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Diagnosis and Management of Pemphigus: recommendations by an International Panel of Experts

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Abstract

Background: Several European countries recently developed international diagnostic and management guidelines for pemphigus, which have been instrumental in the standardization of pemphigus management, OBJECTIVE: We now present results from a subsequent Delphi consensus to broaden the generalizability of recommendations. Methods: A preliminary survey, based on the European Dermatology Forum (EDF) and the European Academy of Dermatology and Venereology (EADV) guidelines, was sent to a panel of international experts to determine the level of consensus. The results were discussed at the International Bullous Diseases Consensus Group in March 2016 during the annual American Academy of Dermatology (AAD) conference. A second survey was sent following the meeting to more experts to achieve greater international consensus. Results: The 39 experts participated in the first round of the Delphi-survey while 54 from 21 countries completed the second round. The number of statements in the survey was reduced from 175 topics in Delphi I to 24 topics in Delphi II based on Delphi results and meeting discussion. Limitations: Each recommendation represents the majority opinion and therefore may not reflect all possible treatment options available. Conclusions: We present here the recommendations resulting from this Delphi process. This international consensus includes intravenous CD20 inhibitors as a first line therapy option for moderate to severe pemphigus.
Accepted Manuscript
Diagnosis and Management of Pemphigus: recommendations by an International
Panel of Experts
Dedee F. Murrell, MA, BMBCh, MD, FACD, Sandra Peña, MD, Pascal Joly, MD,
PhD, Branka Marinovic, MD, PhD, Takashi Hashimoto, MD, PhD, Luis A. Diaz, MD,
Animesh A. Sinha, MD, PhD, Aimee S. Payne, MD, PhD, Maryam Daneshpazhooh,
MD, Rüdiger Eming, MD, Marcel F. Jonkman, MD, PhD, Daniel Mimouni, MD, Luca
Borradori, MD, Soo-Chan Kim, MD, PhD, Jun Yamagami, MD, PhD, Julia S. Lehman,
MD, Marwah Adly Saleh, MD, PhD, Donna A. Culton, MD, PhD, Annette Czernik,
MD, John J. Zone, MD, David Fivenson, MD, Hideyuki Ujiie, MD, PhD, Katarzyna
Wozniak, MD, PhD, Ayşe Akman-Karakaş, MD, Philippe Bernard, MD, PhD, Neil
J. Korman, MD, PhD, Frédéric Caux, MD, PhD, Kossara Drenovska, MD, PhD,
Catherine Prost-Squarcioni, MD, PhD, Snejina Vassileva, MD, PhD, Ron J. Feldman,
MD, PhD, Adela Rambi Cardones, MD, Johann Bauer, MD, Dimitrios Ioannides, MD,
PhD, Hana Jedlickova, MD, PhD, Francis Palisson, MD, Aikaterini Patsatsi, MD,
PhD, Soner Uzun, MD, Savas Yayli, MD, Detlef Zillikens, MD, Masayuki Amagai, MD,
PhD, Michael Hertl, MD, Enno Schmidt, MD, PhD, Valeria Aoki, MD, PhD, Sergei A.
Grando, MD, PhD, DSc, Hiroshi Shimizu, MD, PhD, Sharon Baum, MD, Guiseppe
Cianchini, MD, Claudio Feliciani, MD, Pilar Iranzo, MD, Jose M. Mascaró, Jr., MD,
Cezary Kowalewski, MD, Russell Hall, MD, Richard Groves, MD, Karen E. Harman,
MB, BChir, DM, FRCP, M. Peter Marinkovich, MD, Emanual Maverakis, MD, Victoria
P. Werth, MD
PII: S0190-9622(18)30207-X
DOI: 10.1016/j.jaad.2018.02.021
Reference: YMJD 12328
To appear in: Journal of the American Academy of Dermatology
Received Date: 23 March 2017
Revised Date: 18 January 2018
Accepted Date: 3 February 2018
Please cite this article as: Murrell DF, Peña S, Joly P, Marinovic B, Hashimoto T, Diaz LA, Sinha AA,
Payne AS, Daneshpazhooh M, Eming R, Jonkman MF, Mimouni D, Borradori L, Kim S-C, Yamagami
J, Lehman JS, Saleh MA, Culton DA, Czernik A, Zone JJ, Fivenson D, Ujiie H, Wozniak K, Akman-
Karakaş A, Bernard P, Korman NJ, Caux F, Drenovska K, Prost-Squarcioni C, Vassileva S, Feldman RJ,
Cardones AR, Bauer J, Ioannides D, Jedlickova H, Palisson F, Patsatsi A, Uzun S, Yayli S, Zillikens D,
Amagai M, Hertl M, Schmidt E, Aoki V, Grando SA, Shimizu H, Baum S, Cianchini G, Feliciani C, Iranzo
P, Mascaró Jr. JM, Kowalewski C, Hall R, Groves R, Harman KE, Marinkovich MP, Maverakis E, Werth
VP, Diagnosis and Management of Pemphigus: recommendations by an International Panel of Experts,
Journal of the American Academy of Dermatology (2018), doi: 10.1016/j.jaad.2018.02.021.
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Diagnosis and Management of Pemphigus: recommendations by an International Panel of Experts. 1
Dedee F. Murrell
1
, MA, BMBCh, MD, FACD, Sandra Peña
2,3
, MD, Pascal Joly
4
, MD, PhD, Branka Marinovic
5
, 2
MD, PhD, Takashi Hashimoto
6
, MD, PhD, Luis A. Diaz
7
, MD, Animesh A. Sinha
8
, MD, PhD, Aimee S.Payne
3
, 3
MD, PhD, Maryam Daneshpazhooh
9
, MD, Rüdiger Eming
10
, MD, Marcel F. Jonkman
11
, MD, PhD, Daniel 4
Mimouni
12
, MD, Luca Borradori
13
, MD, Soo-Chan Kim
14
, MD, PhD, Jun Yamagami
15
, MD, PhD, Julia S. 5
Lehman
16
, MD, Marwah Adly Saleh
17
, MD, PhD, Donna A. Culton
7
, MD, PhD, Annette Czernik
18
, MD, John J. 6
Zone
19
, MD, David Fivenson
20
, MD, Hideyuki Ujiie
21
, MD, PhD, Katarzyna Wozniak
22
, MD, PhD, Ayşe 7
Akman-Karakaş
23
, MD, Philippe Bernard
24
, MD, PhD, Neil J. Korman
25
, MD, PhD, Frédéric Caux
26
, MD, PhD, 8
Kossara Drenovska
27
, MD, PhD, Catherine Prost-Squarcioni
28
, MD, PhD, Snejina Vassileva
27
, MD, PhD, Ron J. 9
Feldman
29
, MD, PhD, Adela Rambi Cardones
30
, MD, Johann Bauer
31
, MD, Dimitrios Ioannides
32
, MD, PhD, 10
Hana Jedlickova
33
, MD, PhD, Francis Palisson
34
, MD, Aikaterini Patsatsi
35
, MD, PhD, Soner Uzun
23
, MD, 11
Savas Yayli
36
, MD, Detlef Zillikens
37
, MD, Masayuki Amagai
15
, MD, PhD, Michael Hertl
38
, MD, Enno 12
Schmidt
37
, MD, PhD, Valeria Aoki
39
, MD, PhD, Sergei A. Grando
40
, MD, PhD, DSc, Hiroshi Shimizu
21
, MD, 13
PhD, Sharon Baum
41
, MD, Guiseppe Cianchini
42
, MD, Claudio Feliciani
43
, MD, Pilar Iranzo
44
, MD, Jose M. 14
Mascaró Jr.
44
, MD, Cezary Kowalewski
22
, MD, Russell Hall
30
, MD, Richard Groves
45
, MD, Karen E. Harman
45
, 15
MB, BChir, DM, FRCP, M. Peter Marinkovich
46
, MD, Emanual Maverakis
47
, MD and Victoria P. Werth
2,3
, MD 16
17
1
Department of Dermatology at St George Hospital, University of New South Wales, Sydney, Australia. 18
2
Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA. 19
3
Department of Dermatology at the Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 20
USA. 21
4
Department of Dermatology, Rouen University Hospital, Rouen, France 22
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5
Department of Dermatology and Venereology, Zagreb University Hospital Center and School of Medicine, 23
Zagreb, Croatia. 24
6
Kurume University Institute of Cutaneous Cell Biology, Kurume, Japan 25
7
Department of Dermatology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
26
8
Department of Dermatology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, 27
Buffalo, NY, USA.
28
9
Department of Dermatology, Autoimmune Bullous Diseases Research Center, Tehran University of Medical 29
Sciences, Tehran, Iran.
30
10
Department of Dermatology and Allergology, University Hospital, Philipps-Universität Marburg, Marburg, 31
Germany.
32
11
University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 33
12
Department of Dermatology, Rabin Medical Center, Beilinson Campus,, Petach Tikva, Israel; Sackler School of 34
Medicine, Tel Aviv University, Tel Aviv. Israel 35
13
Department of Dermatology, University Hospital of Bern, Bern, Switzerland.
36
14
Department of Dermatology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, 37
Korea
38
15
Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.
39
16
Department of Dermatology, Mayo Clinic College of Medicine, Rochester, MN, USA.
40
17
Department of Dermatology, Faculty of Medicine, Cairo University, Egypt.
