Efficacy of Ustekinumab in Refractory Palmoplantar Pustular Psoriasis

C. Morales-Múnera; E. Vilarrasa, L. Puig

Disclosures

The British Journal of Dermatology. 2013;168(4):820-824. 

In This Article

Discussion

The distinction between PPP and PPPP is still up for debate. Genetic studies suggest that PPP does not share an association with the PSOR1 gene locus, and they provide support for considering these diseases as genetically distinct entities.[14] On the other hand, there is some evidence supporting overlap between PPP and plaque psoriasis, on the basis of similar clinical findings and common genetic variations.[7,15] We have adopted stringent criteria in our series, by not including cases of patients with PPP without lesions of plaque psoriasis, or with nonpustular (hyperkeratotic) palmoplantar psoriasis, in order to avoid confusion in the interpretation of the results.

PPPP is an infrequent manifestation of the psoriasis spectrum, characterized by greater affectation of patients' quality of life, higher incidence of disease-related pain, and functional limitation,[16] for which no consistently successful therapeutic options have yet been reported.

The efficacy of biological agents in psoriasis vulgaris has been widely demonstrated in several clinical trials, but this is not the case for other forms of psoriasis, such as scalp psoriasis, nail psoriasis, nonpustular palmoplantar psoriasis and PPPP. Available data are limited in these variants of psoriasis because they are usually excluded from clinical trials.

In the case of PPPP, only isolated case reports and small case series are available. Successful treatment with efalizumab has been reported, but early recurrences, even in the course of treatment, have also been noted.[10] Reports on patients treated with anti-TNF-α agents have shown variable results, from worsening to complete resolution of PPPP.[11,12]

Regarding ustekinumab, there are several publications on the treatment of nonpustular palmoplantar psoriasis, PPPP and PPP, with contradictory results.[4,7–9,17–19]

de Unamuno-Bustos et al.[8] reported that a patient with severe PPP, which had previously failed to respond to topical corticoids, acitretin, ciclosporin, etanercept and adalimumab, was completely cleared after two injections of ustekinumab 45 mg every 12 weeks, with a follow-up of 8 months.

Gerdes et al.[9] reported a small series of four patients with recalcitrant PPP who were treated with ustekinumab, suggesting that this biological agent may provide a slow, but good, therapeutic response in some patients. They reported complete resolution of PPP lesions in one patient treated with ustekinumab 45 mg, partial response in another patient treated with ustekinumab 45 mg, and unsatisfactory results in the other two patients, one of whom was treated with 45 mg and the other with 90 mg.

Aggravation of inflammatory changes, fissuration and palmoplantar hyperkeratosis have been reported following 6 weeks of ustekinumab treatment in a 35-year-old woman with ankylosing spondylitis, who had previously developed an erythematous pustular eruption on her palms and soles during infliximab treatment.[17]

In an investigator-initiated, open-label clinical trial, ustekinumab was administered to 20 patients with moderate-to-severe refractory psoriasis of the palms and soles (with pustules at baseline in 50% of them), who had previously failed to improve with the use of topical corticosteroids.[7] Twelve patients had an improvement of at least 2 points in the Palm-Sole PGA, but only seven of them achieved a complete resolution. The authors did not provide data on a subanalysis of patients with PPPP, but stated that 90 mg seems to be the effective dose, allowing achievement of clinical clearance in six out of nine patients by week 16.[7]

Regarding hyperkeratotic nonpustular palmoplantar psoriasis, ustekinumab has been reported as very effective in a small series of two cases[18] and in a case report.[19]

We used ustekinumab at the dose recommended for moderate-to-severe chronic psoriasis vulgaris, as there are no standard dosages for PPPP. We observed favourable responses to ustekinumab soon after the start of treatment, and complete resolution of PPPP lesions was achieved in all patients as early as after the third injection (by week 20 of treatment). Furthermore, all patients exhibited remarkable improvements in their DLQI scores after the second injection. Likewise, we saw complete clearance of plaque psoriasis in four patients (patients 2, 3, 4 and 5) and almost complete clearance in one (patient 1). Remarkably, all of our patients are still on ustekinumab treatment, and no flares of psoriasis or side-effects have been observed in the course of follow-up, which has been longer than 19 months in two patients.

Thus, the results in our series are similar to those reported by de Unamuno-Bustos et al.,[8] whereas the only difference is that their patient had PPP (without psoriasis). Our results cannot be compared either with those of Gerdes et al.,[9] whose patients also had classical PPP, or those of Au et al.,[7] because their patient population included PPPP and nonpustular palmoplantar psoriasis, and two different doses of ustekinumab (45 mg and 90 mg) were used.

The evaluation of treatment results in PPPP is sometimes confusing. Classical scores such as PASI, BSA and PGA are not adequate to characterize the degree of palmoplantar involvement, so we decided to use PPP PASI[13] as a tool to measure the severity of PPP, in an attempt to homogenize the clinical inclusion criteria and provide a means to compare our results with those of future publications.

Ustekinumab is a fully human monoclonal antibody targeting the p40 subunit shared by interleukin (IL)-12 and IL-23, thereby preventing its interaction with their receptors, and blocking subsequent signalling, differentiation and cytokine production. IL-23 has a main role in the development of Th17 cells.[20] Th17 cells are known to produce IL-17A and IL-17F,[21] which have been linked to tissue neutrophil recruitment.[22] As there is growing appreciation of the role of IL-17 isoforms in the pathogenesis of pustular forms of psoriasis, including PPP,[23] anti-IL-17 (secukinumab, ixekizumab) or anti-IL-17r (brodalumab) biological agents might eventually prove to be other effective therapeutic options for this disease.

Our results provide additional data in support of the efficacy and safety of ustekinumab in the treatment of PPPP, but double-blind, randomized clinical trials comparing ustekinumab and other treatments are required to establish treatment algorithms in PPPP, as well as in other infrequent and refractory treatment manifestations (or perhaps genetically defined variants) of psoriasis.

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