Rituximab in the Treatment of Epidermolysis Bullosa Acquisita: A Systematic Review

Abstract

Objective

Epidermolysis bullosa acquisita (EBA) is a rare dermatosis of the mucous membrane and/or skin. Employing biologic treatment modalities, specifically rituximab (RTX), have become pivotal measure in treating patients with blistering diseases. This study aims to summarize the current evidence on the safety and efficacy of RTX in EBA.

Methods

An extensive search was performed in MEDLINE/PubMed, Embase, Scopus, and Web of Science databases until the end of August 19th, 2023. Two independent reviewers screened the papers, and collected data. Two hundred thirty-three studies were screened using Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines.

Results

Thirty-one studies were enrolled. The most common reason of RTX administration in patients with EBA was recalcitrant diseases. Clinical response and disease remission was recorded as 92.7 percent (63 patients) and 73.8 percent (45 patients) of the patients, respectively. A relapse rate of 39.5 percent (15 patients) in the mean follow-up of 23.0 months was reported in the studies. Of the patients, 28.2 percent (11 patients) experienced RTX-related side events, mostly mild and transient infusion reactions.

Conclusion

The results of this systematic review demonstrated that RTX is safe and effective in patients with EBA. This biological treatment modality can be routinely used in managing EBA.

Epidermolysis bullosa acquisita is a rare bullous dermatoses triggered by IgG autoantibodies against collagen VII (COL7). The classical non-inflammatory mechanobullous subtype (MB) presents with trauma-induced tense blisters mainly limited to the skin. Contrariwise, in the inflammatory subtype, widespread vesiculobullous involvement is observed.1,2 Importantly, clinical presentations can switch from one subtype to the other over time, and also, the two subtypes may present simultaneously.3,4

Finding the optimal treatment for patients with EBA is still challenging. Rituximab, a chimeric anti-CD20 monoclonal antibody, has shown potential as an alternative treatment in the past few years.5–8 It is expressed on a wide range of B cells, from pre-B cell stage and on mature B cells in the bone marrow and in the periphery.9 Since B cells play a crucial role in the pathogenesis of EBA, this disease might benefit from this treatment.4

Herein, a systematic review of the current literature regarding RTX in EBA is performed. These data would be invaluable for choosing the best therapeutic regimen for patients suffering from EBA.

METHODS

The systematic review of the literature was conducted based on Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guideline.10 The keywords related to “EBA” and “RTX” were determined using electronic databases and similar articles. The search syntheses were designed, and a systematic search was performed on MEDLINE/PubMed, Embase, Scopus, and Web of Science on August 19th, 2023 (Supplementary Table 1, see online version of this article). The references and citations of the relevant articles were also manually searched for the probable missing articles. Two independent reviewers screened the papers and collected data. All detected records were inserted into the Endnote X8 (Clarivate Analytics, Philadelphia), and duplicate reports were removed. Original studies that assessed the efficacy or safety of using RTX in patients with EBA were included. No limitation was set for language or study type. The EBA diagnosis had to be confirmed by histological, direct/indirect immunofluorescence, ELISA, and/or immunoblotting assessments. Studies with no sufficient data were excluded.

TABLE 1.

Summary of literature review regarding demographic data, efficacy, and treatment durability of rituximab in patients with epidermolysis bullosa acquisita

DEMOGRAPHIC	MECHANOBULLOUS	NON-MECHANOBULLOUS	TOTAL
PATIENTS, N	23	19	68
Age at onset, y
MEAN	54	52.7	52.9
RANGE	28-88	20-77	17-88
NM	6	6	13
Gender, n (%)
FEMALE	8 (47.1%)	13 (72.2%)	35 (51.5%)
MALE	9 (52.9%)	5 (27.8%)	33 (48.5%)
NM	6	1	0
Previous treatments, n (%)
SYSTEMIC CORTICOSTEROIDS	5 (31.2%)	16 (94.1%)	32 (60.4%)
DAPSONE	3 (18.8%)	6 (35.3%)	16 (30.2%)
AZATHIOPRINE	2 (12.5%)	3 (17.6%)	9 (16.9%)
MYCOPHENOLATE MOFETIL	3 (18.8%)	1 (5.9%)	9 (16.9%)
IVIG	1 (6.2%)	0 (0%)	7 (13.2%)
CYCLOSPORINE	4 (25.0%)	2 (11.8%)	9 (16.9%)
COLCHICINE	2 (12.5%)	1 (5.9%)	4 (7.5%)
OTHERS	2 (12.5%)	2 (11.8%)	8 (15.1%)
NM	7	2	15
EBA duration until RTX infusion, months
MEAN	82.7	23.0	51.3
RANGE	6-240	0.5-84	0.5-240
NM	6	4	14
Adjuvant therapy, n (%)
SYSTEMIC CORTICOSTEROIDS	5 (31.2%)	16 (94.1%)	32 (60.4%)
DAPSONE	3 (18.8%)	6 (35.3%)	16 (30.2%)
AZATHIOPRINE	2 (12.5%)	3 (17.6%)	9 (16.9%)
IVIG	3 (18.8%)	1 (5.9%)	9 (16.9%)
COLCHICINE	1 (6.2%)	0 (0%)	7 (13.2%)
MYCOPHENOLATE MOFETIL	4 (25.0%)	2 (11.8%)	9 (16.9%)
IMMUNOADSORPTION	2 (12.5%)	1 (5.9%)	4 (7.5%)
OTHER	2 (12.5%)	2 (11.8%)	8 (15.1%)
NM	7	2	15
Disease control, n (%)
YES	22 (95.6%)	16 (84.2%)	63 (92.7%)
NO	1 (4.3%)	3 (15.8%)	5 (7.3%)
NM	0	0	0
Clinical remission, n (%)
YES	10 (58.8%)	11 (64.7%)	45 (73.8%)
NO	7 (41.2%)	6 (35.3%)	16 (26.2%)
NM	6	2	7
RTX-related side effects, n (%)
YES	3 (30%)	4 (28.6%)	11 (28.2%)
NO	7 (70%)	10 (71.4%)	28 (71.8%)
NM	13	5	29
Treatment durability
Relapse, n (%)	6 (60%)	3 (23.1%)	15 (39.5%)
Follow-up, m	23.9	24.1	23.0
NM	13	6	30

