Subcorneal Pustular Dermatosis Overview of Subcorneal Pustular Dermatosis

Subcorneal pustular dermatosis was first described by Sneddon and Wilkinson in 1956.^{[1, 2]} It is a rare, benign, chronic relapsing sterile pustular eruption typically involving the flexural sites of the trunk and proximal extremities. It most commonly affects woman aged 40 years or older. The etiology of this entity is unknown, and its exact nosologic classification is still controversial. Studies also suggest that some cases of subcorneal pustular dermatosis represent a variant of pustular psoriasis. These cases have been reported to evolve clinically from initially presenting as subcorneal pustular dermatosis to lesions that are more typical of pustular or plaque psoriasis.

Direct and indirect immunofluorescence results are commonly negative in the subcorneal pustular dermatosis Sneddon-Wilkinson subtype. These findings suggest that subcorneal pustular dermatosis Sneddon-Wilkinson subtype may not be an autoantibody-mediated disease. A 2008 report also tested patients for autoantibodies to desmogleins 1 and 3. These autoantibodies are considered pathogenic in pemphigus. Patients with subcorneal pustular dermatosis Sneddon Wilkinson subtype tested negative to the autoantibodies for desmogleins 1 and 3, further leading to a conclusion of alternate pathogenic mechanisms.^[3]

However, other studies that have identified another subgroup of subcorneal pustular dermatosis. This has been classified as the immunoglobulin A (IgA) pemphigus subtype. These patients have been shown to have IgA deposition against desmocollin 1 on immunofluorescence study results. Some experts have considered this subgroup to be a rare variant of pemphigus rather than subcorneal pustular dermatosis.^[4]

For more information, see Psoriasis.

The exact pathophysiology of subcorneal pustular dermatosis is unknown. The accumulation of neutrophils in the subcorneal layer suggests the presence of chemoattractants in the uppermost epidermis. Interleukin (IL)-1 beta, IL-6, IL-8, IL-10, leukotriene B4, and complement fragments C5a and C5a are neutrophil chemoattractants that have been found at increased levels in scale extracts of patients with subcorneal pustular dermatosis compared with that of controls.

Tumor necrosis factor-alpha levels have been found to be significantly elevated in the serum and blister fluid of patients with subcorneal pustular dermatosis.^[5] Successful treatment of recalcitrant subcorneal pustular dermatosis with an antitumor necrosis factor-alpha antibody has been reported.^[6] However, this observation was not confirmed in a recent report in which infliximab failed to achieve long-lasting control of the disease.^[7] The stimulus for these chemoattractants is unknown. No etiologic pathogen has been identified.

Immunofluorescence studies are negative in the subcorneal pustular dermatosis Sneddon Wilkinson subtype. However, a rare subtype of subcorneal pustular dermatosis has been reported to have a positive immunofluorescence with IgA deposition restricted to the upper epidermis and directed against desmocollin. As noted above, the clinical and histopathological characteristics have led experts to classify this variant as the subcorneal pustular dermatosis IgA pemphigus subtype.

Additionally, despite many attempts, no infectious agent or other immunogenic trigger has yet been identified in subcorneal pustular dermatosis patients. The eruption is regarded as sterile, although it may sometimes become secondarily infected with Staphylococcus aureus or streptococcal species. Preceding Mycoplasma pneumoniae infection was implicated in one report, but this case had an acute presentation that responded to 3 months of dapsone without relapse.^[8]

Subcorneal pustular dermatosis is a rare condition, and no estimate of prevalence or incidence is available. Cases have been reported worldwide, but no particular geographical predominance is apparent. Subcorneal pustular dermatosis affects middle-aged or elderly women more commonly than men.

Subcorneal pustular dermatosis is most common in individuals aged 40 years or older. It has been reported in children, but these cases tend to have atypical features more suggestive of psoriasis. Several reported cases of subcorneal pustular dermatosis in children have evolved into psoriasis.