41
18
Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
42
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19
Department of Dermatology, School of Medicine, University of Utah, Salt Lake City, Utah, USA. 43
20
St Joseph Mercy Health System, Department of Dermatology, Ann Arbor, Michigan, USA.
44
21
Department of Dermatology, Hokkaido University Graduate School of Medicine, Japan
45
22
Department of Dermatology and Immunodermatology, Medical University of Warsaw, Warsaw, Poland.
46
23
Department of Dermatology and Venereology, Faculty of Medicine, Akdeniz University, Antalya, Turkey.
47
24
Department of Dermatology, Reims University Hospital, University of Champagne-Ardenne, Reims, France.
48
25
Department of Dermatology and the Murdough Family Center for Psoriasis, University Hospitals Case Medical 49
Center, Cleveland, Ohio, USA.
50
26
Department of Dermatology, Avicenne Hospital, University Paris 13, Bobigny, France.
51
27
Department of Dermatology and Venereology, Medical Faculty, University of Medicine, Sofia, Bulgaria
52
28
Department of Dermatology, Department of Histology, Reference Center for Autoimmune Bullous Diseases, 53
Avicenne Hospital, University Paris 13, Bobigny, France.
54
29
Department of Dermatology, Emory University School of Medicine, Atlanta, Georgia, USA.
55
30
Dermatology, Duke University Medical Center, Durham, NC, USA.
56
31
Division of Molecular Dermatology, Department of Dermatology, Paracelsus Medical University Salzburg, 57
Salzburg, Austria. 58
32
First Department of Dermatology, Aristotle University, Thessaloniki, Greece.
59
33
Department of Dermatovenereology, St. Anna University Hospital, Masaryk University, Brno, Czech Republic.
60
34
Facultad de Medicina, Clínica Alemana, Santiago, Chile.
61
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35
Second Dermatology Department, Aristotle University School of Medicine, Papageorgiou General Hospital, 62
Thessaloniki, Greece. 63
36
Dermatology Department, School of Medicine, Karadeniz Technical University , Trabzon , Turkey.
64
37
Department of Dermatology, University of Lubeck, Lubeck, Germany.
65
38
Department of Dermatology, University Hospital, Marburg, Germany.
66
39
Departamento de Dermatologia, Universidade de Sao Paulo, Sao Paulo 04038, Brazil
67
40
Department of Dermatology, University of California, Irvine, California; Department of Biological Chemistry 68
Cancer Center, University of California, Irvine, California; Research Institute, Institute for Immunology, 69
University of California, Irvine, California.
70
41
Sheba Medical Center, Dermatology Department, Tel-Hashomer, Ramat-Gan, Israel.
71
42
Department of Immunodermatology, Istituto Dermopatico dell'Immacolata, IRCCS, Rome, Italy; Laboratory of 72
Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata, IRCCS, Rome, Italy.
73
43
Clinica Dermatologica, Universita’ Di Parma, Italy 74
44
Department of Dermatology, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain. 75
45
University Hospitals Leicester, Leicester Royal Infirmary, Infirmary Square, Leicester. LE1 5WW. United 76
Kingdom.
77
46
Department of Dermatology, Stanford University School of Medicine, Stanford, California; Center for Clinical 78
Sciences Research, and Division of Dermatology, Department of Veterans Affairs Palo Alto Healthcare System, 79
Palo Alto, California.
80
47
Department of Dermatology, School of Medicine, University of California, Davis, USA.
81
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82
Address correspondence to: 83
Dedee F. Murrell, MA, BMBCh, MD, FACD 84
Department of Dermatology 85
St George Hospital 86
Gray Street, Kogarah, Sydney, NSW 2217,Australia 87
E-Mail d.murrell @ unsw.edu.au 88
89
Victoria P. Werth, MD 90
Professor of Dermatology and Medicine, Department of Dermatology 91
University of Pennsylvania, Philadelphia, Pennsylvania. 92
Tel.: 215-615-2940, Fax: 866-755-0625, Email: werth@mail.med.upenn.edu. 93
94
Funding: This work is partially supported by the Department of Veterans Affairs (Veterans Health 95
Administration, Office of Research and Development, Biomedical Laboratory Research and Development) 96
(VPW). Dr. Pena’s clinical research is funded by an NIH training grant. 97
98
No human subjects were used in the study and therefore IRB approval was not necessary. 99
100
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Conflict of Interest: Dr.Murrell is an investigator and speaker for Roche. She is an investigator and on an 101
advisory board for Principia Biopharma; and is on an advisory board for Immune Pharmaceuticals and Lilly. Dr. 102
Joly is a consultant for Roche, Principia Biopharma , Lilly and Biogen. Dr. Payne is a consultant for Syntimmune 103
and TG Therapeutics and receives grants Sanofi. Dr. Eming is an investigator for both Biotest AG and Fresenius 104
Medical Care and is a speaker for Biotest AG and Novartis. Dr. Jonkman is a monitor for Roche. Dr. Prost is an 105
investigator for Roche. Dr. Yayli is an investigator for Roche. Dr. Zillikens is on the advisory board for Roche 106
and a consultant for Euroimmun,UCB, Fresenius, Almirall, and oGEN-x. Dr. Zillikens has received grants and is 107
a speaker for Euroimmun, Miltenyi/Biogen, Fresenius/Roche, Biotest AG, Almirall, and Dompe/Janssen. Dr. 108
Amagai receives speaker honoraria and grants from Nihon Pharmaceutical Co., Ltd, and reseach support from 109
Medical & Biological Laboratories Co., Ltd. Dr. Hertl is on an advisory board for Roche, Biogen, and Novartis 110
and has received grants from Biotest and Fresenius; and is a speaker for Janssen. Dr. Schmidt has received grants 111
from Euroimmun and Fresenius; and is a speaker for Biotest and Fresenius. Dr. Hall is a consultant for Stieffel at 112
GSK Company, Eli Lilly, Syntimmune, and Immune Sciences and is on the DSM board for Roche and has 113
received grants from Immune Sciences. Dr. Peña, Dr. Marinovic, Dr. Hashimoto, Dr. Diaz, Dr. Sinha, Dr. 114
Daneshpazhooh, Dr. Mimouni, Dr. Borradori, Dr. Kim, Dr. Yamagami, Dr. Lehman, Dr. Saleh, Dr. Culton, Dr. 115
Czernik, Dr. Zone, Dr. Fivenson, Dr. Ujiie, Dr. Wozniak, Dr. Akman-Karakaş, Dr. Bernard, Dr. Korman, Dr. 116
Caux, Dr. Drenovska, Dr. Vassileva, Dr. Feldman, Dr. Cardones, Dr. Bauer, Dr. Ioannides, Dr. Jedlickova, Dr. 117
Palisson, Dr. Patsatsi, Dr. Uzun, Dr. Aoki, Dr. Grando, Dr. Shimizu, Dr. Baum, Dr. Cianchini, Dr. Feliciani, Dr. 118
Iranzo, Dr. Mascaró Jr., Dr. Kowalewski, Dr. Groves, Dr. Harman, Dr. Marinkovich, Dr. Maverakis, and Dr. 119
Werth have no conflict of interest to declare. 120
121
Keywords: pemphigus vulgaris, pemphigus foliaceus, treatment, guidelines, consensus, CD20 inhibitor 122
123
Word Count: Abstract: 208, Text: 2780, References: 12, Figures: 2, Tables: 2 124
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Abstract
125
Background: Several European countries recently developed international diagnostic and management guidelines 126
for pemphigus, which have been instrumental in the standardization of pemphigus management, 127
Objective:
We now present results from a subsequent Delphi consensus to broaden the generalizability of 128
recommendations. 129
Methods: A preliminary survey, based on the European Dermatology Forum (EDF) and the European Academy 130
of Dermatology and Venereology (EADV) guidelines, was sent to a panel of international experts to determine 131
the level of consensus. The results were discussed at the International Bullous Diseases Consensus Group in 132
March 2016 during the annual American Academy of Dermatology (AAD) conference. A second survey was sent 133
following the meeting to more experts to achieve greater international consensus. 134
Results: The 39 experts participated in the first round of the Delphi-survey while 54 from 21 countries completed 135
the second round. The number of statements in the survey was reduced from 175 topics in Delphi I to 24 topics in 136
Delphi II based on
Delphi results and meeting discussion.
137
Limitations
:
Each recommendation represents the majority opinion and therefore may not reflect all possible 138
treatment options available.
139
Conclusions: We present here the recommendations resulting from this Delphi process. This international 140
consensus includes intravenous CD20 inhibitors as a first line therapy option for moderate to severe pemphigus. 141
142
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Introduction
143
Pemphigus encompasses a spectrum of rare mucocutaneous bullous diseases that are autoimmune in
144
origin. Due to the rarity of these diseases, it can take patients months before being diagnosed with
145
pemphigus, during which time many are treated for other blistering diseases (1, 2). Even once the
146
diagnosis is made, treatment regimens can vary greatly as there is no defined standard of care due to the
147
paucity of large-scale clinical trials evaluating their efficacy (1).
148
There have been recent national attempts to standardize the diagnosis and management of pemphigus
149
from individual countries, including the UK, France, Japan, and Germany (3- 6). However, it was the
150
European Dermatology Forum (EDF) and the European Academy of Dermatology and Venereology
151
(EADV), which passed the first international guidelines for the management of pemphigus (7). While
152
these efforts have been instrumental in the standardization of pemphigus management, the lack of
153
involvement from countries outside of Europe may render these guidelines non-generalizable to other
154
countries.
