Recognizing toxic epidermal necrolysis-like acute cutaneous lupus erythematosus ASAP

By Warren R. Heymann, MD, FAAD
November 10, 2021
Vol. 3, No. 45

ASAP, the well-recognized acronym for “as soon as possible,” takes on special significance for dermatologists confirming the diagnosis of toxic epidermal necrolysis (TEN). In 2004, Ting et al introduced an alternative definition of the ASAP acronym — Acute Syndrome of Apoptotic Pan-epidermolysis, encompassing classical drug-induced TEN and the TEN-like entities: TEN-like graft-versus-host disease, TEN-like pseudoporphyria, and TEN-like acute cutaneous lupus erythematosus (ACLE). (1) Drug-induced linear IgA dermatosis may also present clinically as TEN. (2) The common denominator in ASAP is hyperacute apoptotic epidermal injury resulting in potentially life-threatening massive epidermal separation from the dermis. This commentary will focus on the expanding literature on TEN-like ACLE.

For lupus patients, bullae may be appreciated in three circumstances (with the realization that lupus patients can have other blistering disorders ranging from poison ivy, herpes zoster, bullous pemphigoid, etc.): 1) bullous lupus erythematosus (BLE); 2) Rowell syndrome (RS); and 3) TEN-like ACLE.

BLE is a rare bullous dermatosis in patients with systemic lupus erythematosus. It is characterized by clinical and histologic features, resembling either bullous pemphigoid or dermatitis herpetiformis, and a heterogeneous immunologic profile, characterized by autoimmunity to components of type VII collagen, much like epidermolysis bullosa acquisita. Histologically, it is characterized by a subepidermal blister with abundant neutrophils. Direct immunofluorescence (DIF) demonstrates deposits of IgG, IgA, IgM, and complement at the basement membrane zone. (3)

RS manifests as a combination of lupus erythematosus (LE) and erythema multiforme (EM)-like lesions and a characteristic immunologic pattern, including a speckled ANA pattern, positive anti-Ro/SSA or anti-La/SSB, and positive rheumatoid factor. Histologically, necrotic keratinocytes and a negative DIF are noted. The precise diagnostic criteria for RS are still under debate. (4)

TEN-like ACLE is considered rare. Of 9,074 patients diagnosed with cutaneous LE and/or SLE, 6 patients justified the diagnosis of SJS/TEN-like lupus erythematosus. (5) (Personally, I can think of at least 3 cases I have encountered. It is not science, but I always assume — perhaps mistakenly — that any disease I have seen more than once cannot be all that rare.)

In their review of 43 cases of TEN-like ACLE (37 women, 6 men), Romero et al found that the diagnosis of SLE or subacute cutaneous lupus erythematosus (SCLE) was either previously confirmed or established at the time of diagnosis of TEN-like ACLE in 41 patients. Fever was present in 59% of patients. The onset of TEN-like ACLE was either subacute (full evolution of lesions > 14 days) in 73% or acute in 27% for those patients where timing could be assessed. Thirteen cases did not clarify the nature of disease onset. The skin lesions often presented initially on sun-exposed sites (29 patients) and involved one or more mucous membranes (21 patients). A new medication may have caused the TEN-like ACLE in 67% of the patients. Systemic corticosteroids either alone or combined with hydroxychloroquine, intravenous immunoglobulin, or mycophenolate mofetil were the most commonly used treatment. Patients with TEN-like ACLE patients had an 89% survival. (6) In the series of 9074 patients, 50% had epidermal necrolysis as the initial presentation of lupus with a median time from onset of 1.5 months (0-48 months). The median duration between initial rash and epidermal detachment was 4.5 days (3-14 days). All had internal organ involvement (hematologic and renal) and high SLE Disease Activity Index scores. Most patients recovered with systemic corticosteroids, antimalarial drugs, and/or immunosuppressants. None had disease recurrence. (5)

TEN-like ACLE may also be observed in the pediatric population. Battarai et al reported the case of an 11-year-old girl with a 30-day history of fever, photosensitivity, and alopecia. According to the authors, “a total of 13 patients of TEN-like lupus have been reported worldwide in the pediatric age group (female-to-male ratio of 12:1). Age at disease onset ranged from 2 to 18 years. All the reported cases had clinical and serological evidence of lupus and histopathological evidence of TEN-like changes. Only 4 cases including our case had epidermal necrolysis as the presenting manifestation of lupus. Nine out of 13 children (69%) had evidence of major organ involvement (CNS, renal, and cardiac). All (13) were treated with corticosteroids. Six (6) among 13 patients also received IVIg. Few of them were also treated with plasmapheresis and immunosuppressants like cyclophosphamide, mycophenolate mofetil, and azathioprine. Among 13 children with TEN-like lupus, 10 (76%) recovered, and the mortality rate was 23% (3/13), higher than the general mortality of childhood lupus (~10%). A high mortality in children with TEN-like lupus might be due to late diagnosis, delay in treatment, and associated severe systemic manifestations and infections.” (7)

Other considerations. Santiago et al reported a case of TEN-like subacute cutaneous lupus erythematosus (SCLE) presenting simultaneously with small cell carcinoma of the lung; both resolved with surgical lobectomy of the cancer. (8) Collantes-Rodriguez et al reported 50+ year-old man who developed eruptive melanocytic nevi within months of resolution of his TEN-like lupus. (9)

In conclusion, recognition (ASAP!) of TEN-ACLE is crucial to avoid misdiagnosis and allow institution of appropriate therapy. Further study on how to manage massive apoptotic injury (mediated by Fas and Fas-ligand interactions and elevated cytokines) is warranted.

