Chapter 21. Pustular Eruptions of Palms and Soles

Pustular eruptions of the palms and soles include palmoplantar pustulosis (PPP), acrodermatitis continua (Hallopeau disease), and infantile acropustulosis. The entities present with chronic and persistent eruptions of sterile, purulent vesicles.

A drug-induced rash clinically resembling PPP has been described in patients treated with tumor necrosis factor-α (TNF-α)-antagonists.

PPP is a chronic pustular dermatosis localized on the palms and soles only. High resistance to treatment and a high recurrence rate are characteristic. Histologically, it is characterized by intraepidermal vesicles filled with neutrophils.

Although many textbooks describe PPP along with psoriasis, it has an entity of its own.

The involvement of palms and soles has a great impact on life quality and the ability to work.

Epidemiology and Genetics

PPP has a worldwide distribution. It is a rare condition, but the exact incidence is not known. Females show a higher prevalence than males, with a ratio of approximately 3:1. Onset of the disease occurs mostly between the ages of 20 and 60 years; rarely, the condition occurs after the sixth decade of life, and in 10% of the patients the onset is before the age of 20 years.

HLA typing of patients with PPP reveals no increased frequency of any of the known psoriasis-linked alloantigens.1 In a direct comparison among chronic-plaque psoriasis, guttate psoriasis, and PPP, the three major candidate genes within the PSORS1 region [(1) HLA-Cw*6, (2) HCR*WWCC, and (3) CDSN*5] showed a high association to guttate and chronic plaque psoriasis, not, however, to PPP.2 Investigation of the apolipoprotein E alleles e2, e3, and e4 in chronic plaque and guttate psoriasis as well as in PPP in acitretin responders and nonresponders showed that the frequency of the e4 allele was significantly higher in the psoriasis groups but not in PPP patients as compared to healthy controls.3 In chronic plaque psoriasis and psoriatic arthritis an association with TNF-α-238 and -308 promoter polymorphisms have been found; however, the association has not been found in PPP.4 Studies from Japan provide evidence for phenotypic and genetic heterogeneity of PPP according to its association/provocation with tonsillitis. In patients in whom PPP was not associated with tonsillitis, the phenotype frequency of the TNF-β2 allele of the TNF-β gene and of the allele B of the TNF-α gene was significantly higher as compared to controls.5

Genetic association studies in a Caucasian cohort revealed that genes encoding for cytokines of the IL-10 family, namely, IL-19, IL-20, and IL-24 show haplotypes conferring increased risk for PPP.6

These findings further substantiate the notion that PPP and psoriasis represent different entities.

Etiology and Pathogenesis

The cause of PPP is not known. An imbalance of the protease/antiprotease system in the skin consisting of decreased antileukoprotease (elafin/SKALP) activity in pustular psoriasis has been discussed as a possible mechanism of pustule formation.7 Exacerbation of PPP has been observed after patch testing with metals and was accompanied by elevated leukotriene B4 levels in plasma and pustules.8

In a long-term survey from Japan, the incidence of PPP was found to be positively correlated to heavy smoking (more than 20 cigarettes per day), tonsillitis, and seasonal factors such as high humidity and high temperature.9,10

The most striking association in PPP is smoking. In two Swedish surveys, 95% of PPP patients were smokers at onset of disease and cessation of smoking was the most important measure to treat the disease.11,12 There is evidence from immunohistochemical studies that nicotinic acetylcholine receptors are modulated in lesional skin from smoking PPP patients when compared to disease-free smokers and healthy controls suggesting an abnormal response to nicotine in PPP.13 The possible involvement of neutrophils infiltrating sweat glands and ducts expressing choline acetyltransferase and the α-3 and α-7 nicotinic acetylcholine receptors as a target for nicotine/smoking was discussed as an important mechanism for manifestation and/or maintenance of PPP.14

Investigating the tissue of tonsils of PPP-patients a unique formation of lymphoid follicles surrounded by reticular crypt epithelial cells was found which was absent in tonsils of controls.15 Culturing crypt epithelial cells it was shown that p53-related expression factors contributed to an upregulation of IL-6 gene expression. The possible importance of IL-6 for PPP has been emphasized previously and it has been shown that tonsillectomy leads to improvement of lesions.16 In another study, the expression of inducible costimulator (ICOS), a costimulatory receptor on activated T cells was higher in the tissue of tonsils of PPP-patients as compared to controls.17 Tonsillectomy or treatment of dental foci resulted in a marked and sustained improvement of lesions suggesting a major role of focal infections as a trigger for PPP. The role of T cells in the tonsils for PPP is further substantiated by the demonstration of an increased expression of cutaneous lymphocyte-associated antigen (CLA) on CD3+ T cells in tonsils and in diseased skin together with an enhanced expression of the CLA-ligand E-selectin.18

