD 210 mg PLB VOYAGE 1 (36) Blauvelt 2017 837 GUS 100 mg ⑤⑥⑦⑩ YES ADA 40 mg PLB SPIRIT-P1 (37) Mease 2017 417 IXE 80 mg 2 w ①②⑤ YES IXE 80 mg 4 w ⑥⑦⑧ ADA 40 mg ⑨⑩ PLB SPIRIP-P2 (38) Nash 2017 363 IXE 80 mg 2 w ①②③ YES IXE 80 mg 4 w ⑤⑥⑦ PLB ⑧⑨⑩ reSURFACE 1 (39) Reich 2017 772 TIL 100 mg ⑤⑥⑦ YES TIL 200 mg PLB (Continued) Frontiers in Medicine | www.frontiersin.org 5January 2021 | Volume 7 | Article 618163 Torres et al. Biologic Therapy for Psoriatic Disease TABLE 1 | Continued Study Enrolled patients NMA Author Year NDrug Dosage Outcomes reSURFACE 2 (39) Reich 2017 1,090 TIL 100 mg ⑤⑥⑦ YES TIL 200 mg ETN 50 mg PLB IXORA-S (40) Reich 2017 302 IXE 80 mg ⑤⑥⑦ YES UST 45/90 mg CLARITY (41) Bagel 2018 1102 SEC 300 mg ⑤⑥⑦ YES UST 45/90 mg (42) Elewski 2018 217 ADA 40 mg ⑩NO PLB UltIMMa-1 (43) Gordon 2018 506 RIS 150 mg ⑤⑥⑦ YES UST 45/90 mg PLB UltIMMa-2 (43) Gordon 2018 491 RIS 150 mg ⑤⑥⑦ YES UST 45/90 mg PLB CIMPASI-1 (44) Gottlieb 2018 234 CZP 200 mg ⑥⑦ YES CZP 400 mg PLB CIMPASI-2 (44) Gottlieb 2018 227 CZP 200 mg ⑥⑦ YES CZP 400 mg PLB CIMPACT (45) Lebwohl 2018 559 CZP 200 mg ⑤⑥ YES CZP 400 mg ETN 50 mg PLB TRANSFIGURE (46) Reich 2018 198 SEC 150 mg ⑤⑥ ⑦⑩ YES SEC 300 mg PLB FUTURE 5 (47) Mease 2018 774 SEC 150 mg ①②③ ⑤⑦⑧ YES SEC 300 mg PLB SustaIMM (48) Ohtsuki 2019 171 RIS 75 mg ⑤⑥⑦ YES RIS 150 mg PLB ECLIPSA (50) Araujo 2019 47 UST 45/90 mg ⑨NO TNFi IMMvent (52) Reich 2019 605 RIS 150 mg ⑤⑥⑦ YES ADA 40 mg ECLIPSE (53) Reich 2019 1048 GUS 100 mg ⑤⑥⑦ YES SEC 300 mg DISCOVER-2 (49) Mease 2020 741 GUS 100 mg ①②③⑤ ⑥⑦⑧⑨ NO PLB SPIRIT H2H (51) Mease 2020 566 ADA 40 mg ①②③⑤ ⑥⑧⑨⑩ YES IXE 80 mg DISCOVER-1 (54) Deodhar 2020 624 GUS 100 mg ①②③⑤ ⑥⑦⑧⑨ NO PLB EXCEED (55) McInnes 2020 853 SEC 300 mg ①②③⑤ NO ADA 40 mg ⑥⑦⑧⑨ (Continued) Frontiers in Medicine | www.frontiersin.org 6January 2021 | Volume 7 | Article 618163 Torres et al. Biologic Therapy for Psoriatic Disease TABLE 1 | Continued Study Enrolled patients NMA Author Year NDrug Dosage Outcomes ORION (56) Ferris 2020 78 GUS 100 mg ⑤⑥⑦ YES PLB IMMerge (57) Warren 2020 327 RIS 150 mg ⑤⑥⑦ YES SEC 300 mg N, number; NMA, network meta-analysis; GRAPPA, Group for Research and Assessment of Psoriasis and Psoriatic Arthritis; RCT, randomized clinical trial; ADA, adalimumab; ETN, etanercept; INF, infliximab; GOL, golimumab; CZP, certolizumab; UST, ustekinumab; SEC, secukinumab; IXE, ixekizumab; GUS, guselkumab; BRD, brodalumab; RIS, risankizumab; TIL, tildrakizumab; BRK, briakinumab; MTX, methotrexate; PLB, placebo. ①ACR20, ②ACR50, ③ACR70, ④PASI50, ⑤PASI75, ⑥PASI90, ⑦PASI100, ⑧dactylitis assessment, ⑨enthesitis assessment, ⑩nail assessment. YES—the study was in NMA; NO—the study was not included in NMA. TABLE 2 | Extension studies from RCT focusing on outcomes of GRAPPA domains. Study Enrolled patients NMA Author Year NTime of outcome (weeks) Drug Dosage Outcomes IMPACT 2 (58) Kavanaugh 2007 200 52 IFX 5 mg/kg ①②③④ ⑤⑥⑧⑨ PLB (59) Menter 2008 1,212 52 ADA 40 mg ⑥⑦ PLB REVEAL (60) Gordon 2012 522 156 ADA 40 mg PASI improvement PLB GO-REVEAL (61) Kavanaugh 2012 405 52 GOL 50 mg ①②③④ ⑤⑧⑨⑩ GOL 100 mg PLB PHOENIX 1 (62) Kimball 2012 766 156 UST 45 mg ④⑤⑥ UST 90 mg PLB GO-REVEAL (63) Kavanaugh 2013 405 104 GOL 50 mg ①②③④ ⑤⑧⑨⑩ GOL 100 mg PLB PHOENIX 1 (64) Kimball 2013 766 260 UST 45 mg ④⑤⑥ UST 90 mg PLB GO-REVEAL (65) Kavanaugh 2014 405 268 GOL 50 mg ①②③④ ⑤⑧⑨⑩ GOL 100 mg PLB PSUMMIT 1 Kavanaugh 2014 927 52 UST 45 mg Radiographic progression PSUMMIT 2 (66) UST 90 mg PLB PSUMMIT 1 (67) Kavanaugh 2015 615 100 UST 45 mg ①②③⑤ ⑥⑧⑨ UST 90 mg PLB PHOENIX 2 (68) Langley 2015 1,212 260 UST 45 mg ⑤⑥ UST 90 mg PLB UNCOVER 3 (69) Dennehy 2016 491 60 IXE 80 mg 2 w ⑩ IXE 80 mg 4 w ETN 50 mg PLB (Continued) Frontiers in Medicine | www.frontiersin.org 7January 2021 | Volume 7 | Article 618163 Torres et al. Biologic Therapy for Psoriatic Disease TABLE 2 | Continued Study Enrolled patients NMA Author Year NTime of outcome (weeks) Drug Dosage Outcomes UNCOVER 2 (70) Gordon 2016 1,224 60 IXE 80 mg 2 w ⑤⑥⑦ IXE 80 mg 4 w ETN 50 mg PLB UNCOVER 3 (70) Gordon 2016 1,346 60 IXE 80 mg 2 w ⑤⑥⑦ IXE 80 mg 4 w ETN 50 mg PLB (71) van der Heijde 2016 606 52 SEC 10 mg/kg Radiographic progression SEC 75 mg SEC 150 mg PSTELLAR (72) Blauvelt 2017 325 112 UST q12 wk ⑤⑥⑦ UST q24 wk UNCOVER 3 (73) Blauvelt 2017 1,346 108 IXE 80 mg 2 w ⑤⑥⑦ IXE 80 mg 4 w ETN 50 mg PLB CLEAR (74) Blauvelt 2017 676 52 SEC 300 mg ⑤⑥⑦ UST 45/90 mg FUTURE 2 (75) McInnes 2017 397 104 SEC 75 mg ①②③ ⑥⑧⑨ SEC 150 mg SEC 300 mg PLB (76) Mease 2017 422 54 TOF 5 mg ①②③ ⑤⑧⑨ TOF 10 mg ADA 40 mg PLB LIBERATE (77) Reich 2017 250 52 APR 30 mg ④⑤ ⑥⑩ ETN 50 mg PLB UNCOVER 3 (78) van der Kerkhof 2017 809 60 IXE 80 mg 2 w ⑩ IXE 80 mg 4 w ETN 50 mg PLB (79) Griffiths 2018 100 GUS 100 mg ⑤⑥⑦ ADA 40 mg PLB UNCOVER 3 (80) Leonardi 2018 1,346 156 IXE 80 mg 2 w ⑤⑥⑦ IXE 80 mg 4 w ETN 50 mg PLB (81) Ohtsuki 2018 191 52 GUS 50 mg ④⑤⑥ ⑦⑩ GUS 100 mg PLB LIBERATE (82) Reich 2018 250 104 APR 30 mg ⑤⑩ ETN 50 mg PLB (Continued) Frontiers in Medicine | www.frontiersin.org 8January 2021 | Volume 7 | Article 618163 Torres et al. Biologic Therapy for Psoriatic Disease TABLE 2 | Continued Study Enrolled patients NMA Author Year NTime of outcome (weeks) Drug Dosage Outcomes UNCOVER 2/3 (83) Kemény 2019 2570 156 IXE 80 mg 2 w ⑤⑥⑦ IXE 80 mg 4 w ETN 50 mg PLB IXORA-S (84) Paul 2019 302 52 IXE 80 mg ⑤⑥⑦ UST 45/90 mg SUSTaIMM (48) Ohtsuki 2019 171 52 RIS 75 mg ⑤⑥⑦ RIS 150 mg PLB N, number; NMA, network meta-analysis; GRAPPA, Group for Research and Assessment of Psoriasis and Psoriatic Arthritis; RCT, randomized clinical trial; ADA, adalimumab; ETN, etanercept; IFX, infliximab; GOL, golimumab; UST, ustekinumab; SEC, secukinumab; IXE, ixekizumab; GUS, guselkumab; RIS, risankizumab; APR, apremilast; TOF, tofacitinib; PLB, placebo. ①ACR20, ②ACR50, ③ACR70, ④PASI50, ⑤PASI75, ⑥PASI90, ⑦PASI100, ⑧dactylitis assessment, ⑨enthesitis assessment, ⑩nail assessment. FIGURE 2 | GRAPPA domains—evaluated therapies. 52 in the EXCEED study is also listed but not included on the NMA (55). An NMA was performed for the three outcomes (ACR20, ACR50, and ACR70). The included studies are identified in Table 1. A network plot for ACR70 is included in Figure 3, as an example of the network plots of these three NMAs. The NMA results from the network of biologic therapies for the outcome ACR70 response are included in Table 4. Axial Disease Data including biologic therapies for axial disease, in the context of PsD, are scarce, possibly because there is no validated instrument to assess this domain. Nowadays, the only trial addressing specifically PsD patients with the axial disease is still ongoing and this data is not yet published. This trial— MAXIMIZE—evaluates the efficacy and safety of SEC 300 or 150 mg in managing axial manifestations in patients with PsA, who have failed to respond to at least 2 non-steroidal anti-inflammatory drugs (NSAIDs) over 4 weeks, according to Assessment of Spondyloarthritis International Society (ASAS) recommendations for the treatment of axial spondyloarthritis (ClinicalTrials.gov NCT02721966) (86). Enthesitis There are at least 6 indices to evaluate enthesitis outcomes (4-point enthesitis measure, Leeds Enthesis Index (LEI), Frontiers in Medicine | www.frontiersin.org 9January 2021 | Volume 7 | Article 618163 Torres et al. Biologic Therapy for Psoriatic Disease TABLE 7 | Continued Improvement PASI75 PASI90 PASI100 Study Weeks Drug n/total (%) n/total (%) n/total (%) Griffiths 2015 UNCOVER 2 (29) 12 PLB 4/168 (2.4) 1/168 (0.6) 1/168 (0.6) 12 IXE Q4W* 269/347 (77.5) 267/347 (76.9) 107/347 (30.8) 12 ETA 149/358 (41.6) 67/358 (18.7) 19/358 (5.3) p-value <0.0001 <0.0001 <0.0001 Griffiths 2015 UNCOVER 3 (29) 12 PLB 14/193 (7.2) 6/193 (3.1) 0/193 (0.0) 12 IXE* 325/386 (84.2) 352/386 (91.2) 135/386 (35.0) 12 ETA 201/382 (52.6) 98/382 (25.6) 19/358 (5.3) p-value <0.0001 <0.0001 <0.0001 Lebwohl 2015 12 PLB 