Dear Editor, Pemphigoid is a heterogeneous group of rare and chronic autoimmune subepidermal bullous diseases, characterized by circulating autoantibodies against structural proteins in the hemidesmosomes. Long-term therapy with systemic oral prednisone and immunosuppressants is often required and has been associated with severe adverse reactions.1, 2 Rituximab, an anti-CD20 monoclonal antibody, is increasingly used in pemphigoid, mainly in patients who failed conventional immunosuppressive therapies. Our study aimed to evaluate the clinical outcomes and the patient-reported outcome measures (PROMs) of patients with bullous pemphigoid (BP) and mucous membrane pemphigoid (MMP) who were treated with rituximab. We performed a single-centre retrospective observational study of patients with BP and MMP who were treated with rituximab between November 2016 and January 2020, and who have previously failed conventional immunosuppressive therapies. A single course of two infusions of 1000 mg of rituximab was administered within an interval of 2 weeks (M0 and M0·5), followed by 500 mg at month 6 (M6) and month 12 (M12). Clinical outcomes according to definitions of an international consensus conference were applied.3, 4 Reported adverse events and PROMs including Dermatology Life Quality Index (DLQI), Treatment of Autoimmune Bullous Disease Quality of Life (TABQOL) and Hospital Anxiety Scale (HADS) were collected. A lower score indicates a better outcome. P < 0·05 was considered significant.

In total, seven patients with BP and 16 patients with MMP were included; eight were male (35%) and 15 were female (65%) with a median age of 64 years [interquartile range (IQR) 58–70]. The median BP Disease Area Index score at M0 (n = 18) was 4·0 (IQR 1·8–7·0), owing to concomitant use of immunosuppression or immunomodulators. Mucosal involvement in MMP included ocular (n = 8, 50%), nasal (n = 6, 38%), oral (n = 12, 75%), laryngeal (n = 3, 19%), pharyngeal (n = 8, 50%) and genital involvement (n = 5, 31%).

Disease control was achieved in 19 patients (83%), six of whom had BP (86%) and 13 of whom had MMP (81%). Remission (partial or complete) was achieved in 17 patients (74%), five of whom had BP (71%) and 12 of whom had MMP (75%). Complete remission off therapy was achieved by two patients (29%) with BP and five patients (31%) with MMP (Table 1). At M0, 21 patients (91%) received adjuvant immunosuppression or immunomodulators (Table 1). This decreased to 17 patients (74%) at M6 and nine patients (39%) at M12. In particular, the number of patients receiving prednisone decreased from 18 patients (78%) at M0 to 13 patients (57%) at M6. Only six patients (26%) were treated with prednisone at M12. B cells were rapidly depleted in the peripheral blood at M0·5 in all patients. During treatment, the DLQI score showed a decrease of 50% between M0 and M6 (n = 19, P = 0·012). The TABQOL score showed a decrease of 41% between M0 and M12 (n = 14, P = 0·001). Finally, the HADS score decreased by 50% between both M0 and M6 (n = 18; P = 0·01) and M0 and M12 (n = 14; P = 0·044).

Table 1. Highest clinical outcome reached and reported adverse events (AEs) after rituximab treatment in patients with pemphigoid Total (n = 23) BP (n = 7) MMP (n = 16) Clinical outcome DC 19 (83) 6 (86) 13 (81) Median TTDC, weeks (IQR) 14·0 (4·0–23·0) 13·0 (5·0–21·5) 14·0 (5·0–21·5) Remission, PR/CR 17 (74) 5 (71) 12 (75) PR on therapy 2 (9) 0 (0) 2 (13) Median TTPR, weeks (n) 28·0 – 28·0 PR off therapy 6 (26) 1 (14) 5 (31) Median TTPR off therapy, weeks (IQR) 59·0 (20·3–69·8) 52 66·0 (18·5–72·5) CR on therapy 2 (9) 2 (29) 0 (0) Median TTCR, weeks 56·5 56·5 – CR off therapy 7 (30) 2 (29) 5 (31) Median TTCR off therapy, weeks (IQR) 62·0 (52·0–68·0) 57·5 62·0 (46·0–87·5) Relapse 8 (35) 2 (29) 6 (38) Median time to relapse, weeks (IQR) 56·0 (12·8–81·5) 32·5 61·5 (24·3–95·8) Adjuvant systemic therapy M0 (%) 21 (91) 7 (100) 14 (88) Prednisone 18 (78) 6 (86) 12 (75) Dapsone 4 (17) 2 (29) 2 (13) Methotrexate 1 (4) 1 (14) 0 (0) Cyclophosphamide 3 (13) 0 (0) 3 (19) Azathioprine 1 (4) 0 (0) 1 (6) M6 (%) 17 (74) 6 (86) 11 (69) Prednisone 13 (57) 5 (71) 8 (50) Dapsone 4 (17) 2 (29) 2 (13) Methotrexate 0 (0) 0 (0) 0 (0) Cyclophosphamide 1 (4) 0 (0) 1 (6) Azathioprine 1 (4) 0 (0) 1 (6) M12 (%) 9 (39) 5 (71) 4 (25) Prednisone 6 (26) 4 (57) 2 (13) Dapsone 3 (13) 2 (29) 1 (6) Methotrexate 0 (0) 0 (0) 0 (0) Cyclophosphamide 1 (4) 0 (0) 1 (6) Azathioprine 1 (4) 0 (0) 1 (6) AEs Number of patients with AEs (%) 22 (96) Malaise 19 (86) Pain 9 (41) Dyspnoea 8 (36) Headache 3 (14) Rash 2 (9) Lymphopenia 11 (50) Anaemia 8 (36) Tromboctyopenia 1 (5) Leucocytosis 1 (5) Late-onset neutropenia 1 (5) Hypogammaglobulinaemia 12 (55) Reduced number of CD8 T cells 9 (41) Reduced number of CD3 T cells 8 (36) Reduced number of CD4 T cells 8 (36) Infections, bacterial or viral 21 (95) Candida 4 (18) BP, bullous pemphigoid; CR, complete remission; DC, disease control; IQR, interquartile range; MMP, mucous membrane pemphigoid; M0, first infusion of 1000 mg of rituximab; M6, third infusion of 500 mg of rituximab at month 6; M12, fourth infusion of rituximab at month 12; PR, partial remission; TTCR, time to CR; TTDC, time to DC; TTPR, time to PR. Data are presented as n (%) unless otherwise stated.

