European Guidelines for Pemphigus Management PDF

DOI: 10.1111/jdv.16752 JEADV GUIDELINES Updated S2K guidelines on the management of pemphigus vulgaris and foliaceus initiated by the european academy of dermatology and vene...

DOI: 10.1111/jdv.16752 JEADV GUIDELINES Updated S2K guidelines on the management of pemphigus vulgaris and foliaceus initiated by the european academy of dermatology and venereology (EADV) P. Joly,1,* B. Horvath,2 A Patsatsi,3 S. Uzun,4 R. Bech,5 S. Beissert,6 R. Bergman,7 P. Bernard,8 9 L. Borradori, M. Caproni, F. Caux, G. Cianchini,12 10 11 M. Daneshpazhooh,13 D De,14 M. Dmochowski,15 K. Drenovska,16 J. Ehrchen,17 C. Feliciani,18 M. Goebeler,19 R. Groves,20 C. Guenther,21 S. Hofmann,22 D. Ioannides,23 C. Kowalewski,24 R. Ludwig,25 26 27 28,29 Y.L. Lim, B. Marinovic, A.V. Marzano, J.M. Mascaro ! Jr,30 D. Mimouni,31 D.F. Murrell,32 C. Pincelli,33 C.P. Squarcioni,34 M. Sa !rdy,35 J. Setterfield,36 E. Sprecher,37,38 39 40 41 42 43 44 S. Vassileva, K. Wozniak, S. Yayli, G. Zambruno, D. Zillikens, M. Hertl, E. Schmidt43 1 Department of Dermatology, Rouen University Hospital and INSERM U905, Centre de r! efe!rence des maladies bulleuses autoimmunes, Normandie University, Rouen, France 2 Department of Dermatology, University Medical Center Groningen, Center for Blistering Diseases, University of Groningen, Groningen, the Netherlands 3 Autoimmune Bullous Diseases Unit, 2nd Dermatology Department, Papageorgiou General Hospital, Αristotle University School of Medicine, Thessaloniki, Greece 4 Department of Dermatology, Akdeniz University Faculty of Medicine, Antalya, Turkey 5 Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark 6 Department of Dermatology, University Hospital Carl Gustav Carus, Dresden, Germany 7 Department of Dermatology, Rambam Health Care Campus and The Ruth and Bruce Rappaport, Faculty of Medicine, Haifa, Israel 8 University of Reims-Champagne-Ardenne, Reims, France 9 Department of Dermatology, University Hospital of Bern, University of Bern, Bern, Switzerland 10 Department of Health Sciences, Section of Dermatology, USL Toscana Centro, Rare Diseases Unit, European Reference Network- Skin Member, University of Florence, Florence, Italy 11 Department of Dermatology and Referral Center for Autoimmune Bullous Diseases MALIBUL, Avicenne Hospital, AP-HP, University Paris 13, Bobigny, France 12 Department of Dermatology, Cristo Re Hospital, Rome, Italy 13 Autoimmune Bullous Diseases Research Center, Department of Dermatology, Razi Hospital, Tehran University of Medical Sciences, Tehran, Iran 14 Department of Dermatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India 15 Autoimmune Blistering Dermatoses Section, Department of Dermatology, Poznan University of Medical Sciences, Poznan, Poland 16 Department of Dermatology, Medical University, Sofia, Bulgaria 17 Department of Dermatology, University of Mu €nster, Mu€nster, Germany 18 Dermatology unit, Azienda ospedaliero -universitaria, Universita di Parma, Parma, Italy 19 Department of Dermatology, Venereology and Allergology, University Hospital Wu €rzburg, Wu€rzburg, Germany 20 St John’s Institute of Dermatology, London, UK 21 Department of Dermatology, University Hospital, Technical University Dresden, Dresden, Germany 22 Department of Dermatology, Allergy and Dermatosurgery, Helios University Hospital Wuppertal, University Witten, Herdecke, Germany 23 1st Department of Dermatology-Venereology, Hospital of Skin and Venereal Diseases, Aristotle University Medical School, Thessaloniki, Greece 24 Department Dermatology and Immunodermatology, Medical University of Warsaw, Warsaw, Poland 25 Department of Dermatology, University Hospital, Technical University Dresden, Dresden, Germany 26 National Skin Centre, Singapore, Singapore 27 Department of Dermatology and Venereology, University Hospital Centre Zagreb, School of Medicine, University of Zagreb, Zagreb, Croatia 28 Dermatology Unit, Fondazione IRCCS C#a Granda Ospedale Maggiore Policlinico, Milan, Italy 29 Department of Physiopathology and Transplantation, Universit# a degli Studi di Milano, Milan, Italy 30 Department of Dermatology, Hospital Cl!ınic de Barcelona, Universitat de Barcelona, Barcelona, Spain 31 Department of Dermatology, Rabin Medical Center, petha-Tikwa and Sackler School of Medicine, Tel Aviv University, Tel aviv, Israel 32 Department of Dermatology, St George Hospital, University of NSW, Sydney, NSW, Australia 33 DermoLab, Institute of Dermatology, University of Modena and Reggio Emilia, Modena, Italy 34 Department of Dermatology and Referral Center for Autoimmune Bullous Diseases MALIBUL, Avicenne Hospital, AP-HP, University Paris 13, Bobigny, France 35 Department of Dermatology, Venereology, and Dermatooncology, Semmelweis University, Budapest, Hungary JEADV 2020, 34, 1900–1913 © 2020 European Academy of Dermatology and Venereology  14683083, 2020, 9, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jdv.16752 by CochraneItalia, Wiley Online Library on [18/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License EADV pemphigus guideline 1901 36 Department of Oral Medicine, St John’s Institute of Dermatology; Guy’s and St Thomas’ NHS Foundation Trust, London, UK 37 Division of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel 38 Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel 39 Department of Dermatology, Medical University, Sofia, Bulgaria 40 Department of Dermatology and Immunodermatology, Medical University of Warsaw, Warsaw, Poland 41 Department of Dermatology, Karadeniz Technical University Faculty of Medicine, Trabzon, Turkey 42 Genetics and rare Disease Research Division, Bambino Gesu # Children’s Hospital, IRCCS, Rome, Italy 43 Department of Dermatology and Lu €beck Institute of Experimental Dermatology (LIED), University of Lu €beck, Lu €beck, Germany 44 Department of Dermatology, University of Marburg, Marburg, Germany *Correspondence: P. Joly. E-mail: [email protected] [Correction added on 28 August 2020, after first online publication: the name of author ‘B. Horvath’ has been corrected in this version.] Abstract Background Pemphigus encompasses a group of life-threatening autoimmune bullous diseases characterized by blis- ters and erosions of the mucous membranes and skin. Before the era of immunosuppressive treatment, pemphigus was almost always fatal. Due to its rarity, only few randomized controlled therapeutic trials are available. Recently, rituximab has been approved as first-line treatment for moderate and severe pemphigus vulgaris in Europe and the United States. Objectives The Autoimmune blistering diseases Task Force of the European Academy of Dermatology and Venereol- ogy (EADV) has initiated a throughout update of the guideline for the management of patients with pemphigus. Results The guidelines for the management of pemphigus were updated, and the degree of consent among all task force members was included. The final version of the guideline was consented by the European Dermatology Forum (EDF) and several patient organizations. Received: 20 March 2020; Accepted: 29 May 2020 Disclosures Pascal Joly is consultant for Roche, Amgen, Principia Biopharma, argenx, AstraZeneca and Thermo Fisher. Enno Sch- midt is consultant for UCB, Incyte, argenx, Roche, Genetech, AstraZeneca, Admirx, Synthon, Imevax and Thermo Fisher. In addition, he received honoraria form Novartis, Biotest and Fresenius. He has research grants with UCB, Incyte, argenx, Admirx, Synthon and Biotest. Jan Ehrchen is consultant for Boehringer Ingelheim, Sobi and Novartis, and received speaker fees from Pfizer, Chugai, Actelion and Janssen. Matthias Goebeler is investigator in a clinical trial spon- sored by argenx. Stefan Beissert received speaker fees and is consultant for Roche. Aikaterini Patsatsi is consultant for Principia Biopharma, Janssen, Leo, Novartis, AbbVie, Lilly, UCB, Genesis Pharma – Greece. Detlef Zillikens has obtained support for research and development work, lecturing and consulting from AbbVie, argenx, Biotest, Euroimmun, Frese- nius, Janssen and UCB Pharma within the last 3 years. Michael Hertl received unrestricted grants from Topas Therapeu- tics, Hamburg, Germany, argenx, Brussels, Gent, Janssen Cilag, Brussels and Novartis. Giovanna Zambruno is member of the IDMC for a trial on pemphigus (ClinicalTrials.gov Identifier: NCT03334058) sponsored by arGEN-X BVBA and Zwij- naarde, Belgium. Soner Uzun is consultant for Roche. Savas Yayli is investigator for Roche and Principia Biopharma. Miklo ! s Sa !rdy is consultant for Janssen, Novartis, Leo Pharma, Egis, AbbVie and Sanofi. Jose! M. Mascaro ! Jr. has received speaker fees from Clover Soluciones Globales de Marketing, Ferrer Internacional, LEO Pharma Spain, Loki & Dimas, and M.S.D. de Espana S.A. Carlo Pincelli is consultant for PinCell srl and Mylan. Dimitrios Ioannides is investiga- tor in clinical trials for pemphigus sponsored by Principia and GlaxoSmithKline. He is consultant and investigator in trials for other skin diseases for AbbVie, Genesis, Janssen, Lilly, Leo, Novartis and UCB. Fre!de !ric Caux is consultant for Prin- cipia Biopharma and is investigator in clinical trials sponsored by Principia Biopharma and Roche. Dedee F Murrell is consultant for Roche, Principia Bio, Lilly, GSK, Novartis and Sanofi. Marian Dmochowski, Claudia Guenther, Philippe Bernard, Jane Setterfield, Marzia Caproni, De Dipankar, Katarzyna Wozniak, Angelo Valerio Marzano, Daniel Mimouni, Silke Hofmann, Rikke Bech, Yen Loo Lim, Cezary Kowalewski, Kossara Drenovska, Maryam Daneshpazhooh, Giuseppe Cianchini, Claudia Guenther, Reuven Bergman, Branka Marinovic, Catherine Prost Squarcioni, Claudio Feliciani, Richard Groves and Snejina Vassileva have no conflict of interest. JEADV 2020, 34, 1900–1913 © 2020 European Academy of Dermatology and Venereology  14683083, 2020, 9, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jdv.16752 by CochraneItalia, Wiley Online Library on [18/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 1902 Joly et al. Funding statement The guideline update was partly supported by the European Network for Rare skin Disorders (ERN) and the European Academy of Dermatology and Venereology (EADV). Introduction alone.18 Additionally, prednisone could be stopped after only Pemphigus encompasses a group of life-threatening autoimmune 6 months of treatment in around 70% of patients initially trea- bullous diseases characterized by flaccid blisters and erosions of ted with rituximab, leading to a twofold decrease in the number the mucous membranes and/or skin.1–5 The severity of the disease of severe treatment side-effects.18 is based on its progressive course which is accompanied by an For this reason, the Autoimmune blistering diseases task force increased body catabolism with loss of body fluids and proteins of the European Academy of Dermatology and Venereology and secondary bacterial and viral infections which may lead to (EADV) has initiated a thorough update of the previous guideli- sepsis and cardiac failure. Before the advent of systemic corticos- nes for the management of patients with pemphigus.13 teroids, pemphigus was almost always fatal within two years after making the diagnosis. Pathophysiologically, the underlying Methodology of guideline preparation intraepithelial blister formation is caused by IgG autoantibodies To facilitate this process, a writing group, i.e. PJ, BH, AP, SU, against the desmosomal adhesion proteins, desmoglein 3 (Dsg 3) DZ, MH and ES, appointed by the Autoimmune blistering diseases and/or desmoglein 1 (Dsg1), on the cell surface of epidermal ker- task force of the EADV wrote the first version of the updated atinocytes.5,6 Pemphigus is rare, and its incidence has been esti- guidelines following two telephone conferences. Thereafter, all 62 mated to about 2 new patients per 1 million inhabitants per year members of the EADV Autoimmune blistering diseases task force in Central Europe.7,8 Two main clinical variants are known, pem- (notation group) were invited to assign scores (ranging from 0 to phigus vulgaris (PV) and pemphigus foliaceus (PF). The patho- 5 according to the increasing degree of consensus) to each of the genic role of anti-desmoglein 1 and 3 IgG has been clearly recommendations statements using the syntax shown below. This established since the injection of patients’ sera or affinity-purified process identified the statements of major agreement or disagree- IgG from pemphigus sera into neonatal mice reproduces clinically ment. Indicated major statements were then voted upon, and the and immunopathologically the cardinal symptoms of pemphigus degree of consensus was indicated for all statements. Based on the within 24 h.1,5. In most patients, disease activity is closely corre- marks of the notation group, the writing group then prepared a lated with serum levels of desmoglein-reactive autoantibodies.9,10 second and a third version of the guidelines, until each of the Due to its rarity, only few randomized controlled trials (RCT) are statements was given a mark >4 by the voting group. In this pro- available in pemphigus, most of them limited by the low numbers cess, a consensus meeting was held during the annual meeting of of patients enrolled and the lack of statistically significant differ- the EADV in Madrid, Spain, September 2019. The manuscript ences between the study groups. A few studies compared different was then reviewed by the different European patient organiza- doses of prednisone/prednisolone, i.v. corticosteroid pulses versus tions. The revised version of the guideline was finally passed to placebo, azathioprine versus mycophenolate mofetil, and the use the European Dermatology Forum (EDF) for final consensus. of adjuvant treatment with methotrexate, cyclosporine, cyclophos- phamide or high-dose intravenous immunoglobulins.11,12. The combination of systemic corticosteroids (prednisone/pred- Grade of recommendation Syntax nisolone, 1.0–1.5 mg/kg/day) and potentially corticosteroid-spar- Strong