Subcorneal pustular dermatosis (SPD), also known as Sneddon-Wilkinson disease, is a rare, chronic, relapsing pustular eruption characterized by subcorneal pustules that contain neutrophils on histopathology. See the image below.
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Circinate plaques and pustules on nonerythematous base in a patient with subcorneal pustular dermatosis.
Signs and symptoms
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.
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 tend to coalesce and often form annular, circinate, and serpiginous patterns.
See Presentation for more detail.
Diagnosis
The workup includes the following:
Serum protein electrophoresis – To detect associated paraproteinemia
Skin bacterial culture – To exclude impetigo and secondary bacterial infections
Skin scraping and fungal culture – To exclude dermatophyte infections
Skin biopsy – For histologic analysis
See Workup for more detail.
Management
Dapsone is the treatment of choice. Acitretin should be considered as an alternative or additional treatment for those who are intolerant of, or unresponsive to, dapsone.
Phototherapy alone or in combination with dapsone and/or retinoids can be effective at controlling SPD.
Subcorneal pustular dermatosis (SPD) 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 SPD. These findings suggest that SPD may not be an autoantibody-mediated disease. However, it was found that some patients with SPD show epidermal intercellular immunoglobulin A (IgA) deposits on direct and indirect immunofluorescence, which places them in the group of IgA pemphigus.[4, 7]
SPD 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, SPD can be classified as one of the neutrophilic dermatoses together with pyoderma gangrenosum, Sweet syndrome, and erythema elevatum diutinum,[16] whereas 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 SPD, which makes the nosologic classification of this entity remain controversial.[7]
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 SPD 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 SPD.[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 SPD has also been described.[20]
Immunofluorescence studies are negative in the SPD of Sneddon-Wilkinson. However, a rare subtype of SPD 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 SPD. In a large 2016 series of 49 patients with intercellular IgA dermatosis and 13 cases with SPD, it was confirmed that the SPD type of intercellular IgA dermatosis is clinically and histopathologically indistinguishable from classic SPD without immunoreactants.[7]
Additionally, despite many attempts, no infectious agent or other immunogenic trigger has yet been identified in patients with SPD. 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]
The etiology of subcorneal pustular dermatosis (SPD) is unknown. SPD is a sterile eruption. Because multiple subtypes have been recognized, SPD has more than one etiology.
Some cases of SPD have been considered a variant of pustular psoriasis. Note that clinical and histologic differentiation of SPD from pustular psoriasis can be difficult, although spongiform changes on histology favor the latter. Furthermore, a significant number of cases initially diagnosed as SPD are later diagnosed as psoriasis.
Other cases of SPD are argued to be a rare variant of pemphigus, known as SPD 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 SPD. Unlike pemphigus, a predominance of neutrophils and an absence or moderate acantholysis is observed; additionally, the condition is usually responsive to dapsone.
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. SPD affects middle-aged or elderly women more commonly than men.
SPD 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]
Subcorneal pustular dermatosis (SPD) is chronic and relapsing but benign. The association of SPD with paraproteinemia or lymphoproliferative disorders, especially multiple myeloma, may alter the prognosis.
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 SPD (developing both before and after the diagnosis of SPD). 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 SPD 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]
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.
View Image
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.
The association of paraproteinemia with subcorneal pustular dermatosis (SPD) is well documented. One study showed 4 of 10 patients with SPD 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.
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 SPD and can be found in other conditions such as pustular psoriasis, acute generalized exanthematous pustulosis, pemphigus foliaceus, bacterial impetigo, and dermatophytosis.