EBA, epidermolysis bullosa acquisita; RTX, rituximab, IVIg, intravenous immunoglobulin; NM, not mentioned

The screening process was done in two stages on titles/abstracts and full-texts. The following data were extracted: study characteristics, patients’ demographics, EBA subtype, disease duration until infusion, previous treatments, indication of RTX infusion, protocol of RTX infusion, adjuvant therapy, time to obtain clinical response, clinical remission, side effects of RTX, and treatment durability. All mentioned steps were done by two independent investigators (NK and SD).

RESULTS

The systematic search resulted in 565 articles, 238 of which were non-duplicate reports. After the screening of title and abstracts, 63 studies were selected for full-text review. Accordingly, 31 articles including 68 patients with EBA were found eligible for data extraction (Figure 1).5–7,11–38 The mean age of the patients was 52.9 years old, with 35 (51.5%) women and 33 (48.5%) men. The EBA subtype was defined in 43 patients, including 23 (53.5%) with MB type, 19 (44.2%) with non-MB type, and one (2.3%) with mixed form. The indications of RTX administration in patients with EBA were mostly recalcitrant diseases (55.9 % in 38 patients). The appropriate clinical response to RTX was observed in 92.7 percent (63 patients) patients. Disease remission was considered the endpoint of treatment in 28 studies (61 patients), demonstrating an overall remission rate of 73.8 percent (45 patients). Treatment durability was assessed in 17 studies (38 patients); disease relapse rate was measured as 39.5 percent (15 patients) in the mean follow-up of 23.0 months. Of the patients, 28.2 percent (11 patients) experienced RTX-related side effects, which were primarily mild and transient. The severe side effects were pneumonia in two individuals (leading to death in both), and deep vein thrombosis in one. The results of the literature review are summarized in Tables 1 and 2.

FIGURE 1.

PRISMA flow diagram of the systematic review

TABLE 2.

List of studies on the efficacy, safety, and treatment durability of rituximab in treating patients with epidermolysis bullosa acquisita

