- Email: [email protected]
Rituximab Treatment Of Pemphigus Foliaceus- A Retrospective Study Of 12 Patients
Accepted Manuscript Rituximab Treatment Of Pemphigus Foliaceus- A Retrospective Study Of 12 Patients Irene Palacios-Álvarez, MD PhD, Constanza Riquelme-Mc Loughlin, MD, Laia CurtoBarredo, MD, Pilar Iranzo, MD, Irene García-Díez, MD, Agustín España, MD PhD. PII:
S0190-9622(18)32059-0
DOI:
10.1016/j.jaad.2018.05.1252
Reference:
YMJD 12576
To appear in:
Journal of the American Academy of Dermatology
Received Date: 13 November 2017 Revised Date:
2 May 2018
Accepted Date: 30 May 2018
Please cite this article as: Palacios-Álvarez I, Riquelme-Mc Loughlin C, Curto-Barredo L, Iranzo P, García-Díez I, España A, Rituximab Treatment Of Pemphigus Foliaceus- A Retrospective Study Of 12 Patients, Journal of the American Academy of Dermatology (2018), doi: 10.1016/j.jaad.2018.05.1252. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
ACCEPTED MANUSCRIPT Manuscript title: RITUXIMAB TREATMENT OF PEMPHIGUS FOLIACEUS- A
2
RETROSPECTIVE STUDY OF 12 PATIENTS
3
Authors: Irene Palacios-Álvarez MD PhD,1 Constanza Riquelme-Mc Loughlin MD,2
4
Laia Curto-Barredo MD,3 Pilar Iranzo MD,2 Irene García-Díez MD,3 Agustín España
5
MD PhD.1
6
Affiliations:
SC
RI PT
1
1. Department of Dermatology. Clínica Universidad de Navarra, Pamplona, Spain.
8
2. Department of Dermatology. Hospital Clinic, Barcelona, Spain
9
3. Department of Dermatology. Hospital del Mar, Barcelona, Spain
M AN U
7
Corresponding author: Agustín España Alonso. Department of Dermatology. Clínica
11
Universidad de Navarra.
12
Funding Sources. None declared
13
Conflicts of interest regarding this study: None declared.
14
- Word count for the main text: 500
15
- Number of references: 5
16
- Figure count: 0
17
- Table count: 1
18
“This study has been approved by our Institutional Review Board.”
AC C
EP
TE D
10
2
ACCEPTED MANUSCRIPT Pemphigus foliaceus (PF) is a chronic autoimmune blistering disease related to
20
pathogenic serum auto-antibodies against desmoglein-1. Initial treatments for PF
21
include systemic corticosteroids, immunossuppressants and dapsone.1 Rituximab, a
22
chimeric monoclonal antibody that targets the CD-20 molecule on B-cells, has been
23
shown to be effective in severe and refractory cases of pemphigus.2 Meta-analysis have
24
tried to analyse its efficacy in PF, but results are based on heterogeneous case series and
25
reports. Our aim was to evaluate the clinical response to rituximab in a series of patients
26
with PF.
27
The medical records of 12 patients with PF treated with rituximab from January 2007 to
28
May 2017 were reviewed. Mean patient age was 55.75±12.4 years, and the median
29
disease duration was 46 months (range 2 months-11 years). All the patients had been
30
treated according to the European Guidelines.1
31
After the first infusion of rituximab, 6 patients (50%) showed a complete response (CR)
32
off and 5 patients (42%) a partial response. Relapses occurred in 6 patients (50%) after a
33
median of 12 months (range 7-55 months).
34
Adverse events were reported in 4 cases (33.3%). We did not observe a trend towards
35
infection if immunosuppressive drugs or doses of prednisone higher than 10 mg/day
36
were used as comedication (p=0.627). Cumulative rituximab dose, dose per cycle or the
37
number of cycles of rituximab and sex were not associated with a greater risk of
38
infection (p=0.4777, p=69654, p=0.5758 and p=0.5301 respectively) (Table 1).
39
Rituximab is considered to be effective in pemphigus, with an estimated CR rate of 76-
40
87% after the first cycle.2-4 The largest published series of PF found a CR rate of 50%,5
41
which was lower than the response rates in pemphigus vulgaris (PV), but was identical
42
to our series. These lower response rates could be the result of the selection of the most
43
severe and complicated patients, with a longer disease duration.