recommendation Is recommended ing immunosuppressive drugs, mostly azathioprine and Recommendation May be recommended mycophenolate mofetil, was regarded as standard first-line therapy Recommendation pending May be considered by most clinicians.13 Negative recommendation Is not recommended Over the past 15 years, more than 1,000 pemphigus patients treated with rituximab (monoclonal antibody against the CD20 molecule on B lymphocytes) have been reported in the litera- Initial evaluation of pemphigus ture.14 Rituximab has first been used to treat severe forms (recal- The initial clinical examination should seek basic evidence for the citrant or relapsing types) and later as first-line treatment diagnosis of pemphigus, as well as screening for co-morbidities. reaching complete remissions in 80–90% of patients.15–18 Recently, a randomized controlled trial with newly diagnosed Major objectives patients with PV and PF showed that 89% of patients assigned To confirm the clinical diagnosis of pemphigus. to the rituximab group achieved complete remission off therapy To search for risk factors, severity factors and potential co- versus 34% of patients assigned to treatment with prednisone morbidities based on history and initial clinical evaluation. JEADV 2020, 34, 1900–1913 © 2020 European Academy of Dermatology and Venereology cardini della terapia sono steroide e agenti steroidsparing, azatioprina e micofenolato  14683083, 2020, 9, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jdv.16752 by CochraneItalia, Wiley Online Library on [18/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License EADV pemphigus guideline 1903 To specify the type of initial involvement (skin, mucosa) and oral corticosteroid treatment and evolving complications of its extent. immunosuppressive therapy. To evaluate the prognosis depending on the age of the Evaluate anticipated pregnancy, actively practiced contracep- patient, and general condition. tion (especially if immunosuppressive treatment is being To measure extent and distribution of the lesions by Autoim- considered). mune Bullous Skin Intensity and Severity Score (ABSIS) or Ask for recent drug intake which may potentially induce Pemphigus Disease and Area Index (PDAI). pemphigus, such as angiotensin-converting enzyme (ACE) To measure the impact on patients’ quality of life using der- inhibitors, angiotensin receptor blockers, beta-blockers, matology-specific score (DLQI) and tools specific for cephalosporins, phenylbutazone, pyritinol, thiopronine and autoimmune blistering diseases (ABQOL, TABQOL).19,20 rifampicin. D-penicillamine, which was classically involved To start treatment expecting to achieve disease control and in drug-induced pemphigus, is almost no longer used. It may complete remission as soon as possible. be considered whether to discontinue ACE inhibitors, angio- tensin receptor blockers, beta-blockers, cephalosporins, Professions involved phenylbutazone, pyritinol and thiopronine in the case of a The treatment plan for patients with pemphigus is the responsi- clear temporal association between the occurrence of pem- bility of an experienced dermatologist, usually a hospital-based phigus lesions and the drug intake. dermatologist in a tertiary referral centre, a specialized centre or Evaluation of the impact on quality of life using validated a member of a network. questionnaires, e.g. DLQI, and/or the ABQOL and TABQOL Other health professionals who may have supportive func- questionnaires specific for autoimmune bullous diseases may tions are as follows: be considered (4.2 ! 1.2). The consultant dermatologist in general practice. Check for updated vaccination. Inquire about a possible trip The patient’s general practitioner. in a country in which vaccination with a live vaccine is All other specialists whose expertise is necessary, based on required (to perform this vaccination before using immuno- the patient’s general clinical condition, co-morbidities, such suppressive treatment.) as internists, cardiologists, stomatologists, ophthalmologists, otorhinolaryngologists, gastroenterologists, gynaecologists, Physical examination urologists, proctologists, rheumatologists, oncologists and General. It is recommended to assess the following aspects: psychologists. The extent of skin and mucous membrane lesions, the degree Health nurses in selected cases in which home care is of mucosal damage and functional impairment (dysphagia, dys- required and applicable, e.g. elderly or disabled patients phonia, weight loss, impairment of vision, dyspareunia). It is with residual mucosal or skin lesions following hospitaliza- recommended to quantify the extent of skin and mucosal lesion tion using one of the two validated scoring systems: the Pemphigus Dietician, physiotherapist Disease Area Index (PDAI) or the Autoimmune Bullous Skin Nurse specialist/practitioner Intensity and Severity Score (ABSIS) (4.5 ! 1.0).21,22 It is recommended that a dermatologist experienced in the The patient’s general condition and co-morbidities are as fol- management of pemphigus is involved in setting up the ini- lows: tial treatment plan. Bodyweight. It is recommended that other health professionals (as listed Arterial blood pressure. above) are involved in the management of the patient General condition, co-morbidities (neoplastic, cardiovascu- according to the sites of involvement, disease severity, co- lar, musculoskeletal, diabetes, etc.). morbidities and complications. The majority of authors do not recommend performing the classical Nikolsky’s sign, considering that there are other tools to Clinical examination measure disease activity, and that it is not necessary to induce new lesions in patients who already have skin erosions. Medical history It is recommended to document the following points: Pemphigus vulgaris (PV). Usually begins with oral mucosal Specify the time of first onset of symptoms. lesions: buccal and/or gingival painful, persisting erosions which Specify functional symptoms, i.e. pain, pruritus, intensity of interfere with eating. Less common are non-cicatricial ocular dysphagia, ocular and ENT symptoms, dysuria, anogenital lesions, and nasal, laryngeal, oesophageal, genital and anal ero- problems and weight loss. sions are also possible. Record haematological, oncologic, endocrine, cardiovascular Cutaneous involvement (which may appear several weeks or and infectious medical history to search for risk factors of months after the first appearance of mucosal lesions) presents JEADV 2020, 34, 1900–1913 © 2020 European Academy of Dermatology and Venereology  14683083, 2020, 9, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jdv.16752 by CochraneItalia, Wiley Online Library on [18/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 1904 Joly et al. with flaccid bullae with clear content, developing on non-erythe- and 2/3 perilesional skin (placed in 4% formaldehyde solution) matous skin quickly transforming into postbullous erosions. should