Patient history

Patients typically present with a history of a relapsing pustular eruption involving the flexural areas of the trunk and proximal extremities. Individual pustular lesions arise within a few hours. Pruritus and irritation can occur but are not usually prominent symptoms. Systemic and toxic symptoms are not associated with acute episodes. Patients typically do not have any symptoms or signs of mucosal involvement.

Patients may present with histories notable for monoclonal gammopathies (IgA more often than immunoglobulin G),^{[9, 10]} lymphoproliferative disorders (especially multiple myeloma),^[11] and pyoderma gangrenosum.^{[12, 13]} These conditions are well-recognized associations with subcorneal pustular dermatosis (developing both before and after the diagnosis of subcorneal pustular dermatosis).

Other anecdotally associated conditions include inflammatory bowel disease, rheumatoid arthritis,^{[14, 15, 16]}systemic lupus erythematosus, hyperthyroidism and hypothyroidism, APUDoma (amine precursor uptake and decarboxylation cell–derived tumor), polycythemia rubra vera, Sjögren syndrome,^[17] thymoma,^[18] and SAPHO (synovitis, acne, pustulosis, osteitis)syndrome.

Patients should be queried about a personal and family history of psoriasis because differentiating subcorneal pustular dermatosis from pustular psoriasis can be difficult. Similarly, patients should be questioned about recent drug exposure because acute generalized exanthematous pustulosis is also in the differential diagnosis.

Physical examination

The primary lesions are flaccid pustules, measuring several millimeters in diameter, on normal or mildly erythematous skin. The classic lesion has been described as a "half-half" blister, in which purulent fluid accumulates in the lower half of the blister.

The most commonly affected areas include the axillae, groin, neck, and submammary regions. The proximal flexural aspects of the extremities are sometimes affected. Palmar, plantar, face and mucous membrane involvement is unusual.

The pustules can be isolated or grouped and tend to coalesce and form annular, circinate, or serpiginous patterns. The pustules are superficial and rupture easily, resulting in a superficial crust.

Mild hyperpigmentation often remains after pustular lesions have resolved.

The etiology of subcorneal pustular dermatosis is unknown. Subcorneal pustular dermatosis is a sterile eruption. Because multiple subtypes have been recognized, subcorneal pustular dermatosis has more than one etiology.

Some cases of subcorneal pustular dermatosis have been considered a variant of pustular psoriasis. Note that clinical and histological differentiation of subcorneal pustular dermatosis from pustular psoriasis can be difficult, although spongiform changes on histology favor the latter. Furthermore, a significant number of cases initially diagnosed as subcorneal pustular dermatosis are later diagnosed as psoriasis.

Other cases of subcorneal pustular dermatosis are argued to be a rare variant of pemphigus, known as subcorneal pustular dermatosis type IgA pemphigus. This subgroup of patients shows positive immunofluorescence with epidermal intercellular IgA deposits. The positive immunofluorescence can develop years after the initial diagnosis of subcorneal pustular dermatosis. Unlike pemphigus, a predominance of neutrophils and an absence or moderate acantholysis is observed; additionally, the condition is usually responsive to dapsone.

The differential diagnosis of subcorneal pustular dermatosis includes the following:

• Acute generalized exanthematous pustulosis
• Dermatitis herpetiformis
• Dermatophytosis
• Eosinophilic pustular folliculitis
• Impetigo
• Necrolytic migratory erythema
• Pemphigus foliaceus
• IgA pemphigus
• Pustular psoriasis

Other problems to be considered include the following:

• Acute generalized exanthematous pustulosis
• Annular pustular psoriasis
• Dermatophytosis
• Generalized pustular psoriasis of pregnancy
• Necrolytic migratory erythema

Serum protein electrophoresis

The association of paraproteinemia with subcorneal pustular dermatosis is well documented. One study showed 4 of 10 patients with subcorneal pustular dermatosis had a monoclonal gammopathy. Most reported cases have been with IgA monoclonal gammopathies, either kappa or lambda light-chain type. However, immunoglobulin G gammopathies are also reported.

