Efficacy and safety of adjuvant immunoadsorption in pemphigus

Pemphigus is a potentially lethal autoimmune bullous disease characterized by autoantibodies against desmoglein 1 and 3, leading to flaccid blisters and severe erosions of the skin and mucous membranes. Because of its rarity only a few controlled prospective clinical trials have been performed, mostly without significant differences between the treatment groups due to the tow number of included patients. Pemphigus requires long-term use of high-dose corticosteroids combined with adjuvant immunosuppressants. This therapy leads to considerable comorbidity demanding novel treatment modalities. The removal of circulating autoantibodies by immunoadsorption (lA) provides a rational therapeutic option. Adjuvant lA has been shown to induce the rapid removal of circulating autoantibodies followed by dramatic clinical improvement in all and clinical remission in the majority of 40 pemphigus patients reported so far in various cohort studies. The present prospective controlled multicenter trial aims at investigating the clinical efficacy and safety of lA in patients with active pemphigus. Standard treatment with prednisolone (1 mg/kg/d) plus azathioprine or mycophenolate mofetil, respectively, is compared to the same regimen plus adjuvant lA in 82 patients. Two to four cycles of lA, each consisting of lA treatment on four consecutive days, are administered every three weeks. Primary endpoint is the time to remission defined as healing of all blisters and erosions.

Pemphigus vulgaris and pemphigus foliaceus are rare life-threatening autoimmune bullous diseases characterized by blisters and erosions on the skin and surface-close mucous membranes. Autoantibodies are directed against two adhesion proteins of the skin, their serum levels correlate with the extent of lesions, and have been shown to be pathogenic in several experimental models. In the light of the limited treatment options, removal of serum autoAb by immunoadsorption (IA) appeared therefore as a rational therapeutic option. Here,72 patients with clinical active pemphigus vulgaris (n=58) and pemphigus foliaceus (n=14) with lesions covering > 1.0% of body surface area or > 2cm² of mucous membranes were randomized to two treatment arms. Both groups received prednisolone at an initial dose of 1.0 mg/kg/d and immunosuppressive medication: azathioprine (1.5-2.5 mg/kg/d; according to serum TPMT activity) or mycophenolate mofetil (2 g/d) / mycophenolate sodium (1440 mg/d). One group received adjuvant IA comprising a total of two to four treatment cycles (on four consecutive days) in three-week intervals. Patient characteristics at randomisation were well balanced and showed no statistically significant differences. The primary end point, i.e. the time to remission between treatment arms showed no statistically significant differences. However, the cumulative dose of prednisolone in the IA group was significantly lower compared to the control group (p = 0.0330). Furthermore, for patients with high diseases activity at baseline, the likelihood to reach remission was twice as high in the IA arm compared to the control group (HR, 2.052; 95%CI, 0.875 – 4.813). No statistical differences were observed in the number of mild, moderate, and severe as well as in the total number of adverse events between the treatment arms. Recruitment, however, was stopped prematurely by the Data and Safety Monitoring Committee (DSMC) that suspected several severe adverse events in the IA group to be directly linked to the IA procedure. The present investigated-initiated trial showed that adjuvant IA is a corticosteroid-saving procedure that may be a valuable option in the initial treatment on patients with extensive disease activity to rapidly lower serum levels of pathogenic autoantibodies.