be taken for routine histopathological analysis: intraepi- The lesions may be localized or generalized and predominate dermal suprabasal acantholysis in PV or acantholysis at the gran- at seborrhoeic areas (chest, face, scalp, interscapular region) and ular layer in PF. Epidermal acantholysis, suprabasal cleft mechanically stressed regions as well as on the extremities. formation, dyskeratotic keratinocytes, vacuolar change of the The disease is usually not associated with major pruritus. basilar epidermis and epidermal exocytosis of inflammatory cells Fingernail involvement is possible. (PNP). Pemphigus foliaceus (PF). Cutaneous involvement: transient, Direct immunofluorescence microscopy Skin biopsy of perile- flaccid bullae or puff pastry-like exfoliation transforming into sional skin or mucosa (up to 1 cm from a recent lesion), put crusty erosions in seborrhoeic skin areas (chest, scalp, face, inter- into a cryotube for transportation in a cylinder of liquid nitro- scapular region). gen, or in saline (delivery < 36 h) or Michel’s fixative for DIF More extensive cutaneous involvement in sporadic and ende- analysis: IgG and/or C3 deposits at the surface of epidermal/ep- mic pemphigus foliaceus (‘Fogo Selvagem’, Brazilian pemphigus, ithelial keratinocytes. Tunisian pemphigus). No mucosal involvement. The epithelial cell surface staining for in vivo IgG deposition is normally granular or linear as observed by DIF examination. Paraneoplastic pemphigus (PNP). To be suspected in the context Epithelial cell surface deposits can sometimes be associated with of concomitant malignancy, particularly non-Hodgkin’s lym- linear deposits of IgG or C3 along the dermal–epidermal junc- phoma, chronic lymphocytic leukaemia, thymoma or Castle- tion, suggestive of PNP, or pemphigus erythematosus, or the man’s disease. In not all cases, the underlying malignancy has coexistence of pemphigus and pemphigoid. been diagnosed at the time of diagnosis. In specialized laboratories, plucked hairs can be utilized for Moreover, the symptoms of PNP can precede the malignancy. DIF for the diagnosis of pemphigus. Mucosal involvement: initially limited cheilitis and/or ulcerative stomatitis, persisting painful erosions which lead to severe dyspha- Immune serological tests gia. Cicatricial conjunctivitis, keratitis and genital involvement are Indirect immunofluorescence microscopy. common. Pharyngeal involvement is possible; the nasal cavity and oesophagus can also be affected leading to phagodynia. IIF examination of patient’ serum on monkey oesophagus Cutaneous polymorphic lesions with symptoms resembling or human skin to search for autoantibodies against surface mild lichen planus-like to graft-versus-host disease-like, ery- proteins of epidermal keratinocytes. The smooth and reticu- thema multiforme-like, bullous pemphigoid-like or pemphigus lar staining pattern is also referred to as ‘chicken wire’, vulgaris-like eruption. Palmar involvement is common. ‘honeycomb’ or ‘fishnet-like’. Pulmonary involvement (alveolitis, bronchiolitis obliterans, IIF microscopy based on cells that recombinantly express pulmonary fibrosis) is a characteristic and life-threatening com- Dsg 1 and Dsg 3 on the cell surface (Biochip; Euroimmun). plication. In case of atypical presentation, suspected PNP, or the suspi- cion of an unrelated autoimmune bullous disorder, additional Diagnosis immunopathological tests may be performed, such as IIF micro- scopy on rat bladder and/or immunoblot/immunoprecipitation. The diagnosis of pemphigus is based on four criteria 1 Clinical presentation (see 2.3) ELISA Detection of anti-Dsg1 (PF/mucocutaneous PV) and/or 2 Histopathology anti-Dsg3 IgG autoantibodies (Abs) (mucosal PV) by ELISA 3 Direct immunofluorescence (DIF) examination of a perile- (Table 1). sional skin or mucosal biopsy The detection of anti-Dsg IgG autoantibodies by ELISA is 4 Serological detection of autoantibodies against epithelial cell positive in more than 95% of cases. surface by indirect immunofluorescence (IIF) and/or enzyme- In general, ELISA values correlate with the extent and/or linked immunosorbent assay (ELISA Dsg1 and Dsg3). activity of disease (see remark above and prognostic value for It is recommended to perform the following investigations for relapse, helping to guide treatment). the diagnosis: A lesional biopsy for histopathology A perilesional biopsy for DIF examination Table 1 Commercially available ELISAs Serology Desmoglein 1 MBL, Euroimmun Desmoglein 3 MBL, Euroimmun Histopathology Preferentially, a 3- to 5-mm punch biopsy of a Envoplakin (210 kDa) Euroimmun recent ( 15 and ≤ 45 (azathioprine 1 to 2.5 mg/kg/day or mycophenolate mofetil Severe pemphigus: PDAI score > 45.23 2 g/day or mycophenolate sodium 1,440 mg/day), particu- larly in patients with an increased risk of severe corticos- First-line treatment of moderate and severe types of pemphi- teroid side-effect related to an expected prolonged use of gus. Since there is no evidence in the literature that moderate corticosteroids, or if there is no possibility to treat the and severe types of pemphigus must be treated in a different patient with rituximab.1,,29,30 Clinicians should be cautious way, the proposals below refer to both moderate and severe for side-effects, relative and absolute contraindication of types of the disease. systemic corticosteroid therapy (4.8 ! 0.4). The following first-line therapies of moderate and severe pem- In patients with neoplasia (paraneoplastic pemphigus or other phigus are recommended: type of pemphigus associated with cancer), it is recommended Rituximab (two infusions of 1 g two weeks apart) associ- to consult with an oncologist, before the use of anti-CD20 mon- ated with systemic corticosteroids (prednisone 1 mg/kg/ oclonal antibodies (4.9 ! 0.4). day) with a progressive tapering in order to stop corticos- teroids after 6 months (4.9 ! 0.4).18,31,32 Maintenance treatment after the initial cycle of ritux- NB1: Rituximab can be administered as a monotherapy or imab. Patients’ status 6 months after the first cycle of rituximab associated with topical corticosteroids16,27 in patients with abso- (month 6)—In patients who are in complete remission on/off lute contraindication to systemic corticosteroid therapy. therapy at month 6, and initially presented with a severe pem- (4.7 ! 