The genetic background of palmoplantar pustulosis (PPP) is complex and differs from that of other types of psoriasis. |
Recent studies have focused on the role of the interleukin (IL)-17 pathway, the IL-36 pathway (with overexpression of IL-8), and the microbiome in the etiopathogenesis of PPP. |
Ongoing clinical trials in PPP are devoted to an IL-1 inhibitor (anakinra), an IL-8 receptor type B inhibitor (RIST4721/AZD4721), an IL-17 receptor A inhibitor (brodalumab), IL-36 inhibitors (ANB019 and BI 655,130 [spesolimab]), and an inhibitor of the granulocyte colony-stimulating factor receptor (CSL324). |
1 Introduction
2 Clinical Presentation
3 Triggering Factors
3.1 Smoking
3.2 Infections and Stress
3.3 Metal Allergy
3.4 Triggering Drugs
4 Concomitant Diseases
4.1 Thyroid Disease
4.2 Metabolic Syndrome
4.3 Atopy
4.4 Arthritis
4.5 Coeliac Disease
5 Quality of Life and Psychiatric Disorders
6 Genetic Studies
6.1 IL36RN Mutations
6.2 CARD14 and AP1S3 Mutations
6.3 PSORS1
6.4 Tumor Necrosis Factor (TNF)-238 and -308 Promoter Polymorphisms
7 Histology
8 Etiopathogenesis
8.1 Acrosyringia
8.2 Tonsillitis
8.3 Interleukin (IL)-17 Pathway
8.4 IL-36 Pathway
8.5 Lipocalin 2
8.6 Microbiome
9 Treatment
9.1 Topical Treatment
9.2 Phototherapy
9.3 Systemic Treatment
9.4 Targeted Therapies Approved for Psoriasis Vulgaris
Study | Study type | Subjects (N) | Treatment | Treatment duration | Outcome | Adverse events/comment |
---|---|---|---|---|---|---|
ADA (TNF inhibitor) | ||||||
Philipp et al. [107] | Retrospective study | 2 PPPP | Case 1: SC ADA 40 mg every 2 wk (without a loading dose) + MTX 5–15 mg every wk | Case 1: 36 mo | Case 1: After 6 mo symptom-free, good clinical appearance until year 3; PGA 1 to PGA 0 | Case 1: Recurrent oral candidiasis (improved after MTX dosage reduction) |
Case 2: SC ADA 40 mg every 10 days + ACI 25 mg/day | Case 2: concomitant ulcerative colitis. Good response. PGA 3 to PGA 1 | Case 2: Headache | ||||
ANA (IL-1 inhibitor) | ||||||
Tauber et al. [116] | Case report | 2 PPPP | SC ANA 100 mg daily | Case 1: 3 mo | Partial clinical outcome Case 1: PPPASI 28.5 at baseline and 20.7 at wk 6. Improvement noticed in 2nd wk after treatment onset. Relapse after 3 mo | |
Case 2: 2 mo | Case 2: PPPASI 19.2. Treatment was stopped in 2nd mo because of fever. One mo after interruption PPPASI was 13 | Case 2: Acute fever | ||||
APR (PDE4 inhibitor) | ||||||
Mikhailitchenko et al. [113] | Retrospective study | 8 | APR 30 mg BID. 2 pts + UST; 1 pt + MTX | 4–30 mo | Response in all 8 pts as either monotherapy or combination therapy (MTX or UST) | Minimal AEs reported in 3/8 (loose stool); 1 pt more severe AEs |
Alomran et al. [110] | Retrospective study | 4 PPPP | APR + IXE (in 1 pt + MTX) | 4–8 mo | Case 1: PPPGA 2 at baseline, PPPGA 3 on anti-IL-17A and PPPGA 1 on combination therapy Case 2: PPPGA 4 at baseline, PPPGA 3 on anti-IL-17A, PPPGA 1 on combination therapy Case 3: PPPGA 2 at baseline, PPPGA 3 on anti-IL-17A, PPPGA 0 on combination therapy Case 4: PPPGA 1 at baseline, PPPGA 0 on combination therapy | Case 1. Folliculitis, transient nausea and diarrhea |
Eto et al. [111] | Case report | 3 | PO | 8 mo | After 2 wk, all pts achieved near-complete symptom resolution. DLQI score showed significant improvement | One mild epigastric distress |
BRO (IL-17 receptor inhibitor) | ||||||
