A 52-year-old white man with a history of hypertension and diabetes presents with an intermittent, ongoing blistering rash on his chest and back that has persisted for more than 3 years. The patient reports that the rash
was sometimes irritated and painful, and he denies pruritus. He had tried over-the-counter antifungal creams for several months with no improvement. On examination, he has no oral ulcers or lesions. He denies history of any skin cancer.
An otherwise healthy 54-year-old white man presents with a 2-year history of an intermittent plaques on his chest and back that worsened with sun exposure. He denies any pruritus, pain, or irritation, but he says that the rash is worsening. The patient has no history of medical problems or allergies, takes no medications, and reports tobacco use at 1 pack per day. He has tried applying over-the-counter topical steroids for 2 weeks without improvement.
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Pemphigus vulgaris (PV) is an autoimmune blistering disease involving the skin and mucous membranes. A high incidence of PV has been observed in Ashkenazi Jewish patients and those of Mediterranean ancestry, an observation that has been strongly related to the human leukocyte antigen (HLA) classes HLA-DRB1*04 and HLA-A*10.1 PV occurs more commonly in women, and the average age of onset of the disease in the United States is between 50 and 70 years.2 The incidence of PV increases with age, especially in women, likely due to altered immune regulation with aging.1
In the majority of patients with PV, oral lesions are present when the disease initially manifests.3,4 Skin lesions typically occur either at the same time as oral lesions or within several months.4 The primary skin lesion of PV is a flaccid blister that is fragile and breaks easily, leaving denuded areas of varying size. The erosions can be large and crusted, and they tend to spread at their periphery.2 Nikolsky sign, which occurs when lateral pressure is applied to the edge of a blister, resulting in separation of the epidermis, is characteristic of PV.2,3 Nikolsky sign can also be elicited in staphylococcal scalded skin syndrome, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Asboe-Hansen sign is also common and is produced when pressure is applied directly over an intact blister, resulting in lateral spread.3 Symptoms of the lesions include pruritus and pain. PV lesions typically heal without scarring; however, transient postinflammatory hyperpigmentation is common and usually resolves with time.3 Common sites of involvement include the scalp, face, axilla, and oral cavity.3
PV is characterized by immunoglobulin G (IgG) antibodies that target desmogleins, cell-to-cell adhesion glycoproteins found in desmosomes. Patients with mucosal-dominant PV typically only have autoantibodies to desmoglein 3, whereas patients with mucocutaneous PV have autoantibodies to both desmoglein 1 and 3.5 Enzyme-linked immunosorbent assay can be performed to detect these autoantibodies to desmoglein.
In PV, cleavage occurs in the stratum spinosum of the epithelium, and the basement membrane remains intact.4 The histopathologic hallmark of the disease is acantholysis, or loss of epidermal cell cohesion, resulting in formation of suprabasal intraepidermal bullae.2,3 The basal epidermal cells may split from each other but remain attached to the basement membrane, appearing as a “row of tombstones.”3 Direct immunofluorescence (DIF) for PV shows IgG bound to the cell surface of keratinocytes in a net-like pattern. The biopsy for DIF when suspecting PV should be performed on normal-appearing perilesional skin.2
Other clinical variations of pemphigus include pemphigus foliaceus, pemphigus erythematosus, and drug-induced pemphigus. Pemphigus foliaceus manifests as superficial scaly and crusted shallow erosions on the skin without oral involvement.2,3 Pemphigus foliaceus is characterized by autoantibodies to desmoglein 1, resulting in subcorneal acantholytic blisters with intercellular deposits of IgG located predominantly in the superficial epidermal layers.3,5 Brazilian pemphigus foliaceus is a variant that is endemic in rural areas of South America, most commonly Brazil. This disease is most common in children, adolescents, and young adults.