0.9). phigus and/or still have a high rate of anti-Dsg antibodies at Or ( if rituximab is contraindicated or not available): month 3, it may be considered to perform an infusion of Systemic corticosteroid therapy (oral prednisone 1 to 500 mg or 1 g of rituximab at month 6.28,33,34 The optimal dose 1.5 mg/kg/day) alone or associated with an (500 mg to 1 g) has not been determined yet (4.7!0.6). Moderate to severe PV/PF 1st line treatment Rituximab two infusions of 1g two weeks apart, associated with systemic corticosteroids (prednisone 1 mg/ kg/day) with a progressive tapering in order to stop corticosteroids after 6 months or Systemic corticosteroids oral prednisone 1 to 1.5 mg/kg/day alone or associated with an immunosupressive drug (azathioprine 1 to 2.5 mg/kg/d or mycophenolate mofetil 2g/d or mycophenolate sodium 1440 mg/d No disease control at week 3-4 Disease control at week 3-4 Continue previous treatment Initially treated with rituximab and prednisone ! increase the prednisone dose up to 1.5 Maintance treatment at 6 months mg/kg/d Rituximab 500 mg or 1g or ! Intravenous corticosteroids pulses In patients in CR on/off Initially treated with systemic prednisone and (1.0 mg/kg/d) alone ! increase the Initially presented with a severe pemphigus prednisone dose to 1.5 mg/kg/d PLUS add and/or still have a high rate of anti-Dsg rituximab (2x1g) antibodies at Month 3 or ! add immunosupressant (azathioprine Rituximab 2g (two infusions of 1g two weeks 1 to 2.5 mg/kg/d or mycophenolate mofetil apart) 2g/d or mycophenolate sodium 1440 mg/d) In patients without CR on/off therapy Initially treated with prednisone (1,5 mg/kg/d) Maintance treatment at 12 and 18 months alone ! add rituximab (2x1g) Rituximab 500 mg at Month 12 and Month 18 or ! add immunosupressant (azathioprine In patients in CR on/off therapy 1 to 2.5 mg/kg/d or mycophenolate mofetil In particular in patients with still positive anti- 2g/d or mycophenolate sodium 1440 mg/d) desmoglein antibodies Figure 3 Treatment algorithm for moderate and severe pemphigus vulgaris and pemphigus foliaceus. CR, complete remission JEADV 2020, 34, 1900–1913 © 2020 European Academy of Dermatology and Venereology  14683083, 2020, 9, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jdv.16752 by CochraneItalia, Wiley Online Library on [18/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License EADV pemphigus guideline 1909 In patients without complete remission on/off therapy at performed over several days to avoid headache and nausea. month 6, it may be recommended to perform two infusions of Aseptic meningitis is a rare but important side-effect of 1 g two weeks apart (2 g in total) (4.8 ! 0.5).28,33 IVIG treatment which needs to be considered, in particular in patients who commonly experience episodes of migraine. Months 12 and 18 after the first cycle (M12 and M18) —In Even though rare, complete IgA deficiency is a contraindi- patients in complete remission on/off therapy, it is recom- cation for IVIG treatment (4.8 ! 1.0). mended to perform one infusion of rituximab (500 mg) at Intravenous corticosteroid pulses: methylprednisolone 0.5– month 12 and another infusion of 500 mg at month 18, in par- 1 g/day or dexamethasone 100 mg/day over 3 consecutive ticular in patients with still positive anti-Dsg antibodies days in initial intervals of 3–4 weeks (4.2 ! 1.5).37 (4.2 ! 1.4).34,35 Immunoadsorption (minimum of 2 cycles over 3–4 consec- The literature does not provide sufficient evidence to recom- utive days which are performed 4 weeks apart). Contraindi- mend systematic infusions of rituximab after month 18 in cations include severe systemic infections, severe patients in complete remission.36 Monitoring of circulating anti- cardiovascular diseases, hypersensitivity against compo- Dsg antibody ELISA values is necessary at least every six months nents of the immunoadsorption column, treatment with (4.7 ! 1.2). angiotensin-converting enzyme inhibitors and extensive It may be considered to perform additional infusions of ritux- haemorrhagic diathesis (4.3 ! 1.3).39,40 imab as maintenance therapy after month 18 in patients with a re-increase of anti-Dsg antibodies after their initial disappearance Conventional immunosuppressive adjuvant Conventional following the initial infusions of rituximab. (4.6 ! 1.1).34,35,36 adjuvants may be considered as first-line therapy when ritux- imab is not available, or not permitted as first line, or in patients Absence of initial disease control (after 3 to 4 weeks of treat- with contraindications to rituximab. ment). In patients initially treated with rituximab and pred- The main immunosuppressants used as first-line treatments nisone—It is recommended to increase the prednisone dose up in pemphigus are azathioprine and mycophenolate mofetil41 to 1.5 mg/kg/day (4.6 ! 0.7). (4.8 ! 1.2). Or Azathioprine (1–2.5 mg/kg/day). Start first week 50 mg/day Intravenous corticosteroid pulses: methylprednisolone 0.5– to detect idiosyncratic reactions (and in case stop immedi- 1 g/day or dexamethasone 100 mg/day over 3 consecutive days ately), and then raise to desired dose. Even though not pre- in initial intervals of 3–4 weeks (4.3 ! 0.9).37 dictive for idiosyncratic reactions, thiopurine methyl transferase (TMTP) activity should be monitored prior to In patients initially treated with systemic corticosteroids alone (at treatment because the recommendations for azathioprine an initial dose of prednisone, 1.0 mg/kg/day)—It is recommended dosing vary based upon TPMT activity.41 In general, adults to increase the prednisone dose to 1.5 mg/kg/day and add ritux- with pemphigus and high TPMT activity are treated with imab (2 9 1 g), or if there is no possibility to treat the patient normal doses of azathioprine (up to 2.5 mg/kg/day), with rituximab, propose the addition of an immunosuppressant patients with intermediate or low TPMT activity should (azathioprine 1 to 2.5 mg/kg/day or mycophenolate mofetil 2 g/ receive a lower maintenance dose (up to 0.5 to 1.5 mg/kg/ day or mycophenolate sodium 1,440 mg/day) (4.6 ! 0.7). day) depending on level of enzyme activity, and patients with lack of TPMT activity should not be treated with aza- In patients treated with systemic corticosteroids alone (at an initial thioprine. dose of prednisone, 1.5 mg/kg/day)—If there is no possibility to Mycophenolate mofetil (MMF) (2 g/day) or mycopheno- treat the patient with rituximab, it is recommended to add a cor- lic acid (1,440 mg/day). In case of MMF, consider to ticosteroid-sparing agent (azathioprine 1 to 2.5 mg/kg/day or raise daily dose by 1 capsule (500 mg) per week until mycophenolate mofetil 2 g/day or mycophenolate sodium the final dose of 2 g/day for better gastrointestinal toler- 1,440 mg/day). Cyclophosphamide is less frequently used due to ance.29 its potentially severe side-effects (4.9 ! 0.3).1 Methotrexate and cyclosporine are not recommended (4.3 ! 1.2). In patients with severe/refractory pemphigus—Three other treat- If conventional immunosuppressants (which must be used as ments may be recommended (in addition to rituximab, or if first line for regulatory reasons in some countries) fail, rituximab there is no response to rituximab treatment, or in addition to an may be applied as second line. immunosuppressant if there is no possibility to treat the patient Cyclophosphamide (p.o. 50 mg/day or i.v. 500–750 mg/ with rituximab): (4.8 ! 2.3) month) may be considered as third-line treatment in recal- Intravenous immunoglobulins (IVIG) 2 g/kg/cycle (over 2– citrant cases of pemphigus due its potentially severe side-ef- 5 consecutive days every 4 weeks).38 Treatment can also be fects. (4.5 ! 