Grafting involved PPP-skin onto SCID/CB-17 mice injected with lymphocytes from tonsils of PPP patients together with heat shock protein 60 induced high antiheat shock protein 65-IgG levels together with an increase of IL-6 and interferon α.19 Recruitment of lymphocytes seems to be mediated by the chemokine CCL20/MIP3 α the receptor of which, CCR6, is significantly expressed on tonsilar T cells of PPP patients as compared to controls. Indeed, Tonsillectomy resulted in a decreased CCR6 expression on peripheral PPP T cells.20

The observation of either PPP or new onset psoriasis in patients treated with anti-TNF-α agents is not yet understood21 but a shift from a TNF-α-driven immune response toward an interferon-dominated inflammatory response is discussed.22 In an animal model, the neutralization of TNF-α-induced skin inflammation resulted in an increased expression of IL-1b, IL-6, IL-17, IL-21, and IL-22 and a suppression of FoxP3-positive regulatory T cells.23 In the light of the importance of T cells and IL-6 for the development of PPP this shift may at least in part explain this appears relevant.

Clinical Findings

The primary lesions are pustules of nearly equal size measuring two to four mm in diameter. Crops of pustules usually arise within a few hours on otherwise normal-appearing palmar and plantar skin (Fig. 21-1). Involvement is usually symmetric but unilateral location on palms and/or soles can be seen. Single lesions then become surrounded by an erythematous ring. Sometimes, the pustules extend to the dorsa of the fingers, the feet, or over the volar wrists (see Fig. 21-1C). Episodes of new pustular eruptions occur at varying intervals and remain strictly confined to the sites of predilection.

As pustules become older, their yellow color changes to dark brown, so that in untreated PPP, the lesions show various shades of color (see Fig. 21-1). Dried pustules are shed within approximately 8 to 10 days.

Symptoms include itching or a burning sensation, which may precede new crops of lesions. However, in severe eruptions, pain and the inability to stand, walk, or do manual work may greatly reduce the quality of life.

Disease Associations

(Box 21-1.) An association of PPP and osteoarthritis of the anterior chest wall was first described in Japan.24 As reported by Swedish authors, involvement of the manubriosternal joint is present in 6% and of the sternoclavicular joints in 10% of patients.25 Scintigraphic investigations showed sternocostoclavicular joint involvement to be present in 16 of 73 (22%) patients.26 For this condition, the term SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) has been established.27 Clinical manifestations of SAPHO syndrome are similar when they occur either with severe acne (mostly acne conglobata) or PPP (see Chapter 80). The primary lesion consists of a sterile abscess containing neutrophils. The site of predilection is the anterior chest wall. Involvement of the sacroiliacal joints may occur.28

PPP is also seen in patients with chronic recurrent multifocal osteomyelitis as well as with noninfectious inflammatory bone lesions.

An association of PPP with gluten-sensitivity has been suggested as far back as 1991.29 In a more recent study of 123 patients with PPP IgA-antibodies against gliadin were found in 18% of patients and against tissue transglutaminase in 10%, respectively.30 In these patients CD3+ and CD8+ T cells were increased in numbers in duodenal biospsies. In 6% of patients diagnosis of celiac disease was made. Patients who tested positive for any of the antibodies showed total or nearly total clearance of skin lesions when they adhered to a gluten-free diet.

Histopathology

Histologically, there is an intraepidermal cavity filled with polymorphonuclear leukocytes associated with spongiform changes within the surrounding epidermis (Fig. 21-2). Eosinophils and mast cells are present in increased numbers in PPP biopsies from lesional skin. Another hallmark is the inability to visualize the epidermal part of the eccrine duct in PPP specimens indicating an involvement of the acrosyringium.31

Laboratory Findings

The lesions of PPP are sterile; a moderately increased white blood cell count may occasionally be observed, but all other laboratory tests are usually normal. In patients with an infectious trigger, infection-associated laboratory parameters, such as C-reactive protein, may be increased. Increased levels of antigliadin and/or tissue transglutaminase antibodies may be found.

