Podrogowa dermatoza krostkowa skutecznie leczona acytretyną

Introduction

Subcorneal pustular dermatosis (SPD), also termed as Sneddon-Wilkinson syndrome, is a rare dermatosis. The clinical picture is dominated by sterile pustules arranged in a polycyclic pattern on erythematous base, located on the trunk, in intertriginous regions and on the flexural surfaces of the extremities [1]. Conspicuous features of the histological picture include subcorneal neutrophil infiltrates without accompanying epidermal spongiosis and acantholysis [2]. Attention should also be drawn to the fact that patients with SPD are at an increased risk of developing IgA monoclonal gammopathy of undetermined significance (IgA MGUS), multiple myeloma and pyoderma gangrenosum compared to the general population [3].

Objective

The aims of the study are to present the case of a patient with skin lesions secondary to SPD, and discuss the differential diagnosis and treatment of this disorder.

Case report

A 28-year-old male man, a manual worker, previously healthy, was admitted to the hospital dermatology unit because of extensive polycyclic erythematous eruptions with individual small pustules located on the periphery. The first skin lesions appeared 2 months prior to hospitalisation during antibiotic therapy with clarithromycin (bacterial infection of the lower airways). Initially, the lesions were numerous, with well-marginated borders. They were located on the skin of the hands, and then involved the trunk, lower extremities and intertriginous regions. Treatment prescribed on an outpatient basis included topical and systemic glucocorticosteroids, however no improvement was observed.
On admission, the examination revealed erythematous lesions on the skin of the trunk, upper extremities (particularly the dorsal surfaces of the hands) and lower extremities, arranged in a festoon-like pattern, with individual pustules on the periphery (figs. 1–4). Some of the eruptions were covered with serous-purulent scabs. Post-inflammatory brown hyperpigmentation occupied considerable areas of the skin. The mucous membranes and the nails of the hands and feet did not show any pathological changes.
A basic panel of laboratory tests was ordered, demonstrating slight deviations from the normal ranges (leukocytosis, hyperglycaemia, increased levels of inflammatory markers, and the presence of protein in urine). A test to determine IgG and IgA pemphigus/pemphigoid antibodies (indirect immunofluorescence – IIF) was negative. A skin specimen obtained from the skin lesions was non-diagnostic.
Considering the severity of skin lesions, it was decided to initiate topical treatment with a skin ointment containing clobetasol propionate, boric acid and salicylic acid, and a cholesterol ointment. A moderate improvement in skin condition was achieved.
After 1 month, the patient was re-admitted to the Department with exacerbation of skin lesions.
Dermatological evaluation showed intensification of infiltrated erythematous lesions with signs of desquamation of the skin of the hands and feet, and multiple pustules arranged in an annular pattern on the sides of the trunk (figs. 5, 6). The scope of laboratory tests was extended to include serum protein electrophoresis (showing a slightly lowered albumin level), as well as virological and serological tests (HIV, HBsAg, anti-HCV – with results in the normal range), and assays to determine the levels of IgG, IgM and IgA antibodies (producing results in the normal range).
A total of three skin specimens were obtained. Two specimens collected from the lesions revealed features consistent with SPD including subcorneal pustules formed by local neutrophil infiltrates, erythrocyte extravasations, absence of acantholysis and spongiosis, lack of mitotic figures, and abundant neutrophil infiltrates around superficial plexuses (figs. 7, 8). In addition, one specimen of unchanged skin around the pustules was collected for direct immunofluorescence (DIF) test, yielding negative results.
While waiting for the results of the tests, the patient’s topical treatment was maintained, and a date was set for another hospitalisation to initiate systemic treatment. In the week preceding the admission there was a sudden aggravation of the lesions accompanied by doughy oedema in the lower legs. No significant evolution of skin lesions was observed except for the eruption of individual small pustules on the palmar surfaces and lateral surfaces of the feet (fig. 9).
During the third hospitalisation, the lipid profile was determined, and a panel of thyroid and rheumatoid tests was performed, but no significant abnormalities were detected. Also, serum protein immunofixation was done without identifying monoclonal protein. The ANA antibody test (performed by IIF on Hep-2 cells) and ANA Profil-3 plus DFS70 immunoblot were negative.
Following the initiation of diuretic treatment, the oedema in the lower legs resolved. On account of limited availability of dapsone and problems with patient compliance, a decision was made to start treatment with acitretin. After 1 month, the therapy led to the remission of lesions and stabilisation of the patient’s condition (fig. 10).