AC C
EP
TE D
M AN U
SC
RI PT
19
3
ACCEPTED MANUSCRIPT Relapses occurred in 6 patients (50%), similar to the reported results for patients with
45
PV (40%-67%), but they occurred earlier.2,3 Contrary to other case series,5 we were
46
unable to find any trends towards CR with the number of cycles, but none of our
47
patients received more than two cycles of rituximab.
48
Adverse events were reported in four patients (33.3%). This rate was higher than in
49
other studies in PV (24%)4 but lower than the 42% found in the largest case series of
50
PF.5 Patient 5 developed tuberculous meningitis, but had been treated with prednisone
51
and immunosuppressants before receiving rituximab, and it is difficult to determine if
52
this infection could only be attributed to rituximab. As well as in the series of de Sena
53
Nogueira Maehara,5 we were unable to show that the cummulative dose or the number
54
of cycles of rituximab were associated with a risk of infection, but contrary to them5 we
55
did not observe an association of infections with sex.
56
In conclusion, rituximab seems to be effective as a third-line therapy for patients with
57
PF. However, CR rates in severe patients with PF with longer disease duration might be
58
lower than expected.
AC C
EP
TE D
M AN U
SC
RI PT
44
4
ACCEPTED MANUSCRIPT ABBREVIATIONS
60
Pemphigus foliaceus (PF)
61
Rituximab (RTX)
62
Complete response (CR)
63
Pemphigus vulgaris (PV)
AC C
EP
TE D
M AN U
SC
RI PT
59
5
ACCEPTED MANUSCRIPT 64
REFERENCES
65
1.
Hertl M, Jedlickova H, Karpati S, et al. Pemphigus. S2 Guideline for diagnosis and treatment – guided by the European Dermatology Forum (EDF) in
67
cooperation with the European Academy of Dermatology and Venereology
68
(EADV). J Eur acad Dermatol. 2015;29:405-14.
69
2.
RI PT
66
Ahmed AR, Shetty S. Autoimmunity Reviews A comprehensive analysis of
treatment outcomes in patients with pemphigus vulgaris treated with rituximab.
71
Autoimmun Rev. 2015;14:323-31. 3.
Wang HH , Liu CW, Li YC, et al. Efficacy of rituximab for pemphigus : a
M AN U
72
SC
70
73
systematic review and meta-analysis of different regimens. Acta Derm Venereol.
74
2015;95:928-32.
75
4.
Cianchini G, Lupi F, Masini C, et al. Therapy with rituximab for autoimmune pemphigus: results from a single-center observational study on 42 cases with
77
long-term follow-up. J Am Acad Dermatol. 2012; 67:617–22.
78
5.
TE D
76
de Sena Nogueira Maehara L, Huizinga J, Jonkman MF. Rituximab therapy in pemphigus foliaceus: report of 12 cases and review of recent literature. Br J
80
Dermatol. 2015;172:1420-3.
AC C
EP
79
ACCEPTED MANUSCRIPT
6
Table 1. Patient characteristics and outcomes after treatment with rituximab.