STUDY	Dasdar et al11
DESIGN	Case series; n=15
GENDER	M	M	M	F	F	F	M
AGE AT DISEASE ONSET OR RTX INFUSION, Y	At onset, 72	At onset, 46	At onset, 43	At onset, 20	At onset, 47	At onset, 53	At onset, 88
EBA VARIANT	non-MCB	non-MCB	non-MCB	non-MCB	MCB	non-MCB	MCB
SITE OF INVOLVEMENT	Mucosal	Mucosal	Mucosal	Mucosal	Mucosal	Mucosal	NM
EBA DIAGNOSIS	Histopathologic examination, direct and indirect immunofluorescence	Histopathologic examination, direct and indirect immunofluorescence	Histopathologic examination, direct and indirect immunofluorescence	Histopathologic examination, direct and indirect immunofluorescence	Histopathologic examination, direct and indirect immunofluorescence	Histopathologic examination, direct and indirect immunofluorescence	Histopathologic examination, direct and indirect immunofluorescence
PREVIOUS TREATMENTS	PSL	PSL	PSL	AZT, dapsone	PSL	PSL, dapsone	MTX, Doxycycline
INDICATION OF RTX	Severe disease	Severe disease	Recalcitrant disease	Recalcitrant disease	Recalcitrant disease	Recalcitrant disease	Recalcitrant disease
EBA DURATION TO RTX INFUSION	1m	1m	31m	48m	18m	12m	19m
RTX PROTOCOL	4 x 500mg	4 x 500mg	4 x 500mg	2 x 1000mg	4 x 500mg	4 x 500mg	4 x 500mg
NUMBER OF CYCLES; DURATION OF TREATMENT	1 cycle	1 cycle	1 cycle	1 cycle	1 cycle	1 cycle	1 cycle
ADJUVANT TREATMENTS	PSL, MTX	PSL	PSL	PSL, dapsone	PSL	PSL, dapsone	MTX
Disease control	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Clinical remission	Yes	Yes	No	No	No	Yes	Yes
SIDE EFFECT OF RTX THERAPY	No	No	No	No	No	Sore throat	No
RELAPSE	No	No	No	Yes, 3m	Yes, 4m	Yes, 9m	Yes, 10m
FOLLOW-UP DURATION FROM RTX	55m	13m	18m	52m	38m	28	32m
OTHER ENDPOINTS	–	–	–	–	–	–	–
STUDY	Dasdar et al11
DESIGN	Case series; n=15
GENDER	F	M	M	F	F	F	M	F
AGE AT DISEASE ONSET OR RTX INFUSION, Y	At onset, 45	At onset, 54	At onset, 54	At onset, 29	At onset, 58	At onset, 57	At onset, 50	At onset, 63
EBA VARIANT	MCB	MCB	MCB	non-MCB	non-MCB	non-MCB	MCB	non-MCB
SITE OF INVOLVEMENT	Mucosal	Mucosal	Mucosal	Mucosal	Cutaneous and mucosal	Cutaneous and mucosal	Mucosal	Cutaneous and mucosal
EBA DIAGNOSIS	Histopathologic examination, direct and indirect immunofluorescence	Histopathologic examination, direct and indirect immunofluorescence	Histopathologic examination, direct and indirect immunofluorescence	Histopathologic examination, direct and indirect immunofluorescence	Histopathologic examination, direct and indirect immunofluorescence	Histopathologic examination, direct and indirect immunofluorescence	Histopathologic examination, direct and indirect immunofluorescence	Histopathologic examination, direct and indirect immunofluorescence
PREVIOUS TREATMENTS	PSL, AZT, MTX	PSL, cyclosporine, MMF, colchicine	PSL, MTX	PSL	MTX	PSL	PSL	PSL, MMF
INDICATION OF RTX	Recalcitrant disease	Recalcitrant disease	Side effects of treatments	Severe disease	Recalcitrant disease	Severe disease	Recalcitrant disease	Recalcitrant disease
EBA DURATION TO RTX INFUSION	60m	240m	12m	2m	48m	1m	7m	20m
RTX PROTOCOL	4 x 500mg	4 x 500mg	2 x 1000mg	4 x 500mg	2 x 1000mg	4 x 500mg	4 x 500mg	4 x 500mg
NUMBER OF CYCLES; DURATION OF TREATMENT	1 cycle	1 cycle	2 cycles	1 cycle	1 cycle	1 cycle	1 cycle	1 cycle
ADJUVANT TREATMENTS	-	Dapsone	MMF, dapsone	PSL, MMF, dapsone	PSL, MTX	PSL	PSL, MTX	PSL, MMF, dapsone
DISEASE CONTROL	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
CLINICAL REMISSION	Yes	No	Yes	Yes	No	Yes	No	Yes
SIDE EFFECT OF RTX THERAPY	Fever, cough, COVID-19	No	No	Urticaria, angioedema, arthralgia, edema	No	Nausea, mild headache	No	Blood pressure rise, dyspnea
RELAPSE	Yes, 20m	No	No	No	No	No	Yes, 11 m	No
FOLLOW-UP DURATION FROM RTX	42m	15m	33m	19m	6m	24m	24m	44m
OTHER ENDPOINTS	–	–	–	–	–	–	–	–
STUDY	Gordilho et al12	Han et al13	Koszegi et al14	Szymański et al15	Schauer et al16		Mendes et al5
DESIGN	Case series; n=7	Case report; n=1	Case report; n=1	Case series; n=1	Case series; n=2		Case report; n=1