Point to Remember: When assessing patients for TEN, remember that entities than classical drug-induced disease may present similarly. There are an increasing number of reports of TEN-like ACLE, and this diagnosis should be considered, especially in children and adults with a photosensitive distribution.

Our expert’s viewpoint

Philip R. Cohen, MD, FAAD
Dermatologist
San Diego Family Dermatology, National City, CA
Adjunct Professor of Dermatology
Touro University California College of Osteopathic Medicine, Vallejo, CA

Toxic epidermal necrolysis-like acute cutaneous lupus erythematosus (TEN-like ACLE) is a form of cutaneous lupus erythematosus that is included as one of the diseases in the category of acute syndrome of apoptotic pan-epidermolysis (ASAP) (1); the distinctive acronym provides a useful memory aid, similar to other newly minted acronyms such as ME KLMNOP (for a new etiology of nail onycholysis and pterygium), MUSK IN A NEST (for collision tumors), and CALM HOG FLED PEN AND GETS BACK (for painful dermal tumors) (10-12). Indeed, based upon not only our patient’s active systemic lupus erythematosus, but also his photodistributed erythematous patches and accompanying vesicles on the helical rims and oral palate, bullous systemic lupus erythematosus was the initial impression; however, progression of his skin lesions and the biopsy result established the diagnosis of TEN-like ACLE after drug-induced (mycophenolate mofetil) toxic necrolytic erythema was entertained and excluded (6). Whether the presence of paraneoplastic disease establishes an increased susceptibility for subacute lupus erythematosus patients to develop TEN-like ACLE remains to be determined (8,13). In summary, there are two essential caveats regarding TEN-like ACLE: (1) the diagnosis of TEN-like ACLE needs to be entertained (especially in patients with either systemic lupus erythematosus or subacute lupus erythematosus) and (2) it may not be easy to readily differentiate TEN-like ACLE from TEN or bullous systemic lupus erythematosus in a lupus erythematosus patient.

1. Ting W, Stone MS, Racila D, Scofield RH, Sontheimer RD. Toxic epidermal necrolysis-like acute cutaneous lupus erythematosus and the spectrum of the acute syndrome of apoptotic pan-epidermolysis (ASAP): a case report, concept review and proposal for new classification of lupus erythematosus vesiculobullous skin lesions. Lupus. 2004;13(12):941-50.

2. Prieto-Barrios M, Velasco-Tamariz V, Tous-Romero F, Burillo-Martinez S, Zarco-Olivo C, Rodriguez-Peralto JL, Ortiz-Romero PL. Linear immunoglobulin A dermatosis mimicking toxic epidermal necrolysis: a case report of etanercept treatment. Br J Dermatol. 2018 Mar;178(3):786-789.

3. Sebaratnam DF, Murrell DF. Bullous systemic lupus erythematosus. Dermatol Clin. 2011 Oct;29(4):649-53.

4. Gallo L, Megna M, Festa B, Stellato P, di Pinto R, Fabbrocini G, Ferrillo M. Rowell Syndrome: A Diagnostic Challenge. J Clin Aesthet Dermatol. 2020 Apr;13(4):40-42.

5. Tankunakorn J, Sawatwarakul S, Vachiramon V, Chanprapaph K. Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis-Like Lupus Erythematosus. J Clin Rheumatol. 2019 Aug;25(5):224-231.

6. Romero LS, Bari O, Forbess Smith CJ, Schneider JA, Cohen PR. Toxic epidermal necrolysis-like acute cutaneous lupus erythematosus: report of a case and review of the literature. Dermatol Online J. 2018 May 15;24(5):13030/qt5r79d67k.

7. Bhattarai D, Vignesh P, Chaudhary H, Bharadwaj N, Saini L, Gupta K, Rawat A. Epidermal necrolysis as the presenting manifestation of pediatric lupus. Pediatr Dermatol. 2020 Nov;37(6):1119-1124.

8. Santiago L, Mascarenhas R, Tellechea Ó, Gonçalo M. Toxic epidermal necrolysis-like subacute cutaneous lupus erythematosus associated with lung carcinoma. BMJ Case Rep. 2019 Oct 13;12(10):e231152

9. Collantes-Rodríguez C, Jiménez-Gallo D, Arjona-Aguilera C, Ossorio-García L, Villegas-Romero I, Báez-Perea JM, Linares-Barrios M. Eruptive melanocytic nevi in a patient with toxic epidermal necrolysis-like cutaneous lupus. Lupus. 2018 Jun;27(7):1220-1222.

10. Forouzan P, Cohen PR. Methyl ethyl ketone-related loss of matrix with nail onycholysis and pterygium (ME KLMNOP): case report of a new etiology for onycholysis and pterygium. Cureus. 2020;12(11):e11597.

11. Cohen PR, Calame A. Multiple skin neoplasms at one site (MUSK IN A NEST): a comprehensive review of basal cell carcinoma and benign or malignant “collision” tumors at the same cutaneous location. Clin Cosmet Investig Dermatol. 2020;13:731-741.

12. Cohen PR, Erickson CP, Calame A. Painful tumors of the skin: “CALM HOG FLED PEN AND GETS BACK”. Clin Cosmet Investig Dermatol. 2019;12:123-132.

13. Richardson TT, Cohen PR. Subacute cutaneous lupus erythematosus: report of a patient who subsequently developed a meningioma and whose skin lesions were treated with isotretinoin. Cutis. 2000;66(3):183-188.

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