Long-term steroid-free pemphigus remission achieved with frontline rituximab

First-line treatment with rituximab appears to induce durable remission in patients with pemphigus, and this is achieved without corticosteroid therapy and any additional maintenance infusion of rituximab.

Long-term data from the Ritux 3 trial showed that the rates of 5- and 7-year disease-free survival (DFS) off therapy were higher for patients who had received rituximab plus short-term prednisone than for those who had received prednisone alone (76.7 percent and 72.1 percent vs 35.3 percent and 35.3 percent, respectively; p<0.001). [JAMA Dermatol 2024;doi:10.1001/jamadermatol.2023.5679]

Over a median follow-up of 7.3 years, 93.5 percent of patients in the rituximab plus prednisone group achieved complete remission as compared with only 38.6 percent of those in the prednisone-alone group. The incidence of relapse was halved in the rituximab plus prednisone group (42.2 percent vs 83.7 percent; p<0.001).

In terms of treatment lines, upfront rituximab therapy was associated with substantially longer DFS compared with second-line treatment (ie, rituximab use following relapse in the prednisone-alone group). The respective 2- and 3-year DFS rates were 75.6 percent and 75.6 percent vs 39.2 percent and 17.4 percent (p=0.007).

No further relapse

“[I]t must be underlined that these patients who maintained sustained complete remission off corticosteroid therapy did not have any additional maintenance infusion of rituximab from the last 500-mg infusion of rituximab at month 18 (end of the Ritux 3 regimen) to the end of the study,” the investigators said.

Repeated rituximab infusions have been proposed to sustain complete remission. This might be unnecessary, according to the investigators. [Br J Dermatol 2015;172:101-110]

“The fact that the rate of DFS without corticosteroids did not change much from 76.7 percent after 5 years to 72.1 percent after 7 years suggests that most of these patients will not further relapse. This high rate of sustained complete remission without corticosteroids is consistent with the long-term disappearance of antidesmoglein (Dsg) antibody, which was observed in 86 percent of these patients,” they pointed out.

Antibody levels

Monitoring anti-Dsg antibody levels after initial rituximab treatment should be able to identify which patients are at high risk of relapse for targeted retreatment, the investigators said.

In the present analysis, a reincrease in anti-Dsg1 and/or anti-Dsg3 antibody levels (≥20 and ≥48 IU/mL, respectively) at month 36 yielded a high positive predictive value of 83 percent for relapse. This suggests the possibility of retreating with rituximab only those patients whose serum anti-Dsg ELISA values became higher than the thresholds, according to the investigators.

Additionally, the negative predictive value of 94 percent obtained using the same thresholds indicates that further rituximab treatment may not be needed because the patients would not relapse, they continued.

“We are currently conducting a randomized clinical trial to test this strategy of retreating patients with a high risk of relapse based on the ELISA values of anti-Dsg antibodies to prevent the occurrence of clinical relapses and to prevent patients from having to take corticosteroids again,” the investigators said.

Safety

Severe adverse events (SAEs) occurred with significantly less frequency in the rituximab plus prednisone group than in the prednisone-alone group (0.67 and 1.32 SAEs per patient; p=0.003), with most SAEs recorded during the first 3 years of the trial. From month 36 to the end of the study, seven patients in the rituximab plus prednisone group and 23 in the prednisone-alone group were treated or retreated with rituximab following a relapse.

Among the patients who had a relapse, four SAEs (one death, two pneumonia, and one neutropenia) were recorded in the rituximab plus prednisone group and five SAEs (one death, one Achilles tendon rupture, and three flares needing an inpatient hospital stay) were reported in the prednisone-alone group.

“Importantly, no additional SAE occurred in the 25 patients from the rituximab plus prednisone group who … sustained complete remission without any therapy from the last infusion of rituximab at month 18 to the end of the study,” the investigators said.

Of the 90 patients included in the Ritux 3 trial, 83 were evaluated at the end of the long-term follow-up with a median of 87.3 months. Of these, 44 patients were in the rituximab plus prednisone group and 39 were in the prednisone-alone group. Rituximab was administered intravenously at 1,000 mg on days 0 and 14 and at 500 mg at months 12 and 18. Prednisone was given at either 1.0 or 1.5 mg/kg per day tapered over 3 or 6 months for the rituximab plus prednisone group and over 12–18 months for the prednisone-alone group.