GENDER	4F, 3M	M	M	F	F	F	M
AGE AT DISEASE ONSET OR RTX INFUSION, Y	At onset, 51 (median)	At onset, 44	At infusion, 58	At onset, 66	At onset, 28	At onset, 67	At onset, 69
EBA VARIANT	6MCB, 1 non-MCB	NM	NM	MCB	MCB	MCB	NM
SITE OF INVOLVEMENT	Cutaneous and mucosal	Cutaneous	Cutaneous and mucosal	Cutaneous and mucosal	Cutaneous and mucosal	Cutaneous and mucosal	Cutaneous and mucosal
EBA DIAGNOSIS	Histopathologic examination, direct and indirect immunofluorescence	Histopathologic examination, direct and indirect immunofluorescence	NM	Histopathologic examination, direct and indirect immunofluorescence	Direct and indirect immunofluorescence, ELISA	Direct and indirect immunofluorescence, ELISA, immunoblotting	Histopathologic examination, direct immunofluorescence, ELISA
PREVIOUS TREATMENTS	PSL (n=7), MMF (n=7), dapsone (n=4), cyclosporine (n=2), AZT (n=1)	PSL, MMF	PSL, cyclosporine, dapsone, tetracycline, AZT, plasmapheresis	Tetracycline, PSL, dapsone, Clobetasol propionate	Systemic CS, AZT, MMF, chloroquine	CS pulse therapy, AZT	Methylprednisolone, dapsone, AZT, topical therapy
INDICATION OF RTX	Severe disease	Recalcitrant disease	Recalcitrant disease	Side effects of treatments	Recalcitrant disease	Recalcitrant disease, side-effect of previous treatments	Recalcitrant disease, side-effect of previous treatments
EBA DURATION TO RTX INFUSION	42m (median)	NM	NM	6y	10y	6m	NM
RTX PROTOCOL	NM	2 x 1000mg at two weeks interval	NM	2 x 1000mg at two weeks interval	2 x 1000mg at two weeks interval	2 x 1000mg at two weeks interval	4 x 375mg/m2 at one week interval
NUMBER OF CYCLES; DURATION OF TREATMENT	3 cycles (1-9 cycles)	1 cycle	4 cycles	1 cycle	1 cycle	1 cycle	1 cycle
ADJUVANT TREATMENTS	NM	NM	NM	PSL	IVIg at one month interval, topical treatment	2 x IVIg, topical treatment	NM
DISEASE CONTROL	Yes	Yes	Yes	Yes	Yes	No	Yes
CLINICAL REMISSION	Complete remission (n=3), partial remission (n=3)	Yes	Yes	Yes	No	No	No
SIDE EFFECT OF RTX THERAPY	NM	NM	NM	NM	NM	Poorly tolerated	NM
RELAPSE	NM	NM	NM	Yes	NM	NM	NM
FOLLOW-UP DURATION FROM RTX	NM	36m	27m	15m	NM	NM	NM
OTHER ENDPOINTS	–	–	–	–	–	-	–
STUDY	Figueredo et al17	Dubois et al18	Yang et al19	Bevans et al6			Lamberts et al20
DESIGN	Case report; n=1	Case report; n=1	Case report; n=1	Case series; n=3			Case series; n=5
GENDER	F	M	M	M	M	F	F	F	F
AGE AT DISEASE ONSET OR RTX INFUSION, Y	At onset, 68	At onset, 30	At onset, 49	At onset, 85	At onset, 52	At onset, 52	At infusion, 59	At infusion, 87	At infusion, 56
EBA VARIANT	non-MCB	NM	MCB	NM	NM	NM	non-MCB	non-MCB	non-MCB
SITE OF INVOLVEMENT	Cutaneous and mucosal (esophageal stricture)	Cutaneous and mucosal	Cutaneous and mucosal (significant involvement of the esophagus and alimentary tract)	Cutaneous and mucosal	Cutaneous and mucosal	Cutaneous and mucosal	NM	NM	NM
EBA DIAGNOSIS	Histopathologic examination, direct immunofluorescence	Direct immunofluorescence, ELISA	Skin biopsy, direct and indirect immunofluorescence, immunoblotting	Histopathologic examination, direct and indirect immunofluorescence, ELISA			Histopathologic examination, direct and indirect immunofluorescence
PREVIOUS TREATMENTS	Systemic CS, dapsone	PSL, AZT, MMF, dapsone, IVIg	PSL, AZT, cyclosporine, dapsone, tetracycline, photophoresis, plasmapheresis	PSL, AZT, dapsone, IVIg	PSL, AZT, MMF, IVIg	P, dapsone, MMF	PSL, dapsone, AZT, CP, MMF, IVIg	PSL, AZT, intravenous CS	PSL, AZT, dapsone, doxycycline
INDICATION OF RTX	Recalcitrant disease	Recalcitrant disease, side-effect of previous treatments	Recalcitrant disease, side-effect of previous treatments	NM	NM	NM	Recalcitrant disease, side-effect of previous treatments
EBA DURATION TO RTX INFUSION	3y	2y	18y	20m	6m	4m	Mean, 29.1 (0.5-84m)
