Interventions for chronic palmoplantar pustulosis
Palmoplantar pustulosis is a chronic inflammatory disease in which sterile, relapsing pustules appear on the palms and soles, possibly in conjunction with other symptoms. The previous Cochrane Review on this topic was published in 2006, before biological treatments were extensively used.
To assess the effects of interventions for chronic palmoplantar pustulosis to induce and maintain complete remission.
We searched the following databases up to March 2019: Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We also searched five trials registers and checked the reference lists of the included studies for further references to relevant randomised controlled trials (RCTs).
We considered RCTs including people with palmoplantar pustulosis or chronic palmoplantar pustular psoriasis assessing topical therapy, systemic therapy, combinations of topical or systemic therapies, or non‐pharmacological therapies compared with placebo, no intervention, or each other.
Data collection and analysis
We used standard methodological procedures expected by Cochrane. Our outcomes included 'Proportion of participants cleared or almost cleared', 'Proportion of participants with adverse effects serious or severe enough to cause withdrawal', 'Proportion of participants with at least 50% improvement in disease severity', and 'Proportion of participants with adverse effects'.
We included 37 studies (1663 participants; mean age 50 years (range 34 to 63); 24% males). These studies reported condition severity differently. Around half of the included trials stated the setting (hospitals, community clinics, or both). More than half of the studies were at high risk of bias in at least one domain.
Our included studies assessed mainly systemic treatments (retinoids, ciclosporin, biologics, etretinate + PUVA (combination of psoralens and long‐wave ultraviolet radiation) therapy combined, and antibiotics), but also topical treatments (dermocorticoids, vitamin D) and phototherapy (PUVA, ultraviolet A1 (UVA1)). Other interventions were assessed by single studies. The most common comparator was placebo.
All results presented in this abstract were assessed in the short term (mean treatment duration was 11 weeks (range 8 to 24 weeks)) and are based on participants with chronic palmoplantar pustulosis. All outcome time point measurements were taken from baseline and assessed at the end of treatment. Short‐term and long‐term outcomes were defined as measurement up to 24 weeks after randomisation and between 24 and 104 weeks after randomisation, respectively.
One trial (188 participants) assessed the topical vitamin D derivative maxacalcitol versus placebo and found that maxacalcitol may be more effective than placebo in achieving clearance (risk ratio (RR) 7.83, 95% confidence interval (CI) 1.85 to 33.12; low‐quality evidence), and the risk of adverse effects (such as mild local irritation, pruritus, and haematological or urinary test abnormalities) is probably similar in both groups (RR 0.87, 95% CI 0.64 to 1.19; moderate‐quality evidence). Severity was not reported.
Two trials (49 participants) assessed PUVA therapy versus placebo or no treatment, providing very low‐quality evidence. Adverse effects were reported with oral PUVA (including nausea, ankle swelling, and non‐purulent conjunctivitis) and with local PUVA (including blistering, erythema, and pruritus).
With regard to the systemic retinoid alitretinoin, one trial (33 participants; moderate‐quality evidence) showed that alitretinoin probably makes little or no difference in reducing severity when compared to placebo (RR 0.69, 95% CI 0.36 to 1.30). A similar number of adverse events were reported in both treatment groups, including headache, cheilitis, nausea, arthralgia, and nasopharyngitis (RR 0.84, 95% CI 0.61 to 1.17). Clearance was not reported.
There may be little or no difference between etanercept and placebo in achieving clearance (RR 1.64, 95% CI 0.08 to 34.28; 1 study; 15 participants; low‐quality evidence); however, the 95% CI was very wide, showing there may be a difference between groups. Severity was not measured.
More patients treated with placebo may achieve reduced severity than those treated with ustekinumab, but the wide 95% CI indicates there might be little or no difference between groups and there might be greater effect with ustekinumab (RR 0.48, 95% CI 0.11 to 2.13; 1 study; 33 participants; low‐quality evidence). Clearance was not reported.
It is uncertain whether guselkumab increases clearance when compared to placebo (2 studies; 154 participants) because the quality of evidence is very low, but guselkumab probably better reduces disease severity (RR 2.88, 95% CI 1.24 to 6.69; 1 study; 49 participants; moderate‐quality evidence).
Secukinumab is probably superior to placebo in reducing severity (RR 1.55, 95% CI 1.02 to 2.35; 1 study; 157 participants; moderate‐quality evidence), but our clearance outcome was not reported. None of these trials reported on occurrence of adverse effects.
Only two of the studies discussed above reported adverse effects serious or severe enough to cause withdrawal. Guselkumab may cause more serious adverse events when compared to placebo, but there is uncertainty due to the very wide 95% CI showing there may be little or no difference and showing more events with placebo (RR 2.88, 95% CI 0.32 to 25.80; 1 study; 49 participants; low‐quality evidence). Secukinumab probably causes more serious adverse events than placebo (RR 3.29, 95% CI 1.40 to 7.75; 1 study; 157 participants; moderate‐quality evidence).