Pinter et al. [109] | Case series | 4 | BRO 210 mg at wk 0, 1; then every 2 wk | 4–44 wk | Three of four pts showed lack of efficacy; one had worsening of PPP. One experienced moderate improvement but AEs led to discontinuation Case 1: PPPASI 10.5 at the start and PPPASI 12.0 at end Case 2: PPPASI 5.9 at the start and PPPASI 8.6 at end Case 3: PPPASI not done Case 4: PPPASI 12.8 at start and 6.3 at end | Case 1: worsening of plaque psoriasis Case 4: Worsening of arthritis, bad taste |
ETA (TNF inhibitor) | ||||||
Bissonnette et al. [106] | Randomized, prospective study | 15 | ETA 50 mg SC twice wkly for 24 wk vs. PL for 12 wk, then 50 mg SC twice wkly for 12–24 wk | 24 wk | At wk 24: significant decrease in median PPPASI score for pts receiving ETA vs. PL (p = 0.038, n = 10) | Most common AEs: injection site reaction, headache, common cold |
GUS (IL-23 inhibitor) | ||||||
Terui et al. [104] | Randomized, double-blind, PL-controlled clinical trial | 41 of 49 | GUS 200 mg SC vs. PL at wk 0 and 4 | 24 wk | At wk 16, PPPASI scores reduced (− 5.65; 95% CI − 9.80 to − 1.50; p = 0.009). Wk 24 − PPPASI-50 responders (GUS, 16/25 [64%]; PL 8/24 [33%]) | 14 (29%) nasopharyngitis, 3 (6%) headache, 3 (6%) contact dermatitis, 3 (6%) injection site erythema |
Terui et al. [105] | Phase III, multicenter, randomized, double-blind, PL-controlled study | 159 | GUS 100 mg SC, 200 mg SC vs. PL at wk 0, 4, 12 and every 8 wk | 52 wk | At wk 16, (LSM change in PPPASI score from baseline was − 15.3 for GUS 100 mg vs. − 7.6 for PL; p < 0.001). PPPASI-75 response at wk 52 was reached in 55.6% of pts with GUS 100 mg and in 59.6% with GUS 200 mg | 68 (43.3%) nasopharyngitis, 6 (3.8%) headache, 45 (28.7%) infections require oral or parenteral antibiotics treatment, 27 (17.2%) injection site reaction |
HuMab 10F8 (IL-8 inhibitor) | ||||||
Skov et al. [114] | Open-label multicenter study with single-dose dose-escalation setup | 31 of 32 | IV HuMab 0.15, 0.5, 1, 2, 4, and 8 mg/kg at 0, 4, 5, 6, 7 wk | 8 wk | Reduction of 52.9% from baseline to wk 1 (p = 0.003); reduction of 55.9% from baseline to wk 8 (p = 0.0002) | Two serious AEs not related to HuMab 10F8; 25/31 pts (81%) had mild or moderate AEs (headache, fatigue, nasopharyngitis, nausea, hematuria) |
SEC (IL-17A inhibitor) | ||||||
Mrowietz et al. [108] | Multicenter, randomized, double-blind clinical trial; 2PRECISE | 237 PPP | SEC 300 mg (n = 79) vs. 150 mg (n = 80) vs. PL (n = 78) | 16 wk | At wk 16, PPPASI-75 response in 21/79 (26.6%) of pts with 300 mg vs. in 11/78 (14.1%) with PL (p = 0.0411) and in 14/80 (17.5%) with 150 mg (p = 0.5722). Primary endpoint of SEC superiority to PL at wk 16 not met | Nasopharyngitis and upper respiratory tract infections |
UST (IL-12 and IL-23 inhibitor) | ||||||
Bissonnette et al. [62] | Prospective randomized, PL-controlled study | 13 PPP; 20 PPPP | UST 45 mg SC (< 100 kg) at wk 0 and 4 and subsequently at approximately 12‐wk intervals | 16 wk | No statistically significant difference between UST and PL in PPPASI-50 at wk 16 in response for pts with PPPP (10%, 20%; p = 1.000) or PPP (20%, 37.5%; p = 1.000) | Cellulitis, pneumonia |
Au et al. [98] | Single-center, open-label clinical trial | 10 PPP, 10 hyperkeratotic PP | UST 45 mg SC (< 100 kg) or 90 mg SC (> 100 kg) wk 0, 4, 16 | 16 wk | At 16 wk: 7/20 (35%) achieved clinical clearance (palm-sole PGA of 0 or 1). But 6/9 (67%) subjects who received 90 mg vs. 1/11 (9%) who received 45 mg achieved clinical clearance (p = 0.02) | No serious AEs. 4/20 subjects (20%) developed an upper respiratory tract infection that resolved in < 2 wk. Two (10%) developed acne or acneiform eruptions and one acute bronchitis |