25/309 (8.1) 12/309 (3.9) 2/309 (0.6) AMAGINE 2 (30) 12 UST 210/300 (70.0) 141/300 (47.0) 65/300 (21.7) 12 BRD 210 mg* 528/612 (86.3) 428/612 (69.9) 272/612 (44.4) p-value <0.001 <0.001 <0.001 Lebwohl 2015 12 PLB 19/315 (6.0) 6/315 (1.9) 1/315 (0.3) AMAGINE 3 (30) 12 UST 217/313 (69.3) 141/313 (45.0) 58/313 (18.5) 12 BRD* 531/624 (85.1) 430/624 (68.9) 229/624 (36.7) p-value <0.001 <0.001 <0.001 Thaci 2015 12 SEC 311/334 (93.1) 264/334 (79.0) 148/334 (44.3) CLEAR (33) 12 UST 277/334 (82.9) 277/334 (82.9) 130/334 (38.9) p-value <0.0001 <0.0001 =0.003 Gordon 2016 12 PLB 17/431 (3.9) 7/431 (1.7) 0/431 (0.0) UNCOVER 1 (70) 12 IXE Q4W 357/432 (82.6) 279/432 (64.6) 145/432 (33.6) p-value <0.001 <0.001 <0.001 Papp 2016 12 PLB 6/220 (2.7) 2/220 (0.9) 1/220 (0.5) (35) 12 BRD 185/222 (83.3) 156/220 (70.9) 93/222 (41.9) p-value <0.001 <0.001 <0.001 Blauvelt 2017 16 PLB 10/174 (5.7) 5/174 (2.9) 1/174(0.6) VOYAGE 1 16 GUS* 300/329 (91.2) 241/329 (73, 3) 123/329 (37.4) (36) 16 ADA 244/334 (73.1) 166/334 (49.7) 57/334 (17.4) p-value <0.001 <0.001 <0.001 Mease 2017 12 PLB 5/67 (7.5) 1/67 (1.5) 1/67 (1.5) SPIRIT 1 12 IXE Q4W* 55/73 (75.3) 38/73 (52.0) 23/73 (31.5) (37) 12 ADA 23/68 (33.8) 15/68 (22.1) 10/68 (14.7) p-value ≤0.01 ≤0.01 ≤0.01 Reich 2017 12 PLB 9/154 (5.8) 4/154 (3.0) 2/154 (1.3) reSURFACE 1 (39) 12 TIL 100 mg 197/309 (63.8) 107/309 (35.0) 43/309 (13.9) p-value <0.0001 <0.0001 <0.0001 Reich 2017 12 PLB 9/156 (5.8) 2/156 (1.3) 0/156 (0.0) reSURFACE 2 (39) 12 TIL 100 mg* 188/307 (61.2) 119/307 (38.8) 38/307 (12.4) 12 ETA 151/313 (48.2) 67/313 (21.4) 15/313 (4.8) p-value 0.0001 0.0001 0.0001 Reich 2017 12 IXE 120/136 (88.2) 99/136 (72.8) 49/136 (36.0) IXORA-S (40) 12 UST 114/166 (68.7) 70/166 (42, 2) 24/166 (14.5) p-value 0.001 0.001 0.001 Bagel 2018 16 SEC 504/550 (91.7) 421/550 (76.6) 249/550 (45.3) CLARITY (41) 16 UST 440/552 (79.8) 299/552 (54.1) 147/552 (26.7) p-value <0.0001 <0.0001 <0.0001 Gordon 2018 12 PLB 10/102 (9.8) 2/102 (2.0) 0/102 (0.0) (Continued) Frontiers in Medicine | www.frontiersin.org 16 January 2021 | Volume 7 | Article 618163 Torres et al. Biologic Therapy for Psoriatic Disease TABLE 7 | Continued Improvement PASI75 PASI90 PASI100 Study Weeks Drug n/total (%) n/total (%) n/total (%) UltiMMa 1 (43) 12 UST* 70/100 (70) 42/100 (42.0) 12/100 (12.0) 12 RIS* 264/304 (86.8) 229/304 (75.3) 109/304 (35.9) p-value <0.0001 <0.0001 <0.0001 Gordon 2018 12 PLB 8/98 (8.1) 2/98 (2.0) 2/98 (2.0) UltiMMa 2 (43) 12 UST 69/99 (69.7) 47/99 (47.5) 24/99 (24.2) 12 RIS 261/294 (88.8) 220/294 (74.9) 149/294 (50.7) p-value <0.0001 <0.0001 <0.0001 Gottlieb 2018 16 PLB 3/51 (6.5) 0/51 (0.0) 0/51 (0.0) CIMPASI 1 (44) 16 CZP 200 mg 63/95 (66.3) 34/95 (35.8) 13/95 (13.7) p-value <0.0001 <0.0001 <0.0001 Gottlieb 2018 16 PLB 6/49 (11.6) 2/49 (2.2) 1/49 (1.8) CIMPASI 2 (44) 16 CZP 200 mg 74/92 (81.4) 48/91 (52.6) 14/91 (15.4) p-value <0.0001 <0.0001 <0.0001 Lebwohl 2018 16 PLB 3/57 (5.3) 5/57 (0.0) – CIMPACT (45) 16 CZP 200 mg 113/165 (68.5) 66/165 (40.0) – p-value <0.0001 <0.0001 Reich 2018 16 PLB 3/65 (4.6) 1/65 (1.5) 0/65 (0.0) TRANSFIGURE (46) 16 SEC 300 mg 56/66 (84.8) 48/66 (72.7) 22/66 (33.3) p-value <0.001 <0.001 Mease 2018 16 PLB 40/332 (12.3) 31/332 (9.3) – FUTURE 5 (47) 16 SEC 150 mg 132/220 (60.0) 81/220 (36.8) – 16 SEC 300 mg 155/222 (70.0) 119/222 (53.6) – p-value <0.05 <0.05 Reich 2019 16 RIS 150 mg 237/301 (91) 218/301 (72) 120/301 (40) IMMvent (52) 16 ADA 218/304 (72) 144/304 (47) 70/304 (23) p-value <0.0001 <0.0001 <0.0001 Reich 2019 12 GUS 477/534 (89) 369/534 (69) 311/534 (58) ECLIPSE (53) 12 SEC 471/514 (92) 391/514 (76) 249/514 (48) p-value NA NA NA Ohtsuki 2019 SustaIMM (48) 16 RIS 75 mg* 52/58 (89.8) – 13/58 (22.4) 16 RIS 150 mg* 52/55 (94.5) – 18/55 (32.7) 16 PLB 5/58 (8.6) – 0/0 p-value <0.001 <0.001 Mease 2020 16 ADA 195/238 (68.9) 158/283 (55.8) 132/283 (46.6) SPIRIT H2H (51) 16 IXE 227/283 (80.2) 203/283 (71.7) 170/283 (60.1) p-value p=0.002 <0.001 <0.001 