Paraneoplastic autoimmune multiorgan syndrome (PAMS): Beyond the single phenotype of paraneoplastic pemphigus

Abstract

Paraneoplastic autoimmune multiorgan syndrome (PAMS) is characterized by a heterogenous group of signs and symptoms including severe desquamative stomatitis, a polymorphous cutaneous eruption, humoral immunity against plakin proteins, contribution of cell-mediated autoimmunity and commonly a progressive respiratory failure. Autoantibodies in PAMS target a wide array of antigens including plakins, cadherins, alpha-2-macroglobulin like 1 (A2ML1), BP180, plakophilin-3, and several neuromuscular antigens. Originally described as paraneoplastic pemphigus in 1990 due to some of its clinical and immunologic similarities to classic pemphigus (pemphigus vulgaris and pemphigus foliaceus), PAMS is a multiorganopathy with several distinct features from these classic forms of pemphigus. Epidemiologically, PAMS is associated with underlying neoplasia and has a differing HLA-II allele predisposition compared to classic forms of pemphigus. Clinically, lesion morphology is polymorphous, and lesion distribution fundamentally differs from that seen in classic pemphigus. PAMS has a significantly higher mortality rate and a poorer response to treatments typically effective in pemphigus. Histologically, PAMS is characterized by the presence of interface dermatitis, vacuolar changes, and dyskeratotic keratinocytes which are not seen in classic pemphigus. PAMS demonstrates not only intercellular IgG as seen in classic pemphigus, but the presence of linear basement membrane zone deposition. Antibodies against desmoglein 3 (Dsg3) map to a broader array of epitopes than in pemphigus vulgaris and there is a higher prevalence of complement binding anti-Dsg3 IgG autoantibodies in PAMS. Autoantibodies can in rare cases be absent in the more cell-mediated form of PAMS. Considering these numerable differences, we review the entity of PAMS, and provide similarities and differences to classic forms of pemphigus.

Keywords: Autoimmune blistering disease; Bronchiolitis obliterans; Desmoglein; Immunobullous disease; Pemphigus.