M/38
Pred, Aza, MFA, IVIG
44
LP
Mpred 4/Aza 100
24
CR off
2
M/48
Pred, MFA, Dap
27
LP
Pred 50
20
PR on
Pred/Dap
3
F/65
Pred, Aza
65
RAP
10
PR on
Pred/Aza
4
M/45
2
LP
10
CR off
5
M/50
16
LP
Pred 15
7
PR on
6
M/73
48
LP
No
8
CR off
7
M/58
60
LP
Pred 10
No1
8
F/77
24
LP
Pred 20
20
9
F/41
50
LP
Pred 5
10
M/50
Pred^ Pred, Aza, MMF, Gold, IVIG Pred, Aza, Dap, Gold, IVIG, CPM Pred, Aza, Dap, Gold Pred, MMF, Dap, IVIG, CPM Pred, Aza, Dap Pred, Aza, Dap, IVIG, Chloro
IVIG/Pred 10/ Nico 1500 Pred 2.5
132
LP
No
11
RI PT
1
No
13‡
M AN U
TE D
CR off
LP
55
RAP
Pred
7
LP
Complications; total End dose of rituximab (g) point* until complications CR off No ‡
Follow-up (months)# 21†
Staphylococcus aureus skin infection; 2.92
61
No
5
Pred 20/Dap 100 PR on No 5 Tuberculous meningitis; † 36 1.95
Pred 7.5
No
110
No
†
CR off No
72†2
6
PR off
Impetigo; 3.04
41
8
PR off
No
29
Flu-like symptoms; 2.4 PR off Viral conjunctivitis; 4.8 8 Impetigo; 4.8 12 M/61 Pred, Dap, Tetra 10 LP Pred 15 7 CR off 10 LP Pred 5 CR off No 15 Aza, azathioprine; Chloro, chloroquine; CPM, cyclophosphamide; CR off, complete response off therapy; Dap, dapsone; F, female; Gold, gold salts; IVIG, high-dose intravenous immunoglobulin; LP, lymphoma protocol; M, male; MFA, mycophenolic acid; MMF, mycophenolate mofetil; Mpred, methylprednisolone; Nico, nicotinamide, Pred, prednisone; PR off, partial response off therapy; PR on, partial response on minimal therapy; RAP, rheumatoid arthritis protocol; Tetra, tetracyclines. *As defined by an international consensus statement for patients with pemphigus. # Since last infusion of rituximab. ^ Patient 4 was diagnosed with pemphigus vulgaris that evolved into pemphigus foliaceus. Only the data since the diagnosis of pemphigus foliaceus are included, but he had previously been treated with other immunosuppressants that are not listed in the table. ‡ Relapse was controlled with low doses of prednisone and with full doses of dapsone. † Lost to follow-up. 1 The patient did not achieve control of the disease despite treatment with rituximab, prednisone and azathioprine and was lost to follow-up. 2 The patient died due to an unrelated cause, and at that time was on complete response off therapy. F/63
Pred, Dap, Tetra
48
LP
Pred 5
8
EP
11
82 83 84 85 86 87 88 89 90 91 92
Time to Time to Rituximab Comedication disease End Minimal relapse protocol during 2nd cycle control point* therapy* (months) (2nd cycle) (mg) (weeks)*
SC
Patient Sex/Age Previous therapies
Duration of disease Rituximab Comedication before protocol during 1st cycle rituximab (1st cycle) (dosage in mg) (months)
AC C
81
CR off
14
LP
No
S0190-9622(18)32059-0
DOI:
10.1016/j.jaad.2018.05.1252
Reference:
YMJD 12576
To appear in:
Journal of the American Academy of Dermatology
Received Date: 13 November 2017 Revised Date:
2 May 2018
Accepted Date: 30 May 2018
Please cite this article as: Palacios-Álvarez I, Riquelme-Mc Loughlin C, Curto-Barredo L, Iranzo P, García-Díez I, España A, Rituximab Treatment Of Pemphigus Foliaceus- A Retrospective Study Of 12 Patients, Journal of the American Academy of Dermatology (2018), doi: 10.1016/j.jaad.2018.05.1252. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
ACCEPTED MANUSCRIPT Manuscript title: RITUXIMAB TREATMENT OF PEMPHIGUS FOLIACEUS- A
2
RETROSPECTIVE STUDY OF 12 PATIENTS
3
Authors: Irene Palacios-Álvarez MD PhD,1 Constanza Riquelme-Mc Loughlin MD,2
4
Laia Curto-Barredo MD,3 Pilar Iranzo MD,2 Irene García-Díez MD,3 Agustín España
5
MD PhD.1
6
Affiliations:
SC
RI PT
1
1. Department of Dermatology. Clínica Universidad de Navarra, Pamplona, Spain.
8
2. Department of Dermatology. Hospital Clinic, Barcelona, Spain
9
3. Department of Dermatology. Hospital del Mar, Barcelona, Spain
M AN U
7
Corresponding author: Agustín España Alonso. Department of Dermatology. Clínica
11
Universidad de Navarra.
12
Funding Sources. None declared
13
Conflicts of interest regarding this study: None declared.
14
- Word count for the main text: 500
15
- Number of references: 5
16
- Figure count: 0
17
- Table count: 1
18
“This study has been approved by our Institutional Review Board.”