1.1). JEADV 2020, 34, 1900–1913 © 2020 European Academy of Dermatology and Venereology  14683083, 2020, 9, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jdv.16752 by CochraneItalia, Wiley Online Library on [18/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 1910 Joly et al. Additional supportive treatment It is recommended that patients receiving oral corticosteroids Intralesional injections of corticosteroids (triamcinolone ace- or immunosuppressive therapy are vaccinated against seasonal tonide) may be considered for isolated lesions of oral influenza, and pneumococci (4.7 ! 0.6). Other standard vacci- mucosa, lips and skin. nations (tetanus, diphtheria, pertussis, polio...) are recom- Topical adjuvant treatment with super-potent corticosteroids mended to be updated. (clobetasol propionate or triamcinolone acetonide gel) directly to oral erosions may be considered in some patients Monitoring in combination with systemic therapy. Pemphigus often shows a chronic (relapsing) course which The use of baths containing antiseptics such as chlorhexidine requires close monitoring of clinical symptoms and of potential may be recommended in patients with extensive skin lesions. side-effects inherent to chronic immunosuppressive treatment. It is recommended to cover erosive lesions with low adhesive Thus, a multidisciplinary approach is commonly required. wound dressings or local emollients, and compresses. Objectives Analgesics (paracetamol, metamizol and opioids) are recom- To evaluate the efficacy and safety of treatment. mended if required. To plan the gradual reduction of immunosuppressive treat- Gels containing local anaesthetics may be recommended for ment, and the duration of maintenance therapy or its discon- application at the mucosal surfaces. tinuation. Proper dental care is recommended. In clinical studies, it is recommended to use the definition of Extensive dental surgery, e.g. dental implants, is not recom- disease and outcome parameters as described by Murrell mended before the healing of oral lesions. et al.21,22 (4.9 ! 0.9). Nutritional management with the help of a dietician or a nutritionist is recommended if malnutrition is related to oral Approach to be maintained after consolidation phase It is rec- involvement or systemic corticosteroid therapy. ommended to taper the systemic corticosteroids over the next 4–6 months if treatment is associated with rituximab Measures in prolonged corticosteroid therapy (4.8 ! 1.2).18 It is recommended to use vitamin D and calcium supplemen- The following tapering regimen may be recommended: tation at initiation of glucocorticoid treatment to prevent osteoporosis (4.8 ! 0.8). Mild pemphigus Moderate/severe pemphigus It is recommended to use bisphosphonates (i.e. alendronate, Month 1 0.5 mg/kg 1 mg/kg risedronate) in patients at risk (postmenopausal women, Month 2 0.3 mg/kg 0.75 mg/kg men >50 years, with pathological initial osteoporosis screen- Month 3 0.2 mg/kg 0.5 mg/kg ing) to prevent osteoporosis (4.9 ! 0.4). Month 4 !0.1 mg/kg 0.3 mg/kg It may be considered to perform regular ophthalmologic Month 5 – 0.2 mg/kg evaluations during treatment with systemic corticosteroids Month 6 – 0.1 mg/kg (4.8 ! 0.7). It may be recommended to use systemic antifungal, antiviral Beyond the last month of corticosteroid treatment (0.1 mg/ and antibiotic treatments only when clinically indicated kg/day), the attitude is not clearly defined. Three possibilities (4.9 ! 0.2). may be considered: i) stopping corticosteroid treatment after It may be considered to apply H2 blockers or proton pump performing an ACTH test; ii) slow tapering (mg per mg every inhibitors to prevent gastric/duodenal ulcers (4.9 ! 0.4). month or more slowly); iii) maintaining a minimal dose of cor- Based on insufficient evidence, the decision should be indi- ticosteroids (usually between 3 and 6 mg/day), especially in vidualized to the patient, for example in case of additional patients with persistent significant levels of circulating anti-Dsg treatment with non-steroidal anti-inflammatory drugs.42 antibodies (4.5 ! 0.9). It is recommended to offer a psychological support if If systemic corticosteroids are used without rituximab, it is required and to pay attention to depression, sometimes recommended to taper the corticosteroids according to the clini- induced by corticosteroid treatment (4.9 ! 0.3). cal response (4.9 ! 0.2). It may be considered to apply physiotherapy if prolonged No clear consensus could be reached between participants on corticosteroid therapy is required (4.6 ! 0.7). the best corticosteroid tapering regimen: it is proposed to It may be considered to use antithrombotic prophylaxis in decrease prednisone dose by 10% - 25% every 2- 3 weeks until case of high risk of thrombosis (4.5 ! 0.3). 15–25 mg/day (4.0 ! 1.1); once at 15–25 mg/day, no consensus again was reached on the best way of tapering prednisone from Vaccinations Adjuvant immunosuppressants and rituximab 1 mg every 3 to 4 weeks to a more rapid tapering using 5 mg contraindicate the use of live vaccines. steps. It may be recommended to taper the prednisolone dose JEADV 2020, 34, 1900–1913 © 2020 European Academy of Dermatology and Venereology  14683083, 2020, 9, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jdv.16752 by CochraneItalia, Wiley Online Library on [18/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License EADV pemphigus guideline 1911 even slower as the rate of anti-Dsg 1 > 50 IU/mL (situation Clinical examination The clinical follow-up is identical to that where the risk of skin relapse is increased) (4.2 ! 1.2). The per- carried out during the initial assessment, and it should seek to sistence of high levels of anti-Dsg1 antibodies by ELISA has a clarify: positive predictive value for skin relapses, while the persistence If the disease is clinically controlled (mucosal, mucocuta- of anti-Dsg3 IgG does not necessarily predict a mucosal relapse neous or cutaneous lesions); (except if > 130 IU/mL) (4.5 ! 0.8).43 IF adverse effects related to treatment are present or absent; Diabetes mellitus, high blood pressure, cardiac insufficiency Treatment of relapse In patients initially treated with ritux- (corticosteroids); imab and systemic corticosteroids: Respiratory disorders, anaemia, hepatitis (dapsone, If the relapse occurs during tapering of prednisone between methotrexate); month 0 and month 4, it is recommended to re-increase Infections, notably respiratory, hepatitis, CMV reactivation oral corticosteroids (depending on the severity of relapse) (corticosteroids, immunosuppressants); (4.8 ! 0.4). Mental disorders (corticosteroids); If the relapse occurs during tapering of prednisone between Myopathy, osteoporosis, avascular bone necrosis, glaucoma, month 4 and month 6, it is recommended to perform an cataract (glucocorticoids); additional cycle of 2 g of rituximab. In this case, a mainte- Haematological abnormalities (leucopenia), (immunosup- nance infusion of rituximab will not be performed at month pressants). 