Evidence is lacking for major chronic palmoplantar pustulosis treatments such as superpotent corticosteroids, phototherapy, acitretin, methotrexate, and ciclosporin. Risk of bias and imprecision limit our confidence.
Maxacalcitol may be more effective than placebo in achieving clearance in the short term (low‐quality evidence), and the risk of adverse effects is probably similar (moderate‐quality evidence). Oral alitretinoin is probably no more effective than placebo in reducing severity, with a similar risk of adverse effects (moderate‐quality evidence).
Regarding biological treatments, we are uncertain of the effect of etanercept on clearance and the effect of ustekinumab on severity (low‐quality evidence). Secukinumab and guselkumab are probably superior to placebo in reducing severity (moderate‐quality evidence). Adverse events not requiring withdrawal were not reported for these treatments.
Reporting of serious adverse effects was incomplete: compared to placebo, secukinumab probably caused more participant withdrawals (moderate‐quality evidence), but we are uncertain of the effect of guselkumab (low‐quality evidence).
Future trials should assess commonly used treatments using validated severity and quality of life scales.
Grace Obeid, Giao Do, Lisa Kirby, Carolyn Hughes, Emilie Sbidian, Laurence Le Cleach
Plain language summary
Treating long‐term palmoplantar pustulosis (pustules on the hands and feet)
We wanted to assess treatments for palmoplantar pustulosis (a persistent condition characterised by small, pus‐filled blisters on the hands and feet), when compared to an inactive substance (placebo), no intervention, or each other. We included 37 studies.
Palmoplantar pustulosis negatively affects a person's life; there is no cure or standard treatment. Over time, the skin becomes thicker and redder, and may develop cracks or flake off as scales.
Symptoms are treated with topical medicines (usually corticosteroids), systemic medicines (medicines injected or taken by mouth that work throughout the entire body; usually medicines based on vitamin A or D), or phototherapy (ultraviolet light treatment).
The studies involved 1663 adults (mostly women) 34 to 63 years of age (average age 50 years). In 19 studies, participants had had palmoplantar pustulosis from two to 16 years (average 6.4 years).
Participants had palmoplantar pustular psoriasis (6 studies), palmoplantar pustulosis (29 studies), or both (2 studies). Study authors reported condition severity differently.
The included studies assessed a variety of different treatments: mainly systemic treatments (including biologic medicines, vitamin A medicines, immunosuppressants, antibiotics, and light therapy combined with a vitamin A medicine), but also topical medicines (containing steroids or vitamin D) and light treatments. Single studies assessed other treatments.
Treatments were most commonly compared against placebo. Treatment length varied; for our key results, this ranged from 8 to 24 weeks (average 11 weeks). When reported, studies were conducted in hospitals, community clinics, or both.
Pharmaceutical companies funded 18 studies.
Low‐quality evidence suggests that maxacalcitol (a topical vitamin D derivative) may work better than placebo in achieving clearance; moderate‐quality evidence indicates that the number of side effects is probably similar in both groups (participants experienced itching, irritation, and blood or urine test abnormalities) (1 trial; 188 participants). Severity was not measured.
We found very low‐quality evidence for PUVA therapy (i.e. psoralen, a drug to sensitise the skin, and ultraviolet light A) versus placebo or no treatment (2 studies; 49 participants), so we are unable to draw conclusions. Side effects with PUVA included skin blisters, redness, itching, swelling, and feeling sick.
Oral alitretinoin probably makes little or no difference in reducing severity when compared to placebo (moderate‐quality evidence; 1 study; 33 participants). A similar result was found for side effects, with headache, sickness, joint pain, high cholesterol, and colds reported in both groups. Clearance was not reported.
Five studies assessed biological treatments (etanercept, ustekinumab, guselkumab, secukinumab), which use substances made from living organisms, or synthetic versions, to target the immune system.
Low‐quality evidence (1 study; 15 participants) suggests that etanercept may make little or no difference in clearance when compared to placebo, but we are very uncertain of this result. Side effects and severity were not measured.
We found low‐quality evidence suggesting that ustekinumab may be worse than placebo in reducing disease severity, but we are very uncertain of this result. Side effects and clearance were not reported (1 study; 33 participants).
Compared to placebo, guselkumab probably reduces severity (moderate‐quality evidence; 1 study; 49 participants), but its effects on clearance are uncertain (very low‐quality evidence; 2 studies; 154 participants). Side effects were not measured.
Moderate‐quality evidence shows that secukinumab was probably superior to placebo in reducing severity, but skin clearance and side effects were not reported (1 study; 157 participants).
Only two studies described above reported withdrawals from treatment due to serious side effects; these are probably more frequent with secukinumab than with placebo (157 participants), and may occur more often with guselkumab than with placebo (49 participants), but we are very uncertain of the guselkumab result.
