Rituximab is an effective treatment in patients with pemphigus vulgaris and demonstrates a steroid-sparing effect

Abstract

Background: Corticosteroids (CS) with or without adjuvant immunosuppressant agents are standard treatment for pemphigus vulgaris (PV). The efficacy of adjuvant therapies in minimizing steroid-related adverse events (AEs) is unproven.

Objectives: To utilize data collected in a French investigator-initiated, phase III, open-label, randomized controlled trial to demonstrate the efficacy and safety of rituximab and seek approval for its use in PV.

Methods: This was an independently conducted post hoc analysis of the moderate-to-severe PV subset enrolled in the Ritux 3 study. Patients were randomized to rituximab plus 0·5 or 1·0 mg kg^-1 per day prednisone tapered over 3 or 6 months, or 1·0 or 1·5 mg kg^-1 per day prednisone alone tapered over 12 or 18 months, respectively (according to disease severity). The primary end point was complete remission at month 24 without CS (CRoff) for ≥ 2 months, and 24-month efficacy and safety results were also reported.

Results: At month 24, 34 of 38 patients (90%) on rituximab plus prednisone achieved CRoff ≥ 2 months vs. 10 of 36 patients (28%) on prednisone alone. Median total cumulative prednisone dose was 5800 mg in the rituximab plus prednisone arm vs. 20 520 mg for prednisone alone. Eight of 36 patients (22%) who received prednisone alone withdrew from treatment owing to AEs; one rituximab-plus-prednisone patient withdrew due to pregnancy. Overall, 24 of 36 patients (67%) on prednisone alone experienced a grade 3/4 CS-related AE vs. 13 of 38 patients (34%) on rituximab plus prednisone.

Conclusions: In patients with moderate-to-severe PV, rituximab plus short-term prednisone was more effective than prednisone alone. Patients treated with rituximab had less CS exposure and were less likely to experience severe or life-threatening CS-related AEs. What's already known about this topic? Pemphigus vulgaris (PV) is the most common type of pemphigus. Corticosteroids, a standard first-line treatment for PV, have significant side-effects. Although their effects are unproven, adjuvant corticosteroid-sparing agents are routinely used to minimize steroid exposure and corticosteroid-related side-effects. There is evidence that the anti-CD20 antibody rituximab is effective in the treatment of patients with severe recalcitrant pemphigus and in patients with newly diagnosed pemphigus. What does this study add? This study provides a more detailed analysis of patients with PV enrolled in an investigator-initiated trial. Rituximab plus prednisone had a steroid-sparing effect and more patients achieved complete remission off prednisone. Fewer patients experienced grade 3 or grade 4 steroid-related adverse events than those on prednisone alone. This collaboration between academia and industry, utilizing independent post hoc analyses, led to regulatory authority approvals of rituximab in moderate-to-severe PV.

Figure 1

Patient disposition. AE, adverse event; ITT, intention‐to‐treat; PF, pemphigus foliaceus; PV, pemphigus vulgaris. *Withdrawal from treatment owing to pregnancy. ^†AEs included corticosteroid‐induced myopathy, necrosis of femoral heads, Cushing syndrome, psychiatric decompensation, chorioretinitis. ^‡One patient receiving prednisone discontinued treatment owing to ineffectiveness of treatment (other) and withdrew from the study owing to serious AEs of dyspnoea and oedema.

Figure 2

Median prednisone dose over time. Mo, month.

Figure 3

Number of patients who were on or off minimal corticosteroid (≤ 10 mg per day) therapy over time.

Figure 4

Pemphigus vulgaris (PV). (a) Oral involvement in a patient with severe PV at baseline [Pemphigus Disease Area Index (PDAI) 38] and (b) at month 4 (PDAI 2) after treatment with rituximab plus prednisone. (c) Oral mucosal involvement in a patient with severe PV before and (d) at month 2 after treatment with rituximab plus prednisone.