It is histologically and immunopathologically indistinguishable from pemphigus foliaceus but is theorized to be the result of an insect-vectored virus.3 Pemphigus erythematosus (or Senear-Usher syndrome) is characterized by erythematous hyperkeratotic lesions over the nose, malar area, upper back, chest, and intertriginous areas without oral involvement.2,3 Its histology is identical to pemphigus foliaceus but has immunopathologic features of both pemphigus and lupus erythematosus.3 Drug-induced pemphigus has been reported to occur most significantly with penicillamine use, but it has also been reported with penicillin, captopril, rifampin, and phenobarbital use.2,3
The primary treatment of PV is immunosuppression. Systemic corticosteroids have historically been the mainstay of treatment, resulting in a dramatic reduction in mortality.3,6,7 However, due to the significant side effects of long-term corticosteroid use, adjunctive nonsteroidal immunosuppressive therapies such as azathioprine, cyclophosphamide, methotrexate, cyclosporine, mycophenolate mofetil, and dapsone are used, as well as intravenous immunoglobulin, plasmapheresis, immunoadsorption, and rituximab.6,7 Most PV deaths now result from side effects of immunosuppressive agents rather than the disease or its sequelae.6,7 Topical steroids may also be used for local effects on PV lesions.
For the patient in our case, a 4-mm punch biopsy was performed and sent for hematoxylin and eosin staining, as well as DIF. The biopsy and DIF results were consistent with PV. Oral prednisone was initiated at 20 mg/d, as was topical steroids. The rash resolved in 1 month. The patient was subsequently tapered off of the oral steroids, and ultimately, his condition was well-controlled on topical steroid therapy.
Tumid lupus erythematosus (TLE) is a rare subset of chronic cutaneous lupus erythematosus. TLE was first reported by Hoffman in 1909 at a meeting of the Berlin Dermatological Society during which he reported on two patients with edematous, indurated, facial lesions, with minimal to absent surface changes, which he called “lupus erythematosus tumidus.”8 Similar lesions were again described in two patients in 1930 by Gougerot and Burnier9 using the term “lupus érythémateux tumidus.” Since then, there has been an increase in reports and recognition of TLE; however, there is still confusion in the literature regarding differentiation of TLE from other cutaneous disorders that manifest in a similar clinical and histologic manner.10-12
TLE occurs with less frequency than the other forms of cutaneous lupus; as such, the precise epidemiologic data for the disease is difficult to determine.13 Several small case series have reported that TLE occurs primarily in young women.14,15 A larger study of 40 patients by Kuhn et al12 showed that TLE occurs slightly more often in men than women (55% vs 45%, respectively), with a mean age of onset of 36 years. The mean time from onset of disease to diagnosis is approximately 5 years, and the mean duration of the disease is approximately 8 years.12
Inappropriate activation of the innate immune mechanisms is thought to play an important role in lupus erythematosus, especially type I interferons.11
TLE appears clinically as smooth, shiny erythematous and edematous nonscarring plaques. Typically, the lesions are without surface changes such as follicular plugging, atrophy, or scale.10,12,13 Like other forms of cutaneous lupus erythematosus, photosensitivity is a prominent exacerbating factor. The lesions of TLE involve sun-exposed areas of skin, characteristically the face and neck.12 Onset typically occurs in the summer due to sun exposure.12 In some cases, the skin lesions of TLE may coalesce in the periphery, resulting in a gyrate or annular configuration.12,14,15 Lesions can disappear spontaneously, even if the disease is chronic, with recurrence occurring in the original distribution.12,13,15
In a study by Alexiades-Armenakas et al,10 antinuclear antibodies were detected in a speckled pattern in five of 11 cases (46%) of TLE that were evaluated serologically, in titers ranging from 1:40 to 1:160. Anti-double-stranded DNA, anticentromere, anti-Sm, anti-Ro/SSA, anti-La/SSB, and anti-RNP antibodies have all been reported in the literature to be negative for TLE.10,14
