Efficacy of Systemic Treatments of Nail Psoriasis: A Systemic Literature Review and Meta-Analysis

Importance: Nail involvement is a common condition in patients with psoriasis. The treatment of nail psoriasis is considered challenging and is often left untreated by physicians. Objective: To assess the efficacy of current systemic treatments on nail psoriasis. Data Sources: PubMed, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for relevant articles from inception to September 1, 2020. Included articles were restricted to English language and human studies. Study Selection: This was a systematic literature review with meta-analysis. Thirty-five random control trials that evaluated systemic therapies for nail psoriasis were selected in the systemic review. Among them, we retained 14 trials for meta-analysis. Data Extraction and Synthesis: This study was conducted in accordance with the preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. All steps were performed by two independent investigators, and any disagreements were resolved by a third investigator. Meta-analysis of aggregated study data was conducted to assess therapeutic efficacy. The use of random-effects model was based on high heterogeneity as a variable endpoint in different studies. Main Outcomes and Measures: Therapeutic effects on nail psoriasis were expressed in terms of effect sizes with 95% CIs. Results: We included 35 random control trials (RCTs) in this systemic review. At baseline, a high prevalence (62.1%) of nail psoriasis was confirmed. The meta-analysis included 14 trials highlighting that biologic and small-molecule therapies were effective in treating nail psoriasis with variable effect size magnitudes [−0.89 (−1.10, −0.68), I2 = 84%]. In particular, tofacitinib and ixekizumab showed the most significant scale of effect size magnitudes in treating nail psoriasis (−1.08 points and −0.93 points, respectively). We also found that a higher dose of tofacitinib and ixekizumab had similar effectiveness, and anti-IL-17 agents seem to be superior in effectiveness compared to anti-TNF-α therapies in the treatment of nail psoriasis. However, these results must be displayed carefully as variable endpoints in different studies. Conclusions and Relevance: This study provides a comprehensive overview of systemic treatments for nail psoriasis. For patients with psoriatic nail damage who are candidates of systemic therapies, the priority should be given to administering biologic and small-molecule therapies, especially anti-IL-17 drugs.

Importance: Nail involvement is a common condition in patients with psoriasis. The treatment of nail psoriasis is considered challenging and is often left untreated by physicians.
Objective: To assess the efficacy of current systemic treatments on nail psoriasis.
Data Sources: PubMed, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for relevant articles from inception to September 1, 2020. Included articles were restricted to English language and human studies.
Study Selection: This was a systematic literature review with meta-analysis. Thirty-five random control trials that evaluated systemic therapies for nail psoriasis were selected in the systemic review. Among them, we retained 14 trials for meta-analysis.
Data Extraction and Synthesis: This study was conducted in accordance with the preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. All steps were performed by two independent investigators, and any disagreements were resolved by a third investigator. Meta-analysis of aggregated study data was conducted to assess therapeutic efficacy. The use of random-effects model was based on high heterogeneity as a variable endpoint in different studies.
Main Outcomes and Measures: Therapeutic effects on nail psoriasis were expressed in terms of effect sizes with 95% CIs.
Results: We included 35 random control trials (RCTs) in this systemic review. At baseline, a high prevalence (62.1%) of nail psoriasis was confirmed. The meta-analysis included 14 trials highlighting that biologic and small-molecule therapies were effective in treating nail psoriasis with variable effect size magnitudes [−0.89 (−1.10, −0.68), I 2 = 84%]. In particular, tofacitinib and ixekizumab showed the most significant scale of effect size magnitudes in treating nail psoriasis (−1.08 points and −0.93 points, respectively). We also found that a higher dose of tofacitinib and ixekizumab had similar effectiveness, and anti-IL-17 agents seem to be superior in effectiveness compared to anti-TNF-α therapies in the treatment of nail psoriasis. However, these results must be displayed carefully as variable endpoints in different studies.