155
In an attempt to garner greater international consensus, the International Bullous Diseases Consensus
156
Group, convened by Dr. Dedee Murrell and Dr. Victoria Werth, met in March 2016 at the annual
157
American Academy of Dermatology (AAD) conference in Washington D.C. with the goal of developing
158
international consensus guidelines for the diagnosis and management of pemphigus vulgaris and
159
pemphigus foliaceus. Prior to the meeting, members of the group, comprised of blistering disease
160
experts, completed a Delphi survey based on the EDF/EADV guidelines. Some of the tests and
161
treatments mentioned may not be available or officially registered in all countries and have been
162
assessed based on their scientific usefulness rather than regulation status. The Delphi technique is a
163
consensus-building process in which questionnaires are given to a group of experts in a series of rounds
164
to ultimately achieve opinion convergence (8). The results of the questionnaire were discussed in the
165
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meeting and a follow-up survey was sent out to further consensus.
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Methods
167
The first round of surveys was delivered via email in February 2016 and completed by 39 expert
168
participants. The results of the survey were tallied and delivered to the group. A median score of 70
169
percent or greater per question was used as the consensus threshold for agreement, while a median score
170
of 30 or lower was established as the consensus threshold for disagreement. Statements that achieved
171
median scores between 30 and 70 were determined as having reached no consensus among participants
172
and discussed during the meeting. Afterwards, these statements were revised according to the opinion of
173
the participants and sent out and completed by 54 individuals in the subsequent round. The survey was
174
designed and distributed using RedCAP software.
175
176
Initial Clinical Presentation of Pemphigus
177
The initial evaluation of suspected pemphigus should seek to determine the signs or symptoms present
178
that would corroborate the diagnosis of pemphigus, as well as to screen for possible comorbidities.
179
Major Objectives
180
To verify the diagnosis of pemphigus
181
To evaluate possible risk factors, severity factors and comorbidities
182
To specify the type of initial involvement (skin, mucosa) and its extent
183
To evaluate the prognosis depending on the age of the patient and general condition (Karnovsky
184
score, optional)
185
There are two clinical scores, Pemphigus Disease and Area Index (PDAI) and/or Autoimmune
186
Bullous Skin Intensity and Severity Score (ABSIS), which are currently being used as clinical
187
outcome parameters and in clinical trials for the evaluation of the extent and activity of pemphigus.
188
Presently, there are no agreed upon cutoff values to define mild, moderate, or severe disease for
189
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either the PDAI or the ABSIS; however, there have been two studies which have attempted to
190
define these values. In one multicenter study based in Japan, researchers evaluated both newly
191
diagnosed as well as relapsing pemphigus patients and determined PDAI cutoff values of 0-8 for
192
mild, 9-24 for moderate, and 25 for severe disease (9). Another multicenter study, conducted
193
internationally, assessed only patients with newly diagnosed pemphigus and determined cut-off
194
values of 15 and 45 for PDAI and 17 and 53 for ABSIS, to distinguish between mild, moderate and
195
severe (significant and extensive) forms of pemphigus (10). While these studies greatly add to our
196
understanding of disease activity scoring, it is premature to definitively state cutoff values presently.
197
Specialists Involved
198
The management of patients with pemphigus is the responsibility of dermatologists with experience
199
in treating bullous diseases. If extensive, the initial management of the disease usually requires
200
hospitalization until clinical control of the bullous eruption is achieved. In limited forms of
201
pemphigus, additional diagnostic examinations and clinical monitoring can be done in either an
202
inpatient or outpatient setting.
203
The overall disease management is coordinated by the dermatologist with the cooperation of the
204
referring dermatologist/family practitioner, the general physician and other medical specialists and
205
hospital doctors from the center of reference and/or geographical area (if a reference center exists in
206
the particular country).
207
Rarely, the disease can occur during childhood, and children should be managed by a
208
multidisciplinary team, jointly by a reference center, a pediatric dermatology department or a
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pediatrician.
210
Other health professionals who may serve as supportive adjuncts are as follows:
211
The referring dermatologist
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The patient’s primary care provider to manage comorbidities and monitor for treatment side-
213
effects
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Other specialists whose expertise is necessary, based on comorbidities and/or mucosal locations of
215
pemphigus, such as internists, cardiologists, stomatologists, ophthalmologists,
216
otorhinolaryngologists, gastroenterologists, gynecologists, urologists, proctologists,
217
rheumatologists, oncologists, dieticians, physiotherapists and psychologists
218
Home health nurses, where available, in selected cases in which home care is required and
219
applicable, e.g. elderly or disabled patients with residual mucosal or skin lesions following
220
hospitalization
221
Nurse specialist/practitioner to aid in the management of stable patients, making phone calls, or
222
changing wound dressings.
223
Diagnosis
224
The diagnosis of pemphigus is based on the following criteria:
225
Clinical presentation
226
Histopathology
227
Direct immunofluorescence microscopy (DIF) of perilesional skin
228
Serological detection of serum autoantibodies against epithelial cell surface by indirect
229
immunofluorescence microscopy (IIF) and/or enzyme-linked immunosorbent assay (ELISA)
230
Diagnosis requires clinical presentation and histopathology that are consistent with pemphigus
231
and either a positive DIF or serological detection of autoantibodies against epithelial cell surface
232
antigens.
233
Clinical Evaluation
234
Medical History
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Timing of symptoms
236
Functional symptoms, i.e. pain, pruritus, intensity of dysphagia, ocular and ENT symptoms,
237
dysuria, anogenital problems and weight loss
238
Contraindications of systemic corticosteroid treatment and developing complications of
239
immunosuppressive treatments
240
Contraception and plans for pregnancy in women of child bearing potential
241
Medication history with special attention to causes of drug-induced pemphigus, including D-
242
penicillamine, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and
243
cephalosporins,
244
Psychological tolerance of possible side-effects due to treatment, especially corticosteroids
245
Quality of life impact due to disease burden
246
Physical examination
247
Extent of skin and mucosal lesions and the degree of disease damage
248
Patient’s overall state of health and comorbidities:
249
General condition (Karnovsky index)
250
Weight
251
Vital signs, including blood pressure and temperature
252
Comorbidities (neoplastic, cardiovascular, musculoskeletal, etc.)
253
254
The changes from the European guidelines are summarized in the supplementary material.
255
The laboratory work up is delineated in Table 1.
256
Therapeutic Management
257
Objectives
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To promotehealing of blisters and erosions
259
To improve functional status
260
To prevent/strictly limit development of new blisters and erosions
261
To improve the quality of life
262
To limit common side-effects usually associated with long-term immunosuppressive or
263
corticosteroid treatment
264
First-Line Treatment
265
The dosing of specific medications is delineated in Table 2.
266
Corticosteroids
267
Anti-CD20 monoclonal antibodies
268
Corticosteroid-Sparing Agents
269
First-Line Corticosteroid-Sparing Agents
270
Azathioprine
271
Mycophenolate mofetil or mycophenolic acid
272
Other Corticosteroid-Sparing Agents
273
Intravenous immunoglobulins (IVIG)
274
Immunoadsorption
275
Cyclophosphamide
276
Supportive treatment that may be recommended:
277
Proper dental care
278
Intralesional injections of corticosteroids (triamcinolone acetonide) for isolated lesions.
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Topical treatment with potent corticosteroids (clobetasol propionate) or calcineurin inhibitors
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applied directly to the lesions, and oral topical corticosteroids (such as triamcinolone acetonide
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gel) directly to oropharyngeal erosions for use in combination with systemic therapy
282
Antiseptic baths
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Covering erosive lesions, if present, using low adhesive wound dressings or local emollients, and
284
compresses.
285
Analgesics (over the counter analgesics and opioids)
286
Gels containing local anesthetics for application at the mucosal surfaces.
287
Nutritional management with the help of a dietician or a nutritionist if malnutrition is related to
288
oral involvement or systemic corticosteroid therapy
289
Prophylaxis against Side Effects in Prolonged Corticosteroid Therapy
290
Osteoporosis baseline screening and prophylaxis
291
Ophthalmologic evaluation
292
Vitamin D and calcium supplementation at initiation of corticosteroids treatment
293
Treatment with bisphosphonates (i.e. alendronate, risedronate) in patients at risk (post-menopausal
294
women and men >50 years who will be on corticosteroid treatment > 3 months) of developing
295
osteoporosis
296
Systemic antifungals, antiviral and antibiotic treatment should be used when clinically indicated
297
H2-blockers or proton pump inhibitor use should be individualized to the patients given lack of
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sufficient evidence.
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Anti-thrombotic prophylaxis in case of high risk of thrombosis
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Psychological support if required
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Physiotherapy if prolonged corticosteroid therapy is required
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Vaccinations
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Adjuvant immunosuppressants and intravenous CD20 inhibitors contraindicate the use of live
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vaccines.
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Patients receiving oral corticosteroids or immunosuppressive therapy may be vaccinated against
306
seasonal influenza, H1N1, tetanus and pneumococci. The level of protection is questionable during
307
systemic immunosuppression.