Histologic features of TLE include superficial and deep perivascular and periadnexal lymphocytic infiltration, and abundant mucin deposition in the reticular dermis.10,12,13,15 Unlike classic lupus erythematosus, there is minimal to no epidermal or dermoepidermal involvement in TLE.14 The constellation of clinical findings with histopathologic presentation permits a specific diagnosis of TLE.12,15
Immunohistochemical findings for TLE show predominantly T lymphocytes, typically with a CD4:CD8 ratio greater than 2:1.10 Results of direct immunofluorescence in TLE are typically negative at the dermoepidermal junction or around the papillary and reticular dermal blood vessels.12
The differential diagnosis for TLE includes Jessner lymphocytic infiltrate, discoid lupus erythematosus, systemic lupus erythematosus, reticular erythematous mucinosis, polymorphous light eruption, deep gyrate erythema, granuloma annulare, and pseudolymphoma.12-14 In particular, Jessner lymphocytic infiltrate may be indistinguishable from TLE and has been theorized by Dekle et al13 to possibly represent a spectrum of the same disease. TLE can be distinguished from DLE by its lack of follicular plugging and clearance without scarring.13 REM has also been considered by some authors to be a variant of TLE or DLE, given the photosensitive nature of lesions and the efficacy of antimalarial agents in treatment; however, the lesions of REM typically occur on the central chest or back.12 PMLE can be differentiated from TLE based on its lack of mucin deposition and predominance of CD8 over CD4 lymphocytes, as opposed to TLE, which demonstrates interstitial mucin deposition and CD4 predominance. 10
Treatment of TLE includes systemic therapy with antimalarial agents such as hydroxychloroquine.10,12 Topical corticosteroids can also be used on TLE lesions for local effects.12
A biopsy was performed in our patient and results were consistent with TLE. Our patient was started on oral hydroxychloroquine, 200 mg twice daily. He was counseled on the importance of tobacco cessation and sun avoidance. At our patient’s 1-month follow-up appointment, his TLE lesions were significantly improved.
Emily Guo, BA, is a medical student and Rana Mays, MD, is a dermatology resident at Baylor College of Medicine in Houston.
- Kridin K, Zelber-Sagi S, Khamaisi M, Cohen AD, Bergman R. Remarkable differences in the epidemiology of pemphigus among two ethnic populations in the same geographic region. J Am Acad Dermatol. 2016;75:925-930.
- Payne AS, Stanley JR. Pemphigus. In: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K, eds. Fitzpatrick’s Dermatology in General Medicine. 8th ed. New York, NY: McGraw-Hill; 2012:586-599.
- Korman N. Pemphigus. J Am Acad Dermatol. 1988;18:1219-1238.
- Eversole LR, Kenney EB, Sabes WR. Oral lesions as the initial sign in pemphigus vulgaris. Oral Surg Oral Med Oral Pathol. 1972;33:354-361.
- Amagai M, Tsunoda K, Zillikens D, Nagai T, Nishikawa T. The clinical phenotype of pemphigus is defined by the anti-desmoglein autoantibody profile. J Am Acad Dermatol. 1999;40:167-170.
- Sinha AA, Hoffman MB, Janicke EC. Pemphigus vulgaris: approach to treatment. Eur J Dermatol. 2015;25:103-113.
- Ahmed AR, Spigelman Z, Cavacini LA, Posner MR. Treatment of pemphigus vulgaris with rituximab and intravenous immune globulin. N Engl J Med. 2006;355:1772-1779.
- Hoffman E. [Isolierter Lupus erythematosus tumidus der Gesichtshaut]. Derm Zeitschr. 1909;16:159-160.
- Gougerot H, Burnier M. [Lupus érythémateux tumidus]. Bull Soc Fr Dermatol Syphiligr. 1930;37:1291-1292.
- Alexiades-Armenakas MR, Baldassano M, Bince B, et al. Tumid lupus erythematosus: criteria for classification with immunohistochemical analysis. Arthritis Rheum. 2003;49:494-500.
- Maize JC Jr, Costner M. Tumid lupus erythematosus: a form of lupus erythematosus. Arch Dermatol. 2010;146:451.
- Kuhn A, Richter-Hintz D, Oslislo C, et al. Lupus erythematosus tumidus—a neglected subset of cutaneous Lupus erythematosus: report of 40 cases. Arch Dermatol. 2000;136:1033-1041.
- Dekle CL, Mannes KD, Davis LS, Sangueza OP. Lupus tumidus. J Am Acad Dermatol. 1999;41:250-253.
- Hsu S, Hwang LY, Ruiz H. Tumid lupus erythematosus. Cutis. 2002;69:227-230.
- Ruiz H, Sánchez JL. Tumid lupus erythematosus. Am J Dermatopathol. 1999;21:356-360.