Presented by: John Durkin, MD and Carrie Ann Cusack, MD
Drexel University College of Medicine
May 16, 2016
Pemphigus vulgaris is an autoimmune blistering disease of the skin. The etiology of PV usually stems from auto antibodies directed against cadherens, specifically desmoglein 1 and desmoglein 3. The antibodies impede the ability of desmoglein 1 and 3 from participation in keratinocyte cell to cell adhesion, leading to blister formation. Desmoglein 1 has limited expression in the mucous membranes while desmoglein 3 is equally expressed in the skin and mucous membranes. It is thought that antibodies directed only against desmoglein 3 will cause mucosal disease as there is limited desmoglein 1 to compensate, while antibodies only against desmoglein 1 do not cause disease because desmoglein 3 is upregulated in order to compensate. Antibodies against both desmoglein 1 and 3 cause both mucosal and cutaneous disease.
On histology one can see a suprabasilar split where the basal keratinocytes lose their attachment to all cells except at the dermal epidermal junction, leaving a tombstoning appearance. Direct immunofluorescence shows intercellular IgG4 and less often C3 which is predominantly in the lower epidermis.
The gold standard of treatment for PV is prednisone with a starting dose of 1 mg/kg. The dose is tailored to clinical response and sometimes serum antibody measurements. Significant morbidity with chronic high dose corticosteroids has led to the use of supplemental immunosuppressive agents such as azathioprine, mycophenolate mofetil, and cyclophosphamide. Plasmapheresis is also used to achieve rapid clinical remission. Several studies have shown the usefulness of IVIg for steroid unresponsive pemphigus vulgaris. More recently, rituximab, a chimeric anti CD-20 monoclonal antibody, has been shown to be a useful treatment for pemphigus vulgaris.
Rituximab, a potent inhibitor of antibody producing B cells, depletes normal and pathogenic B cells while sparing terminally differentiated plasma cells. A review of rituximab in the use of PV showed that 90-95% of patients had clinical remission within less than 6 weeks of treatment. The study also showed that relapse rates were greater than 50%. Proposed mechanisms for relapse and resistance include persistent memory and germinal B cells in the spleen and lymph nodes and the appearance of novel lineages of autoreactive B cells following treatment, and the formation of antibodies against the rituximab molecule. There is concern that overuse of rituximab might increase the chance of severe infections in pediatric populations as well as many experts being concerned about childhood immunization titers. Some physicians have used replacement IVIG or prophylactic antibiotics due to the concern of severe infection.
Several fully humanized anti-CD 20 biologics are under study for the treatment of lymphoma including veltuzumab, obinutuzumab, and ofatumumab and may be potential future treatment options for refractory pemphigus vulgaris. They would offer the benefit of subcutaneous administration and theoretically less autoantibody formation.
Huang A, Madan RK, Levitt J. Future therapies for pemphigus vulgaris: Rituximab and beyond. J Am Acad Dermatol. 2016;
Leshem YA, David M, Hodak E, et al. A prospective study on clinical response and cell-mediated immunity of pemphigus patients treated with rituximab. Arch Dermatol Res. 2014;306: 67-74.
Hammers CM, Chen J, Lin C, et al. Persistence of anti-desmoglein 3 IgG(1) B-cell clones in pemphigus patients over years. J Invest Dermatol. 2015;135:742-749.
Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370:1101-1110.