308
Monitoring
309
Objectives
310
To evaluate the efficacy and safety of treatment
311
To plan the gradual reduction of immunosuppressive treatment, and the duration of maintenance
312
therapy or its discontinuation
313
Definitions for Disease Outcome Parameters (12)
314
Control of disease activity: The time at which new lesions cease to form and established lesions
315
begin to heal
316
End of consolidation phase: The time at which no new lesions have developed for a minimum of 2
317
weeks and approximately 80% of lesions have healed. This is when most clinicians start to taper
318
steroids."
319
Complete remission on therapy: The absence of new or established lesions while the patient is
320
receiving minimal therapy
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Complete remission off therapy: The absence of new and/or established lesions while the patient
322
is off all systemic therapy for at least 2 months
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Relapse/flare: Appearance of 3 new lesions/month that do not heal spontaneously within 1 week,
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or by the extension of established lesions, in a patient who has achieved disease control
325
Minimal therapy: Prednisolone (or the equivalent) at 10 mg/day and/or minimal adjuvant therapy
326
for at least 2 months
327
Approach to Be Maintained After Consolidation Phase
328
Expect slow clinical improvement, often requiring a period of 1–3 months for complete healing of
329
lesions
330
Start tapering steroids as soon as disease control is reached or up to the end of consolidation phase
331
Decrease predniso(lo)ne by 25% every two weeks, until 20 mg per day. Once at 20 mg per day,
332
decrease predniso(lo)ne by 2.5 mg a week; and then at 10 mg/day, decrease dose by 1 mg per day
333
after that.
334
Go back to last dose if >3 lesions reappear during the tapering of oral corticosteroid therapy
335
If relapse occurs (i.e the appearance of 3 new lesions/month that do not heal spontaneously
336
within 1 week, or there is extension of established lesions), increase the oral corticosteroid dose by
337
going back to the second to last dose until control of the lesions is achieved within 2 weeks, then
338
resume taper.
339
If disease control is still not reached despite this, go back to initial dose.
340
If oral corticosteroids are given alone: add an immunosuppressant (especially in case of
341
early-stage relapse occurring despite continued high-dose corticosteroid treatment)
342
If oral corticosteroids are already combined with an immunosuppressant, consider a change
343
in immunosuppressant
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Scheduling and Content of Consultations
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The frequency of consultations (physical exam, additional exams) depends on:
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The patient’s clinical condition including comorbidities
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The severity and disease course specific to the patient’s pemphigus during treatment
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The therapeutics used (monitoring, tolerance, side-effects)
349
The level of disease activity measure by the ABSIS and/or PDAI, (optional)
350
Initially, follow-up visits should be offered every two weeks until clinical disease control is achieved. In
351
the consolidation phase, patients should be seen every 1-2 weeks in order to determine how soon
352
patients could be started on a steroid taper. Then, during tapering phase, for the next 3 months, monthly
353
clinical follow-ups are recommended. Once in partial or complete remission on minimal therapy, visits
354
can be less frequent, such as every 3 months.
355
Clinical Evaluation
356
The clinical follow-up should seek to clarify:
357
Level of disease control
358
Presence of adverse effects due to treatment including:
359
Diabetes, high blood pressure, cardiac insufficiency, myopathy, osteoporosis, avascular bone
360
necrosis, glaucoma, cataract due to corticosteroids
361
Infections, notably respiratory, hepatitis, or hematological abnormalities (leucopenia) as a
362
result of immunosuppression
363
Mental disorders
364
Serological Monitoring Of Disease Activity
365
Determination of serum autoantibodies at the initiation of treatment, after 3 months and every 3–6
366
months based on the evolution, or in case of relapse by:
367
ELISA: anti-Dsg1 and/or Dsg3 IgG
368
If ELISA is not available: IIF microscopy utilizing monkey esophagus
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Overall, serum concentrations of IgG autoantibodies against Dsg1 and Dsg3 correlate with the
370
clinical activity of pemphigus and may thus help in therapeutic decision making
371
The persistence of high levels of anti-Dsg1 by ELISA has a positive predictive value for skin
372
relapses, whereas the persistence of anti-Dsg3 IgG does not necessarily indicate a mucosal relapse
373
Discontinuation of Treatment
374
Discontinuation of treatment is primarily based on the clinical symptoms but may be also
375
supported by the findings of Dsg ELISA, IIF and/or negative DIF microscopy of a skin biopsy.
376
Discontinuation of systemic corticosteroids may be proposed in patients in complete remission on
377
minimal therapy (prednisolone or equivalent at 10 mg/day). The adjuvants may be stopped 6–12
378
months after achieving complete remission on minimal therapy with adjuvants only.
379
Possible Sequelae
380
Pemphigus may cause permanent sequelae not only due to the involvement of skin and mucosa
381
but also due to treatment side effects, justifying request for recognition or help from departmental
382
disability centers where available. The extent of immunosuppressive therapy increases the risk of
383
side-effects.
384
385
Information for patients and their families
386
Education about the disease, its clinical course and prognosis, treatment, relapse signs, and
387
possible side-effects of treatment.
388
Awareness of self-support groups, which may help disseminate information regarding the disease,
389
provide comfort and share the experience of patients regarding daily life. Additionally, it may
390
contribute to a better overall management of the disease by promoting cooperation between
391
patients, patient associations and health professionals.
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Information about referral centers
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Education about triggers such as drugs, operations, radiation and physical trauma
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Counseling on dietary restrictions not necessary due to insufficient evidence
395
Areas for Future Studies
396
These recommendations are a working document whose purpose is to provide clinicians the most up-to-
397
date consensus on the diagnosis and management of pemphigus. Further studies are needed to clarify
398
optimal therapeutic regimens and describe their safety and efficacy in the treatment of pemphigus. Some
399
areas identified by the authors include:
400
Intravenous CD20 inhibitors
401
Although a recent clinical trial has demonstrated superior efficacy and safety of the intravenous
402
CD20 inhibitor, rituximab, with short term lower doses of corticosteroids than standard dose
403
systemic corticosteroids initially with slow tapering (9), several questions remain about how best to
404
use it:
405
How should other medications be combined with intravenous CD20 inhibitors?
406
Should corticosteroids be used in combination with intravenous CD20 inhibitors from the
407
start to gain disease control and reduce unnecessary iatrogenic morbidity for patients?
408
In some patients with comorbidities or mild disease, can CD20 inhibitors be used alone or
409
with a topical corticosteroid?
410
What is the role of other immunosuppressives, IVIG, immunoadsorption, etc., along with
411
CD20 inhibitors?
412
Dosing of CD20 inhibitors
413
Is there a specific disease activity level in which patients can be treated with only oral
414
steroids and not necessarily CD20 inhibitors?
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What is the ideal threshold in patients on systemic corticosteroids or immunosuppressants to
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begin CD20 inhibitor therapy?
417
What is the optimal dose, frequency, total number of maintenance infusions to use?
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Are these drugs indicated in patients with negative anti-DSG antibodies?
419
In cases of relapse, is a single dose of 1000mg/infusion of rituximab (or 375 mg/m2 in
420
lymphoma protocol) enough to achieve remission instead of a full dose cycle of rituximab (2
421
x 1000 mg 2 weeks apart or 4 x 375 m
2
/week)?
422
Long term side effects
423
Will more side effects occur when more patients are treated with multiple maintenance
424
infusions of CD20 inhibitors?
425
Other treatment options
426
What role do other treatment options, like plasmapheresis, play in the treatment of pemphigus?
427
428
Conclusion
429
In summary, we present here the recommendations arising from a Delphi process involving 39
430
pemphigus experts. We make recommendations for evaluation and treatment of pemphigus, including
431
initial evaluation, diagnosis, and management, as well as strategies for maintenance therapy and tapering
432
of medications in remission.
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References
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1.
Mimouni D, Nousari C, Cummins D, Kouba D, David M, Anhalt G. Differences and similarities
435
among expert opinions on the diagnosis and treatment of pemphigus vulgaris. Journal of the
436
American Academy of Dermatology. 2003;49(6):1059-1062. doi:10.1016/s0190-9622(03)02738-
437
5.
438
2.
Venugopal S Murrell D. Diagnosis and Clinical Features of Pemphigus Vulgaris. Immunology
439
and Allergy Clinics of North America. 2012;32(2):233-243. doi:10.1016/j.iac.2012.04.003.
440
3. Joly P, Bernard P, Bedane C, Prost C, Ingen-Housz-Oro S. Pemphigus. Guidelines for the
441
diagnosis and treatment. Centres de reference des maladies bulleuses auto-immunes. Societe
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Francaise de Dermatologie. Ann Dermatol Venereol 2011; 138: 252–258.
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4. Committee for Guidelines for the Management of Pemphigus Disease, Amagai, M., Tanikawa,
444
A., Shimizu, T., Hashimoto, T., Ikeda, S., Kurosawa, M., Niizeki, H., Aoyama, Y., Iwatsuki, K.