INTRODUCTION
Psoriasis is a chronic systemic inflammatory disease that frequently affects the nails. Approximately 40-50% of patients with psoriasis have concurrent nail involvement, with a lifetime incidence of 80-90% (1,2). Nail psoriasis is associated with pain, cosmetic problems, and impaired finger function, with remarkably negative effects on the patient's quality of life (3,4). Nail involvement in patients with psoriasis is considered a predictor for the development of psoriatic arthritis (5). Highresolution magnetic resonance imaging (MRI) showed that the integral supporting structure of the nail is formed by extensor tendon enthesis (6). Through this anatomical link between the nail and the joint, inflammatory responses at the affected joint in patients with psoriatic arthritis (PsA) often extend to the nail bed, suggesting that psoriatic nails can be considered as the tip of the iceberg of systemic inflammation (7). Based on this, nail psoriasis is often resistant to conventional treatments, such as topical and intralesional therapies, which are targeting at local inflammation response. Moreover, the structure of the nail presents therapeutic challenges, such as poor penetration of topical therapy across the nail plate and pain associated with intralesional therapies (8,9). Furthermore, it has been reported that nail psoriasis promptly recurs once patients halt local therapies (10)(11)(12).
Nail psoriasis has a wide spectrum of clinical manifestations, depending on the part of the affected structure, which can be divided into the nail matrix (pitting, leukonychia, red spots in the lunula, and nail plate crumbling) or nail bed (oil drop discoloration, onycholysis, nail bed hyperkeratosis, and splinter hemorrhage) (8). In addition to a clinical description of improvement or exacerbation of nail psoriasis features, there are severity scoring systems, including the Nail Psoriasis Severity Index (NAPSI), Nail Area Severity (NAS), and Psoriasis Nail Severity Score (PNSS).
In recent years, a significant alleviation of psoriatic nails has been reported with the widespread use of small-molecule therapies and biologic agents for cutaneous psoriasis (13). Therefore, this study aimed at providing a systematic review and meta-analysis on the effectiveness of systemic therapies that are currently available for patients with psoriatic nails.

MATERIALS AND METHODS
We conducted a systematic review and meta-analysis of random control trials for the evaluation of treatments for nail psoriasis. This study was conducted in accordance with the preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement (14). It is also registered in PROSPERO (https://www.crd.york.ac.uk/ prospero/; registration number CRD42020204238).

Literature Search
A computer-based literature search was performed to identify relevant articles published from inception to September 1, 2020, in PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL). The main search terms were "psoriasis" and "nail." Vocabulary and syntax were adapted for each database. The literature search was restricted to English language and human studies. In addition, the references of these articles were also screened for relevant articles, and clinical trials registered at ClinicalTrials.gov were searched for details of relevant trials.

Study Selection
The inclusion and exclusion criteria were determined before the search. The included studies fulfilled the following inclusion criteria: (1) study design was limited to RCT; (2) the study participants should be adults (age > 18 years) with a diagnosis of any type of psoriasis without any other nail disorder; (3) the evaluated interventions were restricted to traditional systemic immunomodulating agents, small-molecule therapies, and biologic agents; (4) severity scoring systems should be used to evaluate the involvement of nail psoriasis at baseline and at the end of study or the improvement of psoriatic nail during the treatment phase.

Data Abstraction and Quality Assessment
Two independent reviewers abstracted data using a predefined data extraction form. The following information was extracted from each study: author, year of publication, design of study, blind time period, patient type, details of the interventions, sample size, baseline nail psoriasis involvement, and the improvement at each visit till the end of study. We independently assessed the quality of each included study in accordance with the Cochrane handbook of systematic reviews of interventions 5.2, which covers the following: (1) random sequence generation (selection bias); (2) allocation concealment (selection bias); (3) blinding of participants and treatment providers (performance bias); (4) blinding of outcome assessors (detection bias), (5) incomplete outcome data (attrition bias), (6) selective reporting (reporting bias), and (7) other biases. Disagreements over any risk of bias in particular studies were resolved by a third reviewer.

