To the Editor: The incidence and severity of COVID-19 among patients with autoimmune bullous skin diseases (AIBD) have not been characterized in large populations.1, 2, 3 We assessed the severity and mortality of COVID-19 in patients with AIBD, with a special interest in a potential risk factor related to previous treatment with rituximab.
This study was conducted from February 2020 to June 2020 in 49 dermatology departments located in 12 administrative regions of France. Possible (suggestive clinical symptoms and contact with COVID-19), probable (suggestive computed tomography scan), and confirmed (positive reverse transcriptase polymerase chain reaction result) cases of COVID-19 with AIBD were identified using data from the hospitals’ electronic health records (hospitalized patients) and by spontaneous reporting (nonhospitalized patients). Patients who had received at least 1 infusion of rituximab from September 2019 to June 2020 were identified from the database of each hospital pharmacy. Data on the hospitalization of patients with AIBD and COVID-19 and COVID-19–related deaths were recorded. Region- and age-specific incidence and lethality of hospitalized confirmed COVID-19 in the general population were retrieved from the Santé Publique France website. Detailed methodology is available in the Supplementary Material (available via Mendeley at https://data.mendeley.com//datasets/yg3gv392x6/1).
Of 5180 patients with AIBD, 59 were diagnosed with possible, probable, or confirmed COVID-19, of whom 30 (50.8%) were hospitalized, 7 (11.9%) were admitted to an intensive care unit, and 15 (25.4%) died. We identified 21 patients with bullous pemphigoid, 19 patients with mucous membrane pemphigoid, 18 patients with pemphigus, and 1 patient with pregnancy-associated pemphigoid (Table I ).
Table I.
Age, sex, main comorbidities, AIBD treatments, and management (hospitalization vs outpatient management) of COVID-19–infected patients depending on the type of AIBD
| Data recorded | BP n (%) | MMP n (%) | Pemphigus n (%) | PG n (%) |
|---|---|---|---|---|
| COVID-19 | ||||
| Confirmed | 9 (42.9) | 13 (68.4) | 6 (33.3) | 1 (100) |
| Probable | 4 (19) | 3 (15.8) | 1 (5.6) | 0 (0) |
| Possible | 8 (38.1) | 3 (15.8) | 11 (61.1) | 0 (0) |
| Sex, M/F | 10/11 | 6/13 | 9/9 | 0/1 |
| Age, years, mean ± SD | 81.8 ± 8.2 | 74.9 ± 12.2 | 60.9 ± 18.1 | 32 |
| Body mass index, kg/m2, mean ± SD | 26.2 ± 7.3 | 27.5 ± 5.4 | 26.0 ± 4.5 | NA |
| Karnofsky score, mean ± SD | 54.5 ± 21.1 | 67.4 ± 21.0 | 76.5 ± 39.0 | 90 |
| Medical history | ||||
| Diabetes mellitus | 11 (52.4) | 6 (31.6) | 2 (11.1) | 0 (0) |
| Hypertension | 11 (52.4) | 2 (10.5) | 3 (16.7) | 0 (0) |
| Renal disorder | 5 (23.8) | 1 (5.3) | 0 (0) | 0 (0) |
| Cardiovascular disorder | 5 (23.8) | 3 (15.8) | 0 (0) | 0 (0) |
| Lung disorder | 5 (23.8) | 3 (15.8) | 1 (5.6) | 0 (0) |
| Neurological disorder | 5 (23.8) | 2 (10.5) | 2 (11.1) | 0 (0) |
| Neoplasia | 7 (33.3) | 2 (10.5) | 1 (5.6) | 0 (0) |
| Dyslipidemia | 3 (14.3) | 0 (0) | 1 (5.6) | 0 (0) |
| Other | 3 (14.3) | 3 (15.8) | 0 (0) | 0 (0) |
| Treatment of AIBD∗ (nonexclusive) | ||||
| Systemic corticosteroids | 5 (23.8) | 3 (15.8) | 4 (22.2) | 1 (100) |
| Topical corticosteroids | 12 (57.1) | 6 (31.6) | 2 (11.1) | 0 (0) |
| Conventional immunosuppressants | 7 (33.3) | 3 (15.8) | 1 (5.6) | 0 (0) |
| Rituximab | 1 (4.8) | 9 (47.4) | 13 (72.2) | 0 (0) |
| Dapsone | 1 (4.8) | 14 (73.7) | 0 (0) | 0 (0) |
| Omalizumab | 1 (4.8) | 2 (10.5) | 0 (0) | 0 (0) |
| Cyclines | 1 (4.8) | 4 (21.1) | 0 (0) | 0 (0) |
| Sulfasalazine | 0 (0) | 2 (10.5) | 0 (0) | 0 (0) |
| Management of COVID-19 (nonexclusive) | ||||
| Hospitalization | 12 (57.1) | 10 (52.6) | 1 (5.6) | 0 (0) |
| Intensive care unit | 1 (4.8) | 1 (5.3) | 5 (27.8) | 0 (0) |
| Outpatient management | 8 (38.1) | 8 (42.1) | 12 (66.7) | 1 (100) |
AIBD, Autoimmune bullous skin disease; BP, bullous pemphigoid; MMP, mucous membrane pemphigoid; NA, not applicable; PG, pemphigoid gestationis; SD, standard deviation.