445
and Kitajima, Y. (2014), Japanese guidelines for the management of pemphigus. The Journal of
446
Dermatology, 41: 471–486. doi: 10.1111/1346-8138.12486
447
5. Eming, R., Sticherling, M., Hofmann, S. C., Hunzelmann, N., Kern, J. S., Kramer, H., Pfeiffer,
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C., Schuster, V., Zillikens, D., Goebeler, M., Hertl, M., Nast, A., Orzechowski, H.-D., Sárdy, M.,
449
Schmidt, E., Sitaru, C., Sporbeck, B. and Worm, M. (2015), S2k guidelines for the treatment of
450
pemphigus vulgaris/foliaceus and bullous pemphigoid. Journal der Deutschen Dermatologischen
451
Gesellschaft, 13: 833–844. doi: 10.1111/ddg.12606
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6. Harman, K.E., Albert, S. and Black, M.M. (2003), Guidelines for the management of pemphigus
453
vulgaris. British Journal of Dermatology, 149: 926–937. doi:10.1111/j.1365-2133.2003.05665.x
454
7. Hertl M, Jedlickova H, Karpati S et al. Pemphigus. S2 Guideline for diagnosis and treatment -
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guided by the European Dermatology Forum (EDF) in cooperation with the European Academy
456
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of Dermatology and Venereology (EADV). Journal of the European Academy of Dermatology
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and Venereology. 2014;29(3):405-414. doi:10.1111/jdv.12772.
458
8. Hsu C, Sandford B. The Delphi Technique: Making Sense Of Consensus. Practical Assessment,
459
Research & Evaluation. 2007;12(10). Available at: http://pareonline.net/getvn.asp?v=12&n=4.
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9. Shimizu, T., Takebayashi, T., Sato, Y., Niizeki, H., Aoyama, Y., Kitajima, Y., Iwatsuki, K.,
461
Hashimoto, T., Yamagami, J., Werth, V. P., Amagai, M. and Tanikawa, A. (2014), Grading
462
criteria for disease severity by pemphigus disease area index. J Dermatol, 41: 969–973.
463
doi:10.1111/1346-8138.12649
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10. Boulard, C., Duvert Lehembre, S., Picard-Dahan, C., Kern, J.S., Zambruno, G., Feliciani, C.,
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Marinovic, B., Vabres, P., Borradori, L., Prost-Squarcioni, C., Labeille, B., Richard, M.A.,
466
Ingen-Housz-Oro, S., Houivet, E., Werth, V.P., Murrell, D.F., Hertl, M., Benichou, J., Joly, P.
467
and the International Pemphigus Study Group (2016), Calculation of cut-off values based on the
468
Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) and Pemphigus Disease Area Index
469
(PDAI) pemphigus scoring systems for defining moderate, significant and extensive types of
470
pemphigus. Br J Dermatol, 175: 142–149. doi:10.1111/bjd.14405
471
11. Joly P, Maho-Vaillant M, Prost-Squarcioni C, et al. (in press). First-line use of Rituximab
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combined with short-term-prednisone versus corticosteroid alone in the treatment of patients
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with Pemphigus: a prospective multicenter randomized trial. The Lancet.
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12. Murrell DF, Daniel BS, Joly P, et al. Definitions and outcome measures for bullous pemphigoid:
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Recommendations by an international panel of experts. Journal of the American Academy of
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Dermatology. 2012;66(3):10.1016/j.jaad.2011.06.032. doi:10.1016/j.jaad.2011.06.032.
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Table 1: Laboratory Work-up
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Histopathology
A biopsy should be taken of a recent (<24 h) small vesicle or 1/3 of the peripheral
portion of a blister and 2/3 perilesional skin (placed in 4% formalin solution) for
routine histopathological analysis: intraepidermal suprabasal acantholysis in PV or
acantholysis at the granular layer in PF.
Direct immunofluorescence microscopy (DIF)
Skin biopsy of perilesional skin (up to 1 cm from a recent lesion), put into a
cryotube for transportation in saline (delivery <36 h) in a cylinder of liquid nitrogen
or Michel’s fixative for DIF analysis:
DIF: IgG and/or C3 deposits at the surface of epidermal keratinocytes. The
smooth and reticular staining pattern is also referred to as ‘chicken wire’,
‘honeycomb’ or ‘fishnet-like’.
IgA deposits with an epithelial cell surface pattern in addition to IgG may be
present in a subset of cases.
Epithelial cell surface deposits may be associated with linear or granular
deposits of IgG or C3 along the dermal–epidermal junction, suggestive of
other autoimmune blistering diseases including paraneoplastic pemphigus or
pemphigus erythematosus, or the coexistence of pemphigus and pemphigoid
Immune serological tests
Indirect immunofluorescence microscopy (IIF)
IIF test on monkey esophagus or human skin to search for autoantibodies against
surface proteins of epidermal keratinocytes, similar to the pattern seen on DIF.
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In case of atypical presentation or the suspicion of another autoimmune bullous
disorder, additional immunopathological tests may be performed, such as IIF on rat
bladder and immunoblot/immunoprecipitation
IIF on human cells with recombinant expression of desmoglein 1, desmoglein 3 or
envoplakin (Euroimmun) is an alternative where desmoglein- or envoplakin-specific
ELISA cannot be used
ELISA
Detection of anti-desmoglein 1 (Dsg1) (PF/mucocutaneous PV) and/or anti-
desmoglein 3 (Dsg3) IgG autoantibodies (mucosal or mucocutaneous PV) by ELISA
(MBL, Euroimmun)
The detection of IgG autoantibodies by ELISA is positive in more than 90% of
cases
In general, the ELISA index correlates with the extent and/or activity of disease
(see remark above) and prognostic value for relapse, helping to guide treatment.
Large prospective cohort studies are, however, missing in this context to provide
reliable data about predictive value
Work-Up before Corticosteroid or Immunosuppressive Therapy
Complete blood count
Creatinine, blood electrolytes
Transaminases, gamma GT, alkaline phosphatase
Total serum protein, albumin
Fasting serum glucose
Hepatitis B, C and HIV
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Quantiferon gold or PPD is recommended
Recommended, on indication or optional:
Serum IgA deficiency should be ruled out prior to IVIG treatment
Analysis of thiopurine methyltransferase (TPMT) activity is recommended when
azathioprine is considered in countries where genetic polymorphisms for decreased
TMPT activity levels are more common
Chest X-ray if Quantiferon gold or PPD is abnormal
ß HCG is recommended to exclude pregnancy in women of childbearing potential
Osteodensitometry is recommended prior to corticosteroid treatment
Ocular examination (glaucoma, cataract) is recommended
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Table 2: Medication Dosing
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First-Line Treatment
Corticosteroids
Systemic corticosteroid therapy (predniso(lo)ne at 0.5 mg to 1.5 mg/kg/day)
Systemic corticosteroids (oral or intravenous pulses) can be combined with an
immunosuppressive adjuvant at the onset of therapy, especially in cases of increased risk of
corticosteroid therapy, complications due to expected prolonged use (>4 months) or dose
dependency above minimal therapy (>10 mg/day). However, there is limited evidence that
the addition of adjuvants is superior to treatment with corticosteroids alone.
While limited, studies have not shown IV corticosteroid pulses to have an additional
benefit on top of conventional first-line treatment with oral predniso(lo)ne and
immunosuppressive adjuvants. While more evidence is needed, steroid pulse therapy in
addition to conventional treatment should be reserved for refractory cases of pemphigus.
Treat with the smallest dose for the shortest time possible to minimize risk of adverse
events
Anti-CD20 monoclonal antibodies
Currently there are two intravenous CD20 inhibitors available, rituximab and ofatumumab. All
the published trials so far have used rituximab.
First line treatment in new onset moderate to severe pemphigus and/or for patients who do
not achieve clinical remission with systemic corticosteroids and/or immunosuppressive
adjuvants (11). Allows for more rapid tapering of corticosteroid doses and a major
corticosteroid sparing effect.
A course of intravenous rituximab consists of 2 x 1000 mg (2 weeks apart) or 4 x 375
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mg/m2 (1 week apart).
Treatment can be repeated in case of clinical relapse or as early as 6 months after treatment.
Lower doses are sometimes used for retreatment.
Combine with short-term (<4 months) systemic corticosteroids and long-term (>12 months)
immunosuppressive treatment, although the need for immunosuppressive adjuvants in
rituximab therapy remains unclear.
The incidence of unforeseen fatal infections such as progressive multifocal
leukoencephalopathy (PML) cannot be estimated due to the rarity of pemphigus.
Corticosteroid-Sparing Agents
First-Line Corticosteroid-Sparing Agents
Azathioprine (1–3 mg/kg/day).
Start first week 50 mg/day to detect idiosyncratic reactions such as sudden onset
fevers, oral ulcers, elevated liver function tests and/or DRESS (and in case stop
immediately), and then raise to desired dose. Although not predictive for idiosyncratic
reactions, TPMT activity should be evaluated in countries/ethnicities where there is a
higher incidence of polymorphisms before commencing therapy because
recommended azathioprine doses vary based upon TPMT activity. In general, adults
with pemphigus and high TPMT activity are treated with normal doses of azathioprine
(up to 2.5 mg/kg/day). Patients with intermediate or low TPMT activity should receive
a lower maintenance dose (up to 0.5 to 1.5 mg/kg/day) depending on level of enzyme
activity. Patients that lack TPMT activity should avoid treatment with azathioprine.
Mycophenolate mofetil (30 mg/kg-45 mg/kg/day) or mycophenolic acid (1440 mg/day).
Other Corticosteroid-Sparing Agents
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Intravenous immunoglobulins (IVIG) (2g/kg over 2-5 days per month)
Treatment is generally combined with systemic corticosteroids (initially) and
immunosuppressive adjuvants
Treatment should be performed over several days to avoid side-effects
Aseptic meningitis is a rare but important side-effect of IVIG treatment which needs to
be kept in mind in patients who commonly experience episodes of migraine
Although uncommon, patients with IgA deficiency should receive IgA-depleted IVIG
treatment.