Statistical Analysis
We performed statistical analyses using the Review Manager V5.3 (The Nordic Cochrane Center, The Cochrane Collaboration) and STATA V15.0 (StataCorp). The identified studies used severity scoring systems in the range 0-8 to 0-160; thus, scores will be scaled down to range 0-8 for meta-analysis for aggregation across the trials. We applied the mean difference (MD) with 95% CIs as the change in psoriatic nail involvement. The reduction in the scores over the observation period indicated an improvement in nail psoriasis. We used the random effect model to pool data to evaluate the overall effect. Heterogeneity was assessed using the I 2 statistic. The possibility of publication bias was assessed using a funnel plot and Egger test. Some trials included more than one intervention group, for which the control groups were equalized among the intervention groups.

Systematic Review
We identified 2,030 articles matching the search criteria after removing duplicate publications. We extracted 1,825 articles after reading the title or abstract. Furthermore, we retained 33 articles after a full-text review. The results of two different trials were presented in two articles (15,16). Thus, we included 35 trials in the systematic review. In addition, four trials (17-20) did not mention the portion of nail involvement or enrolled patients with nail psoriasis, the remaining 31 trials included 17,254 patients with psoriasis, and 10,720 (62.1%) had nail involvement. The flow diagram is shown in Figure 1, and Supplementary Figure 1 provides the quality assessment for the included trials.

PDE4 Inhibitor: Apremilast (3 Trials)
In a placebo-controlled study on 266 patients, Paul et al. (21) reported that apremilast resulted in a trend of greater percentage reduction in NAPSI score vs. placebo (29.0 vs. 7.1%, P = 0.052) at week 16. Papp et al. (22) compared apremilast with placebo in 558 patients with nail psoriasis. They demonstrated that apremilast significantly reduced the activity of nail psoriasis after a treatment period of 16 weeks, whereas placebo had no effect (P < 0.0001). However, Reich et al. (23) studied 142 patients to assess the efficacy of apremilast and etanercept. Compared with the placebo group (−10.1%), the etanercept group (−37.3%, P = 0.002) experienced a significant improvement in NAPSI score, whereas apremilast (−18.7%, P = 0.495) had no effect at week 16.

Adalimumab (2 Trials)
Elewski et al. (18) compared adalimumab with placebo in 217 patients, demonstrating that adalimumab induced greater improvement in the quality of life of patents with nail psoriasis. Significant improvement in the NAPSI score was as early as week 8 in 18.8% for the adalimumab group and 3.5% for the placebo group (P < 0.01). Leonardi et al. (28) compared adalimumab vs. placebo in 72 patients. The mean percentage improvement in NAPSI score was significantly greater for adalimumab than for placebo (50 vs. 8%, P = 0.02) at week 16.

Infliximab (2 Trials)
In a study by Reich et al. (29) with 378 patients, 80.7% of patients had a psoriatic nail with a mean NAPSI score of 4.53 at baseline. The mean change in the NAPSI score was 26.0% at week 10 and 56.3% at week 24 in the infliximab group compared with −5.6 and −3.2% in the placebo group (p < 0.0001), respectively. In another study (30) of 43 patients, infliximab-treated patients achieved a higher reduction in NAPSI score (0-8) compared with placebo-treated patients (1.4 vs. −0.3), as early as week 10.

Brodalumab (1 Trial)
Elewski et al. (34) pooled two trials to evaluate the efficacy of brodalumab compared with that of ustekinumab in 593 patients with nail psoriasis. Among these, 283 had nail involvement. At week 52, 63.8% of patients achieved NAPSI = 0 for the brodalumab group vs. 39.1% for the ustekinumab group (P < 0.05).

Anti-IL-23 Agent Ustekinumab (2 Trials)
Rich et al. (35) compared ustekinumab vs. placebo during 12 weeks of treatment in 766 patients. Treatment with ustekinumab 45 or 90 mg resulted in significantly better percentage improvement in NAPSI score than the placebo group (P < 0.001 and P = 0.001, respectively). However, Igarashi et al. (36) reported that there was no significant NAPSI improvement in ustekinumab 45 and 90 mg groups vs. placebo at week 12.

Guselkumab (2 Trials)
Ohtsuki et al. (37) compared guselkumab with placebo in 192 patients. Among patients with nail psoriasis (n = 126), a significant decrease in mNAPSI score (0-8) of −1.2 and −1.5 was observed for the guselkumab 50 and 100 mg groups, compared with −0.2 for the placebo group, at week 16. Foley et al. (38) pooled two studies comparing guselkumab and adalimumab to placebo in 928 patients with fingernail psoriasis. The mean improvements in target NAPSI score were significantly greater for the treatment group (37.5 and 41.70%, respectively) than for the placebo group (0.7%; P < 0.001) at week 16.

