Rapid response of treatment-resistant pemphigus foliaceus to the anti-CD20 antibody rituximab

Sir, Pemphigus foliaceus is a bullous autoimmune disease with acantholytic blistering occurring just below the stratum corneum.1 Autoantibodies target desmoglein 1 (dsg 1) and, in contrast to pemphigus vulgaris, mucous membranes are not affected. Although pemphigus foliaceus shows a milder clinical course than pemphigus vulgaris, it was fatal in about 60% of patients in the preglucocorticoid era. We here report on a patient with pemphigus foliaceus refractory to therapy with various immunosuppressives who responded well to treatment with the chimeric anti‐CD20 monoclonal antibody (mAb) rituximab. A 56‐year‐old woman presented with a 2·5‐year history of pemphigus foliaceus with crusted erosions primarily involving the seborrhoeic areas of trunk and head as well as the upper extremities. Diagnosis was confirmed by histology, direct and indirect immunofluorescence and detection of antibodies to dsg 1 in the patient's serum. There was no evidence of a drug‐induced aetiology. Previous therapies included methylprednisolone, initially 80 mg day−1, in combination with azathioprine (100 mg day−1) for 14 months, followed by ciclosporin (200 mg day−1) in combination with prednisolone for another 15 months, but did not control the disease. Therefore, following a previous protocol,2 we initiated a pulse therapy with cyclophosphamide (500 mg once intravenously) and dexamethasone (100 mg intravenously on three consecutive days) intravenously on three consecutive days. In between pulses, oral cyclophosphamide (50 mg day−1) was administered for the first 6 months. Pulse treatment was repeated 21 times in 4‐week intervals. Subsequently, the patient received 20 three‐day pulses of only dexamethasone in 4–6‐week intervals. These pulse treatments, however, also only partially improved the clinical condition and new lesions continued to develop. We therefore decided to initiate an anti‐CD20 mAb therapy. Four rituximab infusions were given intravenously at a dose of 375 mg m−2 each and frequency of one per week. Two weeks after the final rituximab infusion, the patient received her final 3‐day pulse of dexamethasone (100 mg day−1). Two weeks after discontinuation of rituximab, the patient's lesions had completely healed and new blisters have not developed since. The patient's serum levels of antibodies to dsg 1 dramatically decreased and returned to normal (Fig. 1). In contrast, IgG antibody levels to herpes simplex viruses 1 and 2 (HSV1/2) and varicella zoster virus (VZV) did not change significantly during rituximab therapy (Fig. 1). Treatment with the chimeric antibody was tolerated well; adverse effects were only observed during the first infusion where the patient experienced nausea, vomiting, chills, cough and throat irritation; these improved rapidly after reducing the infusion rate of rituximab and administering antihistamines. Subsequent infusions were tolerated without side‐effects; especially, infections did not occur. Changes in serum levels of antibodies to desmoglein 1 (dsg 1), herpes simplex viruses (HSV)1/2 (IgG) and varicella zoster virus (VZV) (IgG) during treatment with rituximab. On the time axis, week 0 indicates the start of rituximab infusions. Administrations of rituximab and dexamethasone pulses are indicated by arrows. The upper limit of physiological antidsg 1 levels is marked by a dotted line. CD20 is a B lymphocyte‐restricted antigen and is expressed on the cell surface of pre‐B and mature B lymphocytes and a subpopulation of plasma cells.3 CD20 ligation by rituximab results in complement‐mediated and antibody‐dependent cytotoxicity, inhibition of B‐cell proliferation, and induction of apoptosis. Rituximab, which has been introduced for the treatment of B‐cell malignancies, has also been used for therapy of antibody‐mediated autoimmune diseases such as autoimmune haemolytic anaemia and thrombocytopenia, cold agglutinin disease and Wegener's granulomatosis.4–7 In the present study, based on the hypothesis that the chimeric anti‐CD20 antibody would deplete B lymphocytes and remove the antibodies to dsg 1 from the circulation, rituximab was given to a pemphigus foliaceus patient who had been refractory to various immunosuppressive treatment modalities for almost 7 years. Indeed, antibodies to dsg 1, which have been clearly shown to be pathogenically relevant and to correlate with disease activity in pemphigus foliaceus,8, 9 decreased to normal values within 12 weeks after initiation of therapy and blister formation stopped. Interestingly, however, antibody levels against HSV1/2 and VZV were not significantly affected by rituximab. This observation is in line with earlier reports describing normal levels of total serum IgG after rituximab treatment.3 It thus appears conceivable that the cell clone producing antibodies to dsg 1 is CD20+ and is thus being depleted by rituximab while other IgG‐secreting clones are CD20– and therefore not affected.3 Dexamethasone pulses had been used in this patient in intervals of 4 weeks and finally 6 weeks for a period of 2 years just prior to initiating rituximab; however, new lesions continued to develop. Therefore, it is most unlikely that the final pulse treatment, given right after the rituximab infusions, led to the favourable outcome in this patient. Complete remission during a follow‐up period of up to now 28 weeks after last application of dexamethasone furthermore points to an efficacy of rituximab. While rituximab has recently been reported to improve ulcerative stomatitis in two patients with CD20+ follicular lymphoma‐associated paraneoplastic pemphigus,10, 11 its administration has not yet been described in other subsets of pemphigus. Our case, for the first time, illustrates an impressive reduction of serum levels of antibodies to dsg 1 associated with complete clinical remission upon initiation of rituximab therapy. Although further studies with longer follow‐up are required on a larger series of patients, rituximab may represent a promising therapeutic option in patients with pemphigus refractory to other treatment modalities.