Immunoadsorption
First-line treatment option in emergency situations where available
Second-line corticosteroid sparing agent where available
Contraindications include severe systemic infections, severe cardiovascular diseases,
hypersensitivity against components of the immunoadsorption column, treatment with
angiotensin-converting enzyme inhibitors and extensive hemorrhagic diathesis
Cyclophosphamide
Use in cases of limited resources or in severe cases that have not responded to other
treatments
Use as a drug of last resort due to long-term side effects
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Figure 1: Diagnosis of Pemphigus
486
Diagnosis requires clinical presentation and histopathology that are consistent with pemphigus
487
and either a positive DIF or serological detection of autoantibodies against epithelial cell surface
488
antigens.
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Figure 2: Treatment Options
491
The principal objective is to promote the healing of blisters and erosions, prevent development of new
492
lesions, and minimize serious side effects of treatment.
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Table 1:Summary of the changes made to previous guidelines
The following is a summary of the differences with the EDF/EADV guidelines.
The following set of guidelines was revised to include diagnostic and management
interventions for pemphigus vulgaris (PV) and pemphigus foliaceus (PF) only.
The roles of general practitioners, nurse practitioners, and home care health nurses
were defined.
The titles “first-line” and “second-line” adjuvants were changed to “first-line
corticosteroid sparing agents” and “other corticosteroid sparing agents”.
Intravenous CD20 inhibitors were added as a first-line treatment recommendation
for moderate to severe pemphigus
The following qualifying statement was added to the recommendation regarding
analysis of thiopurine methyltransferase (TPMT) activity when azathioprine is
considered: “in countries where genetic polymorphisms for decreased TMPT activity
levels are more common.”
“In case of elevated risk” was removed as a qualifying statement with regards to
checking a Quantiferon or purified protein derivative (PPD) skin test to rule out
tuberculosis prior to initiating treatment.
Statements of facts as opposed to recommendations were removed.
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Capsule summary 1
The European Dermatology Forum and the European Academy of Dermatology and 2
Venereology (EDF/EADV) passed management guidelines for pemphigus. 3
We present the recommendations of international experts, which have resulted from 4
a Delphi consensus gathering exercise based on the EDF/EADV guidelines. 5
This international consensus includes intravenous CD20 inhibitors as a first line 6
therapy option for moderate to severe pemphigus. 7
... PV is caused by environmental and genetic factors that lead to immunological impairments. Auto-antibodies against the desmosomal adhesion proteins of epidermal keratinocytes, desmoglein3 and/or desmoglein 1, lead to the loss of epidermal cell adhesion and development of erosive lesions [1,2]. To date, different cytokines, such as osteopontin, interleukin (IL)-4 and IL-21 have been suggested to be associated with disease pathogenesis and severity [3][4][5]. ...
Article
Full-text available
introduction: IL-15 as a member of the immunoregulatory cytokines family is associated with the development of the autoimmune or chronic inflammatory disease. objectives: The goal of this study was to evaluate the serum levels of IL-15 in patients with pemphigus vulgaris and assess the association of IL-15 with anti-desmoglein antibodies and the severity of the disease. methods: fifty-three individuals affected with active pemphigus Vulgaris and 38 age and gender-matched healthy controls were enrolled in this study. Clinical characteristics and Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) were assessed. Serum levels of IL-15 (pg/mL) and anti-desmoglein antibodies (Dsg1, 3) were measured. Result: The serum level of IL-15 in the patient group was assumed to be statistically higher than that of the control group (3.71 ± 1.5 vs. 0.79 ± 1.03 (p< 0.001)). A positive correlation was found between serum levels of IL-15 and severity of pemphigus Vulgaris measured by ABSIS (r=0.5, p=0.04). No significant relationship was detected between the serum level of IL-15 and antidesmoglein antibodies (Dsg1 or Dsg3). (p=0.6 and p=0.9, respectively). Conclusion: our findings showed that levels of IL‐15 were elevated in the sera of pemphigus patients and were related to disease severity. An increase in serum level of Il-15 in patients with pemphigus Vulgaris and its relation with disease severity suggest that this cytokine may play a role in the pathogenesis of the disease and targeting IL-15 will likely provide a new perspective on the treatment of this disease.
... Relapse in patients with disease remission corresponded to the appearance of ≥ 3 new lesions in a month that did not heal spontaneously within 1 week, and in those with controlled disease corresponded to extension of established lesions (11). ...
Article
Full-text available
Background and Aim There have been concerns regarding the potential exacerbation of autoimmune bullous diseases (AIBDs) following vaccination against COVID-19 during the pandemic. In the current study, vaccine safety was evaluated in patients with AIBDs. Methods In this study, patients with AIBDs were contacted via face-to-face visits or phone calls. Patient demographics, vaccine-related information, pre- and post-vaccine disease status, and complications were recorded. The exacerbation was considered either relapse in the remission/controlled phase of the disease or disease worsening in the active phase. The univariate and multivariate logistic regression tests were employed to determine the potential risk factors of disease exacerbation. Results Of the patients contacted, 446 (74.3%) reported receiving at least one dose of vaccine injection (54.7% female). Post-vaccine exacerbation occurred in 66 (14.8%) patients. Besides, there were 5 (1.1%) patients with AIBD diagnosis after vaccination. According to the analysis, for every three patients who received vaccines during the active phase of the disease one experienced disease exacerbation. The rate of disease exacerbation increased by three percent with every passing month from the last rituximab infusion. Active disease in the past year was another risk factor with a number needed to harm of 10. Conclusion Risk of AIBD exacerbation after the COVID-19 vaccine is not high enough to prevent vaccination. This unwanted side effect, can be reduced if the disease is controlled at the time of vaccination.
... The disease is mediated by autoantibodies mainly against desmoglein (Dsg) 1 and 3, responsible for intercellular adhesion. [1][2][3] Patients with pemphigus may experience disease flare-up from alterations in immune responses throughout pregnancy. 4 Moreover, transplacental transfer of maternal antibodies may cause neonatal pemphigus. ...
Article
Full-text available
Rituximab (RTX) is an effective treatment for pemphigus; however, the drug labeling recommends not to use RTX within 1 year before conception. Objectives: To report pregnancy outcomes of patients with pemphigus who were treated with RTX before or during pregnancy. Methods: We identified 19 pregnancies with RTX exposure before or during pregnancy. All had previously been advised not to get pregnant within 1 year of RTX administration. The cases were categorized into 3 groups of exposure of within 6 months (group A), between 6 and 12 months (group B), and longer than 12 months of conception (group C). The pregnancy outcomes of different RTX exposure intervals were compared. Results: Group A included 9 pregnancies, of which 3 had received RTX accidentally after conception. Group B and C included 4 and 6 pregnancies, respectively. There was no significant difference between the groups regarding pregnancy outcomes. Overall, there were 17 live births, 1 spontaneous abortion, and 1 termination. Of the live births, 3 preterm deliveries and 4 low-birth-weight neonates were noted. Moreover, 1 neonate was hospitalized due to early-onset neonatal sepsis, and 1 had hydronephrosis. Disease flare-up occurred in 5 patients during pregnancy (4 minor and 1 major relapses) and in 5 patients after delivery (3 minor and 2 major relapses). Conclusions: Except for 1 case of neonatal sepsis which survived following medical treatment, no serious relevant adverse pregnancy outcome that could be attributed to RTX exposure before and during early pregnancy in women with pemphigus was detected. Nevertheless, RTX should not be administered within 1 year before planned pregnancy, as not enough data is available yet.
... RTX is a murine-human chimeric monoclonal antibody directed against CD20, a cell surface marker expressed by B cells after the late pre B-cell stage (except plasma cells), and is responsible for prolonged B-cell depletion followed by a 6-month delayed recovery period (19,20). Following clinical trials, metaanalyses, and a prospective multicenter randomized trial (21)(22)(23)(24), RTX is now recommended in first line therapy for moderate to severe pemphigus in combination with oral corticosteroids (25,26). RTX has also been used off-label, alone or in ...
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Mucous membrane pemphigoid (MMP) is a heterogeneous group of rare, chronic, subepithelial autoimmune blistering diseases (AIBDs) with predominant involvement of mucous membranes that can be sight-threatening and life-threatening. Rituximab (RTX) has demonstrated its efficacy in severe MMP refractory to conventional immunosuppressants in small series that differed in RTX scheme, concomitant therapies, and outcome definitions. In a meta-analysis involving 112 patients with MMP treated with RTX, complete remission (CR) was reported in 70.5% of cases. Herein, we report the largest retrospective monocentric study on RTX efficacy in a series of 109 severe and/or refractory patients with MMP treated with RTX with a median follow-up period of 51.4 months. RTX was administered in association with immunomodulatory drugs (dapsone, salazopyrine) without any other systemic immunosuppressant in 104 patients. The RTX schedule comprised two injections (1 g, 2 weeks apart), repeated every 6 months until CR or failure, with a unique consolidation injection (1 g) after CR. The median survival times to disease control and to CR were 7.1 months and 12.2 months, respectively. The median number of RTX cycles required to achieve CR in 85.3% of patients was two. The larynx was the lesional site that took the longest time to achieve disease control. One year after RTX weaning, CR off RTX was obtained in 68.7% of cases. CR off RTX with only minimum doses of immunomodulatory drugs was achieved in 22.0% of patients. Further, 10.1% of patients were partial responders and 4.6% were non-responders to RTX. Relapse occurred in 38.7% of cases, of whom 91.7% had achieved CR again at the last follow-up. In MMP, CR was achieved in a longer time and after more rituximab cycles than in pemphigus, especially for patients with MMP with anti-type VII collagen reactivity. RTX with concomitant immunomodulatory drugs was not responsible for an unusual proportion of adverse events. This large study confirms that RTX is an effective therapy in patients with severe and/or refractory MMP, corroborating previous findings regarding the effects of RTX on AIBDs such as pemphigus.