RTX PROTOCOL	NM	2 x 1000mg at two weeks interval	4 x 375mg/m2 at one week interval (first and second cycles)	4 x 375mg/m2 at one week interval	4 x 375mg/m2 at one week interval	2 x 1000mg at two weeks interval (first cycle) 4 x 375mg/m2 at one week interval (second, third, and fourth cycles)	2 x 500mg at two weeks interval	2 x 500mg at two weeks interval	2 x 1000mg at two weeks interval + 2 x 500mg at months 6 and 12
NUMBER OF CYCLES; DURATION OF TREATMENT	1 cycle	3 cycles;1 y	2 x 1000mg at two weeks interval (third cycles)	2 cycles	2 cycles	4 cycles	1 cycle	1 cycle	1 cycle
ADJUVANT TREATMENTS	5 x IVIg	NM	3 cycles; 3 y	PSL, AZT, dapsone	PSL, MMF	P, D, MMF	Topical CS, PSL	PSL, AZT	Topical CS, PSL, AZT
DISEASE CONTROL	Yes	Yes	NM	Yes	Yes	Yes	No	No	Yes
CLINICAL REMISSION	Yes	Yes	Yes	Yes	Yes	Yes	No	No	Yes
SIDE EFFECT OF RTX THERAPY	NM	NM	Yes	NM	NM	NM	No	No	No
RELAPSE	No	No	Yes	Yes, 12m	No	Yes, 5m	NM	NM	No
FOLLOW-UP DURATION FROM RTX	9m	3y	NM	20m	60m	22m	79m	2m	22m
OTHER ENDPOINTS	–	–	–	–	–	–	–	–	–
STUDY	Lamberts et al20		Oktem et al7
DESIGN	Case series; n=5		Case series; n=5
GENDER	M	F	F	M	M	M	F
AGE AT DISEASE ONSET OR RTX INFUSION, Y	At infusion, 25	At infusion, 43	At onset, 61	At onset, 56	At onset, 31	At onset, 55	At onset, 50
EBA VARIANT	non-MCB	non-MCB	NM	NM	NM	NM	NM
SITE OF INVOLVEMENT	NM	NM	Cutaneous and mucosal	Mucosal	Cutaneous and mucosal	Cutaneous and mucosal	Cutaneous and mucosal
EBA DIAGNOSIS	Histopathologic examination, direct and indirect immunofluorescence		Histopathologic examination, direct and indirect immunofluorescence
PREVIOUS TREATMENTS	PSL, AZT, dapsone, MMF	PSL, dapsone	CS, AZT, dapsone, IVIg, colchicine, extracorporeal photochemotherapy	CS, AZT, dapsone, cyclosporine, colchicine, extracorporeal photochemotherapy	CS, cyclosporine, dapsone, IVIg, colchicine	CS, AZT, dapsone, extracorporeal photochemotherapy	CS, cyclosporine, MMF, colchicine
INDICATION OF RTX	Recalcitrant disease, side-effect of previous treatments		Recalcitrant disease	Recalcitrant disease	Recalcitrant disease	Recalcitrant disease	Recalcitrant disease
EBA DURATION TO RTX INFUSION	Mean, 29.1 (0.5- 84m)		20y	10y	6y	6y	2y
RTX PROTOCOL	2 x 1000mg at two weeks interval + 2 x 500mg at months 6 and 12	2 x 1000mg at two weeks interval	4 x 375mg/m2 at one week interval	4 x 375mg/m2 at one week interval	4 x 375mg/m2 at one week interval	3 x 375mg/m2 at one week interval	4 x 375mg/m2 at one week interval
NUMBER OF CYCLES; DURATION OF TREATMENT	1 cycle	1 cycle	1 cycle	1 cycle	1 cycle	2 cycles; 2 m	1 cycle
ADJUVANT TREATMENTS	Topical CS, PSL, AZT	Topical CS, PSL, dapsone	24 x IVIg at one month interval,	25 x IVIg at one month interval, colchicine	26 x IVIg at one month interval,	12 x IVIg at one month interval, colchicine	10 x IVIg at one month interval,
DISEASE CONTROL	Yes	No	Yes	Yes	Yes	Yes	Yes
CLINICAL REMISSION	Yes	No	NM	NM	NM	NM	NM
SIDE EFFECT OF RTX THERAPY	No	No	No	Fever, shivering, and an urticaria-like	No	No	No
RELAPSE	No	NM	NM	NM	NM	NM	NM
FOLLOW-UP DURATION FROM RTX	14m	43m	25m	26m	28m	24m	10m
OTHER ENDPOINTS	–	–	ABSIS score: skin: Baseline, 33.8 (18-49.5) After treatment,12.9 (1-23.5) Mucosa: Baseline, 1.2 (0-3); After treatment, 0 Oral: Baseline, 11.7 (0-23.5) After treatment,
STUDY	Brassat et al21	Iranzo et al22		Kolesnik et al23	McKinley et al24	Pickert et al25	Li et al26
DESIGN	Case report; n=1	Case series; n=2		Retrospective cohort; n=1	Case report; n=1	Case report; n=1	Case report; n=1
GENDER	M	M	M	F	M	M	F
AGE AT DISEASE ONSET OR RTX INFUSION, Y	At onset, 46	At onset, 28	At onset, 33	At onset, 71	At onset, 13	At onset, 35	At onset, 54
EBA VARIANT	NM	non-MCB	Mixed-type	NM	NM	MCB	NM
SITE OF INVOLVEMENT	Cutaneous and mucosal	Cutaneous and mucosal	Cutaneous and mucosal	NM	Cutaneous and mucosal	Cutaneous	Cutaneous
EBA DIAGNOSIS	Histopathologic examination, direct and indirect immunofluorescence	Histopathologic examination, direct and indirect immunofluorescence, immunoblotting		Histopathologic examination, direct immunofluorescence, ELISA	Histopathologic examination, direct and indirect immunofluorescence	Direct and indirect immunofluorescence, ELISA	Histopathologic examination, direct immunofluorescence
