Introduction

Palmoplantar psoriasis (PP) is a chronic, debilitating disease of the palms and/or soles that affects 11–39% of psoriasis patients [1,2,3]. The morphology of PP can range from thick, hyperkeratotic plaques with fissuring to pustular lesions of the palms and/or soles, and PP is often classified into subtypes based on this morphologic distinction [4, 5]. Hyperkeratotic PP refers to sharply defined erythematous scaly plaques with overlying hyperkeratosis and without the presence of sterile pustules, predominantly at the palms and/or soles [6]. Pustular PP is a variant that includes macroscopic sterile pustules and erythema with intermixed yellow–brown macules localized to the palms and/or soles [6]. PP causes greater physical discomfort and functional disability than psoriasis limited to other body areas, and it is often recalcitrant to treatment [2].

Palmoplantar pustulosis (PPP) is a bilateral, symmetric dermatosis that also affects the hands and/or feet and is clinically distinguished from PP based on the absence of psoriasis at other body sites and a predilection for histologic involvement of the acrosyringium (the terminal duct of eccrine sweat glands) [6, 7]. Pustular PP and hyperkeratotic PP mostly occur concomitantly with psoriasis at other body areas, while PPP consists of pustular lesions typically limited to the palms and/or soles that appear on a clear, non-erythematous background [6,7,8]. However, whether PPP can be considered a clinical spectrum of plaque psoriasis or whether it is an independent disease is open to much debate. Consequently, in the literature, pustular PP and PPP are often not well distinguished. Some studies have identified the involvement of the acrosyringium as being more specific to PPP [7, 9]. Demographically, PPP is characterized by a female predominance and strong association with smoking, whereas no such associations exist for pustular PP [6, 7]. Interestingly, in individuals with PPP, nicotine is thought to be secreted into eccrine glands to promote inflammation and alter the local response to infection [7]. Recent genetic studies have challenged the relationship of PPP with plaque psoriasis, although both these conditions can respond to similar treatments and have a similar impact on quality of life.

Topical therapy and phototherapy are first-line modalities for the management of PP and PPP. However, the majority of patients eventually require treatment with systemic medications [3]. Traditionally, agents such as oral retinoids, methotrexate, and cyclosporin have been utilized, but these medications carry risks of adverse effects that may limit their use in clinical practice.

Biologic agents have been well studied for the treatment of moderate to severe chronic plaque psoriasis, but less is known about the efficacy of these medications for the treatment of PP and PPP. We have therefore performed a systematic review of the use of biologic agents for the treatment of hyperkeratotic PP, pustular PP, and PPP with the aim to provide clinicians with helpful information when considering management options for these disabling conditions.

Methods

The biomedical and healthcare journal databases of Ovid National Library of Medicine’s Medical Literature Analysis and Retrieval System (MEDLINE), Embase, and the Cochrane Library were searched to identify published articles that assessed the efficacy and safety of biologic agents for the treatment of hyperkeratotic PP, pustular PP, and PPP. The detailed search strategy is presented in Electronic Supplementary Material Fig. 2. Abstracts were screened, and articles that appeared to meet the inclusion criteria were assessed further. Reference lists of relevant articles were scrutinized to identify additional reports.

Eligibility Criteria

Publications were included if subjects were diagnosed with PP or PPP based on the assessment by the authors of each publication and if subjects received treatment with one of the currently approved biologics for psoriasis, namely, adalimumab, brodalumab, etanercept, guselkumab, infliximab, ixekizumab, secukinumab, or ustekinumab. Publications were required to report the efficacy and/or safety outcomes of the biologic treatment. Publications describing the treatment of cases of PPP induced by exposure to biologic medications were excluded due to the likely distinct pathophysiology of drug-induced PPP.

Study Selection and Data Extraction

Three reviewers (E.S., I.S., E.L.) independently conducted publication selection (Fig. 1). Any discrepancies were resolved by an additional reviewer (W.L.). Studies were categorized based on the morphology of palmoplantar lesions. Study characteristics (author, year of publication, design, number of patients, intervention, duration of treatment, outcome, and key safety indicators) and subject characteristics (age, sex, comorbidities, morphological variant, severity at baseline, involvement of sites other than the palms and soles, and prior treatments) were extracted using a standardized data abstraction form designed for this review. Efficacy outcomes were recorded in Table 1, defined as a 50% reduction in the PPP Area and Severity Index (PPASI-50) if available, otherwise a 75% reduction in PPASI (PPASI-75) or an Investigator Global Assessment (IGA) score of 0/1 (cleared/minimal disease) was used. If two biologics were studied in one study, both were described in Tables 1, 2, 3 and 4 under the category of the primary biologic that was studied, but the efficacy data of both biologics were used to calculate the summary of clinical improvement outcomes in Table 5. Due to the heterogeneity of outcome measures, outcomes were reported as described by the authors of each publication.