... Notably, methotrexate was not included in recent clinical guidelines based on expert consensus recommendations for PV and PF management. [5][6][7] The lack of clinical studies of methotrexate using PV and PF disease endpoints that have recently been established by international consensus may be a contributing factor. 7 4 However, little has been reported regarding the use of methotrexate in PV and PF since. ...
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Background: Methotrexate is historically recognized as an effective treatment of pemphigus but its utility as a single or alternate steroid-sparing agent was not recognized in recent consensus recommendations in pemphigus management. Objectives: To evaluate the efficacy and safety of a treatment course for pemphigus that involves methotrexate as a single or steroid-sparing agent. Methods: In a retrospective cohort study, we examined patients with pemphigus vulgaris or pemphigus foliaceus who were on ≥ three months of methotrexate therapy. Efficacy and safety were evaluated by established pemphigus disease endpoints. Results: Thirty-four patients with met inclusion criteria. Of these, 25 (73.5%) were on glucocorticoids at time of methotrexate initiation (median follow-up: 5.4 years; median time on methotrexate: 3.7 years). An appreciable proportion achieved disease control (91.2%), with some achieving clinical remission off all systemic therapies (23.5%). For patients on glucocorticoids, median time to control was 42 days, median time to minimal steroid dose tapering (5 mg prednisone) was 161 days, and median time to complete steroid tapering was 308 days. For patients on methotrexate as a single agent, median time to control was 119 days. Among all patients, relapse commonly occurred (88.2%). At last follow-up, 26.5% were managed on topical therapies alone and 11.8% required systemic steroid therapy. Methotrexate was largely tolerated with a low incidence of adverse events leading to treatment discontinuation (2.9%). Conclusions: Methotrexate has potential to be an effective and well-tolerated option for patients and may be considered for use as an alternate single or steroid-sparing agent for pemphigus.
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Pemphigus and pemphigoid are autoimmune blistering diseases that affect mucosa and skin. Several clinical scoring systems, including the pemphigus disease area index (PDAI) and the bullous pemphigoid disease area index (BPDAI), have been validated for managing disease activity and severity. Current guidelines recommend that treatment response be evaluated with clinical scores and that additional second‐line therapies be considered if initial treatment is insufficient for disease control. However, there have been few studies analyzing correlations between PDAI/BPDAI transitions and initial treatment effects. To investigate whether PDAI/BPDAI transitions during the treatment initiation phase correlate with initial treatment responses and whether such information can be used as a guide for necessary additional treatment, we retrospectively analyzed 67 pemphigus patients and 47 pemphigoid patients who received initial treatment at Keio University between 2012 and 2018. The clinical symptoms were evaluated weekly with PDAI/BPDAI. The patients were divided into two groups: in group A, disease was controlled only with oral corticosteroids and immunosuppressants (initial treatment), whereas in group B additional therapies were required due to insufficient responses. In pemphigus, the PDAI ratio of day 7/day 0 was significantly reduced in group A compared to group B (0.548 vs 0.761, P < 0.01) after initial treatment had started. In pemphigoid, the ratios of day 7/day 0 of BPDAI (erosion/blister) and BPDAI (urticaria/erythema) significantly decreased in group A compared to group B (0.565 vs 0.901 and 0.350 vs 0.760, respectively, P < 0.05). Receiver operating characteristic analyses on PDAI, BPDAI (erosion/blister) and BPDAI (urticaria/erythema) revealed that the cut‐off values in the ratios of day 7/day 0 were 0.762, 0.675, and 0.568, respectively. Our results suggest that PDAI/BPDAI transitions during the initial phase of the treatments may be useful to predict the outcome of the treatment provided and the necessity of additional therapies to achieve disease control.
Article
Importance: There is an increasing body of literature that supports the use of rituximab as a first-line steroid-sparing agent in pemphigus vulgaris. However, the cost of rituximab is substantial compared with conventional agents, and there are limited health economic data to justify its use. Objective: To evaluate the cost-effectiveness of rituximab biosimilars relative to mycophenolate mofetil as a first-line steroid-sparing agent for moderate to severe pemphigus vulgaris. Design, setting, and participants: A cost-utility analysis over a 24-month time horizon was conducted from the perspective of the Australian health care sector using a modeled cohort of treatment-naive adult patients with moderate to severe pemphigus vulgaris. A Markov cohort model was constructed to simulate disease progression following first-line treatment with rituximab biosimilars or mycophenolate mofetil. The simulated cohort transitioned between controlled disease, uncontrolled disease, and death. Efficacy and utility data were obtained from available published literature. Cost data were primarily obtained from published government data. One-way and probabilistic sensitivity analyses were performed to assess uncertainty. Primary outcomes were the changes in cost and quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) over the 24 months. Interventions: Rituximab biosimilars and mycophenolate mofetil. Results: The simulated cohort of treatment-naive patients had a mean age of 50.8 years, a female-to-male ratio of 1.24, and moderate to severe disease as classified by the Harman criteria. First-line rituximab biosimilars were associated with a cost reduction of AU$639 and an improvement of 0.07 QALYs compared with mycophenolate mofetil, resulting in an ICER of -AU$8818/QALY. Rituximab biosimilars were therefore more effective and less costly compared with mycophenolate mofetil. Sensitivity analyses demonstrated that rituximab biosimilars remained cost-effective across a range of values for cost, utility, and transition probability input parameters and willingness-to-pay thresholds. Conclusions and relevance: In this cost-utility analysis, rituximab biosimilars were cost-effective compared with mycophenolate mofetil for moderate to severe pemphigus vulgaris. Further investigation into its cost-effectiveness over a longer time horizon is necessary, but the favorable results of this study suggest that the high acquisition costs of rituximab biosimilars may be offset by its effectiveness and provide economic evidence in support of its listing on the Pharmaceutical Benefits Scheme for pemphigus vulgaris.
Article
Background: Rituximab is widely used for treatment of pemphigus patients. B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) play key roles in B cell survival, maturation, and differentiation. Here, the effect of rituximab on BAFF and APRIL in patients with pemphigus vulgaris (PV) was studied. Methods: Fifty PV cases and 56 healthy individuals were recruited. Patients received rituximab for a period of 6 months. The levels of BAFF and APRIL were measured in the serum samples. The frequency of CD19+ B cells was measured by flow cytometry. Results: The level of BAFF was significantly higher in the patients at the baseline level than controls (P = 0.0005). The level of BAFF was significantly higher at the 3rd month follow-up compared to the baseline (P = 0.033). There was a significant increase in the BAFF level at the 6th month follow-up compared to baseline (P = 0.0134). There was no significant difference in the CD19+ B cells/total lymphocytes ratio in the PV patients between the 3rd and 6th month follow-ups. Conclusions: Elevated BAFF in the sera could be associated with PV immunopathogenesis. Inhibition of BAFF after rituximab therapy might interfere with repopulation of B cells and confer a therapeutic approach in PV.
Article
Pemphigus vulgaris (PV), an acquired autoimmune bullous disease, is caused by autoantibodies targeting desmosomal proteins in the skin and mucous membranes. Recent data from the adult PV population supports the use of rituximab, a chimeric anti‐CD20 IgG1 antibody, as a primary treatment strategy, but limited data exist regarding treatment in the pediatric population. We report the case of a 13‐year‐old male with PV treated successfully with systemic corticosteroids and rituximab, and review the literature supporting the treatment of pediatric PV with rituximab.
Chapter
Pemphigus vulgaris is a life-threatening bullous disease characterized by acantholysis resulting in the formation of intraepithelial blebs in the mucous membranes and skin. It is a chronic autoimmune bullous dermatosis caused by the production of autoantibodies against desmoglein 1 and 3. It often begins with blisters and erosions on the oral mucosa, followed by lesions on other mucous membranes and drooping blisters that may spread to the skin. If there is clinical suspicion, the diagnosis can be confirmed by cytological examination, histopathological examination, direct and indirect immunofluorescence tests. Before the introduction of corticosteroids, PV was fatal due to dehydration or secondary systemic infections. The mainstay of treatment is still systemic steroids. Immunosuppressants such as azathioprine, mycophenolate mofetil and methotrexate, high-dose intravenous immunoglobulins, CD20 monoclonal antibody Rituximab treatments are used as an adjuvant with steroids in suitable patients and successful results are obtained.