Serum protein electrophoresis should be repeated periodically because the development of paraproteinemia can occur years after the initial eruption of subcutaneous pustular dermatosis. Furthermore, the increased risk of multiple myeloma in patients with a monoclonal gammopathy is well recognized.

Skeletal survey and bone marrow aspiration should be undertaken if multiple myeloma is suspected.

Skin bacterial culture

Subcorneal pustular dermatosis is a sterile eruption. Impetigo and secondary bacterial infections should be excluded.

Skin scraping and fungal culture

Dermatophyte infections need to be excluded.

Skin biopsy

Skin biopsy of an early lesion is needed for histologic analysis and direct immunofluorescence testing.

The classic histologic finding in subcorneal pustular dermatosis is subcorneal pustules composed primarily of neutrophils and occasional eosinophils. However, this finding is not specific for subcorneal pustular dermatosis and can be found in other conditions such as pustular psoriasis, acute generalized exanthematous pustulosis, pemphigus foliaceus, bacterial impetigo, and dermatophytosis.

In subcorneal pustular dermatosis, unlike in pustular psoriasis, the epidermis usually has minimal spongiosis. The dermis in subcorneal pustular dermatitis shows a perivascular infiltrate of neutrophils and occasional monocytes and eosinophils. Acantholysis is not prominent; however, it has been reported in older lesions.

Direct and indirect immunofluorescence studies are typically negative. Nevertheless, periodic repeat studies are recommended to detect epidermal intercellular IgA staining in order to identify a subgroup referred to as subcorneal pustular dermatosis type IgA pemphigus. Desmocollin-1 has been recognized as the autoantigen in this subgroup.

Dapsone

Dapsone is the treatment of choice. The response is slower than that seen with dermatitis herpetiformis, with resolution usually occurring in about 4 weeks. Once disease control has been established, the dose should be tapered to the lowest dose needed to maintain control. Sulfapyridine and sulfamethoxypyridazine may also be used, but only a few isolated reports support their effectiveness.

Acitretin

Acitretin (and formally etretinate) has been used to successfully treat subcorneal pustular dermatosis and should be considered as an alternative or additional treatment for those who are intolerant of, or unresponsive to, dapsone. Once disease control has been established, the dose should be tapered to the lowest dose needed to maintain control. Isotretinoin at 0.5 mg/kg/d appears to be ineffective.

Phototherapy

Phototherapy with psoralen with UVA (PUVA),^[19] broadband UVB, and narrowband UVB alone or in combination with dapsone and/or retinoids can be successful at controlling subcorneal pustular dermatosis.^[20] Long-term maintenance regimens may be needed.^[21]

Additional therapies

Anecdotal case reports support the use of infliximab, tacalcitol,^[22] mizoribine,^[23] ketoconazole,^[24] tetracycline, minocycline, benzylpenicillin, vitamin E,^[25] azithromycin,^[26] cyclosporine,^{[27, 28]} colchicine, and adalimumab with mycophenolate mofetil.^[29]

Systemic and topical corticosteroids are generally ineffective but may provide some control. They have been used in combination with dapsone to treat associated conditions such as pyoderma gangrenosum and multiple myeloma. A good response to systemic corticosteroids is atypical and is suggestive of a diagnosis of pustular psoriasis.

Long-term follow-up is recommended. Periodic evaluations with serum protein electrophoresis and direct immunofluorescence should be performed every few years.

Paraproteinemia, myeloma, intraepidermal IgA staining, and pustular psoriasis may develop several years after the initial presentation of subcorneal pustular dermatosis. Identifying these conditions, as well as other associated diagnoses, can improve the understanding of the etiology and pathogenesis of subcorneal pustular dermatosis, clarify its relationship with IgA pemphigus and pustular psoriasis, and help define its nosologic classification.

Subcorneal pustular dermatosis is chronic and relapsing but benign. The association of subcorneal pustular dermatosis with paraproteinemia or lymphoproliferative disorders, especially multiple myeloma, may alter the prognosis.