The reappearance of B cells was observed in five patients (22%) at M6 and in 13 patients at M12 (57%). Overall, eight patients (35%) relapsed after a median time of 56 weeks [two patients with BP (29%) and six patients with MMP (38%)] (Table 1). Overall, 22 patients (96%) reported adverse events, the majority of which were infections (n = 21, 95%). Hypogammaglobulinaemia was reported in 12 patients (55%), reduced CD3 and CD4 T cells were reported in eight patients (36%) and reduced CD8 T cells were reported in nine patients (41%) (Table 1). The majority of these patients were treated for bacterial or viral infections. None of these infections were severe or life-threatening. The 1-year mortality was 0%. These results support the beneficial effects of rituximab therapy on the clinical response in patients with pemphigoid, in line with previous studies.5-7 Concomitant immunosuppression or immunomodulators were reduced during rituximab treatment, in particular the percentage of patients using prednisone decreased from 78% to 26% between M0 and M12. A major concern with rituximab treatment is the increased risk of infection. In this study, the majority of patients reported infections, but none were severe. In our cohort, the 1-year mortality was 0%, but this result may be biased owing to the small sample size. Previous studies have observed a lower 1-year mortality rate in patients receiving rituximab compared with those receiving conventional therapy.6, 8

Importantly, we observed a positive effect of rituximab therapy on quality of life and treatment burden in patients with pemphigoid, which was reflected by a significant decrease in the DLQI and TABQOL score and a decline in anxiety scores during rituximab treatment. Limitations of this study include its retrospective nature and the small sample size. In conclusion, our study demonstrated a 74% remission rate in patients with pemphigoid who received rituximab treatment, which had a steroid-sparing benefit, and importantly, we also observed a significant improvement in quality of life and a decrease in treatment burden.

Acknowledgments

permission to use the licensed tool TABQOL was obtained from the Australasian Blistering Diseases Foundation.

Author Contribution

Hanan Rashid: Conceptualization (lead); Data curation (lead); Formal analysis (lead); Investigation (lead); Methodology (lead); Project administration (lead); Resources (lead); Software (lead); Supervision (lead); Validation (lead); Visualization (lead); Writing-original draft (lead); Writing-review & editing (lead). Joost Meijer: Conceptualization (supporting); Data curation (supporting); Formal analysis (supporting); Investigation (supporting); Methodology (supporting); Project administration (supporting); Resources (supporting); Software (supporting); Supervision (supporting); Validation (supporting); Visualization (supporting); Writing-original draft (supporting); Writing-review & editing (supporting). Marieke Bolling: Conceptualization (supporting); Data curation (supporting); Formal analysis (supporting); Investigation (supporting); Methodology (supporting); Project administration (supporting); Resources (supporting); Software (supporting); Supervision (supporting); Validation (supporting); Visualization (supporting); Writing-original draft (supporting); Writing-review & editing (supporting). Barbara Horvath: Conceptualization (supporting); Data curation (supporting); Formal analysis (supporting); Investigation (supporting); Methodology (supporting); Resources (supporting); Software (supporting); Supervision (supporting); Validation (supporting); Visualization (supporting); Writing-original draft (supporting); Writing-review & editing (supporting).