Fig. 1
figure 1

Process of study selection

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Compliance with Ethics Guidelines

This article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.

Results

The initial search yielded 731 articles. After excluding duplicates, we screened 579 reports by title and abstract, of which identified 76 articles for full-text review. Following the full-text review, we ultimately included 44 publications reporting the use of a biologic medication in the treatment of PP and PPP in the analysis, seven and two of which were randomized controlled trials (RCTs) and open-label trials, respectively (Table 1) [10,11,12,13,14,15,16,17,18,19,20,21,22]. The remaining publications were case reports or case series [20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53].

Table 1 Hyperkeratotic palmoplantar psoriasis, efficacy and safety of biologic agents
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A total of 722 cases of hyperkeratotic PP, 63 cases of pustular PP, and 58 cases of PPP were included in the analysis. Almost all patients in the included studies were adults. The specifics of age, gender, comorbidities, and previous therapies are shown in Tables 1, 2, 3 and 4. The previous use of systemic therapy was not consistently reported in all patients. Many patients received prior systemic therapy and some had received prior biologic therapy. Several subjects had responded to phototherapy, and nearly all had not responded to topical therapy.

Table 2 Pustular palmoplantar psoriasis, efficacy and safety of biologic agents
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Table 3 Palmoplantar pustulosis, efficacy and safety of biologic agents
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Table 4 Hyperkeratotic PP, pustular PP, and/or PPP, efficacy and safety of biologic agents
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Efficacy

The results of each publication are summarized in Tables 1, 2, 3 and 4. The characteristics describing each study are reported in Tables S1, S2, S3, and S4. The proportion of patients demonstrating clinical improvement is reported in Table 5.

Table 5 Clinical improvement of palmoplantar psoriasis or palmoplantar pustulosis following treatment with biologic agent
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Hyperkeratotic PP

In the RCT performed by Leonardi et al. [14], a greater number of patients with hyperkeratotic PP treated with adalimumab achieved a clinical score of clear or almost clear at 16 weeks compared to patients treated with placebo (30.6% vs. 4.3%; p = 0.01). Response was maintained at 28 weeks by 80% of these subjects. Of the patients in the RCT or case reports who were treated with adalimumab, 94.7% demonstrated an overall clinical improvement. In another RCT by Bissonnette et al. [13], a greater proportion of patients with hyperkeratotic PP treated with infliximab achieved at least a 50% reduction in clinical severity at 14 weeks compared to patients treated with placebo (66.7% vs. 8.3%; p = 0.01). These authors also reported that infliximab was superior to placebo in the reduction of mean area of involvement (50 decrease vs. 15% increase; p = 0.01). Overall, 75% of all patients studied using infliximab demonstrated clinical improvement. In their clinical trial, Blauvelt et al. [15] observed a significant clinical clearance among those patients treated with guselkumab when compared to those receiving placebo at 16 weeks (85.1% reaching an IGA score of 0 or 1; p < 0.001). Clinical improvement was observed in 90% of all patients studied receiving treatment with guselkumab. In three phase 3 trials conducted by Menter et al. [17], a greater proportion of the patients treated with ixekizumab showed clinical improvement compared to those treated with etanercept or those receiving placebo (PPASI-50: 80 vs. 67.8 vs. 32.9, respectively; p < 0.05). Overall, 82.5% of the patients studied who were using ixekizumab demonstrated clinical improvement. Significant clinical clearance was achieved in a RCT that compared secukinumab at a dose of 300 or 150 mg to placebo [palmoplantar psoriasis IGA (PPIGA) score of 0 or 1: 33.3% (300 mg dose), 22.1% (150 mg dose), vs. 1.5%; p < 0.001 and p = 0.002, respectively] [16]. The proportion of patients in all studies demonstrating clinical improvement after completing treatment with secukinumab was 89.1%. In an uncontrolled open label study of ustekinumab, 20% patients with hyperkeratotic PP achieved clinical clearance after 16 weeks of therapy [10]. Clinical clearance was achieved by 50% of patients receiving a 90 mg dosage regimen, while no patients receiving a 45 mg regimen achieved clearance.

A number of case series and case reports describe effective treatment of hyperkeratotic PP with etanercept, alefacept, infliximab, and ustekinumab (Tables 1, 4) [21, 25, 26, 33, 34, 41,42,43, 52].

Pustular PP

In a small RCT by Bissonnette et al. [11], ustekinumab 45 mg was not superior to placebo in achieving at least a 50% reduction in clinical severity among patients with pustular PP after 16 weeks of therapy (p = 1.00). In an open label study by Au et al. [10], half of the patients with pustular PP treated with ustekinumab achieved clinical clearance after 16 weeks of therapy. A greater proportion of patients receiving a 90 mg regimen of ustekinumab achieved clearance compared to those receiving a 45 mg regimen (80% vs. 20%). In another open label study, 54.5% of patients with pustular or hyperkeratotic PP who were treated with adalimumab reached clinical clearance after 12 weeks of therapy [19].