Bertelsen et al. [102] | Observational descriptive study | 5 PPP, 6 PPPP | UST 45 mg SC (< 100 kg) at wk 0 and 4 and subsequently at approximately 12‐wk intervals | > 3 years | Partial response (n = 6); complete resolution (n = 1); no response or aggravation of symptoms (n = 4) | Flu‐like symptoms, headache, fatigue |
Hegazy et al. [100] | Retrospective study | 9 | UST 45 mg SC (< 100 kg) or 90 mg (> 100 kg). An increased dose to 90 mg every 12 wk was required in three pts to maintain efficacy | 9 mo | Positive response initially in all pts about 4 wk after second dose. At wk 16, 5/9 pts experienced complete response; 4/9 experienced partial response (≥ 50% reduction in lesion counts) | One urinary tract infection |
Morales-Múnera et al. [99] | Retrospective study | 5 PPPP | UST 45 mg SC (< 100 kg) or 90 mg (> 100 kg) at 0, 4, then every 12 wk | 11–23 mo | Positive response seen in all pts 2–3 wk after first dose. Complete resolution of PPPP achieved at wk 20 | No AEs reported |
Buder et al. [101] | Case series | 9 PPPP | UST 45 mg SC (< 100 kg) or 90 mg SC (> 100 kg) at wk 0, 4, 12, 24 | 24–60 mo | Complete resolution (PPPASI 100; n = 2). 75% improvement of PPPASI (n = 4; 44.4%). Mean PPPASI improvement: 71.6% after 24 wk | No severe AEs; one local injection site reaction |
Gerdes et al. [103] | Case series | 4 PPPP | UST 45 mg SC (< 100 kg) or 90 mg SC (> 100 kg) | 12 wk | Good but slow efficacy in only 1/4 pts with PPP. Treatment satisfactory in 2/4 pts. One pt had good clinical response of plaque psoriasis, but PPP lesions only slowly improved | No AEs reported |
Drug name (conditions) | Study title | Design (no. of pts) | Dosage | Endpoints | Stage of clinical development (results) | Trial registration number |
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Anakinra (palmoplantar pustulosis) | APRICOT: Anakinra for pustular psoriasis [117] | Phase IV, two-stage, adaptive, double-blind, randomized, PL-controlled trial (n = 64) | SC 100 mg daily for 8 wk | Primary outcome measures: Fresh pustule count on palms and soles across 1, 4, and 8 wk or PPPASI across 1, 4, and 8 wk Secondary outcome measures: Fresh pustule count on palms and soles or PPPASI. Total pustule count on palms and soles across wk 1, 4, and 8 adjusted for baseline. PPIGA at wk 1, 4, and 8 adjusted for baseline. Time to response of PPP (75% reduction in fresh pustule count), time to relapse, time to achievement of “clear” on PPIGA by 8 wk, development of disease flare (> 50% deterioration in PPPASI), pustular psoriasis at nonacral sites (not hands and feet) as measured by percentage area of involvement at 8 wk, plaque-type psoriasis (if present) measured using PASI at 8 wk | Recruiting (no results posted) | ISRCTN13127147 |
Anakinra (Sneddon-Wilkinson; acrodermatitis continua of Hallopeau; pustular psoriasis; palmoplantar pustulosis) | Anakinra for Inflammatory Pustular Skin Diseases | Phase II study (n = 30) | SC 100 mg daily up to 200 mg at wk 4 | Primary outcome measures: ≥ 50% improvement in TBSAI at wk 12 | Recruiting (no results posted) | NCT01794117 |