During the previous 9 months.
The age- and region-standardized incidence ratio of hospitalized confirmed COVID-19 infection was 0.42 (95% confidence interval [CI], 0.20-0.80; P = .005) for bullous pemphigoid, 1.02 (95% CI, 0.37-2.26; P = .91) for pemphigus, and 1.18 (95% CI, 0.55-2.23; P = .62) for mucous membrane pemphigoid. The apparently low risk of COVID-19 infection in patients with bullous pemphigoid must therefore be interpreted with caution since it is very likely that some older patients with bullous pemphigoid in poor general condition died from an undiagnosed COVID-19 infection in their nursing homes. The incidence ratio of COVID-19 in patients treated with rituximab ranged from 3.62 (95% CI, 1.29-8.85) in patients with AIBD hospitalized with a confirmed diagnosis of COVID-19 to 5.37 (95% CI, 3.15-8.96) in patients with a confirmed, probable, or possible diagnosis of COVID-19 infection (Table II ).
Table II.
Proportions of patients with a confirmed, probable, or possible diagnosis of COVID-19 infection among patients with AIBD, according to whether or not they were treated with rituximab
| Diagnosis of COVID-19 | Patients with AIBD treated with rituximab n/N (%) | Patients with AIBD who did not receive rituximab n/N (%) | Incidence ratio (95% CI) |
|---|---|---|---|
| Possible, probable or confirmed | 22/516 (4.26%) | 37/4664 (0.79%) | 5.37 (3.15-8.96) |
| Probable or confirmed | 13/516 (2.52%) | 24/4664 (0.51%) | 4.90 (2.43-9.40) |
| Confirmed and hospitalized | 6/516 (1.16%) | 15/4664 (0.32%) | 3.62 (1.29-8.85) |
AIBD, Autoimmune bullous skin disease; CI, confidence interval.
The lethality of confirmed COVID-19 (n = 8/21, 38.1%) was 1.63-fold (95% CI, 0.83-2.55; P = .13) higher in hospitalized patients with AIBD than in the general population of the same age (23%). Patients with AIBD and COVID-19 had a 5.9-fold (95% CI, 3.9-8.4) higher 3-month death risk than patients with AIBD without COVID-19.4 , 5 Patients with AIBD and a hospitalized or lethal form of COVID-19 were older than those with a benign form (77.9 ± 11.2 years vs 65.0 ± 19.3 years; P = .006).
The major finding of this study is the notably higher risk of COVID-19 infection in patients with AIBD treated with rituximab, corresponding to a more than 5-fold higher incidence of COVID-19 infection than in patients who did not receive rituximab. Patients with AIBD and COVID-19 had a 5.9-fold higher risk of dying during the first wave of the COVID-19 pandemic in France than patients with AIBD and without COVID-19.
Overall, this study showed that treatment with rituximab is a major risk factor of COVID-19 infection. Given the high lethality of COVID-19 in patients with AIBD, physicians should carefully evaluate the benefit-risk balance of rituximab therapy during this pandemic period.
Conflicts of interest
Dr Joly is a consultant for Roche, Amgen, Principia Biopharma, Argenx, Astra Zeneca, Sanofi-Regeneron, Innovaderm, and ThermoFisher. Dr Caux is a consultant for Principia Biopharma and is an investigator in clinical trials sponsored by Principia Biopharma and Roche. Drs Gillibert, Bohelay, Aouar, Ingen-Housz-Oro, Bedane, Lepelletier, Bohin, Viguier, Dupin, Debarbieux, Jullien, Quéreux, Morice, Mahe, Michel, Litrowski, Jeudy, Richard, Picard, Chosidow, Ledard, Hebert, Duvert-Lehembre, Cordel, Alexandre, and Le Roux-Villet have no conflicts of interest to disclose.
Footnotes
Drs Bohelay and Aouar contributed equally to this article.
Funding sources: None.
IRB approval status: Reviewed and approved by the institutional review board of Rouen University Hospital (no. E2020-59).
Reprints not available from the authors.
Contributor Information
French study Group on auto immune bullous skin diseases, and the French network of rare diseases in Dermatology (FIMARAD):
André Gillibert, Gérôme Bohelay, Karen Aouar, Saskia Ingen-Housz-Oro, Christophe Bedane, Clémence Lepelletier, Emmanuelle Tancrède Bohin, Manuelle Viguier, Nicolas Dupin, Sebastien Debarbieux, Denis Jullien, Gaelle Quereux, Cécile Morice, Antoine Mahe, Catherine Michel, Noemie Litrowski, Géraldine Jeudy, Marie Aleth Richard, Catherine Picard, Olivier Chosidow, Anne-Pham Ledard, Vivien Hebert, Sophie Duvert-Lehembre, Nadège Cordel, Marina Alexandre, Christelle Le Roux-Villet, and Frédéric Caux
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