Pemphigus vulgaris (PV) is a chronic, life-threatening autoimmune bullous disease (AIBD) characterized by erythema, blisters, and erosions on the mucosa and/or skin (1). Autoreactive B cells play a crucial role in the pathogenesis of PV, which can differentiate into plasma cells that secrete autoantibodies targeting desmoglein (Dsg) 1 and 3, leading to acantholysis and blister formation. Rituximab, a chimeric murine/human monoclonal antibody against CD20 on the surface of B cells, has demonstrated efficacy in patients with PV and is now listed as a first-line treatment for moderate to severe cases (2). Although rituximab has guideline-recommended protocols (2) (2×1000 mg, 2 weeks apart or 4×375 mg/m², 1 week apart), there are ongoing discussions about alternative dosing and frequency options (3–6). Moreover, studies focusing on the long-term prognosis of patients receiving rituximab reported relapse rates of 63%-100% after a single cycle of infusion (7, 8). Other limitations of rituximab include the administration of intravenous infusion, severe adverse events (AEs) and the costs of hospitalization.

Ofatumumab is a fully human monoclonal antibody targeting CD20 administered subcutaneously and indicated for multiple sclerosis (MS) (9). Over the years, it has been reported to be used in various autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus and ANCA-associated vasculitis (10–12). Applications of ofatumumab in pemphigus have been reported in several cases including from our center (13, 14). Recently, a cohort study reported that ofatumumab facilitated rapid disease control in patients with pemphigus compared with the conventional group in 36-week observation (15). However, longer-term data on its effectiveness and safety, and the exploration on alternative injection regimen are still needed. Herein, we present a cohort study that lasted for 52 weeks to evaluate the effectiveness and safety of ofatumumab combined with oral glucocorticoids in PV patients. We hope this study can provide foundational knowledge and regimen references for treating PV with ofatumumab.

This cohort study, lasting for 52 weeks, shows that the application of ofatumumab (2×20mg, 2 weeks apart) in patients with PV demonstrated better effectiveness compared with the GC group. At week 52, higher proportion of patients in the OFA group achieved CRDT and MT compared with the GC group. Throughout the entire study, the OFA group received lower daily and cumulative glucocorticoid doses than the GC group. No severe AE related to ofatumumab was reported in the OFA group. The subcutaneous administration of ofatumumab is more convenient, accessible, and acceptable for patients with pemphigus compared to the intravenous infusion of rituximab, which typically requires inpatient clinic visits. Furthermore, due to its fully human structure, ofatumumab is theoretically less immunogenic, potentially reducing the risk of adverse effects associated with anti-drug antibody formation.

The proportion of patients achieving CRDT in our study was 31.2%, appearing lower compared with the data reported in previous studies on rituximab, which ranged from 40% to 100% (3, 5, 6, 8, 18, 19). These differences can be attributed to variations in study designs, patient conditions, treatment protocols and glucocorticoid-tapering regimens. In our cohort study conducted in a real-world setting, we adopted a conservative and individualized tapering protocol to minimize the risk of relapse, resulting in a delayed reduction to a prednisone dose of 10mg/kg/d. Therefore, it’s difficult to directly compare the efficacy of ofatumumab and rituximab based on the endpoint of CR. A well-designed head-to-head study would be suitable for this purpose. At week 52, a significantly higher proportion of patients in the OFA group achieved MT compared with the GC group, suggesting a favorable steroid-sparing effect from the perspective of personalized therapy.

In the newly diagnosed subgroup, we observed a trend toward a higher proportion of patients achieving CRDT compared with those with established disease. This finding aligns with the results from rituximab studies, suggesting that early application of ofatumumab might benefit patients with PV (20, 21).

No patient in our study experienced relapse by week 52, which somehow differed from the relapse data from previous studies (for instance, around 25% in the first year with rituximab (3)). Several factors may explain this difference. Firstly, as descripted above, our tapering protocols differed from those in prior studies. We adjusted prednisone doses based on each patient’s disease condition and immune biomarkers at each visit, generally in a lower tapering speed rather than rescue treatment, aiming to reduce the relapse risk. Another reason was the varying distributions of disease severity, a known risk factor for disease relapse (22). In our study, the OFA group consisted primarily of mild to moderate patients (PDAI: 19.0 (14.2-23.2)), while previous studies typically focused on moderate to severe patients. Additionally, we did observe that a refractory patient in the OFA group whose B cell count increased to 61 cells/μL with a high anti-Dsg1 antibody level by week 32. As a result, a third injection of ofatumumab was administered. Following this adjuvant dose, the anti-Dsg1 antibody level decreased rapidly along with the B cell count, and no relapse occurred by week 52.

Reducing oral glucocorticoid doses is a key objective in the development of new therapies for PV. Since baseline, the daily prednisone doses of the OFA group were significantly lower than those in the GC group over the follow-up. Nevertheless, higher proportion of patients in the OFA group achieved CRDT and MT, and the PDAI showed no significant differences at each visit. As a result, patients in the OFA group took lower cumulative prednisone dose compared with the GC group by week 52. These findings align with the results from the Ritux3 trial (3), supporting the robust steroid-sparing effect of ofatumumab.

Plenty of research proposed the association between B cell repopulation and relapse (7, 23, 24). Our data presented increasing trend in B cell count and anti-Dsg3 antibody level since week 24, similar to the data from rituximab (3). It remained below 40 cells/μL by week 52, which is not entirely consistent with the simulated data from the pharmacokinetics study (25). This discrepancy might because of the application of glucocorticoid, inhibiting lymphocytes proliferation. The anti-Dsg3 level also started to elevate at week 36 but remained below the predictive relapse cutoff of 130 U/mL by week 52, consistent with the absence of relapse (23, 26). This could be explained by the recovery of memory B cells secreting different types of IgG subclass, including non-pathogenic antibodies (27). Overall, further data on B cells and auto-antibodies in patients with pemphigus following anti-CD20 therapy are needed to predict prognosis more accurately.

The OFA group demonstrated good tolerability. IRRs occurred in 25% of patients, consistent with the 24.1% reported in the ASCLEPIOS II trial in MS (9), and similar with the 22% of infusion related reactions observed in the RCT of rituximab in pemphigus (19). One severe AE (gastric hemorrhage) was observed in the OFA group (6.3%), versus 22% observed in the safety data for 52 weeks from rituximab (19). The most common AEs in the OFA group included elevation of liver enzymes and gastrointestinal disorders, likely related to the use of conventional immunosuppressants and glucocorticoids. Whereas, the most frequent AEs reported in the phase III RCT in MS include IRRs, nasopharyngitis, headache, upper respiratory tract infection and urinary tract infection (9). The difference in AEs between the OFA group in our study and phase III RCT in MS may lie on GC application. In addition, the highest AE in GC group was osteoporosis, which was not reported in the OFA group, suggesting an encouraging protective effect of ofatumumab against glucocorticoid-induced side effects.

The main limitation of this study is the small sample size, especially the limited number of severe pemphigus, confining further stratified analysis. The 52-week follow-up also constrains the assessment of long-term outcomes.

In conclusion, this study suggests ofatumumab is well-tolerant, effective and convenient for patients with PV, showing favorable steroid-sparing effects in the entire treatment course. The feature of subcutaneous administration enables ofatumumab a potentially convenient option for patients with PV. Further studies are needed to explore the optimal timing of adjuvant ofatumumab injection. Furthermore, prospective head-to-head trials can be conducted to compare the efficacy of ofatumumab and rituximab in patients with PV.