Featured Student: Joey Cascone

Joey Cascone is a 4th-year medical student in the MD-only program at the University of Missouri-Kansas City rural satellite campus. His research and clinical interests are focused on narrowing the gap in health care disparities for underserved populations, both rural and urban. Joey is particularly interested in the cutaneous manifestations of autoimmune disease and malignancy. He enjoys cooking and baking, playing piano, and playing golf in his spare time.

Introduction

Pemphigus represents a group of autoimmune blistering skin diseases affecting the skin and/or mucous membranes. It results from autoantibodies targeting desmogleins, leading to the disruption of epidermal desmosomes and subsequent blister formation. This debilitating and potentially life-threatening condition carries a mortality rate of up to 26.5%. Historically, pemphigus has been treated with systemic corticosteroids and steroid-sparing immunosuppressants like rituximab (RTX). The rheumatoid arthritis protocol for RTX (2 x 1000 mg, administered two weeks apart) has shown promising results for pemphigus treatment. However, this high dose is associated with adverse effects such as infusion reactions and infections. This study, led by Dr. Shan Cao and colleagues in JAAD, aimed to identify the optimal RTX dosing strategy for moderate-to-severe pemphigus, assessing the safety and effectiveness of ultralow-dose RTX (ULRTX), low-dose RTX (LRTX), and standard-dose RTX (SDRTX).

Study Design and Methods
This prospective, open-label, nonrandomized clinical trial involved 52 adult patients with moderate or severe pemphigus vulgaris or pemphigus foliaceus. The patients were mostly middle-aged and mainly had pemphigus vulgaris. Severity was measured by the Pemphigus Disease Area Index (PDAI). Ten patients had moderate disease (PDAI 15-45), and 41 had severe disease (PDAI > 45). Participants were divided into three non-randomized groups, each receiving RTX at baseline and two weeks later, with doses of ULRTX (100 mg, n = 26), LRTX (500 mg, n = 13), and SDRTX (1000 mg, n = 13). Patients were monitored for 52 weeks. Those in the ULRTX group received an additional 100 mg RTX infusion at 26 weeks if CD20+ B-cell reconstitution rates greatly exceeded those of the other groups. All patients received oral glucocorticoids at a dosage of 0.5 mg/kg/day for moderate disease and 1.0 mg/kg/day for severe disease, with dosages tapered according to S2k guidelines.

The primary end goal of this study was to determine complete remission after disease control for the doses mentioned above, defined as the absence of new lesions, healing of existing lesions, and the ability to taper glucocorticoids safely. Secondary endpoints included reduction in PDAI score, cumulative glucocorticoid dose required for each group, relapse rates, partial remission with minimal therapy, and autoantibody seroconversion.

Results

All patients reached disease control by week 52, with complete remission rates of 92.3% in the ULRTX group and 100% in the LRTX and SDRTX groups. This difference was not statistically significant (p = 0.35). The time to disease control varied significantly: ULRTX at 15.5 days, LRTX at 14.0 days, and SDRTX at 13.0 days (p = 0.02).

The duration to complete remission off therapy was longer in ULRTX (median 224 days) than in LRTX (172 days) or SDRTX (183 days), yet the difference was not significant (p = 0.84). All groups achieved near-complete CD20+ B-cell depletion at two weeks post-treatment. B-cell percentages at 26 weeks were 8.88% for ULRTX, 1.25% for LRTX, and 0.51% for SDRTX. The ULRTX group showed significant B-cell reconstitution at week 26 compared to LRTX (p = 0.026) and SDRTX (p = 0.018), prompting additional 100 mg RTX infusions for all ULRTX patients. No significant differences were seen in PDAI score reduction, cumulative glucocorticoid doses, or relapse rates. A small proportion (7.7%) of ULRTX patients achieved partial remission on minimal therapy, an outcome observed only in this group. All groups exhibited downward trends in anti-desmoglein 1/3 antibody titers; approximately half of each group became seronegative, with no significant variation. Adverse event rates were lowest in ULRTX (11.5%) compared to LRTX (30.8%) and SDRTX (38.5%), though these differences were not statistically significant (p = 0.15). ULRTX also resulted in significant total hospitalization cost savings of 32% compared to LRTX and 53% compared to SDRTX (p < 0.05).

Limitations

The lack of random assignment and the observational nature of this prospective cohort study mean that causality cannot be definitively established. The uneven patient distribution (26 subjects in ULRTX and only 13 in each of the other groups) further weakens the comparison strength. The authors also note additional limitations, including the small sample size from a single center.

Significance

Overall, ultralow-dose rituximab may be as effective as higher-dose regimens for pemphigus with the added benefit of saving costs. Although the lack of a significant difference in adverse events limits definitive clinical conclusions, ULRTX showed the lowest rate of adverse events, supporting a favorable safety profile. Clinicians should also consider that complete remission off therapy took longer in the ULRTX group, although this difference was also not statistically significant. Together, the comparable efficacy, low adverse event rate, and cost benefits suggest that the future of pemphigus treatment may lie in lower doses of rituximab. However, larger studies will be needed to confirm these findings.