PREVIOUS TREATMENTS	PSL, dapsone, MMF	NM	NM	PSL, dapsone	Topical CS, PSL, dapsone, tetracycline	-	Topical clobetasol and tacrolimus, cyclosporine, MMF, PSL, etanercept, IVIg, CP
INDICATION OF RTX	Recalcitrant disease, contradiction of conventional immunosuppressive	NM	NM	Recalcitrant disease, side-effect of previous treatments	CS dependency	NM	Recalcitrant disease, side-effect of previous treatments
EBA DURATION TO RTX INFUSION	2m	NM	NM	8y	15m	2y	2.5y
RTX PROTOCOL	4 x 375mg/m2 at one week interval	4 x 375mg/m2 at one week interval	4 x 375mg/m2 at one week interval	4 x 375mg/m2 at days 4, 11, 18, and 25	2 x 1000mg at four months interval	RTX at one month interval	4 x 375mg/m2 at one week interval
NUMBER OF CYCLES; DURATION OF TREATMENT	1 cycle	2 cycles	NM	1 cycle	1 cycle	1 cycle	1 cycle
ADJUVANT TREATMENTS	PSL	NM	NM	11 x protein A immunoapheresis at days 1, 2, 3 and weekly for 8 weeks, PSL, dapsone, AZT	Dapsone	IVIg at one month interval	PSL
DISEASE CONTROL	Yes	Yes	Yes	Yes	Yes	Yes	Yes
CLINICAL REMISSION	NM	Yes	Yes	Yes	Yes	Yes	Yes
SIDE EFFECT OF RTX THERAPY	NM	NM	NM	No	NM	NM	No
RELAPSE	NM	NM	NM	No	No	NM	No
FOLLOW-UP DURATION FROM RTX	NM	36m	NM	37m	2y	NM	16m
OTHER ENDPOINTS	–	–	–	Bullous pemphigoid disease area index: Before, 20, After 4 w, 0	–	–	–
STUDY	Le Roux-Villet et al27					Kim et al28	Kubisch et al29
DESIGN	Prospective study; n=5					Case report; n=1	Case report; n=1
GENDER	F	F	F	F	M	F	F
AGE AT DISEASE ONSET OR RTX INFUSION, Y	At onset, 56	At onset, 17	At onset, 30	At onset, 79	At onset, 70	At onset, 64	At onset, 71
EBA VARIANT	NM	NM	NM	NM	NM	MCB	non-MCB
SITE OF INVOLVEMENT	Cutaneous and mucosal	Cutaneous and mucosal	Cutaneous and mucosal	Cutaneous and mucosal	Cutaneous and mucosal	Cutaneous and mucosal	Cutaneous and mucosal
EBA DIAGNOSIS	Histopathologic examination, direct and indirect immunofluorescence, immunoblotting					Histopathologic examination, direct and indirect immunofluorescence, ELISA	Histopathologic examination, direct and indirect immunofluorescence, immunoblotting
PREVIOUS TREATMENTS	CP, MTX	dapsone, cyclosporine, AZT, PSL, sulfasalazine	cyclosporine, PSL, sulfasalazine	dapsone, PSL, sulfasalazine	dapsone, CP, MMF, IVIg, PSL	PSL, AZT, dapsone, MTX, colchicine	PSL, dapsone, topical CS, colchicine
INDICATION OF RTX	Recalcitrant disease, contradiction of conventional immunosuppressive					Recalcitrant disease	Side-effect of previous treatments
EBA DURATION TO RTX INFUSION	12m	168m	24m	6m	16m	4y	NM
RTX PROTOCOL	4 x 375mg/m2 at one week interval	4 x 375mg/m2 at one week interval	4 x 375mg/m2 at one week interval	4 x 375mg/m2 at one week interval	4 x 375mg/m2 at one week interval	4 x 375mg/m2 at one week interval	4 x 375mg/m2 at days 9, 16, 23, and 30
NUMBER OF CYCLES; DURATION OF TREATMENT	1 cycle	1 cycle	1 cycle	1 cycle	1 cycle	1 cycle	1 cycle
ADJUVANT TREATMENTS	MTX	Dapsone, AZT, sulfasalazine	cyclosporine, PSL	Dapsone, sulfasalazine	Dapsone, PSL	Dapsone, colchicine, methylprednisolone	7 x protein A immunoapheresis at days 1, 2, 3, 8, 15, 22, and 29, PSL, AZT
DISEASE CONTROL	Yes	Yes	Yes	Yes	Yes	Yes	Yes
CLINICAL REMISSION	Yes	Yes	Yes	Yes	Yes	Yes	Yes
SIDE EFFECT OF RTX THERAPY	No	No	Pneumocystis jirovecii pneumonia, death	No	No	No	NM
RELAPSE	Yes, 12m	Yes, 8m	Yes, 4m	Yes, 10m	No	No	NM
FOLLOW-UP DURATION FROM RTX	18m	26m	4m	10m	12m	10m	NM
OTHER ENDPOINTS	–	–	–	–	–	–	–
STUDY	Meissner et al30	Saha et al31	Cavailhes et al32	Wallet-Faber et al33	Sadler et al34	Niedermeier et al35
DESIGN	Case report; n=1	Case report; n=1	Case report; n=1	Case report; n=1	Case report; n=1	Case series; n=2
GENDER	M	F	M	F	F	M	M
AGE AT DISEASE ONSET OR RTX INFUSION, Y	At onset, 50	At onset, 54	At onset, 76	At onset, 77	At onset, 71	At onset, 63	At onset, 33
