We recently showed that first-line Rituximab (RTX) allowed achieving an 89% rate of complete remission (CR) off therapy at month 24 (M24) in pemphigus patients. In the present study, patients were followed up to Month 90 after RTX treatment to study the immunological mechanisms involved in the sustained CR and identify predictors of long-term relapse.

Data from 32/45 patients in the RTX group from the RITUX 3 trial were analyzed at M36 and M90.  B cells were studied by flow cytometry, and Dsg-specific antibody secreting cells (ASC) were studied by ELISPOT.

Between M36 and M90, 7/34 (20.6%) patients relapsed after a median time of 40 months (39-53), corresponding to a 6-year relapse rate of 30% since 4 of these 7 relapsing patients previously relapsed during the first year after RTX. The proportion of naive B cells increased from 75% at M0 to 82.4% at M36 and 87.9% at M90 (p<0.001), and that of memory B cells decreased from 24.7% at M0 to 17.5% and 11.9% at M36 and M90. Four of six (66%) relapsing patients had anti-Dsg1 and/or anti-Dsg3 ≥20 UI/ml at M36 versus 4/26 (15%) patients with sustained CR (p=0.022), corresponding to a positive predictive value of 50% and a negative predictive value of 92%. Among the 24 patients without anti-Dsg antibodies(abs) at M36, 2(8%) further relapsed. DSG3-specific ASC initially detected in patients before RTX were no longer detectable in patient with sustained CR from M36 to M90.  Conversely, DSG3-specific ASC were detected at M36 (mean level 0.3 ±0.3% in IgG ASC) in patients in CR at M36 who further relapsed. High rates of DSG3-specific ASC at M36 were also detected in the one patient with active disease at M36 (p<0.001). 

Overall, this study showed that i) the major change in the naïve/memory B cell ratio persists for more than 7 years after the last injection of RTX; ii) the detection of DSG3-specific ASC in patients still in clinical remission without serum anti-DSG abs is predictive for the occurrence of relapse.

Long-term immunological follow-up of pemphigus patients treated with rituximab as first line treatment