AC C
EP
TE D
10
2
ACCEPTED MANUSCRIPT Pemphigus foliaceus (PF) is a chronic autoimmune blistering disease related to
20
pathogenic serum auto-antibodies against desmoglein-1. Initial treatments for PF
21
include systemic corticosteroids, immunossuppressants and dapsone.1 Rituximab, a
22
chimeric monoclonal antibody that targets the CD-20 molecule on B-cells, has been
23
shown to be effective in severe and refractory cases of pemphigus.2 Meta-analysis have
24
tried to analyse its efficacy in PF, but results are based on heterogeneous case series and
25
reports. Our aim was to evaluate the clinical response to rituximab in a series of patients
26
with PF.
27
The medical records of 12 patients with PF treated with rituximab from January 2007 to
28
May 2017 were reviewed. Mean patient age was 55.75±12.4 years, and the median
29
disease duration was 46 months (range 2 months-11 years). All the patients had been
30
treated according to the European Guidelines.1
31
After the first infusion of rituximab, 6 patients (50%) showed a complete response (CR)
32
off and 5 patients (42%) a partial response. Relapses occurred in 6 patients (50%) after a
33
median of 12 months (range 7-55 months).
34
Adverse events were reported in 4 cases (33.3%). We did not observe a trend towards
35
infection if immunosuppressive drugs or doses of prednisone higher than 10 mg/day
36
were used as comedication (p=0.627). Cumulative rituximab dose, dose per cycle or the
37
number of cycles of rituximab and sex were not associated with a greater risk of
38
infection (p=0.4777, p=69654, p=0.5758 and p=0.5301 respectively) (Table 1).
39
Rituximab is considered to be effective in pemphigus, with an estimated CR rate of 76-
40
87% after the first cycle.2-4 The largest published series of PF found a CR rate of 50%,5
41
which was lower than the response rates in pemphigus vulgaris (PV), but was identical
42
to our series. These lower response rates could be the result of the selection of the most
43
severe and complicated patients, with a longer disease duration.
AC C
EP
TE D
M AN U
SC
RI PT
19
3
ACCEPTED MANUSCRIPT Relapses occurred in 6 patients (50%), similar to the reported results for patients with
45
PV (40%-67%), but they occurred earlier.2,3 Contrary to other case series,5 we were
46
unable to find any trends towards CR with the number of cycles, but none of our
47
patients received more than two cycles of rituximab.
48
Adverse events were reported in four patients (33.3%). This rate was higher than in
49
other studies in PV (24%)4 but lower than the 42% found in the largest case series of
50
PF.5 Patient 5 developed tuberculous meningitis, but had been treated with prednisone
51
and immunosuppressants before receiving rituximab, and it is difficult to determine if
52
this infection could only be attributed to rituximab. As well as in the series of de Sena
53
Nogueira Maehara,5 we were unable to show that the cummulative dose or the number
54
of cycles of rituximab were associated with a risk of infection, but contrary to them5 we
55
did not observe an association of infections with sex.
56
In conclusion, rituximab seems to be effective as a third-line therapy for patients with
57
PF. However, CR rates in severe patients with PF with longer disease duration might be
58
lower than expected.
AC C
EP
TE D
M AN U
SC
RI PT
44
4
ACCEPTED MANUSCRIPT ABBREVIATIONS
60
Pemphigus foliaceus (PF)
61
Rituximab (RTX)
62
Complete response (CR)
63
Pemphigus vulgaris (PV)
AC C
EP
TE D
M AN U
SC
RI PT
59
5
ACCEPTED MANUSCRIPT 64
REFERENCES
65
1.
Hertl M, Jedlickova H, Karpati S, et al. Pemphigus. S2 Guideline for diagnosis and treatment – guided by the European Dermatology Forum (EDF) in
67
cooperation with the European Academy of Dermatology and Venereology
68
(EADV). J Eur acad Dermatol. 2015;29:405-14.
69
2.
RI PT
66
Ahmed AR, Shetty S. Autoimmunity Reviews A comprehensive analysis of
treatment outcomes in patients with pemphigus vulgaris treated with rituximab.
71
Autoimmun Rev. 2015;14:323-31. 3.
