The skin may hold the key to differentiating classic pemphigus from the heterogenous autoimmune syndrome known as paraneoplastic autoimmune multiorgan syndrome.
It is a distinction of critical prognostic importance, because paraneoplastic autoimmune multiorgan syndrome (PAMS) typically is rapidly fatal, according to Dr. Sergei A. Grando, professor of dermatology and biologic chemistry at the University of California, Irvine. "The vast majority of patients die within several months of diagnosis, usually due to infections or respiratory failure, often taking the form of multiorgan system failure."
Dr. Sergei Grando
Two-thirds of patients with PAMS have a known internal malignancy at the time of their first mucocutaneous eruption. The most common of these neoplasms are non-Hodgkin’s lymphoma, which is present in more than 40% of PAMS patients; chronic lymphocytic leukemia, present in 30%; Castleman disease, present in 10%; and thymoma, present in 6%.
When a patient meets the diagnostic criteria for PAMS without having a known cancer, it is appropriate to launch a search for hidden malignancy, said Dr. Grando.
A key distinction between the skin lesions of PAMS and classic pemphigus is that PAMS involves inflammatory macules, papules, plaques, and blisters occurring on an inflammatory background over the trunk and extremities, including the palms and soles, but sparing the scalp.
In contrast, the generally more vesicular blisters and crusted erosions of pemphigus vulgaris display little erythema and usually occur on a noninflammatory background on the scalp, trunk, and extremities (but sparing the palms and soles). The most common location for skin lesions in PAMS is the palms; in pemphigus vulgaris, it is the scalp.
Also, Nikolsky's sign is positive in pemphigus vulgaris, but negative in PAMS, added Dr. Grando, who was among the investigators who first described PAMS a decade ago (Arch. Dermatol. 2001;137:193-206).
PAMS is characterized by severe and diffuse oral mucous membrane involvement, with persistent painful stomatitis because of blisters and erosions, and frequent involvement of other mucous membranes, including the eyes and genitalia. Cicatrizing conjunctivitis is particularly common in PAMS. In contrast, oral mucous membrane involvement in pemphigus is more discrete, with the eyes or other nonoral mucosa rarely involved.
Photo courtesy Dr. Rania Abdel Hay
Pemphigus vulgaris lesions on the trunk of a patient can be seen.
Another key in the differential diagnosis: PAMS is associated with the HLA-DRB1*03 allele, whereas pemphigus vulgaris and foliaceous are strongly associated with the -04 and -14 alleles, respectively.
A hallmark of PAMS is respiratory involvement, with the sloughing of bronchial epithelial cells contributing to small airway occlusion and bronchiolitis obliterans. Classic pemphigus is free of respiratory involvement.
Both the esophagus and colon may be involved in PAMS, whereas only the esophagus is affected in pemphigus vulgaris.
In a published series of 28 PAMS patients, painful and generalized oral stomatitis was present in all 28, respiratory involvement was in 26, death from respiratory failure occurred in 22, and lichenoid skin involvement was present in 19. Only seven patients had no skin lesions (Br. J. Dermatol. 2003;149:1143-51).
At least five different subtypes of PAMS can be distinguished on the basis of the skin disease manifestations they most resemble. These subtypes of pemphiguslike PAMS include paraneoplastic pemphigus, bullous pemphigoid–like, erythema multiforme–like, lichen planus–like, and graft-vs.-host-disease–like versions of PAMS.
Dr. Grando eschews the term "paraneoplastic pemphigus" as too restrictive. After all, true pemphigus doesn’t usually affect the lungs, he noted.
Photo (c) Elsevier Inc.
This image shows inferior labial mucosa of a patient with paraneoplastic autoimmune multiorgan syndrome.
Whereas most patients with classic pemphigus respond well to high-dose corticosteroids and recalcitrant disease can be effectively treated with cytotoxic agents, cyclosporine, intravenous gamma globulin, and other second-line agents, PAMS is resistant to all conventional forms of therapy.
"What can we offer? Really not much," Dr. Grando said during his presentation at the World Congress of Dermatology in Seoul, South Korea.
The preferred treatment regimen is a combination of prednisone and cyclosporine, with or without cyclophosphamide. Monthly courses of IVIG can buy patients a few extra months, he added.
Dr. Grando declared having no relevant financial interests.