EBA VARIANT	MCB	MCB	NM	non-MCB	MCB	MCB	MCB
SITE OF INVOLVEMENT	Cutaneous and mucosal	Cutaneous and mucosal	Cutaneous and mucosal	Cutaneous and mucosal	Cutaneous and mucosal	Cutaneous and mucosal	Cutaneous and mucosal
EBA DIAGNOSIS	Histopathologic examination, direct and indirect immunofluorescence, immunoblotting, ELISA	Histopathologic examination, indirect immunofluorescence, immunoblotting	Histopathologic examination, direct and indirect immunofluorescence, ELISA	Skin biopsy, direct and indirect immunofluorescence, immunoblotting	Histopathologic examination, direct and indirect immunofluorescence, immunoblotting	Histopathologic examination, indirect immunofluorescence, immunoblotting
PREVIOUS TREATMENTS	IVIg, MMF, colchicine	PSL, AZT, dapsone, cyclosporine, CP, MMF, IVIg, methylprednisolone	Topical CS, dapsone, topical tacrolimus, systemic CS, MMF, MTX, doxycycline	PSL, MMF, clobetasol,	Systemic CS, AZT, cyclosporine, MMF, colchicine, plasmapheresis, gold preparations, IVIg, daclizumab	AZT, MMF, cyclosporine, dapsone, CP, MTX, CS pulse therapy, photophoresis, leflunomide	PSL, AZT, dapsone, MMF, CP, cyclosporine, MTX, CS pulse therapy, IVIg, leflunomide
INDICATION OF RTX	Recalcitrant disease	Recalcitrant disease	Recalcitrant disease, CS dependency	Side-effect of previous treatments	Recalcitrant disease	Recalcitrant disease	Recalcitrant disease
EBA DURATION TO RTX INFUSION	12y	16y	2y	NM	6y	4y	9y
RTX PROTOCOL	4 x 375mg/m2 at one week interval	4 x 375mg/m2 at one week interval	4 x 375mg/m2 at one week interval	4 x 375mg/m2 at one week interval	5 x 144 mg/m2 at one week interval	4 x 375mg/m2 at one week interval	4 x 375mg/m2 at one week interval
NUMBER OF CYCLES; DURATION OF TREATMENT	1 cycle	3 cycles; 1 y	1 cycle	1 cycle	1 cycle	1 cycle	1 cycle
ADJUVANT TREATMENTS	Systemic CS, AZT	MMF	PSL	PSL	AZT	2x immunoadsorpti on at one month interval, MMF	2x immunoadsorpti on at one month interval, MMF
DISEASE CONTROL	Yes	Yes	Yes	Yes	Yes	Yes	Yes
CLINICAL REMISSION	Yes	No	Yes	NM	Yes	No	Yes
SIDE EFFECT OF RTX THERAPY	NM	Skin sepsis	NM	NM	No	NM	NM
RELAPSE	No	NM	No	Yes, 10m	Yes	NM	NM
FOLLOW-UP DURATION FROM RTX	6m	NM	1y	10m	2y	6m	9m
OTHER ENDPOINTS	–	–	–	–	-	ABSIS Score for Oral Mucosa: Before, 11 After, 11 Body Surface; Area Representing Disease Activity: Before, 9, After, 9	ABSIS Score for Oral Mucosa: Before, 0, After, 0; Body Surface Area Representing Disease Activity: Before, 13, After, 2
STUDY	Mercader et al36	Crichlow et al37	Schmidt et al38
DESIGN	Case report; n=1	Case report; n=1	Case report; n=1
GENDER	M	F	M
AGE AT DISEASE ONSET OR RTX INFUSION, Y	At onset, 72	At onset, 58	At onset, 46
EBA VARIANT	NM	NM	NM
SITE OF INVOLVEMENT	Cutaneous and mucosal	Cutaneous and mucosal	Cutaneous and mucosal
EBA DIAGNOSIS	Histopathologic examination, direct and indirect immunofluorescence	Histopathologic examination, direct and indirect immunofluorescence, immunoblotting	Histopathologic examination, direct and indirect immunofluorescence, immunoblotting
PREVIOUS TREATMENTS	PSL, AZT, dapsone, MMF, IVIg,	PSL, AZT, MMF, cyclosporine, IVIg, Methylprednisolone	PSL, AZT, dapsone, colchicine, topical betamethasone, immunoadsorption
INDICATION OF RTX	Recalcitrant disease, side-effect of previous treatments	Recalcitrant disease, side-effect of previous treatments	Recalcitrant disease
EBA DURATION TO RTX INFUSION	7m	3y	5w
RTX PROTOCOL	4 x 375mg/m2 at one week interval	4 x 375mg/m2 at one week interval	4 x 375mg/m2 at one week interval
NUMBER OF CYCLES; DURATION OF TREATMENT	1/4 cycle	1 cycle	1 cycle
ADJUVANT TREATMENTS	NM	PSL, MMF	PSL, AZT, colchicine
DISEASE CONTROL	No	Yes	Yes
CLINICAL REMISSION	No	Yes	Yes
SIDE EFFECT OF RTX THERAPY	Pneumonia, septic shock, death	No	Deep vein thrombosis
RELAPSE	NM	No	No
FOLLOW-UP DURATION FROM RTX	10d	1y	1y
OTHER ENDPOINTS	-	-	-