6 (4.3 ! 1.4). If the relapse occurs after stopping prednisone (after the Serological monitoring of disease activity It is recommended month 6 maintenance infusion of rituximab): few evidence to determine the level of serum autoantibodies at the initiation based data are available from the literature in this particular of treatment, after 3 months and every 3 to 6 months based on situation; we thus recommend an evaluation by an expert in the evolution, or in case of relapse by ELISA: anti-Dsg1 and/or the field of pemphigus (4.8 ! 0.5). Dsg3 IgG (4.5 ! 0.8). If ELISA is not available IIF microscopy In patients not initially treated with rituximab: utilizing monkey oesophagus or Dsg 1/3-expressing cells can If the relapse occurs during tapering of the corticosteroid, it beused (4.7 ! 0.7). is recommended to apply rituximab (1 g two weeks apart) Overall, serum concentrations of IgG autoantibodies against (4.9 ! 0.4). Dsg1 and, to a lesser degree, Dsg3 correlate with the clinical In patients with contraindications to rituximab or when activity of pemphigus and may thus help in therapeutic deci- rituximab is not available, it is recommended to re-increase sion-making. Indeed, due to their poor specificity, anti-Dsg3 the corticosteroids dose and add azathioprine (1 to 2.5 mg/ Abs should be used with caution for the management of pem- kg/day), or mycophenolate mofetil (2 g/day) or mycophe- phigus, since only high titres are good predictor for the occur- nolate sodium (1,440 mg/day) until disease control is rence of a relapse.34,43 achieved, before tapering of systemic corticosteroids Discontinuation of treatment (4.9 ! 0.9). Discontinuation of treatment is primarily based on the clini- cal symptoms in combination with findings of Dsg ELISA Scheduling and content of consultations and/or IIF microscopy (4.9 ! 0.4).25,43 Evaluation of the efficacy of treatment is primarily based on clin- Discontinuation of systemic corticosteroids may be consid- ical symptoms. ered after performing an ACTH test in patients in complete The frequency of disease management (physical examination, remission on minimal therapy (prednisolone or equivalent additional examinations) must be adapted: at ≤ 10 mg/day) with negative circulating anti-Dsg antibod- To the patient’s clinical condition; ies (4.4 ! 1.0). To the severity and disease course during treatment using It is recommended to omit the corticosteroid-sparing adju- clinical scores (ABSIS or PDAI); vants 6–12 months after achieving complete remission on To the therapeutics used (monitoring, tolerance, side-effects). therapy (4.6 ! 1.0). Follow-up visits are recommended every 2–4 weeks until dis- ease control is achieved. (4.7 ! 0.7). Then, follow-up visits are recommended every 4–8 weeks until corticosteroids have Possible sequelae been omitted (4.5 ! 0.8). Pemphigus may cause sequelae due to the involvement of skin, Thereafter, follow-up visits are recommended every 8– conjunctivae, oral, pharyngeal, laryngeal, oesophageal, anogeni- 16 weeks until complete remission off therapy is achieved tal and anal mucosa but also due to side-effects of treatment, and serum anti-Dsg antibodies are normalized justifying request for recognition or help from departmental dis- (4.8 ! 0.5). ability centres. JEADV 2020, 34, 1900–1913 © 2020 European Academy of Dermatology and Venereology DSG1 CORRELA CON ATTIVITA’ DI MALATTIA  14683083, 2020, 9, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jdv.16752 by CochraneItalia, Wiley Online Library on [18/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 1912 Joly et al. Information for patients 8 H€ ubner F, Recke A, Zillikens D, Linder R, Schmidt E. Prevalence and age distribution of pemphigus and pemphigoid diseases in germany. J Invest It is recommended to inform patients and their families about Dermatol. 2016; 136: 2495–2498. the disease, its clinical course and prognosis, treatment, relapse 9 Harman KE, Seed PT, Gratian MJ, Bhogal BS, Challacombe SJ, Black signs, possible adverse events associated with treatment MM. The severity of cutaneous and oral pemphigus is related to desmo- (5.0 ! 0.0). glein 1 and 3 antibody levels. Br J Dermatol. 2001; 144: 775–780. 10 Schmidt E, D€ahnrich C, Rosemann A et al. Novel ELISA systems for anti- Written information is available by the EADV webpage and bodies to desmoglein 1 and 3: correlation of disease activity with serum the patient support groups. autoantibody levels in individual pemphigus patients. Exp Dermatol 2010; It is recommended to inform patients about patient support 19: 458–463. groups for pemphigus (see list below) (4.9 ! 1.0). 11 Martin LK, Werth V, Villanueva E, Segall J, Murrell DF. Interventions for pemphigus vulgaris and pemphigus foliaceus. Cochrane Database Syst Rev The purpose of these associations is to promote knowledge 2009; 1: CD006263. about the disease, provide comfort and share the experience of 12 Martin LK, Werth VP, Villaneuva EV, Murrell DF. A systematic review of patients regarding daily life, and to provide information dissemi- randomized controlled trials for pemphigus vulgaris and pemphigus foli- nation. It may contribute to a better overall management of the aceus. J Am Acad Dermatol 2011; 64: 903–908. 13 Hertl M, Jedlickova H, Karpati S et al. Pemphigus. S2 Guideline for diag- disease by promoting cooperation between patients, patient nosis and treatment–guided by the European Dermatology Forum (EDF) associations and health professionals. Patients are also informed in cooperation with the European Academy of Dermatology and Venere- about referral centres. ology (EADV). J Eur Acad Dermatol Venereol JEADV 2015; 29 :405–414. It may be recommended to alert patients about potential trig- 14 Tavakolpour S, Mahmoudi H, Balighi K, Abedini R, Daneshpazhooh M. Sixteen-year history of rituximab therapy for 1085 pemphigus vulgaris ger factors such as certain drugs, operations, infections, radia- patients: A systematic review. Int Immunopharmacol 2018; 54: 131–138. tion, and sun exposure (4.8 ! 0.5). 15 Schmidt E, Goebeler M Zillikens D. Rituximab in severe pemphigus. Ann It is not recommended to propose dietetic restrictions N Y Acad Sci 2009; 1173: 683–691. 16 Joly P, Mouquet H, Roujeau J-C et al. A single cycle of rituximab for the (4.3 ! 