BUDAPEST, Hungary (EGMN) –Rituximab for the treatment of severe pemphigus continued to rack up impressive results in the 2-year extension of a landmark 3-year multicenter trial.
Indeed, after 5 years of follow-up, 19 of 22 rituximab-treated patients (86%) were in complete or near-complete remission, including 8 who were off all therapies, Dr. Pascal Joly reported at the annual congress of the European Society for Dermatological Research.
Also noteworthy was the finding that no new rituximab-related side effects emerged during years 4 and 5. The only serious side effects over the course of 5 years were a case of pyelonephritis 12 months after a single cycle of rituximab and a fatal septicemia at 18 months in a patient taking etanercept for comorbid rheumatoid arthritis. Both cases were detailed in the initial 3-year report (N. Engl. J. Med. 2007;357:545-52), said Dr. Joly of Rouen (France) University Hospital.
Five of the eight patients in complete remission off all treatment at 5 years achieved their remission several months after their first and only cycle of rituximab and never experienced a relapse in the intervening years, he said.
Based upon these highly encouraging results, a new randomized trial is underway to evaluate an expanded use of rituximab in treating pemphigus. Instead of reserving the biologic therapy for patients with severe pemphigus who are corticosteroid refractory or have contraindications to high-dose steroids, as was the case in the original 5-year French study, the new multicenter study is testing rituximab as first-line treatment. The investigators also are enrolling patients with moderate as well as severe pemphigus vulgaris or foliaceous, he added.
Fourteen patients in the 5-year trial had pemphigus vulgaris, 7 had pemphigus foliaceous, and 1 had paraneoplastic pemphigus.
Thirteen of the 22 patients experienced relapse after a mean delay of 28.2 months. The 2-, 3-, and 5-year relapse rates were 33%, 43%, and 59%, respectively.
Relapse in six patients was treated with a second cycle of rituximab; five of the six achieved complete remission once again. The other seven patients had their relapse treated with stepped-up doses of corticosteroids.
The mean dose of prednisone used by participants dropped from 55 mg/day at baseline to 6 mg/day after 5 years. The decrease was even more impressive in the five patients who entered the trial with steroid-refractory disease; their corticosteroid use went from a mean of 94 mg/day at baseline to 6 mg/day 5 years later, Dr. Joly continued.
The rituximab regimen consisted of four weekly infusions at 375 mg/m2 of body surface area.
Rituximab is a monoclonal antibody directed against the CD20 antigen of B lymphocytes. Beginning 3 weeks after rituximab administration, peripheral B cells became undetectable. B cells remained suppressed for 6 months to 2 years. When they reappeared they displayed a naive phenotype similar to that found in neonatal cord blood.
No changes were detected in levels of T cells, total IgG, or titers of antibodies against tetanus toxoid or pneumococcal capsule polysaccharide in response to rituximab. The pathogenic autoantibodies anti-desmoglein-1 and -3, which are produced by activated B cells, responded to rituximab differentially. Anti-desmoglein-1 titers dropped steeply in all patients with a complete response and increased when patients experienced relapse. In contrast, five patients in prolonged remission maintained high titers of anti-desmoglein-3 throughout and four other patients relapsed despite persistently low anti-desmoglein-3.
In the new randomized trial of rituximab as first-line therapy in moderate to severe pemphigus, the rituximab group receives low-dose prednisone at 0.5-0.75 mg/kg per day for the first 2-3 months of the study.
“Of course, the absence of corticosteroids would make for more spectacular results. 그러나, rituximab typically has a 2- to 3-month delay in action, and it’s difficult not to treat patients during this delay. This is why we’re using low-dose corticosteroids, especially to treat the pain in our patients with mucosal lesions. A dose of 0.5 mg/kg per day of prednisone is not sufficient to lead to clearance in these patients, but it’s a dose that has an anti-inflammatory effect and will decrease their pain,” Dr. Joly explained.
In light of the timing of relapses in the original 5-year study, the new trial incorporates maintenance rituximab at 500 mg given at 12 months and again at 18 months in an effort to avoid relapses in the second and third year. The dose and timing of the maintenance therapy were chosen in consultation with rheumatologists, who have the most experience with rituximab. The biologic agent’s approved indications are for treatment of rheumatoid arthritis unresponsive to anti–tumor necrosis factor therapy and in B cell lymphomas.
The study was supported by the French Society of Dermatology and Roche