RTX, rituximab; EBA, epidermolysis bullosa acquisita; non-MB, non-mechanobullous; MB, mechanobullous; ELISA, enzyme-linked immunosorbent assay; PSL, prednisolone; AZT, azathioprine; MTX, methotrexate; MMF, mycophenolate mofetil; CS, corticosteroids; IVIg, intravenous immunoglobulin; CP, cyclophosphamide; y, year; m, months; w, week; NM, not mentioned.

DISCUSSION

The treatment of EBA as a subtype of autoimmune bullous disease is a real challenge for dermatologists. Due to disease rarity, no randomized controlled trial is available to report on the efficacy and safety of medications on EBA. Patients are commonly refractory to conventional immunosuppressive agents, and many fail to attain disease remission.

According to a systematic review and meta-analysis on the efficacy of EBA treatments, only intravenous immunoglobulin and RTX were associated with complete remission of the disease, among the others.1 Numerous studies have reported the beneficial use of RTX for treating EBA.5–7,11–38 RTX does not affect plasma cells secreting autoantibodies, causing a delay in the commencement of a clinical outcome.39

In some previous studies, RTX was used in combination with intravenous immunoglobulin or immunoadsorption. Accordingly, a study explored the combination therapy of RTX and intravenous immunoglobulin in five patients with recalcitrant EBA.7 All patients showed clinical response to the treatment contributing to a significant reduction in the mean skin surface involvement, mucosal involvement, and oral mucosal severity scores based on the Autoimmune Bullous Skin Disorder Intensity Score. There are also reports of four cases of EBA treated with RTX plus immunoadsorption, which led to complete disease remission of three.23,29,35 The intravenous immunoglobulin and immunoadsorption readily remove pathogenic autoantibodies. However, they have a short therapeutic effect, and the compensatory production of autoantibodies can lead to the rebound phenomenon.6 Combining these two treatment modalities with RTX would provide an immediate clinical effect with sustainable disease remission.

In the literature review, the rate of RTX-related adverse effects was estimated as 28.2 percent. A significant concern regarding RTX safety is the risk of infection. The prolonged B cell depletion and unselective removal of antibodies bear an increased risk of opportunistic infections to the patients. We detected two deaths from pneumonia in the systematic search of patients with EBA treated with RTX.27,36

CONCLUSION

In this study, we aimed to summarize the current evidence on the safety and efficacy of RTX in EBA. The only major safety concern is the higher risk of infection, which should be considered before administration in vulnerable patients. The combination therapy with intravenous immunoglobulin and immunoadsorption could provide further clinical benefits. Future studies could improve our insights into the effectiveness and action mechanisms of RTX therapy in patients with EBA by providing further immunological details.