Secukinumab (3 Trials)
Reich et al. (17) compared secukinumab vs. placebo in 198 patients during week 16. Treatment with secukinumab resulted in significant improvements in nail psoriasis compared with placebo (P < 0.001); NAPSI improvements were −45.3, −37.9, and −10.8% for secukinumab 300 and 150 mg and placebo, respectively. Further alleviation of psoriatic nails was shown by week 32: NAPSI change from baseline was −63.2% for secukinumab 300 mg and −52.6% for secukinumab 150 mg. Two placebo-controlled studies (39,40) evaluated the effectiveness of secukinumab in nail psoriasis. The mean changes in NAPSI were significantly greater for secukinumab than for the placebo group (P < 0.0001).

Ixekizumab (7 Trials)
In a placebo-controlled study with 58 patients, Leonardi et al. (41) highlighted that 75 mg/150 mg q4w ixekizumab markedly alleviated the clinical symptoms of nail psoriasis compared with the placebo group as early as week 2. The SPIRIT-P1 study (42)

Meta-Analysis
Among the trials selected for the systematic review, we included 14 trials that provided the outcome measurement of the alleviation of nail psoriasis between baseline and the end of the study. The characteristics of the selected trials are summarized in Table 1.
We also conducted other comparisons (Figure 3). Based on available data, we conducted effectiveness comparisons between interventions. Interestingly, a higher dose of tofacitinib did not have a better effectiveness in nail psoriasis at week 16 ( Figure 3A). Moreover, Ixekizumab 80 mg/Q2W had a similar outcome in nail psoriasis compared with ixekizumab 80 mg/Q4W at week 12 ( Figure 3B). We also found that at week 12, anti-IL-17 therapies were superior to anti-TNF therapies in treating nail psoriasis ( Figure 3C).

Risk of Bias and Publication Bias Assessment
The included studies were all screened to have a low and unclear risk of bias (Supplementary Figure 3), except in one study (35) where six patients (four in the intervention group and two in the placebo group) dropped out, and the missing data were not imputed. No significant publication bias was detected by using a funnel plot (Supplementary Figure 4) and Egger test (bias,

