Evaluation of combination therapy with ofatumumab and systemic corticosteroids for pemphigus: A multi‐centre cohort study

Pemphigus is an autoimmune disease targeting desmoglein (Dsg) 1 and 3, causing flaccid blisters and erosions.1 Glucocorticoids and immunosuppressants have improved clinical outcomes, but mortality is still high due to infections and cardiovascular events.2 Rituximab effectively treats pemphigus,3 but side effects like infections, resistance and relapse are common.4 The next-generation anti-CD20 monoclonal antibodies, such as veltuzumab and ofatumumab, have successfully treated refractory pemphigus in some case reports.5, 6 The aim of our research is to compare the efficacy and safety of ofatumumab plus methylprednisolone with methylprednisolone plus azathioprine in the treatment of pemphigus. In an observational cohort study, we conducted a 36-week follow-up of 38 pemphigus patients from two hospitals in China, spanning from 1 January 2023 to 30 April 2024. The primary endpoints were time to disease control and skin healing.7 Secondary endpoints included complete remission on therapy rates, relapse rates, corticosteroid doses, pemphigus disease area index (PDAI), dermatology life quality index (DLQI), visual analogue scale (VAS) pain scores,8 CD19+ B-cell percentages, desmoglein-specific antibodies and adverse events (AEs). Based on the screening results, 16 patients were nonrandomly allocated to the ofatumumab group, while 22 patients were assigned to the conventional group. The ofatumumab group showed faster disease control (median 8 [IQR: 5.25–12] days vs. 13 [12–16.5] days, p = 0.0002) and skin healing (median 34 [IQR: 24–49.75] days vs. 56 [44–125.5] days, p = 0.0002) (Figure 1). At 36 weeks, 94% of ofatumumab patients achieved complete remission compared to 14% in the conventional group (p < 0.001). Logistic regression revealed that ofatumumab treatment significantly increased the likelihood of complete remission (OR [95% CI], 4.56 [7.91, 1150.35]; p < 0.001). In weeks 1 and 2, PDAI score reductions in the ofatumumab group were greater than in the conventional group (p = 0.036; p = 0.048). VAS pain scores improved significantly in the ofatumumab group, from 6 (5–7.75) to 2.5 (2–3.75) in week 2, compared to the conventional group (p = 0.027). The mean (SD) DLQI scores decreased rapidly from 15.56 (4.41) to 5.69 (2.65) by week 8 in the ofatumumab group (p = 0.003), maintaining a downward trend (all p < 0.01). Anti-Dsg1 and anti-Dsg3 values decreased over 24 weeks, with ofatumumab patients showing lower anti-Dsg1 at weeks 4 and 8 (p = 0.009; p = 0.014), and greater anti-Dsg3 reduction at week 24 compared with the conventional group (p = 0.0006). Ofatumumab rapidly depleted CD19+ B cells to <1% within 1 week, maintaining low levels for 24 weeks. Patients on ofatumumab plus methylprednisolone received two-thirds of the cumulative methylprednisolone dose compared with the methylprednisolone plus azathioprine group (3796.56 [SD: 1793.47] mg vs. 5702.12 [SD: 1129.06] mg; p < 0.001) (Table 1). The most prevalent AEs were folliculitis, occurring in 6% of the ofatumumab group versus 36% in the conventional group, and physical fatigue, affecting 25% and 23% of patients respectively. In the ofatumumab group, 10 mild–moderate AEs included fever, fatigue, folliculitis, upper respiratory tract infection and herpes zoster, with 2 severe cases of pneumonia. The conventional group had 7 severe AEs like septicaemia, pneumonia and deep vein thrombosis. For multiple sclerosis (MS), ofatumumab is given subcutaneously, starting with 20 mg thrice in 2 weeks, then monthly.9 Dose adjustments are important in pemphigus as MS is more severe. We opted for 2 weekly injections for mild–moderate cases, adding a third in week 3 for severe cases, to minimize costs and hospitalizations.10 The findings suggest that ofatumumab may be an effective treatment option for pemphigus patients. However, further studies with larger samples are needed to verify these observations of ofatumumab in pemphigus. National Natural Science Foundation of China (No. 82373469), Joint Funds for the Innovation of Science and Technology, Fujian Province (No. 2021Y9150), National Natural Science Foundation of China (No. 82271194), Natural Science Foundation of Fujian Province (No. 2023J02017) and Talent Introduction Project of the First Affiliated Hospital of Fujian Medical University (No. YJRC3813), Fujian Provincial Health Technology Project (No. 2020CXA034). The authors declare no conflict of interests. The clinical study protocol was reviewed and approved by the Ethics Committee of the First Affiliated Hospital of Fujian Medical University. All patients received oral information of the study and provided informed consent. The data that support the findings of this study are available from the corresponding author upon reasonable request.