Successful Treatment of Pemphigus Vulgaris With Ofatumumab
December 2018 | Volume 17 | Issue 12 | Editorials | 1338 | Copyright © 2018
Maxwell B. Rapp BS, Alice P. Pentland MD, and Christopher T. Richardson MD PhD
Department of Dermatology, University of Rochester Medical Center, Rochester, NY
Rituximab is a chimeric anti-CD20 monoclonal antibody that is very effective in treating patients with pemphigus vulgaris. Though infrequent, the development of human anti-chimeric antibodies in patients receiving rituximab results in loss of efficacy. Ofatumumab is a second-generation fully-human anti-CD20 monoclonal antibody currently used to treat chronic lymphocytic leukemia. We report a case of a patient with pemphigus vulgaris successfully treated with ofatumumab after developing human anti-chimeric antibodies to rituximab. J Drugs Dermatol. 2018;17(12):1338-1339.
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Rituximab, an anti-CD20 chimeric monoclonal antibody, has recently been granted FDA-approval for the treatment of pemphigus vulgaris (PV). While generally very effective, infrequently rituximab loses efficacy due to the development of human anti-chimeric antibodies (HACA). This can be associated with an infusion reaction or a serum sickness-like reaction and results in treatment failure.1,2 In contrast to rituximab, ofatumumab is a fully-human monoclonal antibody and targets a distinct portion of CD20.3 Ofatumumab is approved for use in chronic lymphocytic leukemia and has been in clinical trials for the treatment of several other conditions, including pemphigus vulgaris. We present a case of a patient with severe treatment-resistant pemphigus vulgaris who developed serum sickness after treatment with Rituximab, presumably due to HACA. To control his severe disease, ofatumumab was instituted. He subsequently had complete resolution of disease activity. There are currently no published case reports of the successful treatment of PV with ofatumumab.
This patient was initially admitted to the hospital with widespread mucosal and cutaneous bullae and erosions (Figure 1A-B). Subsequent workup, including skin biopsy and indirect immunofluorescence titers (IIF; IgG 1:320, IgG4 1:640), was consistent with pemphigus vulgaris. He did not respond to eight days of 100mg IV methylprednisolone nor increasing doses of mycophenolate mofetil (MMF; up to 1.5g twice daily) (Figure 1C-D), so he was treated with rituximab (two 1g infusions two weeks apart). This resulted in significant improvement in disease activity (IIF IgG 1:40, IgG4 1:40) and within months he had tapered off all other treatment.Approximately one year following his first infusion of rituximab, the patient relapsed and received a second course of rituximab, during which he developed a serum sickness-like reaction requiring hospitalization. The second course of rituximab was not as efficacious as the first, and the patient required MMF and systemic steroids, as well as topical steroids and tacrolimus ointment, to achieve some control over the next two years. Given his worsening disease, a third course of rituximab therapy was attempted with no effect. Inadequate B cell depletion was found on flow cytometric analysis. Worsening disease activity requiring multiple hospitalizations and frequent clinic visits, despite continued systemic and topical steroids and 1.5g twice daily MMF, prompted four monthly infusions of IVIg, which had no effect.Given the patient’s intractable disease, multiple treatment failures, and successful use of ofatumumab in patients who developed HACA to rituximab in other conditions,4,5 a trial of ofatumumab was started. The dosing regimen for chronic lymphocytic leukemia (CLL) was used. The patient received 300mg on day one and 1000mg on day eight, followed by eight cycles of 1000mg every 28 days. The patient had a dramatic response after one dose (Figure 2A-D) with rapid subsequent improvement. Complete resolution of skin disease was noted at three months after his last infusion, 11 months since starting ofatumumab (Figure 2E-G). At two years since starting ofatumumab, his IIF titer remains at its lowest point (IgG trace 1:20, IgG4 1:20).
Anti-CD20 antibodies bind to the surface of B cells, leading to cell death. Three potential mechanisms of action of anti-CD20 antibodies include complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and direct cytotoxicity.6 Most anti-CD20 antibodies, including rituximab, bind to the larger of two extracellular loops within the CD20 molecule. In contrast, ofatumumab binds to two sites on the CD20