Diagnosis and Differential Diagnosis

(Box 21-2)

PPP is a distinct entity. The course of the disease, together with the characteristic morphology, permits the proper diagnosis. The disease must be differentiated from dyshidrotic eczematous dermatitis (pompholyx), especially when pustules due to secondary infection are present (see Chapter 16). In that condition, the onset is also acute, but clear vesicles of various sizes are scattered on the palms, soles, and volar and interdigital aspects of the fingers. These may coalesce and secondarily become pustular because of secondary bacterial infection.

Pustular variants of tinea of the palms and soles or pustules developing in infected scabies may resemble PPP. Bacterial cultures or demonstration of hyphae or mites clearly separate these entities from PPP.

Rare clinical variants such as vesicopustular mycosis fungoides palmaris et plantaris,32 localized pustular vasculitis,33 or palmoplantar involvement of generalized pustular psoriasis may also resemble PPP.

Prognosis/Clinical Course

The clinical course of PPP is highly unpredictable. In patients with active disease with ongoing development of fresh pustules at the beginning of treatment relapse within a few days after cessation of any therapy or dose-reduction is highly likely. In phases of remission fewer pustules are produced, but the skin may remain erythematous and hyperkeratotic, sometimes resembling eczema. Cessation of smoking may help to extend disease-free intervals and to decrease activity of PPP.

Treatment

PPP is difficult to treat and all reported treatments have a high recurrence rate. Treatment modalities of PPP are summarized in Box 21-3.

In patients with limited disease or only focal lesions topical therapy with corticosteroids (potent and superpotent) is the treatment of choice. Increased efficacy can be obtained by occlusive therapy. When PPP involves larger parts of palms and/or soles systemic treatment with or without additional topical therapy should be initiated.

In a meta-analysis of several trials a modest efficacy of retinoids (etretinate/acitretin) or PUVA (oral, topical, bath) was established when compared to placebo. The addition of a retinoid to PUVA (re-PUVA) resulted in increased efficacy. Cyclosporine showed good evidence of improvement up to clearance but no data support was given for long-term cyclosporine therapy.34

In a recent open trial in 52 patients with PPP 35% could be controlled by topical therapy. In those patients requiring systemic therapy acitretin was found most efficacious followed by colchicine and methotrexate.35 Efficacy of fumaric acid ester therapy in PPP has been described.36

In six female PPP-patients oral itraconazole (100 mg/day for 4 weeks followed by 100 mg every other day for 4 weeks) lead to a complete clearance in three out of six and in mild improvement in the other three patients. All patients relapsed within 1 month after cessation of therapy but therapeutic response could be regained in two of the three former responders.37

In an open trial in 15 patients 15 mg alefacept i.m. weekly for 16 weeks was found to be successful in the majority of cases.38 However, in another series of 15 PPP patients alefacept 15–30 mg weekly was found efficacious only in some cases with a maximum response at week 10.39 There is debate as to whether TNF-α antagonists may be beneficial in PPP. Whereas in chronic plaque type psoriasis and generalized pustular psoriasis the anti-TNF-α monoclonal antibody infliximab was found to be highly effective, this agent was found to be both beneficial and to worsen PPP.40,41 In the SAPHO syndrome, infliximab led to a complete remission of osteoarticular disease but PPP deteriorated during treatment.42 In a small placebo-controlled trial in 15 PPP-patients etanercept given 2 × 50 mg weekly s.c. for 6 months only few patients showed a significant clinical response.43

(See Box 21-4)

Cessation of smoking and, according to data mainly generated in Asian countries, tonsillectomy may help to prevent new eruptions of PPP. In patients tested positive for antigliadin and/or tissue transglutaminase antibodies and/or with proven celiac disease a gluten-free diet seems to be a preventive measure.

Acrodermatitis continua is a rare, sterile, pustular eruption of the tips of the fingers or toes that slowly extends proximally. Continuous pustulation leads to nail destruction and atrophy of the distal phalanx.

In 1888, Crocker described a relapsing bullous and pustular eruption on hands and feet; this was further delineated by Hallopeau.44,45 Acrodermatitis continua is now classified as a form of acropustular psoriasis.

Epidemiology

There are no data on the prevalence or incidence of acrodermatitis continua.

