1. ¹Division of Hematology-Oncology, Department of Paediatrics, Hôpital Sainte-Justine, 3175, chemin de la Côte-Sainte-Catherine, Montréal, Québec, Canada H3T 1C5
2. ²Department of Dermatology, Hôpital Sainte-Justine, Université de Montréal, Montréal, Canada
3. ³Department of Pathology, Hôpital Sainte-Justine, Université de Montréal, Montréal, Canada
4. ⁴Centre de Recherche, Hôpital Sainte-Justine, Université de Montréal, Montréal, Canada

In a paper published in this journal, Szabolcs et al¹ reported the unusual case of a young boy who experienced bullous pemphigoid in association with chronic graft-versus-host disease (GVHD) after unrelated cord blood transplantation. Successful treatment was achieved by the combination of anti-CD25 and anti-CD20 antibodies along with steroids and other immunosuppressive agents. Pemphigus foliaceus (PF) is also an immune-mediated skin disease and is also unusual after hematopoietic stem cell transplantation (HSCT), as there is no report to date of PF after HSCT. We report here a case of PF after unrelated cord blood transplantation, successfully treated with anti-CD20 antibody.

A 6-year old boy with Philadelphia chromosome-positive B-lineage acute lymphoblastic leukemia in first complete remission received an HLA-mismatched unrelated cord blood transplant in July 2002. The conditioning regimen consisted of fractionated total body irradiation (total dose 1200 cGy), etoposide (60 mg/kg) and cyclophosphamide (3600 mg/m²). Cyclosporine, rabbit antithymocyte globulin (Thymoglobuline, Sangstat, CA, USA, total dose 8 mg/kg) and methylprednisolone (2 mg/kg/day from day -2, tapering beginning on day +20) were given as prophylaxis for GVHD. Donor and recipient differed for one B and one DRB1 allele.

Neutrophils engrafted on day +39 and platelets on day +69. On day +101, he was readmitted for profound thrombocytopenia (platelet count 4 10⁹/l) refractory to platelet transfusions. A bone marrow aspirate showed normal megakaryocytes in an otherwise hypercellular marrow, compatible with a diagnosis of immune thrombocytopenic purpura and complete remission of the leukemia. He was initially treated with intravenous methylprednisolone (4 mg/kg/day in divided doses), weekly immunoglobulins (1 g/kg) and cyclosporine was continued (aiming for whole blood trough levels of 200–300 mg/l). Since only a partial response had been achieved, four doses of vincristine were given on days +155, +183, +194 and +201 (first dose 2 mg/m², subsequent doses of 1 mg/m²) with a good response. Prednisone was tapered and then discontinued after a few weeks. Weekly immunogloglulins (0.5 g/kg) were continued as maintenance therapy.

On day +292, he was re-admitted with a 3-week history of crusted papulovesicular cutaneous lesions on the face, eyes, mouth, inguinal areas and genital organs. Microscopic examination of a skin biopsy demonstrated an acantholytic bullous dermatitis within the granular layer (Figure 1). In many foci, the acantholysis extended down along the follicular epithelium in association with abundant 'corps grains'. Immunofluorescence demonstrated intense IgG-type intercellular deposits within the granular layer and superficial epidermis with decreasing intensity toward the basal layer. Strong IgG labeling of the 'corps grains' was seen (Figure 2). These findings confirmed the diagnosis of PF. The investigation for serum antibodies usually found in paraneoplastic PF was negative. Antibodies against intercellular junctions were detected in the serum (1/160). Treatment with prednisone 2 mg/kg/day and topical steroid cream was started on day +308. Cyclosporine was maintained. Owing to worsening lesions, dapsone 2 mg/kg/day was added on day +317. Amlodipine was changed to labetalol because of reports of amlodipine-related PF. Immunoglobulins were initially maintained at the previous dose (0.5 g/kg/week), but in the face of an absence of clinical response, a 4-day course of immunoglobulins (0.5 mg/kg/day) was given on days +328 to +333. Cutaneous superinfection by S. aureus and P. aeruginosa was treated with antibiotics. Although the lesions of the face, eyes, mouth and armpits improved, new lesions over the trunk and extremities appeared. Repeat biopsy confirmed the persistence of PF. Treatment with four weekly doses of rituximab (anti-CD20 monoclonal antibody, 375 mg/m²/week) was initiated on day +338. In the few weeks following anti-CD20 treatment, there was a dramatic improvement of the skin allowing tapering of the steroid dose progressively. BCR-ABL was found positive for the first time after transplantation on day +436, and he suffered an overt medullary leukemia relapse on day +464. Second remission was obtained with imatinib mesylate and he received a second cord blood transplant 562 days after the first transplantation. At the time of this report, 10 months after the second transplant, he remains in second complete remission, with no dermatologic abnormalities.

Figure 1.

Pemphigus foliaceus after unrelated cord blood transplantation – acantholysis within the granular layer, HPS 20 PDF (3056KB).

Full figure and legend (126K)

Figure 2.

Pemphigus foliaceus after unrelated cord blood transplantation – IgG intercellular deposits within the granular layer, IF IgG 40.

Full figure and legend (95K)

PF is an antibody-mediated autoimmune disease directed against the extracellular portions of desmoglein 1, a component of intercellular junctions. PF may be iatrogenic. In our patient, however, PF progressed after cessation of amlodipine, and was resistant to steroids and dapsone, an unusual finding in iatrogenic PF. PF may also be a paraneoplastic process. In our patient, however, PF preceded relapse by 6 months, BCR-ABL was not detected by PCR in the marrow when PF appeared, PF did not recur with leukemic relapse, and there was no paraneoplastic antibody in the serum. Antibody-mediated immune diseases after hematopoietic stem cell transplantation (HSCT) may be considered as manifestations of chronic GVHD. However, our patient experienced no other features of GVHD, except for immune thrombocytopenia. 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. Surveys of unrelated cord blood transplantations should thus be designed to capture unusual immune adverse events, as the nature and the frequency of these events may be different from those observed after transplantation with other stem cell sources.

The resolution of the skin lesions after administration of rituximab suggests that this treatment was effective in the treatment of this unusual antibody-mediated immune manifestation. Rituximab has been used successfully in the treatment of one case of paraneoplastic pemphigus⁵ and in one case of spontaneous PF.⁶ Rituximab has been used in the treatment of many other autoimmune diseases,⁷ including cytopenias occurring after HSCT.^8,9 Recently, anti-CD20 has been reported useful in the treatment of refractory chronic GVHD.¹⁰ Taken together, these reports suggest that anti-CD20 should be considered early in the treatment of steroid-refractory GVHD and other more unusual immune-mediated complications after HSCT.