McInnes 2020 52 SEC 170/215 (79) 140/215 (54) 99/215 (46) EXCEED (55) 52 ADA 123/202 (61) 87/202 (43) 61/202 (30) p-value 0.0002 <0.0001 0.0007 Ferris 2020 16 GUS 55/62 (88.7) 47/62 (75.8) 31/62 (50.0) ORION (56) 16 PLB 0/16 (0) 0/16 (0) 0/16 (0) p-value <0.001 <0.001 <0.001 Warren 2020 16 RIS 92/164 (56.1) 74/164 (45.1) 44/164 (26.9) IMMerge (57) 16 SEC 80/163 (49.1) 66/163 (40.5) 34/163 (20.9) PASI, Psoriasis Area Severity Index; ADA, adalimumab; ETN, etanercept; IFX, infliximab; GOL, golimumab; CZP, certolizumab; UST, ustekinumab; SEC, secukinumab; IXE, ixekizumab; GUS, guselkumab; BRD, brodalumab; RIS, risankizumab; TIL, tildrakizumab; BRK, briakinumab; MTX, methotrexate; PLB, placebo; *vs. placebo. Frontiers in Medicine | www.frontiersin.org 17 January 2021 | Volume 7 | Article 618163 Torres et al. Biologic Therapy for Psoriatic Disease FIGURE 4 | Network plot of PASI100 showing direct comparisons, at weeks 10–16. The width of the edge is proportional to the number of studies, and the node size is proportional to the sample size. recently published network meta-analysis (94–96). Although the number of RCTs reporting PASI100 response (Table 7) (15, 16,20,21,25,29,30,33,35–37,39–41,43,44,46,48,51– 53,56,57,59,70) as an outcome was superior to the ones reporting ACR70 response, the confidence in the NMA was not superior. Since 2015 some head-to-head trials were designed to evaluate the efficacy of specific drugs in the PASI response outcome (33,40,41,51–53,55,57), and significant differences were found (Table 7). A complete treatment of a patient with PsD should be ideally based on a single drug that is effective in all the manifestations. Currently, from the therapies included in the PASI100 NMAs, only ADA, CZP, IXE, SEC, and UST were approved for PSO and PsA. Thus, in integrative analysis of NMA results, and based only on comparisons of the drugs with placebo, those with the highest probability of reaching the proposed outcome for skin and joint domains are SEC and IXE. For SEC, OR (95% CrI) are 9.430 (5.455, 16.302) and 42.897 (26.848, 68.539) versus placebo for ACR70 and PASI100, respectively. For IXE, OR are 9.315 (4.206, 20.627) and 64.027 (39.805, 102.997) versus placebo for ACR70 and PASI100, respectively. Even though a few previous NMAs analyzed treatment options in PsD including ACR and PASI outcomes, most of them did not find significant differences in the efficacy and safety between the drugs, only detecting that treatments were more efficacious than placebo (97–101). As reported in Table 5, data regarding the enthesitis domain were not so consistent as skin and peripheral arthritis results (1,13,18,22,24,26,28,31,32,37,38,47,50,51,55,61,65,76). In addition to the outcome not being standardized, there were studies reporting more than one outcome without consistent results (50,51). There were drugs that even in comparison with the placebo did not show a consistent significant benefit (22, 28,31,38,76). Long-term evaluation of enthesitis showed that the benefit was maintained with IFX at week 54 (58). Although the benefit of UST was not consistent at weeks 24 and 52(28), at week 100 there was a 100% improvement of MASES from baseline (67) and the same was true for SEC results, which showed inconsistent data at week 24 (31,32), but at week 104 there was 100% resolution of enthesitis in 70% of the patients who had enthesitis at baseline (75). Enthesopathy affects 35– 50% of patients with PsA and should be managed carefully since it can affect the quality of life and work productivity even in the early stages of the disease (102). A recent study showed that enthesitis is the phenotypes of PsD that contribute most to Quality of Life Scores and that this domain should be evaluated, bilaterally, in all PsD patients, particularly in those referring joint pain (103). Nevertheless, the clinical evaluation of enthesitis is not standardized and lacks accuracy