ANB019 (palmoplantar pustulosis) | A Study to Evaluate the Efficacy and Safety of ANB019 in Subjects with Palmoplantar Pustulosis [118] | Phase II, randomized, PL-controlled, double-blind, multiple-dose study (n = 50) | SC every 4 wk | Primary outcome measures: Number of subjects with PPPASI 50 at wk 16. Number of participants with AEs at wk 24 Secondary outcome measures: Change from baseline in PPSI, PPIGA, DLQI at wk 16. Determination of pharmacokinetics of ANB019 in pts with palmoplantar pustulosis (serum concentration) at wk 24 | Recruiting (no results posted) | NCT03633396 |
BI 655130/spesolimab (palmoplantar pustulosis) | Initial Dosing of BI 655130 in Palmoplantar Pustulosis Patients [119] | Phase IIa, multicenter, double-blind, randomized, PL-controlled, study (n = 59) | IV low and high dose | Primary outcome measures: No. of subjects with PPPASI 50 at wk 16, no. of subjects with AEs Secondary outcome measures: No. of subjects with PPPASI-75 at wk 16, no. of subjects with PPP PGA 0 or 1 | Recruitment completed (no results posted) | NCT03135548 |
BI 655130/spesolimab (palmoplantar pustulosis) | A Study to Test How Effective and Safe Different Doses of BI 655130 Are in Patients with a Moderate to Severe Form of the Skin Disease Palmoplantar Pustulosis [120] | Phase IIb, multicenter, double-blind, randomized, PL-controlled, dose-finding study (n = 140) | SC different doses | Primary outcome measure: Percent change in PPPASI from baseline at wk 16 Secondary outcome measures: Change from baseline in PPP Pain VAS score at wk 4 and 16, PPPASI change from baseline, PPPASI-50, PPPASI-75, PPP PGA clear/almost clear, PPP PGA pustules clear/almost clear at wk 16. Percent change in PPPASI from baseline at wk 52 | Recruiting (no results posted) | NCT04015518 |
CSL324 (hidradenitis suppurativa; palmoplantar pustulosis) | Safety and Pharmacokinetics of Repeat Doses of CSL324 in Subjects with Hidradenitis Suppurativa and Palmoplantar Pustulosis | Phase I, multicenter, open-label, 2-regimen, repeat-dose study (n = 40) | IV | Primary outcome measure: Incidence of treatment-emergent adverse events and adverse events of special interest Secondary outcome measures: Maximum concentration of CSL324 in serum, half-life of CSL324 in serum for last dose administered, presence of anti-CSL324 antibodies in serum | Recruiting (no results posted) | NCT03972280 |
KHK4827/brodalumab (palmoplantar pustulosis) | A Study of KHK4827 in Subjects with Palmoplantar Pustulosis | Phase III, PL-controlled, double-blind comparative study (n = 120) | SC 210 mg every 2 wk | Primary outcome measure: Percent change in PPPASI from baseline at wk 16 Secondary outcome measures: Change from baseline in PPSI total score at wk 16, PPPASI change from baseline, PPPASI-50, PPPASI-75, PPP PGA clear/almost clear at wk 16, change from baseline in DLQI at 16 wk | Recruiting (no results posted) | NCT04061252 |
RIST4721/AZD4721 (palmoplantar pustulosis) | A Study to Evaluate RIST4721 in Palmoplantar Pustulosis | Phase IIa, randomized, PL-controlled, double-blind study (n = 35) | PO 300 mg once daily for 28 days | Primary outcome measures: Relative change in fresh and total pustule count Secondary outcome measures: Absolute change in total and fresh pustule count, portion of subjects achieving ≥ 50% reduction in fresh and total pustule count | Recruitment completed (no results posted) | NCT03988335 |