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 , 6 , 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.
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).
Acknowledgments
permission to use the licensed tool TABQOL was obtained from the Australasian Blistering Diseases Foundation.
Funding sources: none.
Conflicts of interest: B.H. reports fees from Janssen‐Cilag (Advisory Boards, Educational grants, Consultations, Investigator Initiative Studies), AbbVie (Advisory Boards, Educational grants, Consultations, Investigator Initiative Studies), Novartis Pharma (Advisory Boards, Consultations, Investigator Initiative Studies), UCB Pharma (Advisory Boards, Consultations), Leo Pharma (Consultations), Solenne B.V. (Investigator Initiative Studies), Celgene (Consultations, Investigator Initiative Studies), Akari therapeutics (Consultations, Investigator Initiative Studies), Philips (Consultation), Roche (Consultation), Regeneron (Consultation) and Sanofi (Consultation).
Data availability: data available on request from the authors.
References
- 1. Kirtschig G, Middleton P, Bennett C et al. Interventions for bullous pemphigoid. Cochrane Database Syst Rev 2010; 2010:CD002292. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Kirtschig G, Murrell D, Wojnarowska F, Khumalo N. Interventions for mucous membrane pemphigoid and epidermolysis bullosa acquisita. Cochrane Database Syst Rev 2003; 2003:CD004056. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Murrell DF, Marinovic B, Caux F et al. Definitions and outcome measures for mucous membrane pemphigoid: recommendations of an international panel of experts. J Am Acad Dermatol 2015; 72:168–74. [DOI] [PubMed] [Google Scholar]
- 4. Murrell DF, Daniel BS, Joly P et al. Definitions and outcome measures for bullous pemphigoid: recommendations by an international panel of experts. J Am Acad Dermatol 2012; 66:479–85. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Polansky M, Eisenstadt R, DeGrazia T et al. Rituximab therapy in patients with bullous pemphigoid: a retrospective study of 20 patients. J Am Acad Dermatol 2019; 81:179–86. [DOI] [PubMed] [Google Scholar]
- 6. Yoo DS, Lee JH, Kim SC, Kim JH. Mortality and clinical response of patients with bullous pemphigoid treated with rituximab. Br J Dermatol 2021; 185:210–12. [DOI] [PubMed] [Google Scholar]
- 7. Le Roux‐Villet C, Prost‐Squarcioni C, Alexandre M et al. Rituximab for patients with refractory mucous membrane pemphigoid. Arch Dermatol 2011; 147:843–9. [DOI] [PubMed] [Google Scholar]
- 8. Cho YT, Chu CY, Wang LF. First‐line combination therapy with rituximab and corticosteroids provides a high complete remission rate in moderate‐to‐severe bullous pemphigoid. Br J Dermatol 2015; 173:302–4. [DOI] [PubMed] [Google Scholar]