and the reliability is highly dependent on the observer (104). A recent study compared MASES, SPARCC, and LEI, the three enthesitis index, and showed that MASES had a better correlation with disease activity and functional measures (105). On the other hand, another study has reported a better performance in LEI and SPARCC indices, which showed a higher discriminatory ability and treatment responses suggested to be related to the fact that MASES evaluates fewer peripheral sites, which may be clinically relevant in the context of PsA, a predominantly peripheral disease (106). Similarly to enthesitis, the outcomes measured in the dactylitis domain were not standardized as is explicit in Table 6 (1,18, 24,26,28,31,32,37,38,47,51,55,61,76). Moreover, there were data with the same drug in different studies that were not consistent (31,32,37,38). Long-term data showed that the benefit with IFX was maintained at week 54 (58). For UST, the median percent improvement in the enthesitis score at week 100 was 100% (67) whereas for SEC treatment 90% of the patients presented complete dactylitis resolution at week 104 (75). A major limitation in dactylitis evaluation is that physical examination is the basis for the clinical assessment of dactylitis and imaging tools have been used only to complement the clinical examination. Nevertheless, the criteria for image resolution are not uniform and therefore data from different studies are not comparable (107,108). Like enthesitis, dactylitis also has a huge impact on the quality of life and in the structural impact of PsD, and data from enthesitis and dactylitis highlight the difficulty in treating these manifestations and the long period of treatment that is needed to achieve remission. Recently, a real-world PsA population multinational study has shown that enthesitis, dactylitis, inflammatory back pain, and sacroiliitis are significantly associated with the worsening of the patient’s quality of life and/or work productivity, through evaluation of an extensive patient-reported outcomes (PROs) list—namely EQ5D, HAQ-DI, Psoriatic Arthritis Impact of Disease (PsAID)12, and Work Productivity and Activity Impairment (WPAI) (109). Frontiers in Medicine | www.frontiersin.org 18 January 2021 | Volume 7 | Article 618163 Torres et al. Biologic Therapy for Psoriatic Disease TABLE 8 | NMA results from the network of biologic therapies in the outcome PASI100. ADA BRK BRD CZP ETN GUS IXE PLB RIS SEC TIL UST ADA 0.511 (0.247–1.057) 0.412 (0.279–0.610) 3.005 (0.531–16.998) 4.078 (2.825–5.887) 0.518 (0.363–0.738) 0.514 (0.393–0.671) 32.891 (20.602–52.505) 0.426 (0.320–0.567) 0.767 (0.556–1.058) 1.590 (0.830–3.047) 1.152 (0.831–1.597) BRK 1.956 (0.946–4.046) 0.807 (0.374–1.740) 5.877 (0.929–37.192) 7.977 (4.211–15.111) 1.013 (0.476–2.155) 1.005 (0.501–2.017) 64.335 (29.280–141.359) 0.833 (0.395–1.758) 1.500 (0.722–3.116) 3.110 (1.332–7.263) 2.253 (1.076–4.717) BRD 2.424 (1.640–3.548) 1.239 (0.575–2.673) 7.285 (1.276–41.571) 9.887 (6.322–15.462) 1.256 (0.847–1.862) 1.245 (0.837–1.854) 79.742 (48.415–131.341) 1.033 (0.718–1.486) 1.859 (1.329–2.601) 3.855 (1.925–7.718) 2.793 (2.230–3.498) CZP 0.333 (0.059–1.883) 0.170 (0.027–1.077) 0.137 (0.024–0.783) 1.357 (0.237–7.759) 0.172 (0.030–0.984) 0.171 (0.030–0.969) 10.946 (2.063–58.067) 0.142 (0.025–0.805) 0.255 (0.045–1.444) 0.529 (0.087–3.225) 0.383 (0.068–2.168) ETN 0.245 (0.170–0.354) 0.125 (0.066–0.237) 0.101 (0.065–0.158) 0.737 (0.129–4.212) 0.127 (0.083–0.193) 0.126 (0.094–0.169) 8.066 (4.866–13.368) 0.104 (0.070–0.157) 0.188 (0.129–0.274) 0.390 (0.222–0.686) 0.282 (0.191–0.418) GUS 1.931 (1.355–2.752) 0.987 (0.464–2.100) 0.796 (0.537–1.181) 5.801 (1.016–33.129) 7.873 (5.169–11.994) 0.992 (0.678–1.452) 63.510 (38.479–104.815) 0.823 (0.576–1.175) 1.481 (1.177–1.862) 3.070 (1.554–6.065) 2.224 (1.602–3.087) IXE 1.947 (1.490–2.544) 0.995 (0.496–1.998) 0.803 (0.539–1.195) 5.849 (1.032–33.159) 7.938 (5.908–10.667) 1.008 (0.689–1.476) 64.027 (39.805–102.997) 0.829 (0.589–1.168) 1.493 (1.063–2.095) 3.095 (1.664–5.758) 2.243 (1.605–3.134) PLB 0.030 (0.019–0.049) 0.016 (0.007–0.034) 0.013 (0.008–0.021) 0.091 (0.017–0.485) 0.124 (0.075–0.206) 0.016 (0.010–0.026) 0.016 (0.010–0.025) 0.013 (0.008–0.021) 0.023 (0.015–0.037) 0.048 (0.024–0.097) 0.035 (0.022–0.056) RIS 2.347 (1.763–3.125) 1.200 (0.569–2.531) 0.968 (0.673–1.393) 7.052 (1.242–40.037) 9.571 (6.376–14.368) 1.216 (0.851–1.736) 1.206 (0.856–1.698) 77.192 (47.727–124.861) 1.800 (1.330–2.436) 3.732 (1.908–7.299) 2.704 (2.022–3.616) SEC 1.304 (0.945–1.800) 0.667 (0.321–1.385) 0.538 (0.385–0.753) 3.919 (0.693–22.174) 5.319 (3.650–7.749) 0.675 (0.537–0.850) 0.670 (0.477–0.940) 42.897 (26.848–68.539) 0.556 (0.411–0.752) 2.074 (1.077–3.992) 1.502 (1.165–1.938) TIL 0.629 (0.328–1.205) 0.322 (0.138–0.751) 0.259 (0.130–0.519) 1.890 (0.310–11.518) 2.565 (1.458–4.511) 0.326 (0.165–0.643) 0.323 (0.174–0.601) 20.687 (10.326–41.438) 0.268 (0.137–0.524) 0.482 (0.251–0.928) 0.724 (0.374–1.405) UST 0.868 (0.626–1.203) 0.444 (0.212–0.929) 0.358 (0.286–0.448) 2.608 (0.461–14.746) 3.540 (2.390–5.242) 0.450 (0.324–0.624) 0.446 (0.319–0.623) 28.551 (17.930–45.468) 0.370 (0.277–0.495) 0.666 (0.516–0.858) 1.380 (0.712–2.676) OR and CrI are presented. Comparisons with high confidence rating based on CINeMA evaluation are identified in bold. OR higher than 1 favor the intervention specified in the row. NMA, network meta-analysis; PASI, Psoriasis Area Severity Index; CINeMA, Confidence in Network Meta-Analysis; OR, odds ratio; CrI, credible interval; ADA, adalimumab; ETN, etanercept; IFX, infliximab; GOL, golimumab; CZP, certolizumab; UST, ustekinumab; SEC, secukinumab; IXE, ixekizumab; GUS, guselkumab; BRD, brodalumab; RIS, risankizumab; TIL, tildrakizumab; BRK, briakinumab; MTX, methotrexate; PLB, placebo. Frontiers in Medicine | www.frontiersin.org 19 January 2021 | Volume 7 | Article 618163 Torres et al. Biologic Therapy for Psoriatic Disease TABLE 9 | Nail psoriasis assessment in patients with psoriasis. Study Author Year Intervention Outcome Time of outcome Result (12) Reich 2005 IFX vs. placebo Percentage of improvement NAPSI Week 10 26.0 (42.3) vs. −5.9 (54.3) (p<0.0001) Week 24 56.3 (43.3) vs. −3.2 (62.3) (p<0.0001) (18) Kavanaugh 2009 GOL 50 mg vs. placebo Percentage of change NAPSI Week 14 25% vs. 0% (p=0.015) GOL 100 mg vs. placebo 53% vs. 0% (p<0.001) GOL 50 mg vs. placebo Week 24 33% vs. 0% (p<0.001) GOL 100 mg vs. placebo 54% vs. 0% (p<0.001) GO-REVEAL (61) Kavanaugh 2012 GOL 50 mg vs. placebo NAPSI (percentage change from baseline) Week 52 51.6 ±46.8 vs. 56.2 ±48.1 GOL 100 mg vs. placebo 65.8 ±51.9 vs. 56.2 ±48.1 Ortonne 2013 ETN 50 mg BIW NAPSI Week 12 −13.6 (−16.7 to −10.5) ETN 50 mg QW −15.7 (−19,0 to −12.5) PHOENIX 1 (27) Rich 2014 UST 45 mg vs. placebo NAPSI baseline score Week 12 26.7% vs. 11.8% (p<0.001) UST 90 mg vs. placebo 24.9% vs. 11.8% (p<0.001) UST 45 mg vs. placebo Week 24 46.5% vs. 29.1% (65) Kavanaugh 2014 GOL 50 mg vs. placebo NAPSI Week 256 1.7 ±2.5 vs. 1.1 ±1.9 GOL 100 mg vs. placebo 1.1 ±1.8 vs. 1.1 ±1.9 BELIEVE (33) Thaci 2015 ADA NAPSI baseline reduction Week 8 15.1% Week 16 39.5% (26) Mease 2015 CZP 200 mg Q2W vs. placebo mNAPSI change from baseline Week24 – 1.6 VS. −1.1 (p=0.003) CZP 400 mg Q4W vs. placebo −2.0 vs. −1.1 (p<0.001) UNCOVER 3 (69) Dennehy 2016 IXE Q2W vs. placebo vs. ETN Improvement in nail psoriasis Week 12 38% vs. 28% vs. −4.7% IXE Q4W vs. placebo vs. ETN 40% vs. 48% vs. −4,7% SPIRIT-P1 (37) Mease 2017 IXE Q2W vs. placebo vs. ADA NAPSI Week 12 −7.7 (1.4) vs. −1.1 (1.4) vs. −6.8 (1.4) p<0.05* IXE Q4W vs. placebo vs. ADA −15.5 (1.5) vs. −2.4 (1.7) vs. −10.7 (1.5) p<0.05* IXE Q2W vs. placebo vs. ADA Week 24 −8.4 (1.5) vs. −1.1 (1.4) vs. −6.8 (1.4) p<0.05* IXE Q4W vs. placebo vs. ADA −14.0 (1.5) 2.4 (1.7) vs. −10.7 (1.5) p<0.05* SPIRIT-P2 (38) Nash 2017 IXE Q2W vs. placebo Proportion