For these key results, outcomes were assessed between 8 and 24 weeks, which we deemed short term.
This evidence is current to March 2019.
Quality of the evidence
The key comparisons reported clearance most often, but evidence quality was mainly very low. Only two key studies reported side effects causing withdrawal (low‐ and moderate‐quality evidence). The evidence underlying our severity and side effects outcomes was variable in quality (very low to moderate).
Small participant numbers, results with wide margins of error, and selective reporting have limited our confidence in the evidence.
Grace Obeid, Giao Do, Lisa Kirby, Carolyn Hughes, Emilie Sbidian, Laurence Le Cleach
Implications for practice
Evidence is lacking for major treatments used in chronic palmoplantar pustulosis including superpotent dermocorticoids such as clobetasol propionate and betamethasone dipropionate, phototherapy, acitretin, methotrexate, and ciclosporin.
We found low‐quality evidence suggesting that the topical vitamin D derivative maxacalcitol may be more effective in achieving clear or almost clear status than placebo, and the likelihood of adverse events (e.g. mild local irritation, pruritus) is probably similar between the two groups (moderate‐quality evidence). For this comparison, the outcome ‘Proportion of participants achieving a 50% reduction in disease severity’ was not reported.
We found moderate‐quality evidence indicating that oral alitretinoin probably is no more effective than placebo in achieving 50% reduction in disease severity, and there is probably no difference in adverse effects (e.g. headache, cheilitis, nausea) between groups. The outcome ‘Proportion of participants cleared or almost cleared’ was not reported.
Regarding biological treatments (etanercept (anti‐tumour necrosis factor (TNF), ustekinumab (anti‐interleukin (IL)‐17/IL‐23), guselkumab (anti‐IL‐23), and secukinumab), low‐quality evidence suggests that etanercept may be no more effective than placebo in achieving clear or almost clear status, but this suggestion is based on a study of only 15 participants. The outcome ‘Proportion of participants achieving a 50% reduction in disease severity’ was not reported. We are unsure of the effect of ustekinumab in achieving a 50% reduction in disease severity when compared to placebo due to the small number of participants in the evidence base (low‐quality evidence). The outcome ‘Proportion of participants cleared or almost cleared' was not reported.
We are not certain of the effect that guselkumab has on clearance as the evidence was of very low quality, but guselkumab probably increases the chance of achieving 50% reduction in disease severity when compared to placebo (moderate‐quality evidence). Moderate‐quality evidence indicates that secukinumab (anti‐IL‐17) is probably more effective than placebo in achieving 50% reduction in disease severity. The outcome ‘Proportion of participants cleared or almost cleared’ was not reported. None of these biologics resulted in adverse events not requiring withdrawal.
Only two studies (5.4%) reported adverse effects serious or severe enough to have caused withdrawal. Guselkumab may cause more serious adverse events compared to placebo, but there is uncertainty due to the small number of participants included (low‐quality evidence). Secukinumab probably causes more serious adverse events than placebo (moderate‐quality evidence).
Limited evaluation of "classical" topical or systemic treatments and assessment of safety and quality of life and lack of long‐term efficacy precluded conclusions about efficacy and tolerance of treatments used in palmoplantar pustulosis.
The two ongoing studies may alter the conclusions of this review.
Implications for research
Further studies are needed to assess efficacy and tolerance of interventions for chronic palmoplantar pustulosis.
Future randomised controlled trials should ensure that they follow CONSORT guidelines (Moher 2001). This includes ensuring that the trial protocol is made publicly available before the trial commences, and that the published report includes all pre‐planned outcomes. Trials should include a number of participants that allows sufficient power to detect a difference for the outcomes assessed. To reduce bias, trialists should ensure that participants, study personnel, and outcome assessors are blinded to treatment allocation.
Inclusion criteria should describe precise clinical diagnostic criteria and should state whether or not specific clinical manifestations of psoriasis are required.
Interventions preferred for future research include superpotent topical corticosteroids under occlusion; vitamin D derivatives; the association of topical corticosteroids and vitamin D derivatives; acitretin, methotrexate, ciclosporin, phototherapy, and biologics; and combined treatment such as acitretin + phototherapy should be explored. The first comparisons to be assessed should include superpotent topical corticosteroids under occlusion, acitretin, and methotrexate.
These treatments are currently used for this indication; therefore, use of placebo could be considered as unethical despite absence of a clear demonstration of efficacy.
A core outcome set is needed in chronic palmoplantar pustulosis, including a validated scale to assess severity, quality of life, work impairment, pain, and pruritus and ease of compliance to the intervention or treatment. We advise that this should be done in consultation with the Cochrane Skin Outcomes Set Initiative (CS‐COUSIN). Safety should be monitored and fully reported in all future trials.
Assessment should be conducted at short term for remission (within three months) and at long term (at least one year) to assess maintenance of remission.