Subcorneal Pustular Dermatosis

Background

Subcorneal pustular dermatosis (SPD) is a rare, chronic, relapsing pustular eruption characterized by subcorneal pustules that contain neutrophils on histopathology. It was first described by Sneddon and Wilkinson in 1956.^{[1, 2]} This condition is more common in middle-age and older women but has been reported to occur also in children.^{[2, 3, 4, 5]} Clinical findings are discrete, flaccid pustules or grouped vesicles that present predominantly on the flexor surfaces. In rare cases, unusual involvement of the face, palms, and soles has been described.^[6]

Despite marked improvement in investigation techniques, the pathogenesis of this entity is still controversial. Direct and indirect immunofluorescence results are commonly negative in the subcorneal pustular dermatosis. These findings suggest that subcorneal pustular dermatosis may not be an autoantibody-mediated disease. However, it was found that some patients with subcorneal pustular dermatosis show epidermal intercellular immunoglobulin A (IgA) deposits on direct and indirect immunofluorescence, which places them in the group of IgA pemphigus.^{[4, 7]}

Subcorneal pustular dermatosis has been described in association with IgA monoclonal gammopathies,^{[8, 9, 10]} multiple myeloma,^[11] and inflammatory diseases such as rheumatoid arthritis (RA)^{[12, 13]} and Crohn disease.^{[14, 15]}

According to some authors, subcorneal pustular dermatosis can be classified as one of the neutrophilic dermatoses together with pyoderma gangrenosum, Sweet syndrome, and erythema elevatum diutinum,^[16] while others classify it within the group of autoinflammatory pustular neutrophilic diseases, together with pustular psoriasis variants.^[17] In addition, it must be noted that autoimmune intercellular IgA dermatosis with autoantibodies to desmocollin is almost indistinguishable from classic subcorneal pustular dermatosis, which makes the nosological classification of this entity remain controversial.^[7]

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Pathophysiology

The exact pathophysiology of subcorneal pustular dermatosis (SPD) is unknown. The accumulation of neutrophils in the subcorneal layer suggests the presence of chemoattractants in the uppermost epidermis, but the stimulus for these chemoattractants was not found. Interleukin (IL)‒1 beta, IL-6, IL-8, IL-10, leukotriene B4, and complement fragment 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 (TNF)‒alpha levels have been found to be significantly elevated in the serum and blister fluid of patients with subcorneal pustular dermatosis.^{[5, 6]} However, TNF-blockers were not found to be effective in all patients, although there are reports on successful treatment with this class of drugs.^{[18, 19]} A case of a TNF-alpha-inhibitor–induced subcorneal pustular dermatosis has also been described.^[20]

Immunofluorescence studies are negative in the subcorneal pustular dermatosis of Sneddon-Wilkinson. 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 a variant of IgA pemphigus resembling subcorneal pustular dermatosis. In a large 2016 series of 49 patients with intercellular IgA dermatosis and 13 cases with subcorneal pustular dermatosis, it was confirmed that the subcorneal pustular dermatosis type of intercellular IgA dermatosis is clinically and histopathologically indistinguishable from classic subcorneal pustular dermatosis without immunoreactants.^[7]

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.^[21]

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Etiology

The etiology of subcorneal pustular dermatosis (SPD) 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.

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Epidemiology

Subcorneal pustular dermatosis (SPD) 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, without differences described in clinical features and prognosis between children and adults, but some cases tend to have atypical features more suggestive of psoriasis.^{[22, 23, 24]}

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Prognosis

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

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History

Subcorneal pustular dermatosis (SPD) is a benign, chronic, vesiculopustular eruption, usually affecting adults, although childhood cases have also been described.^{[2, 3, 4, 5]} 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. However, malaise, fever, arthralgias, abnormalities of hepatic enzymes, and sclerosing glomerulonephritis have been reported in several cases.^[25] 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)^{[8, 9]} ; lymphoproliferative disorders (especially multiple myeloma)^[11] ; pyoderma gangrenosum^{[10, 26]} ;  and other inflammatory diseases such as rheumatoid arthritis,^{[12, 13, 27] ,}systemic lupus erythematosus,^[28] Sjögren syndrome,^[29] diffuse scleroderma,^[30] ulcerative colitis,^[31] and Crohn disease.^{[14, 15]} These conditions are well-recognized associations with subcorneal pustular dermatosis (developing both before and after the diagnosis of subcorneal pustular dermatosis). Further associations were found with other dermatoses characterized by skin infiltration with neutrophils, such as pyoderma gangrenosum and SAPHO (synovitis, acne, pustulosis, osteitis) syndrome.^[32] Other anecdotally associated conditions include aplastic anemia,^[33]  Mycoplasma pneumoniae infection,^{[34, 35, 36]}  Coccidioides immitis infection,^[37]  hyperthyroidism,^[38] APUDoma (amine precursor uptake and decarboxylation cell–derived tumor),^[39] and thymoma.^[40]

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.^[41]

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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-and-half" blister, in which purulent fluid accumulates in the lower half of the blister. New eruptions of pustules have the tendency to coalesce and often form annular, circinate, and bizarre serpiginous patterns.

See the images below.

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Circinate plaques and pustules on nonerythematous base in a patient with subcorneal pustular dermatosis.

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Subcorneal pustular dermatosis with numerous pustules on erythematous base.

This tends to occur symmetrically, affecting axillae, groin, abdomen, submammary areas, and the flexor side of the limbs. There are no differences in clinical features and prognosis of the disease between children and adults.^{[23, 24, 42]} Palmar, plantar, face, and mucous membrane involvement is unusual, but is described in individual case reports.^{[43, 44]}

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.

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Approach Considerations

Serum protein electrophoresis

The association of paraproteinemia with subcorneal pustular dermatosis (SPD) 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 and urine 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.^[37]

Skin biopsy

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

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Histologic Findings

The classic histologic finding in subcorneal pustular dermatosis (SPD) 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. See the image below.

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Subcorneal pustules with neutrophil accumulation and minimal spongiosis.

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.^{[4, 7]}

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Approach Considerations

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 (SPD) 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),^[45] broadband UVB, and narrowband UVB alone or in combination with dapsone and/or retinoids can be successful at controlling subcorneal pustular dermatosis.^[46] Long-term maintenance regimens may be needed.^[47]

Additional therapies

Anecdotal case reports support the use of infliximab, tacalcitol,^[48] maxacalcitol,^[49] mizoribine,^[50] ketoconazole,^[51] tetracycline, minocycline, benzylpenicillin, vitamin E,^[52] azithromycin,^[53] cyclosporine,^{[54, 55]} colchicine, pentoxifylline,^[56] intravenous immunoglobulins,^[57] and adalimumab with mycophenolate mofetil.^[58] Antimyeloma treatment should be considered in cases of subcorneal pustular dermatosis associated with IgA monoclonal gammopathy of undetermined significance, refractory to other therapies.^[59]

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.

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Long-Term Monitoring

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 (SPD). 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.

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