Discussion

Subcorneal pustular dermatosis is a rare, chronic dermatosis characterised by periods of exacerbation and remission, which was first described jointly by Ian Sneddon and David Wilkinson in 1956 [4]. Women aged over 40 years old are the most commonly affected group, and the classic manifestation of the disease includes the presence of sterile pustules with a symmetric distribution within the trunk (especially in the intertriginous regions) and flexural surfaces of the extremities [2, 4]. There are no widely accepted diagnostic criteria for SPD, so the diagnosis requires a detailed clinical-histopathological evaluation of patients. In each case, the differential diagnosis of SPD should include pustular psoriasis and IgA pemphigus [5]. Other diseases requiring differentiation from SPD are pemphigus foliaceus, dermatitis herpetiformis, acute generalised exanthematous pustulosis (AGEP), impetigo contagiosa, and necrolytic migratory erythema (glucagonoma syndrome) [6, 7].
Establishing a correct diagnosis of SPD is particularly important in view of the fact that different drugs are effective in these diseases, and also because Sneddon-Wilkinson syndrome coexists relatively commonly with IgA MGUS and multiple myeloma. In 2009, Ahmad and Ramsay reported the case of a 45-year-old female patient with pyoderma gangrenosum. Five years after developing the disease, the patient experienced an eruption of skin lesions characteristic of SPD, and after another 7 years she developed multiple myeloma [8]. There are literature reports of patients diagnosed with SPD who, after several years of stable disease, developed almost simultaneously pyoderma gangrenosum and multiple myeloma [9].

Differential diagnosis

The similarity of subcorneal pustular dermatosis to pustular psoriasis and IgA pemphigus has led to inaccuracies in SPD classification. Some authors consider SPD to be a variant of pustular psoriasis [10], while others believe it to be a subcorneal type of IgA pemphigus [11]. The information given below is useful in differentiating between SPD, pustular psoriasis and IgA pemphigus.
The most common of the listed dermatoses is pustular psoriasis [12, 13]. All the three diseases are known to have a higher rate in women than in men [13–15]. Subcorneal pustular dermatosis and pustular psoriasis are the most prevalent in the population aged 40 to 60 years old [1, 15, 16]. In contrast, the risk of developing IgA pemphigus has not been found to be linked to age [13].
A relatively high incidence of pustular psoriasis is noted in children (1.0–5.4% of all cases of psoriasis in children) [17, 18]. A racial predisposition has been observed only for pustular psoriasis, with the incidence in Asian and Hispanic populations exceeding the incidence recorded in Caucasian populations [13].
Clinical examination performed in the course of each of the discussed diseases reveals multiple sterile pustules, mainly on erythematous base, with a tendency to form annular patterns [12, 19, 20]. In SPD and IgA pemphigus, the lesions are located on the trunk, flexural surfaces of the extremities and in the intertriginous regions. In contrast, the abdomen, buttocks and extremities are among the most commonly affected areas in pustular psoriasis [2, 20, 21]. Subcorneal pustular dermatosis pustules are marked by a characteristic “half-and-half” feature, with the upper half of the blister containing a transparent fluid, and the lower half being filled with a sterile purulent material. “Half-and-half” pustules are also referred to as “hypopyon pustules” [6]. A distinguishing feature of pustular psoriasis is the manner in which skin lesions resolve (confluent pustules disappearing in the form of “collarette-like” exfoliation).
Patients with SPD and IgA pemphigus typically do not manifest systemic symptoms [6, 22]. The presence of skin lesions typical of SPD with accompanying symptoms of anaemia, kidney failure, hypercalcaemia or pathological bone fractures is an indication for a detailed diagnostic work-up for multiple myeloma [23, 24]. In pustular psoriasis, an excess of proinflammatory cytokines results in systemic symptoms including fever, chills, depression of mood, loss of appetite, nausea, and severe pain [2, 25]. A possible sign of IgA pemphigus is pruritus which, according to some authors, occurs in up to 50% of cases [26].
The results of basic laboratory tests in most patients with SPD and IgA pemphigus do not show any significant deviations from normal ranges (possibly except for minor abnormalities in CBC and creatinine levels, and elevated inflammatory marker levels) [7, 27]. Expansion of the diagnostic panel allows for the exclusion of associated diseases such as systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, hyperthyroidism and hypothyroidism. When SPD is suspected, it requires the exclusion of IgA MGUS (coexisting with SPD in 40% of cases) and IgA myeloma (urine and serum tests for paraproteinaemia) [4]. IIF test is one of the methods to differentiate between SPD and IgA pemphigus [28]. The use of COS-7 line cells transfected by desmocollin increases the sensitivity of the assay [29]. When pustular psoriasis is suspected, the indicated laboratory tests are determined by the criteria proposed by Umezawa et al. (≥ 1 criterion must be met): (1) leukocytosis with a left shift in Arneth-Schilling count, (2) elevated inflammatory parameters (ESR, CRP), (3) hypoproteinaemia, (4) hypocalcaemia.
The histological picture of SPD and SPD-like IgA pemphigus is characterised by the presence of sterile subcorneal neutrophilic pustules with non-infiltrated lower epidermal layers [30, 31]. No features of spongiosis or acantholysis are present. In IEN type IgA pemphigus, a pathognomonic sign is the presence of neutrophil aggregations above the basal epidermal layer [32]. Pustular psoriasis is manifested by parakeratosis, hyperkeratosis and subpapillary epidermal thinning.
Typically, Munro’s microabscesses and pericapillary lymphocyte clusters are observed. This form of psoriasis is often associated with neutrophil infiltrates surrounded by necrotic epidermis (“spongious pattern” – pustules of Kogoj) [30]. A summary of information needed for the differential diagnosis of SPD is listed in table 1.

