Combination treatment of bullous pemphigoid with anti-CD20 and anti-CD25 antibodies in a patient with chronic graft-versus-host disease

Abstract

Summary:In this case report we describe a novel treatment with two chimeric monoclonal antibodies (MoAb) targeting the autoimmune B cell clone responsible for bullous pemphigoid (BP) as a manifestation of steroid refractory chronic graft-versus-host disease (GVHD) that developed after unrelated cord blood transplantation. Monitoring the BP-specific circulating antibodies and CD25-expressing activated T lymphocyte subset led us to combine anti-CD20 (Rituximab) mediated B cell ablation with anti-CD25 (Daclizumab) therapy to block CD4 + T cell help. Complete clinical and serologic response was achieved within 4 weeks of initiation of therapy allowing global immunosuppression to be dramatically reduced. Bone Marrow Transplantation (2002) 30, 327-329. doi:10.1038/sj.bmt.1703654 Keywords: transplantation; GVHD; bullous pemphigoid; rituximab; daclizumab A 10-year-old boy was diagnosed with B-precursor ALL at 18 months of age. After 6 months of treatment he had CNS recurrence followed shortly by a bone marrow relapse. He received standard chemotherapy for 3 years with craniospinal irradiation. Four years off therapy he sustained a second isolated bone marrow relapse. During chemotherapy he was noted to have a testicular relapse that was treated with involved-field irradiation and additional chemotherapy. He was in his fourth remission when he arrived at our center.Following total body irradiation (1350 cGy total), 3 days of melphalan (135 mg/m 2 total) and ATG (90 mg/kg total) he was transplanted with an O+, male, 4/6 HLA-matched unrelated umbilical cord blood graft in March 1999 and engrafted with full donor chimerism. The patient and donor were mismatched at one HLA-A and HLA-DRB1 loci, During the first 3 months post transplant the patient experienced pancreatitis, acute renal failure secondary to rhabdomyolysis, and pulmonary hemorrhage. He developed grade 3 acute GVHD of the gut 5 weeks after transplant that was controlled with steroids, FK506, and 10 weeks of anti-CD25 monoclonal antibody (daclizumab). The patient had multiple readmissions for pulmonary edema and respiratory failure secondary to renal insufficiency and hemolytic uremic syndrome that continued to require intermittent hemodialysis. Four months after transplant he was readmitted with hypertensive encephalopathy presumed secondary to FK-506 toxicity. While FK-506 was discontinued he developed GVHD of the skin, controlled by the combination of steroids and the addition of azathioprine and mycophenolate mofetil.Despite continued immunosuppressive therapy with mycophenolate mofetil at 30 mg/kg/day and methylprednisolone at 1 mg/kg/day (Table 1), 7 months after transplant pruritic hemorrhagic bullae developed over his entire body. Skin biopsy of a bulla revealed a subepidermal blister with spongiosis, and hemorrhagic infiltration of lymphocytes, and eosinophils. Direct immunofluorescence of tissue sections revealed linear deposits of IgG and C3 at the basement membrane. Indirect immunofluorescence (IDIF) on 1 m NaCl split skin 1 revealed a linear band of I...

Successful anti-CD20 antibody treatment of pemphigus foliaceus after unrelated cord blood transplantation

“…The most commonly reported antibody-mediated immune diseases after HSCT are hypo-or hyperthyroidism, myasthenia gravis and immune cytopenias. 2 There are only a few case reports of antibody-mediated skin diseases after allogeneic HSCT, 1,3,4 and, to our knowledge, PF has never been reported after HSCT. Together with the recent report of bullous pemphigoid after cord blood transplantation, 1 this report shows that immune complications rarely or never reported after bone marrow transplantation may arise after cord blood transplantation.…”

B-cell involvement in chronic graft-versus-host disease

“…68 Additionally, treatment with rituximab led to an incomplete response in a bullous pemphigoid-cGVHD patient. 69 But when adding daclizumab, an anti-CD25 antibody, a complete clinical response in combination with a complete decrease in bullous pemphigoid titer was observed. Daclizumab may have interrupted the helper function of CD4 + T cells, which facilitate the secretion of autoantibodies against bullous pemphigoid antigen 2 (BPAG2) by CD20-plasma cells.…”

“…For this purpose, a number of studies have analyzed the potential of rituximab in patients with cGVHD and have observed several positive effects, mostly including skin manifestations of cGVHD. 69,71,72,[86][87][88][89][90] A summary of all these studies is presented in Table 3. However, among many of the responding cGVHD patients, rituximab failed to establish a complete recovery.…”

“…Cutler et al Durable normalization of thrombocytopenia and complete response 1 out of 1 of oral lichen planus, skin, xerophthalmia. Szabolcs et al 69 In bullous pemphigoid-cGVHD, treatment led to a decrease in 1 out of 1 bullous pemphigoid titer, however inadequate. Addition of daclizumab was necessary to achieve complete clinical response as well as complete decrease of BP titer.…”

“…50 Also, the fact that several positive effects of treatment with rituximab in cGVHD patients have been found, further strengthens the involvement of B cells in cGVHD. 69,71,72,[86][87][88][89][90] Alternatively, a potential role of B cells as antigen-presenting cells in cGVHD can be considered. Antibodies in the plasma membrane (B-cell antigen receptors) may facilitate the uptake of extracellular antigens via receptor-mediated endocytosis.…”