DISCUSSION
This systemic review provides an up-to-date synthesis of published evidence regarding the efficacy of systemic treatments on nail psoriasis and represents a meta-analysis on the efficacy of small-molecule therapies and biologic agents in treating psoriatic nails. In this review, 62.1% of patients with psoriasis had nail involvement, which is consistent with a previous study (1). Nail psoriasis is considered an indicator of systemic immune Frontiers in Medicine | www.frontiersin.org response (5). One included trial (43) showed that nail psoriasis is associated with a greater PASI, longer course of plaque psoriasis, and a higher proportion of PsA (data not provided). Interestingly, two trials (16,35) pointed out that the effectiveness of interventions on nail psoriasis is regardless of the presence or absence of PsA. Although PASI scores were not firmly associated with NAPSI scores at baseline, several trials (35,43,44,48) showed that there is a connection between NAPSI and PASI effects during the treatment phase. In general, nail responses were considerably lagged behind cutaneous responses. It's interesting to find out that greater cutaneous responses indicated better nail responses, as the Spearman's correlation between improvements in NAPSI and PASI scores showed a moderate but significant increased over time (35,48). Ninety-two percent of the studies included in the systematic review were published after 2010, and majority of trials evaluated small-molecule therapies and biologic agents in psoriasis treatment. They highlighted that available and effective remedies for nail psoriasis have been multiplied in the past decade. However, we noticed that three studies had contradictory outcomes of apremilast in nail psoriasis. Furthermore, one other study (36) unexpectedly reported that ustekinumab failed to provide a significant improvement in NAPSI compared with placebo. Ustekinumab is usually injected subcutaneously at week 0, 4, and then every 12 weeks. It seems unfair for the evaluation of ustekinumab on nail psoriasis that patients received only two doses at week 12 of evaluation.
Relatively few studies were retained in this systematic review evaluating conventional therapies for nail psoriasis and this review also showed their unsatisfied efficacy. This phenomenon was unexpected because acitretin, methotrexate, and cyclosporine play a historical role in systemic psoriasis treatments. However, the available evidence of their efficacy in clinical trials is inadequate, as most studies were either case reports, retrospective or unblinded in design. Anyway, it should be noted that conventional therapies may take a significantly longer time to show improvements in nail psoriasis, which will not be observed by short-term RCTs.
Our meta-analysis emphasized that all evaluated interventions have an eminent beneficial effect in the treatment of nail psoriasis.
Tofacitinib showed the most significant scale of effect size in alleviating nail psoriasis (−1.08 points) at week 16. We noticed that the onset of alleviation in nail psoriasis was as early as week 8 in the tofacitinib group (16,24). The improvement continued throughout the 16 weeks treatment phase. The efficacy of tofacitinib in patients with chronic plaque psoriasis has been previously demonstrated (49). However, one study (50) reported that the tofacitinib 5 and 10 mg/BID groups failed to achieve a significant change in NAPSI compared to the placebo group at month 3 (data not provided). The other therapies also showed significant results: anti-IL-17 (ixekizumab, −0.93 points), anti-TNF (etanercept, adalimumab, infliximab, and golimumab, −0.62 points), and anti-IL-23 (ustekinumab and guselkumab, −0.88 points). The different end timepoints may account for the high heterogeneity between the studies; three studies on week 12 and two studies on week 14 for anti-TNF subgroup analysis (I 2 = 59%) and one on week 12 and one on week 16 for anti-IL-23 subgroup-analysis (I 2 = 75%). We also found that for nail psoriasis, a higher dose of therapies was not the herald of better effectiveness, which is consistent with dose-independent improvement in cutaneous psoriasis, as these therapies may have exceeded the most effective dose (51). Moreover, our meta-analysis showed that anti-IL-17 agents seem to be superior to anti-TNF-α therapies in the treatment of nail psoriasis, consistent with their corresponding effectiveness in cutaneous psoriasis (52).
For patients with psoriatic nails, it was recommended to start with topical anti-psoriatic treatment for at least 4-6 months (13). Conventional systemic therapies were indicated for secondline treatment options for more severe nail psoriasis (13). However, it was also reviewed that these included therapies for cutaneous psoriasis could alleviate coexisting nail disease without noteworthy adverse effects (8). Therefore, the priority of these therapies should be increased for patients with nail psoriasis.
The most important limitation of this meta-analysis is that we could not include all the clinical trials selected in the systematic review because not all of them provided computable changes in the NAPSI score from baseline to the end of the study. Moreover, as variable endpoints (from week 12 to 16), phases (phase II, III) in different studies, and statistical errors due to a relatively small number of patients enrolled in some trials, these results must be displayed meticulously. Also, regarding the slow rate of nail growth to replace the deformed part of the nail plate, the efficacy endpoint for nail evaluation should be optimized in future trials.
Another limitation is that in our systematic review, nearly all of the studies evaluated the effectiveness of interventions on fingernails. One trial (17) showed that the decrease in the toenail NAPSI score is much slower than the fingernail NAPSI score. It is not out of the blue that the average growth rate of the toenails is slower than that of the fingernails, estimated at 1.62 vs. 3.47 mm/month (53). As a result, toenail psoriasis should take a much longer treatment course to achieve the desired outcome.

CONCLUSION
In this study, we highlighted that the available biologic therapies and small molecule agents for psoriasis are efficient for nail psoriasis. As nail damage affects more than half of patients with psoriasis, systemic treatment of psoriatic nails should be systematically evaluated in future RCTs as the primary or secondary outcome.

DATA AVAILABILITY STATEMENT
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

AUTHOR CONTRIBUTIONS
XZ and YH: conceptualization. BX: writing. YH: supervision. XZ: software and methodology, data curation. XZ and BX: investigation and formal analysis. All authors contributed to the article and approved the submitted version.