LAUSR

Dear Editor, Pemphigus vulgaris (PV) is an intraepidermal autoimmune blistering disease that develops due to circulating autoantibodies directed against structural components of desmosomes, most commonly desmogleins 1 and 3. For decades, the mainstay of PV therapy were corticosteroids and steroid-sparing agents; however, recent guidelines included rituximab as the first-line therapy of PV. We present a patient with paradoxical worsening of PV after the first cycle of rituximab therapy. A 56-year-old woman presented with a 5-month history of multiple blisters and erosions on her trunk, scalp, oral mucosa, and genital area (Figure 1A,B). The diagnosis of PV was confirmed by direct immunofluorescence (DIF; intercellular IgG and C3 deposits within the epidermis), histology (suprabasal acantholysis), indirect immunofluorescence (IgG intercellularly, titer 1:160), and ELISA for Dsg1 and Dsg3 antibodies (47.25 and 191.27 RU/ml, respectively). The patient was treated with prednisolone at the initial dose of 1 mg/kg/day, that is, 60 mg/day, and azathioprine 100 mg/day, resulting in significant improvement. Thirteen months later, while on prednisolone 30 mg/ day, the disease exacerbated, with the rise in values of both Dsg1 and Dsg3 antibodies (138.77 and 274.40 RU/ml). The first cycle of rituximab, including 1000 mg on days 1 and 15, was administered. At the follow-up visit 4 weeks after the second infusion, new erosions with clinical signs of secondary bacterial infection were noticed. Oral ciprofloxacin of 500 mg bid was employed, and on its seventh day, erythematous macules occurred abruptly on the patient's trunk, coalescing rapidly with the development of large, flaccid blisters and intensely erythematous erosions (Figure 1C,D). The diagnosis of ciprofloxacin-induced toxic epidermal necrolysis (TEN) has been suspected. Pulse-methylprednisolone therapy was administered immediately at the initial dose of 80 mg/day i.v. However, DIF revealed intercellular IgG and C3 deposits, and histology showed suprabasal acantholysis without epidermal necrosis or vacuolar degeneration of basal keratinocytes. The values of anti-Dsg1 and Dsg3 were 174.10 and 184.02 RU/ml. Swabs from the erosions revealed Klebsiella pneumoniae; therefore, ertapenem 1 g i.v./day was given for 7 days. After 6 days of pulse-methylprednisolone therapy, significant improvement occurred, and the treatment with 30 mg/day of prednisolone was continued. Rituximab is a chimeric anti-CD20 monoclonal antibody, which induces apoptosis of B-lymphocytes after binding to CD20 molecules on their surface. Rare cases of paradoxical worsening of PV after rituximab treatment were reported. In our patient, worsening occurred after the second infusion of the first cycle of rituximab therapy, which could be explained by the production of human antichimeric antibodies to rituximab due to incomplete B lymphocyte depletion after the first infusion of rituximab. Furthermore, rituximab may also cause depletion of regulatory B cells (Bregs), such as B10 cells, which also express CD20. The imbalance between Bregs and pathogenic clones of B cells could induce worsening of PV. Feldman suggested that a disturbance of the balance between Bregs and pathogenic clones of B cells could cause worsening of the disease. It has also been hypothesized that specific anti-Dsg3 T cells may be involved in this process. Since severe exacerbation of PV in our patient occurred on the seventh day of ciprofloxacin therapy, with a sudden onset of rapidly