A Systematic Review With Network Meta-Analysis of the Available Biologic Therapies for Psoriatic Disease Domains

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. 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.

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       x ACR20, y ACR50, z ACR70, { PASI50, | PASI75, } PASI90,~PASI100, dactylitis assessment, enthesitis assessment, nail assessment. 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).

Dactylitis
As enthesitis, dactylitis is also evaluated through different approaches. It can be assessed by counting dactylitis digits-a simple counting and scoring method or Leeds Dactylitis Index (LDI) (85). Moreover, there is also no consensus regarding the better method to assess dactylitis, and therefore it was not possible to perform an NMA due to the heterogeneity found in the different RCTs (85). Also, some studies only evaluate the percentage of patients with complete resolution of dactylitis. A summary of the results of the different studies is included in
An NMA was performed for the three outcomes: PASI75, PASI90, and PASI100. The included studies are identified in Table 1. A network plot for PASI100 is included in Figure 4, as an example of the network plots of these three NMAs.

Nails
As described for enthesitis and dactylitis, the assessment of nail psoriasis is not consensual at this time, with Nail Psoriasis Severity Index (NAPSI) and modified NAPSI being the most commonly used indices. Due to the low number of studies evaluating nail psoriasis and inconsistent use of these indices, we were not able to perform an NMA (85). A summary of the results of the different studies is included in Table 9 (12, 18, 27, 32, 34, 36-38, 42, 46, 51, 61, 65, 69, 77, 78, 81, 88, 89).

DISCUSSION
The use of biologic therapies in the treatment of PsD is recommended across the six domains of the disease (2). A complete, effective, and safe treatment for all the manifestations of PsD is the main goal in the management of this condition. However, the heterogeneity of the manifestations challenges the achievement of this goal. OR and CrI are presented. Comparisons with high confidence rating based on CINeMA evaluation are identified in bold and OR higher than 1 favor the intervention specified in the row. NMA, network meta-analysis; CINeMA, Confidence in Network Meta-Analysis; OR, odds ratio; CrI, credible interval; ADA, adalimumab; IFX, infliximab; GOL, golimumab; CZP, certolizumab; UST, ustekinumab; SEC, secukinumab; IXE, ixekizumab; PLB, placebo.
Frontiers in Medicine | www.frontiersin.org Recent advances in the knowledge of the pathophysiology of the disease led to the extensive study and approval of different mechanisms of action, including TNFi such as IFX, ETN, GOL, CZP, and ADA; IL-17i such as SEC, IXE, and BRD; and IL-12 and/or IL23i such as UST, GUS, RIS, and TIL. Nevertheless, direct comparisons between them are scarce and therefore NMA is the preferred method to indirectly compare drugs, aiming to help clinicians in the choice of the best treatment.
The report of the outcomes of each GRAPPA domain is not standardized (Tables 5, 6, 9) except for the peripheral arthritis and skin domains, which use mainly ACR and PASI responses, respectively (Tables 3, 7). Thus, we were only able to perform NMAs based on ACR and PASI responses, evaluated at weeks 24 or 10-16, respectively. Although we also performed NMAs for ACR20, ACR50, PASI75, and PASI90, based on the current expectations on the efficacy of new biologic treatments and on the confidence in the results, we decided to present the efficacy of the different biologic therapy using ACR70 ( Table 4) and PASI100 (Table 8), the most challenging outcomes. The confidence rating on direct and indirect estimates was calculated using CINeMA to improve the transparency and limit the subjectivity of the process (90)(91)(92). Comparisons with a high confidence rating, based on the CINeMA evaluation (91), are represented in bold. The level of confidence of the other comparisons is either low or very low, and consequently, the surface under the cumulative rating (SUCRA) will result in misleading inferences (90,93). Thus, a SUCRA was not done and, therefore, it was impossible to rank the available biologic treatments. In the ACR70 NMA (Table 4), the results of the comparisons between drugs are not reliable, except when compared with the placebo. From the 12 RCTs reporting ACR70 responses at week 24 (Table 3) (1,11,18,24,26,28,31,32,37,38,49,51), only one performed head-to-head comparisons, at week 24, and there was no superiority regarding this specific endpoint (51). The other head-to-head study is EXCEED, with a primary endpoint at 52 weeks, showing also no superiority regarding ACR70. Nevertheless, and as expected, compared with the placebo, all drugs were significantly better in achieving ACR20/50/70.
In the PASI100 response NMA (Table 8), as for ACR70, the comparisons with high confidence levels were few and therefore it was not possible to rank the drugs regarding their probability to achieve differences in PASI100 between weeks 10 and 16. The comparisons with placebo were reliable, and the drugs that lead to a higher probability in achieving PASI100 were BRD, RIS, IXE, and GUS. Although based on CINeMA analysis we were not able to have high confidence in all of our comparisons, the results from placebo comparison were partially following    recently published network meta-analysis (94)(95)(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)(98)(99)(100)(101).
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 EQ-5D, HAQ-DI, Psoriatic Arthritis Impact of Disease (PsAID)12, and Work Productivity and Activity Impairment (WPAI) (109).    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)(114)(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 IL-17 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 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.