Bullous pemphigoid (BP) is the most frequent autoimmune blistering disease.1 Patients with BP have an increased morbidity and mortality resulting mainly from advanced age and underlying disorders, but also from adverse events of the immunosuppressive therapies used for this condition.1,2 Topical and oral corticosteroids are the mainstay treatment for BP.1 Second line treatment includes several non-validated therapies such as tetracyclines, azathioprine, mycophenolate, methotrexate, chlorambucil or dapsone.1,2 This challenging benefit–risk balance leads to a constant search for newer and safer therapies.

Rituximab has been used for the treatment of autoimmune bullous diseases. Standard doses approved for lymphomas (375mg/m2 weekly for 4 weeks) and rheumatoid arthritis (RA) (two infusions of 1000mg repeated in 2 weeks) are the most used protocols, and have shown to be effective in pemphigus vulgaris (PV),3,4 BP,2,5,6 and other autoimmune bullous diseases.7 A low-dose rituximab protocol of two infusions of 500mg has also been used for PV, showing a good safety profile and therapeutic response.3,4 Thus, we hypothesized this lower dose might be effective also in BP. Herein we report our experience in the treatment of BP with low-dose rituximab.

Five male and one female patients with a mean age of 78.6 years (range 65–89) were included. Their mean Charlson comorbidity index was 5.6 (range 3–9). The mean history of BP before rituximab treatment was 6.7 months (range 2–16), and it was associated with Alzheimer's disease in two patients and dipeptidyl peptidase-4 (DPP-4) inhibitors intake in one patient. Prior to rituximab, all patients had received conventional systemic therapy including prednisone (six patients), doxycycline (four patients) or azathioprine (three patients), in addition to clobetasol propionate cream 0.05% (six patients). The patients were followed-up for a mean of 52 weeks (range 6–77). Table 1 and Fig. 1 show patients’ characteristics and end points, respectively.

Figure 1.

Disease phases and end points after rituximab treatment. Each bar represents a patient and its length shows the duration of follow-up. After a single cycle of low-dose rituximab (at week 0), the time to disease control (blue), the time to end of consolidation (red), the time to late end point (yellow) and its duration (green) are shown. One patient had a relapse (black line), requiring retreatment with more than minimal adjuvant therapy (light blue).

CR adj: complete remission with more than minimal adjuvant therapy (also referred to “complete remission during tapering”); CR OFF: complete remission off all therapy; CR ON: complete remission with minimal therapy; PR OFF: partial remission off all therapy; PR ON: partial remission with minimal therapy.

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Early end points

We observed a rapid and marked response after the two infusions of rituximab (probably influenced also by the premedication with methylprednisolone) (Fig. 2). The mean time to disease control was 1.9 weeks (range 1–3), and the mean time to end of consolidation phase was 4 weeks (range 3–5).

Figure 2.

Clinical picture of patient 4 the day of the first infusion of rituximab 500mg (A) and the day of the second infusion after 2 weeks (B).

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Rituximab is a humanized chimeric monoclonal antibody directed against CD-20 antigen on B lymphocytes, with several approved and off-label indications. It has been recently approved by the US Food and Drug Administration (FDA) in 2018, and the European Medicines Agency (EMA) in 2019 as a treatment for PV. Since then, there are increasing articles reporting the treatment of BP with rituximab at standard doses (Table 2).2,5,6 Lymphoma protocol is more commonly used than RA protocol, although one study found no difference in the efficacy between them.6 At these standard doses, complete remission ranged between 35%2 and 85%5 of the patients, and partial remission between 15%5 and 40%.2 These studies reported serious adverse events, mainly infectious, and even cases of deaths. Overall, data suggest that rituximab at standard doses is effective in BP, and also useful as an steroid- and immunosuppressant-sparing therapy but may have serious adverse effects.2,5,6 In addition, a recently published study has shown that mortality in patients with BP treated with rituximab is lower than in those receiving standard treatment.9

Low-dose rituximab has been reported to be effective in a myriad of autoimmune diseases, such as myasthenia gravis, rheumatoid arthritis or immune thrombocytopenia.10 In Dermatology, low-dose rituximab has been mainly used in PV, with satisfactory data in effectiveness and safety.3,4 A meta-analysis by Wang et al. found no difference between standard doses and low-dose in time to disease control, complete remission rate and relapse rate in patients with PV.11

In our study, we present six patients with BP treated with low-dose rituximab (two infusions of 500mg), which is 39% of the dose used in hematology and 50% of the dose used in rheumatology, with an acceptable effectiveness and safety profile. The administration of high doses of methylprednisolone has probably produced this rapid beneficial effect as observed in other diseases,12 but good long-term control of the disease is derived from the use of rituximab. Only 1 patient of our series experienced a mild adverse event, compared to several serious adverse events with standard doses.2,5,6 CR (including off therapy, minimal therapy and more than minimal therapy) was achieved in 40% of the patients (compared to 352–85%5 with standard doses), and PR in 60% of the patients (compared to 155–40%2 with standard doses) (Table 2). Only 1 patient relapsed and had to continue with immunosuppressive therapy, supporting that low-dose rituximab is also useful to avoid steroids and immunosuppressants, decreasing the morbidity and adverse events in advanced age BP patients.

We highlight that these are dependent patients, with high comorbidity and polymedication, leading to a low adherence to first-line treatment (high-potency topical corticosteroids). The aim of this treatment is to improve the quality of life of the patients, reducing their needed care without increasing side effects.

Our study had several limitations, including its retrospective nature, small sample size and a short follow-up period that does not allow to see the effects in the very long term. However, to our knowledge this is the first series of BP treated with low-dose rituximab and it will be useful for future prospective studies.

In conclusion, low-dose rituximab for the treatment of BP achieved acceptable remission rates and steroid-sparing activity, with a better safety profile and a lower cost, compared to standard doses. Although future studies are needed, this pilot study suggests that low-dose rituximab could be a therapeutic option for BP.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.