1.3). treatment of severe pemphigus. N Engl J Med 2007; 357: 545–552. List of pemphigus support groups 17 Ahmed AR, Spigelman Z, Cavacini LA, Posner MR. Treatment of pem- phigus vulgaris with rituximab and intravenous immune globulin. N Engl International Pemphigus and Pemphigoid foundation: www. J Med 2006; 355: 1772–1779. pemphigus.org 18 Joly P, Maho-Vaillant M, Prost-Squarcioni C et al. First-line rituximab Association Pemphigus Pemphigo€ıde-France: www.pemphi combined with short-term prednisone versus prednisone alone for the gus.asso.fr treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel- group, open-label randomised trial. Lancet Lond Engl 2017; 389: 2031– Pemfriends: www.pemfriends.co.uk 2040. Pemphigus und Pemphigoid Selbsthilfegruppe e. V.: www.pe 19 Sebaratnam DF, Hanna AM, Chee S et al. Development of a quality-of- mphigus-pemphigoid-selbsthilfe.de life instrument for autoimmune bullous disease: the Autoimmune Bul- lous Disease Quality of Life questionnaire. JAMA Dermatol 2013; 149: Associazione Nazionale Pemfigo/Pemfigoide Italy: www.pemf 1186–1191. igo.org 20 Tjokrowidjaja A, Daniel BS, Frew JW et al. The development and valida- Netwerk Nederland Pemphigus en Pemfigo€ıd: www.pemphi tion of the treatment of autoimmune bullous disease quality of life ques- gus.nl tionnaire, a tool to measure the quality of life impacts of treatments used in patients with autoimmune blistering disease. Br J Dermatol 2013; 169: Pemfigus Hastaları Yardımlas!ma ve Dayanıs!ma Derne$gi: 1000–1006. www.pemfigus.org.tr 21 Murrell DF, Dick S, Ahmed AR et al. Consensus statement on definitions of disease, end points, and therapeutic response for pemphigus. J Am References Acad Dermatol 2008; 58: 1043–1046. 1 Schmidt E, Kasperkiewicz M, Joly P. Pemphigus. Lancet Lond Engl 2019; 22 H!ebert V, Boulard C, Houivet E et al. Large international validation of 394: 882–894. ABSIS and PDAI pemphigus severity scores. J Invest Dermatol. 2019; 139: 2 Joly P, Litrowski N. Pemphigus group (vulgaris, vegetans, foliaceus, her- 31–37. petiformis, brasiliensis). Clin Dermatol. 2011; 29: 432–436. 23 Boulard C, Duvert Lehembre S, Picard-Dahan C et al. Calculation of cut- 3 Kneisel A, Hertl M. Autoimmune bullous skin diseases. Part 1: Clinical off values based on the Autoimmune Bullous Skin Disorder Intensity manifestations. J Dtsch Dermatol Ges J Ger Soc Dermatol JDDG 2011; 9: Score (ABSIS) and Pemphigus Disease Area Index (PDAI) pemphigus 844–856; quiz 857. scoring systems for defining moderate, significant and extensive types of 4 Kneisel A, Hertl M. Autoimmune bullous skin diseases. Part 2: diagnosis pemphigus. Br J Dermatol 2016; 175:142–149. and therapy. J Dtsch Dermatol Ges J Ger Soc Dermatol JDDG 2011; 9: 927– 24 Basset N, Guillot B, Michel B, Meynadier J Guilhou JJ. Dapsone as initial 947. treatment in superficial pemphigus. Report of nine cases. Arch Dermatol 5 Kasperkiewicz M, Ellebrecht CT, Takahashi H et al. Pemphigus. Nat Rev 1987; 123: 783–785. Dis Primer 2017; 3: 17026. 25 Almugairen N, Hospital V, Bedane C et al. Assessment of the rate of 6 Amagai M, Klaus-Kovtun V, Stanley JR. Autoantibodies against a novel long-term complete remission off therapy in patients with pemphigus epithelial cadherin in pemphigus vulgaris, a disease of cell adhesion. Cell treated with different regimens including medium- and high-dose corti- 1991; 67: 869–877. costeroids. J Am Acad Dermatol 2013; 69: 583–588. 7 Jelti L, Cordel N, Gillibert A et al. Incidence and mortality of pemphigus 26 Werth VP, Fivenson D, Pandya AG et al. Multicenter randomized, dou- in France. J Invest Dermatol. 2019; 139: 469–473. ble-blind, placebo-controlled, clinical trial of dapsone as a JEADV 2020, 34, 1900–1913 © 2020 European Academy of Dermatology and Venereology  14683083, 2020, 9, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jdv.16752 by CochraneItalia, Wiley Online Library on [18/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License EADV pemphigus guideline 1913 glucocorticoid-sparing agent in maintenance-phase pemphigus vulgaris. first-line therapy: A post hoc analysis of a randomized clinical trial. JAMA Arch Dermatol 2008; 144: 25–32. Dermatol 2020; 156: 1–8. 27 Ingen-Housz-Oro S, Valeyrie-Allanore L, Cosnes A et al. First-line treat- 35 Colliou N, Picard D, Caillot F et al. Long-term remissions of severe pem- ment of pemphigus vulgaris with a combination of rituximab and high- phigus after rituximab therapy are associated with prolonged failure of potency topical corticosteroids. JAMA Dermatol 2015; 151: 200–203. desmoglein B cell response. Sci Transl Med 2013; 5: 175ra30. 28 Cianchini G, Lupi F, Masini C, Corona R, Puddu P, De Pit#a O. Therapy 36 Sanchez J, Ingen-Housz-Oro S, Chosidow O, Antonicelli F Bernard P. with rituximab for autoimmune pemphigus: results from a single-center Rituximab as Single Long-term Maintenance Therapy in Patients With observational study on 42 cases with long-term follow-up. J Am Acad Difficult-to-Treat Pemphigus. JAMA Dermatol 2018; 01: 363–365. Dermatol 2012; 67: 617–622. 37 Werth VP. Treatment of pemphigus vulgaris with brief, high-dose intra- 29 Beissert S, Mimouni D, Kanwar AJ, Solomons N, Kalia V, Anhalt GJ. venous glucocorticoids. Arch Dermatol 1996; 132: 1435–1439. Treating pemphigus vulgaris with prednisone and mycophenolate mofe- 38 Amagai M, Ikeda S, Shimizu H et al. A randomized double-blind trial of til: a multicenter, randomized, placebo-controlled trial. J Invest Dermatol intravenous immunoglobulin for pemphigus. J Am Acad Dermatol 2009; 2010; 130: 2041–2048. 60: 595–603. 30 Beissert S, Werfel T, Frieling U et al. A comparison of oral methylpred- 39 Behzad M, M€ obs C, Kneisel A et al. Combined treatment with nisolone plus azathioprine or mycophenolate mofetil for the treatment of immunoadsorption and rituximab leads to fast and prolonged clinical pemphigus. Arch Dermatol 2006; 142: 1447–1454. remission in difficult-to-treat pemphigus vulgaris. Br J Dermatol 2012; 31 H!ebert V, Vermeulin T, Tanguy L et al. Comparison of real costs in the 166: 844–852. French healthcare system in newly diagnosed patients with pemphigus for 40 Kasperkiewicz M, Shimanovich I, Meier M et al. Treatment of severe first-line treatment with rituximab vs. standard corticosteroid regimen: pemphigus with a combination of immunoadsorption, rituximab, pulsed data from a national multicentre trial. Br J Dermatol. 2019; 183: 121–127. dexamethasone and azathioprine/mycophenolate mofetil: a pilot study of https://doi.org/10.1111/bjd.18563. Epub ahead of print. 23 patients. Br J Dermatol 2012; 166: 154–160. 32 Chen DM, Odueyungbo A, Csinady E et al. Rituximab is an effective 41 Meggitt SJ, Anstey AV, Mohd Mustapa MF, Reynolds NJ Wakelin S. Bri- treatment in patients with pemphigus vulgaris and demonstrates a ster- tish Association of Dermatologists’ guidelines for the safe and effective oid-sparing effect. Br J Dermatol. 2019; 182: 1111–1119. https://doi.org/ prescribing of azathioprine 2011. Br J Dermatol 2011; 165: 711–734. 10.1111/bjd.18482. Epub ahead of print. 42 Guslandi M. Steroid ulcers: Any news? World J Gastrointest Pharmacol 33 Jelti L, Prost-Squarcioni C, Ingen-Housz-Oro S et al. Update of the Ther 2013; 4: 39–40. French recommendations for the management of pemphigus. Ann Der- 43 Abasq C, Mouquet H, Gilbert D et al. ELISA testing of anti-desmoglein 1 matol Venereol 2019; 146: 279–286. and 3 antibodies in the management of pemphigus. Arch Dermatol. 2009; 34 Mignard C, Maho-Vaillant M, Golinski ML et al. Factors associated with 145:529–535. short-term relapse in patients with pemphigus who receive rituximab as JEADV 2020, 34, 1900–1913 © 2020 European Academy of Dermatology and Venereology