of patients who had a response Week 24 34.8% vs. 11.0% (p<0.0005) IXE Q4W vs. placebo 20% vs. 7.0% (p<0.0001) UNCOVER 3 (78) van der Kerkhof 2017 IXE Q2W vs. placebo NAPSI from baseline Week 12 35.2% vs. −34.3% p<0.001 IXE Q4W vs. placebo 36.7% vs. −34.3% p<0.001 IXE Q2W vs. ETN 35.2 (6.9) vs. 20.0 (5.9) p>0.005 IXE Q4W vs. ETN 36.7% vs. 20% p=0.048 IXE Q2W vs. placebo NAPSI =0 Week 12 17.5% vs. 4.3% p<0.001 IXE Q4W vs. placebo 19.7% vs. 4.3% p<0.001 IXE Q2W vs. ETN 17.5% vs. 10.2% p<0.05 IXE Q4W vs. ETN 19.7% vs. 10.2% p<0.05 (36) Blauvelt 2017 GUS vs. placebo vs. ADA NAPSI percent improvement Week 16 34.4 ±42.46 vs. −0.9 ±57.89 vs. 38.0 ±53.87 p<0.001** GUS vs. ADA Week 24 49.8 ±44.16 vs. 49.4 ±60.04 GUS vs. ADA Week 48 68.1 ±43.00 vs. 61.4 ±49.20 (Continued) Frontiers in Medicine | www.frontiersin.org 20 January 2021 | Volume 7 | Article 618163 Torres et al. Biologic Therapy for Psoriatic Disease TABLE 9 | Continued Study Author Year Intervention Outcome Time of outcome Result LIBERATE (77) Reich 2017 APR vs. placebo NAPSI (percentage of change) Week 16 −18.7 (40.2) vs. −17.0 (25.0) p=0.4959 ETN vs. placebo −35.9 (28.9) vs. −17.0 (25.0) p=0.0024 (42) Elewski 2018 ADA vs. placebo mNAPSI75 Week 26 46.6% vs. 3.4% (p<0.001) Improvement NAPSI Week 26 56.2% vs. 11.5% (p<0.01) UST 90 mg vs. placebo 48.7% vs. 29.1% (81) Ohtsuki 2018 GUS 50 mg vs. placebo Change in NAPSI Week 16 −1.2 (1.61) vs. −0.2 (1.13) p<0.001 GUS 100 mg vs. placebo −1.5 (1.78) vs. −0.2 (1.13) p<0.001 TRANSFIGURE (46) Reich 2018 SEC 150 mg vs. placebo NAPSI (percentage of change) Week 16 −37.9% vs. −10.8% (p<0.001) SEC 300 mg vs. placebo −45.3% vs. −10.8% (p<0.001) (88) Elewski 2019 ADA Percentage of achievement mNAPSI75 Week 16 27.3 Week 26 53.4 Week 52 65.0 SPIRIT H2H (51) Mease 2020 IXE vs. ADA Fingernails NAPSI =0 Week 24 58.1% vs. 71.7% (p<0.001) ADA, adalimumab; ETN, etanercept; IFX, infliximab; GOL, golimumab; CZP, certolizumab; UST, ustekinumab; SEC, secukinumab; IXE, ixekizumab; GUS, guselkumab; RIS, risankizumab; PLB, placebo; NAPSI, Nail Psoriasis Severity Index; mNAPSI, modified Nail Psoriasis Index. *IXE vs. placebo, **GUS vs. placebo. Inflammatory back pain and sacroiliitis are common axial manifestations in PsA patients and can arise in 30 to 70% of patients (110,111). There is an ongoing discussion on whether axial manifestations in PsA are equivalent to those seen in axial spondyloarthritis and consequently if they may be treated in the same way (112). In fact, the evidence of the efficacy of biologic therapies in the PsA axial domain is still scarce. However, some studies and case reports have suggested a positive impact of TNFi, IL-17i, and IL-12/23i in axial involvement-related outcomes in PsD patients, namely, BASDAI and ASAS-PR, showing that it could be possible to achieve remission and minimal disease activity (113– 115). To our knowledge, the only randomized clinical trial addressing treatment efficacy in this specific domain patient profile is the MAXIMIZE trial (ClinicalTrials.gov NCT02721966) (86)—a study evaluating SEC efficacy in axial manifestations improvement in PsA patients. In fact, from the data released in the latest international congresses, results suggest that IL17 inhibition, namely, with SEC, is effective in axial PsA treatment, evaluated by ASAS response and Berlin MRI score (116). Nail psoriasis is common among patients with moderateto-severe PsO and more prevalent in patients with PsA (117). Different studies assessed the efficacy of biologic agents in the treatment and resolution of nail psoriasis (Table 9) (12,18, 26,27,34,37,38,42,46,51,61,65,69,73,77,78,81,88). All of them showed the benefit of the tested drug compared to the placebo. The head-to-head comparison between IXE and ADA showed superiority at week 24 of IXE (51). The response is sustained in long-term studies (46,69,81). Of note, most studies reporting NAPSI represent subgroup analysis