A 66-year-old man with chronic myelomonocytic leukemia type 2 underwent pretransplant conditioning with fludarabine plus melphalan with subsequent matched, unrelated-donor allogeneic hematopoietic stem cell transplant (HCT). Graft vs. host disease (GVHD) prophylaxis included a low dose of methotrexate and oral tacrolimus.
The patient was evaluated for an exanthematous eruption on the abdomen at day 77 post transplant. A bone marrow biopsy and peripheral blood chimerism study (100% donor DNA and 0% recipient DNA) confirmed that his leukemia was in complete remission and that his transplant had been successful. A skin biopsy revealed lichenoid interface dermatitis. Direct immunofluorescence (DIF) was negative. The patient had no gastrointestinal tract symptoms or pulmonary symptoms. These findings were most consistent with grade 1 GVHD; oral tacrolimus therapy was continued, and topical triamcinolone 0.1% cream was added. The eruption cleared after several weeks. At day 200 post transplant, the patient exhibited a widespread exanthematous eruption with blisters and erosions on the trunk (Fig. 1a), glans penis, and proximal extremities, as well as desquamative gingivitis (Fig. 1b), without systemic symptoms. The patient began treatment with IV methylprednisolone for the presumed flare of GVHD.
Bullous pemphigoid complicating cutaneous graft vs. host disease.
Acute GVHD is a frequent complication of HCT and has fatality rates of up to 15%. Its etiopathogenesis is related to targeting by donor T cells of recipient antigens because of lack of self-tolerance. The organs targeted vary, but the skin, liver, and gastrointestinal tract are frequently involved.
Bullous pemphigoid is an autoimmune, subepidermal, mucocutaneous blistering condition that occurs most frequently in elderly persons. It is characterized by large, tense bullae, typically on the trunk and extremities, with oral involvement in approximately 20% of patients. Evaluation with DIF shows linear immunoglobulin (Ig) G and C3 along the basement membrane zone (BMZ); indirect immunofluorescence shows an epidermal pattern of deposition. The target antigens are portions of the bullous pemphigoid 180 (BP180) and bullous pemphigoid 230 (BP230) molecules present in hemidesmosomes. Disease activity correlates with serum levels of antibodies to the NC16A portion of BP180.
Reports of overlap between these two disorders are rare.[3-12] Hofmann and colleagues reported on the frequency of cutaneous BMZ antibodies in the serum of a prospectively collected cohort of patients who had HCT with and without GVHD compared with frequencies in psoriasis patients and healthy control subjects. They noted a significant increase in the frequency of circulating anti-BMZ antibodies in patients with HCT and GVHD (10 of 42, 23.8%) in comparison with patients with HCT without GVHD (none of 18, 0%) (P = 0.025) and healthy control subjects (one of 40, 2.5%) (P = 0.007). One patient with psoriasis had anti-BMZ antibodies (one of 11, 9.1%). Two patients in the group with HCT and GVHD and circulating autoantibodies also had clinical evidence of a blistering disease. The antibodies in patients with GVHD were targeted to several different antigens of the BMZ.
In our patient, initial biopsies stained with hematoxylin and eosin were consistent with grade 3–4 GVHD. However, DIF evidenced discontinuous linear to granular BMZ staining with IgG, IgM, and C3. Repeat biopsies for routine histopathologic examination and DIF supported the diagnosis of bullous pemphigoid arising in the clinical setting of GVHD (Figs. 2 and 3). Of note, no acantholysis was present. Indirect immunofluorescence testing on monkey esophagus showed both intercellular staining and BMZ staining with IgG at a titer of 1 : 40. An epidermal pattern was present on human salt-split skin. Indirect immunofluorescence on rat bladder was negative. Serum testing with enzyme-linked immunosorbent assay revealed a markedly elevated BP180 antibody level (>150 U) and reference values of BP230, as well as anti-desmogleins 1 and 3 antibodies (1.6 U and 4.0 U, respectively).
The clinical picture was most consistent with bullous pemphigoid complicating GVHD. Our patient's repeat DIF of perilesional skin showed continuous strong linear deposition of C3 and granular to linear IgG and IgM along the BMZ, compatible with bullous pemphigoid. In our experience, discontinuous linear to granular BMZ staining with multiple conjugates on DIF is not a feature of cutaneous GVHD. It is possible that autoimmunity to BP180 developed as an epiphenomenon secondary to ongoing interface dermatitis in the clinical setting of cutaneous GVHD, as suggested by Hofmann et al. Rituximab (Rituxan™; Genentech, Inc., San Francisco, CA, USA) therapy was begun in conjunction with a tapering high-dose prednisone treatment and oral tacrolimus therapy. At the 5-month follow-up, the patient's disease was improving, and his BP180 antibody level had decreased (31 U). Intravenous immunoglobulin (Privigen™; CSL Behring, King of Prussia, PA, USA) was added as adjunct therapy after the completion of rituximab treatment. After a further four months, the patient's BP180 antibody level was 10 U, and clinical disease activity was much improved.
We present this rare case of overlap to highlight two important points. Firstly, a broad differential diagnosis is imperative when blistering conditions are encountered, particularly in a transplant recipient. Perilesional biopsy for DIF should be performed in patients with GVHD in whom a vesiculobullous mucocutaneous eruption develops. Secondly, the treatment of cutaneous GVHD and bullous pemphigoid may overlap, and rituximab may be an effective treatment option.