Etiology and Pathogenesis

The etiology of acrodermatitis continua remains enigmatic. Even triggering factors have not been described yet. Pustule formation may involve similar pathways as discussed for PPP, but due to the rarity of the disease this has not been studied.

Clinical Findings

Acrodermatitis continua most often begins at the tips of one or two fingers (Fig. 21-3), less often on the toes. The nail folds are affected very early, and trauma is thought to play an initiating role. The first signs consist of small pustules, which, on bursting, leave an erythematous, shiny area in which new pustules develop. These then tend to coalesce, forming polycyclic lakes of pus. As the disease extends proximally, the affected area shows either glossy erythema or a crusted, keratotic, and fissured surface with newly formed pustules underneath (see Fig. 21-3). Pustulation of the nail bed and the nail matrix almost always occurs and quite often leads to loss of the nail plate or severe onychodystrophy (see Fig. 21-3). Acrodermatitis continua of long duration may show complete destruction of the nail matrix and thus lead to anonychia. The skin becomes shiny and severely atrophic, and there is atrophic thinning of the distal part of the phalanx.

The disease may remain confined to the original site, sometimes up to several years, but more often it spreads proximally to cover the hand, dorsum of forearm, or foot. In such instances more than one extremity is involved. Acrodermatitis continua may be associated with generalized pustular psoriasis of the Zumbusch type (see Chapter 18).

Histopathology

The main histopathologic feature of acrodermatitis continua is a subcorneal cavity filled with neutrophils. Epidermal cell necrosis and spongiosis does not occur, but the roof and shoulder zones adjacent to the pustule show aggregated leukocytes between the epidermal cells, forming spongiform pustules. There is a moderate lymphohistiocytic infiltrate in the upper dermis, together with focal edema.

Lesions of long duration show severe atrophy of the papillary dermis and thinning of the epidermis.

Laboratory Findings

Systemic abnormalities are absent, and laboratory tests are usually within normal ranges. The pustules are sterile. In advanced cases, X-ray may reveal atrophy of the distal phalanx and arthropathy of the interphalangeal joints.

Differential Diagnosis

Acrodermatitis continua at an early stage must be differentiated from acute paronychia caused by bacteria or fungi and from herpetic lesions (see Chapter 193). Cultures and smears help rule out infectious causes. The distal localization and the tendency of the pustules to become confluent, forming denuded, erythematous, or crusted lesions, distinguishes acrodermatitis continua from PPP or pustular dyshidrotic eczema. Atrophy and loss of nails do not occur in these conditions. Contact dermatitis with secondary infection and pustulation has less clearly defined margins, runs a different clinical course, and lacks the persistence typical for acrodermatitis continua.

Prognosis/Clinical Course

Acrodermatitis continua shows a chronic course with a tendency of the lesions to spread proximally. Spontaneous improvement is rare, and episodes of acute pustulation occur without apparent cause. The development of pustules at other sites, or even the eruption of generalized pustular psoriasis, supports the idea that acrodermatitis continua is a variant of psoriasis. When uncontrolled, irreversible destruction of the complete nail apparatus occurs.

Treatment

As in pustular psoriasis, no specific drug is able to induce lasting remissions. Potent or superpotent topical steroids, preferentially under occlusion, are useful in blocking pustulation. Caution is advised in cases already showing atrophy. PUVA suppresses the eruption of new pustules and can be employed for long periods as maintenance treatment (see Chapter 238).

Treatment with a combination of systemic acitretin and local calcipotriol/calcipotriene was successful in one patient in a left–right comparison.46 In recalcitrant patients, dapsone may be tried.47 Recently, topical treatment with tacrolimus 0.1% ointment alone or in sequential combination with calcipotriol was found successful.48 Numerous case reports describe the successful use of anti-TNF-α agents in acrodermatitis continua.49 With respect to the recalcitrant nature of the diseases combination therapy of adalimumab, etanercept, or infliximab with either acitretin or methotrexate may be advisable in order to maintain treatment response when stopping anti-TNF-α-therapy while continuing acitretin or methotrexate.

In principle, regimens used for treatment of PPP may also be used for therapy of acrodermatitis continua (see Box 21-3). The therapeutic result lasts as long as the drugs are given, and relapses occur after withdrawal.

Prevention

There are no data on preventive measures for acrodermatitis continua.

Infantile acropustulosis is discussed in Chapter 107.