In SPD, 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 SPD type IgA pemphigus. Desmocollin-1 has been recognized as the autoantigen in this subgroup.[4, 7]
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 formerly 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 ultraviolet A (PUVA),[45] broadband ultraviolet B (UVB), and narrowband UVB alone or in combination with dapsone and/or retinoids can be successful at controlling SPD.[46] Long-term maintenance regimens may be needed.[47]
Additional therapies
Anecdotal case reports support the use of infliximab,[48] tacalcitol,[49] maxacalcitol,[50] mizoribine,[51] ketoconazole,[52] tetracycline, minocycline, benzylpenicillin, vitamin E,[53] azithromycin,[54] cyclosporine,[55, 56] colchicine,[57] pentoxifylline,[58] intravenous immunoglobulins,[59] apremilast,[60] and adalimumab with mycophenolate mofetil.[61] Antimyeloma treatment should be considered in cases of SPD associated with IgA monoclonal gammopathy of undetermined significance, refractory to other therapies.[62]
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 (SPD). Identifying these conditions, as well as other associated diagnoses, can improve the understanding of the etiology and pathogenesis of SPD, clarify its relationship with IgA pemphigus and pustular psoriasis, and help define its nosologic classification.
Dapsone is the treatment of choice. Acitretin should be considered as an alternative or additional treatment for those who are intolerant of, or unresponsive to, dapsone.
Clinical Context:
Dapsone is a sulfone that has anti-inflammatory and immunosuppressive properties, in addition to antibacterial properties. It prevents bacterial utilization of para-aminobenzoic acid (PABA) for the synthesis of folic acid by acting as a competitive antagonist of PABA.
Lidija Kandolf Sekulovic, MD, PhD, Professor, Head of the Department of Dermatology and Venereology, Medical Faculty, Military Medical Academy, Belgrade, Serbia
Disclosure: Nothing to disclose.
Coauthor(s)
Tanja Tirnanić, MD, Dermatovenereologist, City Institute for Skin and Venereal Diseases, Serbia
Disclosure: Nothing to disclose.
Specialty Editors
Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA
Disclosure: Nothing to disclose.
Jeffrey P Callen, MD, Professor of Medicine (Dermatology), Chief, Division of Dermatology, University of Louisville School of Medicine
Disclosure: Received income in an amount equal to or greater than $250 from: Biogen US (Adjudicator for study entry cutaneous lupus erythematosus); Priovant (Adjudicator for entry into a dermatomyositis study); IQVIA (Serono - adjudicator for a study of cutaneous LE) <br/>Received honoraria from UpToDate for author/editor; Received royalty from Elsevier for book author/editor; Received dividends from trust accounts, but I do not control these accounts, and have directed our managers to divest pharmaceutical stocks as is fiscally prudent from Stock holdings in various trust accounts include some pharmaceutical companies and device makers for these trust accounts for: Stocks held in various trust accounts: Allergen; Amgen; Pfizer; 3M; Johnson and Johnson; Merck; Abbott Laboratories; AbbVie; Procter and Gamble;; Celgene; Gilead; CVS; Walgreens; Bristol-Myers Squibb.
Chief Editor
Dirk M Elston, MD, Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine
Disclosure: Nothing to disclose.
Additional Contributors
Naveed Sami, MD, FAAD, Assistant Professor, Department of Dermatology, University of Alabama School of Medicine
Disclosure: Nothing to disclose.
Takeji Nishikawa, MD, Emeritus Professor, Department of Dermatology, Keio University School of Medicine; Director, Samoncho Dermatology Clinic; Managing Director, The Waksman Foundation of Japan Inc
Disclosure: Nothing to disclose.
Vlada Groysman, MD, Medical Director, Cahaba Dermatology and Skin Health Center; Clinical Assistant Professor of Dermatology, University of Alabama at Birmingham School of Medicine
Disclosure: Nothing to disclose.
Acknowledgements
The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors John D Wilkinson, MD, MBBS, MRCS, FRCP; John Reed, MBBS, MRCP; Sarah E Dick, MD; and Abby S Van Voorhees, MD, to the development and writing of the source articles.
Agarwal A, Shivaswamy KN, Barani R et al. Subcorneal pustular dermatosis and thymoma:an association or a coincidence?. Indian J Dermatol. 2006. 51:272-4.
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