including recruited patients who had manifestations of nail psoriasis. However, from the data described there are only drugs with studies designed specifically to evaluate nail Psoriasis: ETN (89), ADA (42), and SEC (46). Importantly, these studies were specifically designed to evaluate nail outcomes and have demanding recruitment criteria, with NAPSI scores more severe and, therefore, much more difficult to treat. Therefore, the results obtained with these 3 drugs may be considered more robust and significant concerning their impact on nail treatment. Of note, all studies demonstrated an improvement in the evaluated scores. However, scores and time points were not the same, making comparisons impossible. Taking all the results from the systematic review and network meta-analysis together in Figure 2, IL-17i are the drugs tested in more manifestations, namely, SEC that had specific studies for all the domains, even though axial domain data were not yet published. This result is in line with what was recently published in two NMA (98,118). The first one concluded that SEC demonstrated good efficacy across the evaluated outcomes (ACR, PASI, and PsARC at 12–16 weeks) and all the treatments demonstrated superiority to placebo (98). The other study demonstrated that SEC may be the most efficacious and the safest biologic for short-term treatment of PsA (118). Limitations One of the main limitations of this study is the high variability of study designs, inclusion and exclusion criteria, and patients’ characteristics. It is important to Frontiers in Medicine | www.frontiersin.org 21 January 2021 | Volume 7 | Article 618163 Torres et al. Biologic Therapy for Psoriatic Disease note that for enthesitis, dactylitis, and nail psoriasis the evaluated outcomes are heterogeneous and do not allow the performance of a network meta-analysis. The results of the NMAs highlight the limitations of this method, and caution is needed in the interpretation of these results to avoid misleading inferences. CONCLUSIONS PsD is a very complex disease in which the same patient may present several manifestations with a great impact on functional and quality of life. Nowadays, we should be more demanding in the analysis of therapeutic outcomes, focusing on achieving remission in all PsD manifestations. Although there are several effective therapies, this study showed that the concept of a holistic and efficacious treatment for patients with PsD is achievable and that IL-17i are the drugs most extensively tested in this context. Specifically, SEC demonstrated good efficacy in all the evaluated GRAPPA domains, allowing a complete short-term treatment for patients with multiple manifestations of the disease. DATA AVAILABILITY STATEMENT The original contributions presented in the study are included in the article/supplementary materials, further inquiries can be directed to the corresponding author/s. AUTHOR CONTRIBUTIONS TT and AB conceptualized the study, designed PICO criteria, managed the literature search, and wrote the first draft of the manuscript. PF and JF interpreted the data and critically revised the manuscript. All the authors approved the final manuscript. FUNDING Support for this assistance was funded by Novartis Farma Portugal. ACKNOWLEDGMENTS Editorial assistance in the preparation of this article was provided by Irina Duarte Ph.D. of X2-Science Solutions. REFERENCES 1. Antoni C, Krueger GG, de Vlam K, Birbara C, Beutler A, Guzzo C, et al. Infliximab improves signs and symptoms of psoriatic arthritis: results of the IMPACT 2 trial. Ann Rheumat Dis. (2005) 64:1150–7. doi: 10.1136/ard.2004.032268 2. Coates LC, Kavanaugh A, Mease PJ, Soriano ER, Laura Acosta-Felquer M, Armstrong AW, et al. Group for research and assessment of psoriasis and psoriatic arthritis 2015. Treatment recommendations for psoriatic arthritis. Arthr Rheumatol. 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