In addition, case series and case reports describe effective treatment of pustular PP with adalimumab, etanercept, infliximab, and ustekinumab [24, 26, 28, 30, 34, 35, 37, 39, 45, 51, 52, 54]. In contrast, other case reports show ineffective treatment with adalimumab or mixed responses to ustekinumab (Tables 2, 4) [27, 54].

Palmoplantar Pustulosis

In a RCT of patients with PPP conducted by Bissonnette et al. [12], treatment with etanercept was not found to be superior to placebo at the primary endpoint of 12 weeks of therapy (p = 0.426). Interestingly, smoking may have played a role in treatment efficacy, as the authors noted that three of three nonsmokers achieved clinical improvement with etanercept therapy while only three of seven active smokers demonstrated improvement. In a small RCT by Bissonnette et al. [11], ustekinumab 45 mg was not found to be superior to placebo at 16 weeks of therapy (p = 1.00).

Case reports and case series describe effective treatment of PPP with etanercept, infliximab, and ustekinumab [20, 29, 31, 32, 46,47,48,49,50, 53, 54]. Multiple reports of treatment with infliximab describe a period of initial improvement with eventual recurrence (Tables 3, 4) [36, 38, 40].

Safety

Serious adverse events (SAEs) were infrequently reported. The majority of cases occurred in patients treated with infliximab, and the SAEs included cellulitis, hepatitis, an urticarial infusion reaction, a serum sickness-like infusion reaction, and autoimmune hepatitis [13, 34, 36, 38]. One subject with a history of a positive tuberculin skin test developed reactivation tuberculosis while undergoing treatment with etanercept for pustular PP [30]. In the GESTURE RCT that used secukinumab as treatment for hyperkeratotic PP, 5.9% of patients developed SAEs while on a 150 mg therapeutic regimen and 2.9% of patients developed SAEs while on a 300 mg therapeutic regimen, compared to 2.9% that developed SAEs while using placebo. However, the authors of this study did not report the statistical significance of the SAEs. None of these SAEs were cardiac-related, and there were no opportunistic infections or fatalities [16].

Special Populations

Three patients with chronic hepatitis C virus (HCV) were treated with biologic medications for PP without hepatologic complications [30, 34, 45]. One patient with chronic HCV displayed an infusion-related urticarial reaction during infliximab treatment, leading to discontinuation of the medication [34]. One patient with comorbid untreated latent tuberculosis developed reactivation tuberculosis after 4 years of therapy with etancercept [34]. One pediatric patient was treated with etanercept with no reported SAEs [28].

Discussion

The advent of biologic medications has greatly enhanced the treatment of moderate to severe plaque psoriasis. Current evidence suggests that biologic agents may also be effective therapeutic options for the treatment of hyperkeratotic PP, with less evidence supporting their use in pustular PP and PPP.

For hyperkeratotic PP, results from RCTs (level 1 evidence) suggest that adalimumab, guselkumab, ixekizumab, infliximab, and secukinumab are effective treatment options. While ustekinumab has not been evaluated in a RCT of patients with hyperkeratotic PP, in an open label study (level 3 evidence), one-half of patients receiving a 90 mg regimen achieved clinical clearance.

For pustular PP, ustekinumab 45 mg did not appear to be more effective than placebo (level 1 evidence) in patients participating in a small RCT. However, the majority of patients (80%) with pustular PP receiving a 90 mg regimen of ustekinumab in an open label study did achieve clinical clearance [10]. With the exception of ustekinumab, limited information on pustular PP treatment can be found in the literature. We found only eight pustular PP patients treated with infliximab, three patients with etanercept, and one patient each treated with adalimumab and anakinra. We found no reports of pustular PP treatment with alefacept, guselkumab, ixekizumab, or secukinumab. Of note, in all of the pustular PP case reports, patients were treated with the standard dose of biologic for plaque psoriasis. The lack of response in many of these cases suggests the possibility that pustular PP may require higher doses of biologics than hyperkeratotic PP or body plaque psoriasis in order to achieve efficacy.

For the treatment of PPP, the results of two small RCTs suggest that treatment with etanercept and ustekinumab 45 mg may not be more effective than placebo (level 1 evidence). However, the study of ustekinumab included only five patients in the active treatment arm, and no patient received a 90 mg regimen of this biologic [11, 54]. Overall, infliximab appeared to have the greatest efficacy for PPP compared to other biologics, followed by ustekinumab. It is important to note that the quality of these conclusions is limited since most of the data were from case reports or case series.