Treatment

The drug of choice in SPD without concomitant diseases is dapsone (in doses of 50 to 200 mg/day) [6, 33]. After the remission of lesions, gradual dose reduction is preferred, since sudden withdrawal is associated with frequent relapses within 1–4 weeks (often the minimum dose is used as maintenance therapy) [34]. Other drugs inhibiting the formation of neutrophil infiltrates, such as colchicine, sulphapyridine and sulphamethoxypyrazine, may also be used, but they are characterised by lower efficacy. In cases of treatment failure, contraindications (e.g. glucose 6-phosphate dehydrogenase deficiency) or as in our patient problems with the availability of sulphone therapy, oral retinoids (acitretin and etretinate; with isotretinoin apparently ineffective in the treatment of this condition) are used. Their advantages include better tolerance and faster onset of action (usually up to 2 weeks after starting therapy) compared to dapsone [4, 35–37]. Potent topical glucocorticosteroids (e.g. clobetasol 0.05% ointment) also show efficacy in some SPD cases [33].
An increasingly important role in the treatment of SPD has been attributed to phototherapy (narrow- and wide-band UVB, UVA, PUVA and re-PUVA). Skin lesions usually resolve after completing 15–30 irradiation cycles [34].
Case reports have also demonstrated the benefit of treatment with other agents (e.g. infliximab, cyclosporine, methotrexate, mizoribine, tacalcitol, ketoconazole, minocycline, tetracycline, vitamin E), however, there is insufficient evidence of their efficacy in a larger group of patients [6, 34]. Von dem Borne et al. described an intriguing case of a patient with multiple myeloma and SPD, in whom myeloma remission (achieved with melphalan chemotherapy) also produced the remission of skin lesions [23].

Conclusions

The differential diagnosis of SPD continues to pose a great clinical and histopathological challenge. There are reports of patients developing IgA deposits in the skin many years after the initial diagnosis of SPD, which suggests that SPD and IgA pemphigus belong to a common continuum of manifestations of a single disorder [4]. Additional information on the pathophysiology of these diseases is needed to be able to definitely determine the links existing between them. The classification system proposed by Wallach et al. seems to be the optimum method of categorising these relationships [38]. According to this division, IgA pemphigus and SPD are separate disease entities, but they belong to the same larger group of disorders referred to as “superficial neutrophilic dermatoses”. However, since 1956, SPD has still remained an enigma, often causing puzzlement by its diverse manifestations.

Conflict of interest

The authors declare no conflict of interest.

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