In pemphigus vulgaris (PV), autoantibodies against Dsg1 and Dsg3 have been shown to induce loss of kera-tinocyte adhesion upon binding to desmosomal target autoantigens leading to the release of TNF- and IL-1 from epidermal keratinocytes, which presumably enhance the process of blister formation. In vivo, an increased expression of TNF-a and IL-1 is found in the direct environment of the intra-epidermal loss of adhesion. In vitro, cultures of human keratinocytes are resistant to the acantholytic effect of pathogenic, Dsg3-specific autoantibodies upon pre-treatment with anti-TNF- antibodies. This protective effect of blocking TNF-a can be reproduced in vivo. Feliciani et al. (2000) showed that the injection of anti-Dsg3 IgG in TNF receptor 1/2 deficient mice led more rarely to blister formation than the injection of the identical autoanti-bodies in syngeneic "wild type" mice with an intact TNF receptor.
Based on these observations, the potent TNF-inhibitor, infliximab, was used in a 43-year-old male with a therapy refractory PV with a history of pulmonary embolism, arterial hypertension, steroid-induced osteoporosis and diabetes mellitus who presented with disseminated cutaneous blisters and extensive erosions of the oral mucosa (Jacobi et al. 2005). The patient was given three doses of infliximab (5 mg/kg/day i.v.) over
6 weeks at weeks 0, 2 and 6. Leflunomide (20 mg/day) and prednisone (0.25 mg/kg/day) were continued during the infliximab regimen as adjuvant treatment and with the aim of preventing formation of anti-infliximab antibodies (HACA). Within 48 h of the first dose of infliximab, blister formation ceased, and within the first 4 days cutaneous blisters and mucosal erosions gradually disappeared (Fig. 8.7). Infliximab infusions were discontinued 8 weeks after initiation when the patient developed varicella zoster of the left S1/2 der-matome, which was treated successfully with i.v. acy-clovir. Of note, the patient's clinical status remained stable with few cutaneous erosions during the previously insufficient therapy with leflunomide (20 mg/d) and prednisone (0.25 mg/kg/day). After a relapse 4 months later the disease was controlled by several cycles of immunoadsorption therapy in combination with mycophenolate mofetil (3 g/day).
Further case reports confirm the successful management of severe pemphigus with infliximab. A 62-year-old male with PV and generalized bullous lesions and a severe oral stomatitis was managed with systemic cor-ticosteroids for 6 years, mycophenolate mofetil, cyclo-sporin A, azathioprine, cyclophosphamide, methotrex-ate, thalidomide and plasmapheresis without much success. As a last resort, the patient received infliximab (5 mg/kg/d i.v.) at 0, 2 and 6 weeks and then every 8 weeks. No other drugs were needed as concomitant medication. The patient improved dramatically after five infusions leading to total clearance of active lesions at week 22 without severe side effects. After the 13th infusion, treatment with infliximab discontinued because new cutaneous and oral lesions had appeared. The disease was eventually controlled with oral corti-costeroids and rituximab.
There is a report on the effective treatment of PV with the TNF-a antagonist, etanercept, in a 62-year-old
woman with long-standing cutaneous PV and concomitant seronegative arthritis. Upon initiation of treatment with etanercept for arthritis, the cutaneous blisters gradually disappeared. Lin et al. (2005) reported the successful treatment of recalcitrant PV and pemphigus vegetans with etanercept and carbon dioxide laser.
The human anti-TNF-a monoclonal antibody, adali-mumab, has in combination with mycophenolate mofe-til been successfully employed in the subcorneal pustular dermatosis subtype of IgA pemphigus. A 41-year-old male with IgA pemphigus failed multiple treatments, including acitretin, broadband ultraviolet B therapy, dapsone, methotrexate and oral steroids. He showed improvement to alefacept, but treatment was discontinued because of a low peripheral CD4+ T-cell count. Cyclosporine was also effective, but was discontinued secondary to elevated creatinine levels. Adali-mumab (40 mg s.c. every other week) was started, and after the third dose his skin completely cleared. Mycophenolate mofetil (1 g/day) was used as concomitant medication. The patient has been symptom-free for 5 months, besides the occasional occurrence of a few pustules.
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