Although case series and case reports offer less rigorous evidence for the efficacy of biologic agents in PP and PPP, they do illustrate a few notable trends. For example, ustekinumab has been shown to be effective in multiple cases of PP and PPP refractory to tumor necrosis factor-alpha (TNF-α) inhibitor therapy [10, 43, 45, 47, 48]. Additionally, infliximab appears to have a higher risk of SAEs compared to other biologics, and it may also demonstrate loss of efficacy over the course of treatment [13, 34, 36,37,38, 40]. In one RCT, patients treated with secukinumab 150 mg showed a greater percentage of SAEs than those receiving placebo (5.9% vs 2.9%, respectively), but there was no dose effect, with the secukinumab 300 mg group having a SAE rate of 2.9%, which was identical to that of the group receiving placebo [16]. These data indicate that secukinumab may not be truly associated with SAEs, since there is not an observable dose–response relationship or trend.

Importantly, while there have been reports of new-onset PPP or exacerbation of existing PPP during TNF-α inhibitor therapy [55,56,57,58], only one clearly reported case of exacerbation of PPP, in response to infliximab, was identified in our review of patients with baseline PP and PPP [37]. In one RCT, four patients (40.0%) with PPP treated with etanercept experienced increases in disease severity over the first 12 weeks of treatment, but it is not clear whether these were drug-induced exacerbations or simply reflective of a nonresponse to treatment and disease progression [12].

Notably, two recent studies based on subanalysis of Phase II data for secukinumab demonstrated high rates of response among patients with hyperkeratotic PP, with up to 71% of patients achieving clinically significant improvement [59, 60]. Further studies of novel biologic agents developed for the treatment of moderate to severe plaque psoriasis may yield new therapeutic options for PP and PPP.

The difference in response to biologics observed between PP and PPP may be explained by some notable differences in their genetic profiles. The psoriasis susceptibility gene locus (PSORS1) that is strongly linked to psoriasis is not found in patients with PPP. Additionally, both a missense mutation in the interleukin (IL)-36 receptor antagonist (IL36RN) and caspase recruitment domain family member 14 (CARD14) have been identified in patients with PPP, which could influence patient response to treatment with biologics [9, 61]. However, both PP and PPP involve IL-17 as a mediator of inflammation, in addition to interferon-gamma and TNF-α. The shared histologic features of the diseases, consisting of spongiform pustules and inflammatory infiltrates, may account for some of the overlap in treatment response and clinical appearance [7, 9]. There is a need for future studies to explore these genetic differences further.

Several limitations to our analysis make it difficult to assess the efficacy of biologic medications in PP and PPP. First, patients with PP and PPP are often excluded from clinical trials due to recruitment requirements that patients be diagnosed with stable plaque psoriasis with no pustular component and demonstrate involvement of at least 10% of the body surface area. Second, some of the RCTs using biologics for these skin diseases, especially for pustular PP, although completed, are not published yet and therefore could not be included in our review. Third, reporting bias in case reports and case series makes it difficult to determine the true rates of response to biologic agents. Fourth, differences in the use of metrics to quantify the severity of PP and PPP impose challenges when comparing rates of response across studies. In addition, only one small RCT was available for pustular PP and another for PPP, with the majority of RCTs specific to hyperkeratotic PP.

Currently, a number of different scales are used to assess the severity of PP and PPP, and in many case reports and case series no metrics are used at all. Future studies should attempt to standardize the heterogeneity of clinical metrics to allow for a more rigorous comparison of the efficacy of biologic medications in PP and PPP. In some RCTs, only mean changes in clinical scores are reported without information on patient-specific responses. In the most basic schema, the number of patients who achieve clearance and the number who demonstrate objective improvement should be reported. Further, studies should consistently report the presence or absence of psoriasis at other body areas and stratify results based on this information.

Nonetheless, patient reported outcomes and functional metrics, such as the survey developed by Farley et al., may be more important than visual metrics in evaluating response to treatment in PP and PPP [5]. Complete clearance may not be necessary if patients achieve sufficient improvement to perform activities of daily living and occupational tasks without pain or discomfort [2].

Conclusion

Overall, biologics are effective and well-tolerated for the treatment of hyperkeratotic PP, as demonstrated by the > 80% efficacy for adalimumab, guselkumab, ixekizumab, secukinumab, and ustekinumab. The strong support for effective hyperkeratotic PP treatment is derived from multiple large RCTs, and thus providers may consider tailoring their treatment to include biologics earlier when a patient presents with this recalcitrant chronic disease. Infliximab and ustekinumab showed moderate efficacy for pustular PP, but the data were limited to small trials or case reports. Less data are available for the treatment of PPP; however, to date infliximab is the most efficacious treatment. Future studies are needed to further assess the efficacy of biologic medications in the treatment of PP and PPP. In addition, future research should be performed to compare the efficacy and safety of biologics with traditional systemic therapy and phototherapy for these debilitating and therapeutically challenging conditions.