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Background: High doses of corticosteroids are considered the standard treatment for pemphigus. Because long-term corticosteroid treatment can cause severe and even life-threatening side-effects in patients with this disease, we assessed whether first-line use of rituximab as adjuvant therapy could improve the proportion of patients achieving complete remission off-therapy, compared with corticosteroid treatment alone, while decreasing treatment side-effects of corticosteroids. Methods: We did a prospective, multicentre, parallel-group, open-label, randomised trial in 25 dermatology hospital departments in France (Ritux 3). Eligible participants were patients with newly diagnosed pemphigus aged 18-80 years being treated for the first time (not at the time of a relapse). We randomly assigned participants (1:1) to receive either oral prednisone alone, 1·0 or 1·5 mg/kg per day tapered over 12 or 18 months (prednisone alone group), or 1000 mg of intravenous rituximab on days 0 and 14, and 500 mg at months 12 and 18, combined with a short-term prednisone regimen, 0·5 or 1·0 mg/kg per day tapered over 3 or 6 months (rituximab plus short-term prednisone group). Follow-up was for 3 years (study visits were scheduled weekly during the first month of the study, then monthly until month 24, then an additional visit at month 36). Treatment was assigned through central computer-generated randomisation, with stratification according to disease-severity (severe or moderate, based on Harman's criteria). The primary endpoint was the proportion of patients who achieved complete remission off-therapy at month 24 (intention-to-treat analysis). This study is registered with ClinicalTrials.gov, number NCT00784589. Findings: Between May 10, 2010, and Dec 7, 2012, we enrolled 91 patients and randomly assigned 90 to treatment (90 were analysed; 1 patient withdrew consent before the random assignment). At month 24, 41 (89%) of 46 patients assigned to rituximab plus short-term prednisone were in complete remission off-therapy versus 15 (34%) of 44 assigned to prednisone alone (absolute difference 55 percentage points, 95% CI 38·4-71·7; p<0·0001. This difference corresponded to a relative risk of success of 2·61 (95% CI 1·71-3·99, p<0·0001), corresponding to 1·82 patients (95% CI 1·39-2·60) who would need to be treated with rituximab plus prednisone (rather than prednisone alone) for one additional success. No patient died during the study. More severe adverse events of grade 3-4 were reported in the prednisone-alone group (53 events in 29 patients; mean 1·20 [SD 1·25]) than in the rituximab plus prednisone group (27 events in 16 patients; mean 0·59 [1·15]; p=0·0021). The most common of these events in both groups were diabetes and endocrine disorder (11 [21%] with prednisone alone vs six [22%] with rituximab plus prednisone), myopathy (ten [19%] vs three [11%]), and bone disorders (five [9%] vs five [19%]). Interpretation: Data from our trial suggest that first-line use of rituximab plus short-term prednisone for patients with pemphigus is more effective than using prednisone alone, with fewer adverse events. Funding: French Ministry of Health, French Society of Dermatology, Roche.
Article
Background: Two pemphigus severity scores, Autoimmune-Bullous-Skin-Disorder-Intensity-Score (ABSIS) and Pemphigus-Disease-Area-Index (PDAI), have been proposed to provide an objective measure of disease activity. However, the use of these scores in clinical practice is limited by the absence of cut-off values which allow differentiation between moderate, significant and extensive types of pemphigus. Objective: To calculate cut-off values defining moderate, significant and extensive pemphigus based on the ABSIS and PDAI scores. Methods: In 31 Dermatology Departments in six countries, consecutive patients with newly diagnosed pemphigus were assessed for pemphigus severity, using the ABSIS, PDAI, Physician-Global-Assessment (PGA) and Dermatology-Life-Quality-Index (DLQI) scores. Cut-off values defining moderate, significant and extensive subgroups were calculated based on the 25(th) and 75(th) percentiles of the ABSIS and PDAI scores. Median ABSIS, PDAI, PGA and DLQI scores of the three severity subgroups were compared to validate these subgroups. Results: Ninety-six patients with pemphigus vulgaris (n=77) or pemphigus foliaceus (n=19) were included. Median PDAI activity and ABSIS total scores were 27.5 [range:3-84] and 34.8 points [range:0.5-90.5], respectively. Cut-off values corresponding to the first and third quartiles of the scores were 15 and 45 for the PDAI, and 17 and 53 for the ABSIS. The moderate, significant and extensive subgroups were thus defined, and had distinguishing median ABSIS (p<0.0001), PDAI (p<0.0001), PGA (p<0.0001) and DLQI (p=0.03) scores. Conclusions: This study suggests cut-off values of 15/45 and 17/53 for PDAI and ABSIS respectively, to distinguish moderate, significant and extensive pemphigus forms. Identifying these pemphigus activity subgroups should help physicians to classify and manage pemphigus patients. This article is protected by copyright. All rights reserved.
Article
Pemphigus is a group of autoimmune blistering diseases that affect the skin and mucous membranes. A reliable and accurate disease severity tool to assess pemphigus severity is crucial for managing pemphigus and for clinical trials. The purpose of this study was to compare the pemphigus disease area index activity score (PDAI), the Japanese pemphigus disease severity score (JPDSS) and the physician's subjective impression, and also to find appropriate severity grading cut-offs for the PDAI. We also evaluated the correlation between PDAI activity score and the JPDSS. Thirty-seven pemphigus patients and 110 assessments were analyzed in this study. The optimal points of pemphigus disease severity score in PDAI were: mild (0–8), moderate (9–24) and severe (≥25). In mild or moderate cases, the JPDSS was well correlated with the PDAI, but in severe cases the JPDSS reached a plateau at a PDAI score of approximately 30. The PDAI evaluates disease severity more accurately than the JPDSS, particularly in severe cases. The PDAI is not only a useful tool to measure the extent of cutaneous lesions, but also an excellent scoring system for evaluating pemphigus disease severity.
Article
Background Pemphigus encompasses a group of life-threatening autoimmune bullous diseases characterized by blisters and erosions of the mucous membranes and skin. Before the era of immunosuppressive treatment, the prognosis of pemphigus was almost fatal. Due to its rarity, only few prospective controlled therapeutic trials are available.Objectives For this reason, a group of European dermatologists with a long-standing interest and expertise in basic and clinical pemphigus research has sought to define diagnostic and therapeutic guidelines for the management of patients with pemphigus.ResultsThis group identified the statements of major agreement or disagreement regarding the diagnostic and therapeutic management of pemphigus. The revised final version of the pemphigus guideline was finally passed on to the European Dermatology Forum (EDF) for a final consensus with the European Academy of Dermatology and Venereology (EADV) and the European Union of Medical Specialists (UEMS).
Article
The Committee for Guidelines for the Management of Pemphigus was organized as one element of the Japanese Dermatological Association (JDA) and the Ministry of Health, Labour, and Welfare (MHLW) Research Project on Measures for Research Committee for Intractable Skin Disease. Pemphigus has been defined as a group of intractable autoimmune blistering diseases caused by anti-desmoglein 1 and/or anti-desmoglein 3 IgG autoantibodies by the MHLW. The diagnosis of this condition and the criteria for assessing its severity are based on suggestions from the MHLW Research Group. The clinical practice guidelines presented here are those that are currently recommended in Japan. However, symptoms and complications can vary widely among individual pemphigus patients, so not all therapies will be required to be in complete agreement with these guidelines.
Article
Autoimmune bullous diseases are associated with autoimmunity against structural components that maintain cell-cell and cell-matrix adhesion in the skin and mucous membranes. They include those where the skin blisters at the basement membrane zone and those where the skin blisters within the epidermis (pemphigus vulgaris, pemphigus foliaceus, and other subtypes of pemphigus). The variants of pemphigus are determined according to the level of intraepidermal split formation. There are 5 main variants of pemphigus: pemphigus vulgaris, pemphigus foliaceus, pemphigus erythematosus, drug-induced pemphigus, and paraneoplastic pemphigus. This review focuses only on pemphigus vulgaris.
Article
As a result of a lack of large-scale controlled studies, the diagnosis and management of pemphigus vulgaris (PV) has been solely on the basis of expert opinion, rather than on empirical evidence. We have completed a survey of worldwide experts on the diagnostic and therapeutic approaches to PV. We conducted a telephone-based survey of 24 physicians from academic, tertiary care centers worldwide with an average of 20 years experience treating pemphigus. Survey questions included referral patterns, diagnostic techniques, and therapeutic regimens. Of those surveyed, 50% receive referrals within 6 months after onset of symptoms, 17% within 1 year, and 8% within 3 years. Diagnosis is secured by 96% using skin biopsy specimen with direct immunofluorescence, and by indirect immunofluorescence alone for 4%. None of the participating physicians make the diagnosis of PV solely on clinical and histologic evidence. Of the physicians, 75% initially treat with prednisone and 25% use other agents or attempt to eliminate potential triggers. The physicians who initially used noncorticosteroid drugs did so with no relation to the nature or extent of the disease. Of those surveyed, 50% use prednisone doses of 1 mg/kg/d, 31% use 1 to 1.5 mg/kg/d, and 19% use 1.5 to 3 mg/kg/d. Azathioprine is used as an adjuvant by 44%, mycophenolate mofetil by 20%, cyclophosphamide by 16%, and methotrexate by 8%. Complete discontinuation of prednisone was the goal for 37% whereas others were satisfied with doses from 2.5 to 10 mg/d. Wide variation exists in diagnostic techniques and treatment of PV, even among the world's experts. The lag time from symptom onset to referral emphasizes the need for heightened awareness. There is clearly a need for consensus standards with regard to patient stratification and randomized controlled trials.