Wang HH , Liu CW, Li YC, et al. Efficacy of rituximab for pemphigus : a
M AN U
72
SC
70
73
systematic review and meta-analysis of different regimens. Acta Derm Venereol.
74
2015;95:928-32.
75
4.
Cianchini G, Lupi F, Masini C, et al. Therapy with rituximab for autoimmune pemphigus: results from a single-center observational study on 42 cases with
77
long-term follow-up. J Am Acad Dermatol. 2012; 67:617–22.
78
5.
TE D
76
de Sena Nogueira Maehara L, Huizinga J, Jonkman MF. Rituximab therapy in pemphigus foliaceus: report of 12 cases and review of recent literature. Br J
80
Dermatol. 2015;172:1420-3.
AC C
EP
79
ACCEPTED MANUSCRIPT
6
Table 1. Patient characteristics and outcomes after treatment with rituximab.
M/38
Pred, Aza, MFA, IVIG
44
LP
Mpred 4/Aza 100
24
CR off
2
M/48
Pred, MFA, Dap
27
LP
Pred 50
20
PR on
Pred/Dap
3
F/65
Pred, Aza
65
RAP
10
PR on
Pred/Aza
4
M/45
2
LP
10
CR off
5
M/50
16
LP
Pred 15
7
PR on
6
M/73
48
LP
No
8
CR off
7
M/58
60
LP
Pred 10
No1
8
F/77
24
LP
Pred 20
20
9
F/41
50
LP
Pred 5
10
M/50
Pred^ Pred, Aza, MMF, Gold, IVIG Pred, Aza, Dap, Gold, IVIG, CPM Pred, Aza, Dap, Gold Pred, MMF, Dap, IVIG, CPM Pred, Aza, Dap Pred, Aza, Dap, IVIG, Chloro
IVIG/Pred 10/ Nico 1500 Pred 2.5
132
LP
No
11
RI PT
1
No
13‡
M AN U
TE D
CR off
LP
55
RAP
Pred
7
LP
Complications; total End dose of rituximab (g) point* until complications CR off No ‡
Follow-up (months)# 21†
Staphylococcus aureus skin infection; 2.92
61
No
5
Pred 20/Dap 100 PR on No 5 Tuberculous meningitis; † 36 1.95
Pred 7.5
No
110
No
†
CR off No
72†2
6
PR off
Impetigo; 3.04
41
8
PR off
No
29
Flu-like symptoms; 2.4 PR off Viral conjunctivitis; 4.8 8 Impetigo; 4.8 12 M/61 Pred, Dap, Tetra 10 LP Pred 15 7 CR off 10 LP Pred 5 CR off No 15 Aza, azathioprine; Chloro, chloroquine; CPM, cyclophosphamide; CR off, complete response off therapy; Dap, dapsone; F, female; Gold, gold salts; IVIG, high-dose intravenous immunoglobulin; LP, lymphoma protocol; M, male; MFA, mycophenolic acid; MMF, mycophenolate mofetil; Mpred, methylprednisolone; Nico, nicotinamide, Pred, prednisone; PR off, partial response off therapy; PR on, partial response on minimal therapy; RAP, rheumatoid arthritis protocol; Tetra, tetracyclines. *As defined by an international consensus statement for patients with pemphigus. # Since last infusion of rituximab. ^ Patient 4 was diagnosed with pemphigus vulgaris that evolved into pemphigus foliaceus. Only the data since the diagnosis of pemphigus foliaceus are included, but he had previously been treated with other immunosuppressants that are not listed in the table. ‡ Relapse was controlled with low doses of prednisone and with full doses of dapsone. † Lost to follow-up. 1 The patient did not achieve control of the disease despite treatment with rituximab, prednisone and azathioprine and was lost to follow-up. 2 The patient died due to an unrelated cause, and at that time was on complete response off therapy. F/63
Pred, Dap, Tetra
48
LP
Pred 5
8
EP
11
82 83 84 85 86 87 88 89 90 91 92
Time to Time to Rituximab Comedication disease End Minimal relapse protocol during 2nd cycle control point* therapy* (months) (2nd cycle) (mg) (weeks)*
SC
Patient Sex/Age Previous therapies
Duration of disease Rituximab Comedication before protocol during 1st cycle rituximab (1st cycle) (dosage in mg) (months)
AC C
81
CR off
14
LP
No