Abstract
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, 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 Venereology (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.
| Original language | English |
|---|---|
| Journal | Journal of the European Academy of Dermatology and Venereology |
| Volume | 34 |
| Issue number | 9 |
| Pages (from-to) | 1900-1913 |
| Number of pages | 14 |
| ISSN | 0926-9959 |
| DOIs | |
| Publication status | Published - 01.09.2020 |
Funding
International Pemphigus and Pemphigoid foundation: www.pemphigus.org Association Pemphigus Pemphigo?de-France: www.pemphigus.asso.fr Pemfriends: www.pemfriends.co.uk Pemphigus und Pemphigoid Selbsthilfegruppe e. V.: www.pemphigus-pemphigoid-selbsthilfe.de Associazione Nazionale Pemfigo/Pemfigoide Italy: www.pemfigo.org Netwerk Nederland Pemphigus en Pemfigo?d: www.pemphigus.nl Pemfigus Hastalar? Yard?mla?ma ve Dayan??ma Derne?i: www.pemfigus.org.tr It is recommended to inform patients and their families about the disease, its clinical course and prognosis, treatment, relapse signs, possible adverse events associated with treatment (5.0???0.0). Written information is available by the EADV webpage and the patient support groups. It is recommended to inform patients about patient support groups for pemphigus (see list below) (4.9???1.0). The purpose of these associations is to promote knowledge about the disease, provide comfort and share the experience of patients regarding daily life, and to provide information dissemination. It may contribute to a better overall management of the disease by promoting cooperation between patients, patient associations and health professionals. Patients are also informed about referral centres. It may be recommended to alert patients about potential trigger factors such as certain drugs, operations, infections, radiation, and sun exposure (4.8???0.5). It is not recommended to propose dietetic restrictions (4.3???1.3). International Pemphigus and Pemphigoid foundation: www.pemphigus.org Association Pemphigus Pemphigo?de-France: www.pemphigus.asso.fr Pemfriends: www.pemfriends.co.uk Pemphigus und Pemphigoid Selbsthilfegruppe e. V.: www.pemphigus-pemphigoid-selbsthilfe.de Associazione Nazionale Pemfigo/Pemfigoide Italy: www.pemfigo.org Netwerk Nederland Pemphigus en Pemfigo?d: www.pemphigus.nl Pemfigus Hastalar? Yard?mla?ma ve Dayan??ma Derne?i: www.pemfigus.org.tr IIF examination of patient? serum on monkey oesophagus or human skin to search for autoantibodies against surface proteins of epidermal keratinocytes. The smooth and reticular staining pattern is also referred to as ?chicken wire?, ?honeycomb? or ?fishnet-like?. IIF microscopy based on cells that recombinantly express Dsg 1 and Dsg 3 on the cell surface (Biochip; Euroimmun). In case of atypical presentation, suspected PNP, or the suspicion of an unrelated autoimmune bullous disorder, additional immunopathological tests may be performed, such as IIF microscopy on rat bladder and/or immunoblot/immunoprecipitation. IIF examination of patient? serum on monkey oesophagus or human skin to search for autoantibodies against surface proteins of epidermal keratinocytes. The smooth and reticular staining pattern is also referred to as ?chicken wire?, ?honeycomb? or ?fishnet-like?. IIF microscopy based on cells that recombinantly express Dsg 1 and Dsg 3 on the cell surface (Biochip; Euroimmun). In case of atypical presentation, suspected PNP, or the suspicion of an unrelated autoimmune bullous disorder, additional immunopathological tests may be performed, such as IIF microscopy on rat bladder and/or immunoblot/immunoprecipitation. Clinical presentation (see 2.3) Histopathology Direct immunofluorescence (DIF) examination of a perilesional skin or mucosal biopsy Serological detection of autoantibodies against epithelial cell surface by indirect immunofluorescence (IIF) and/or enzyme-linked immunosorbent assay (ELISA Dsg1 and Dsg3). It is recommended to perform the following investigations for the diagnosis: A lesional biopsy for histopathology A perilesional biopsy for DIF examination Serology Preferentially, a 3- to 5-mm punch biopsy of a recent (<24?h) vesicle or 1/3 of the peripheral portion of a blister and 2/3 perilesional skin (placed in 4% formaldehyde solution) should be taken for routine histopathological analysis: intraepidermal suprabasal acantholysis in PV or acantholysis at the granular layer in PF. Epidermal acantholysis, suprabasal cleft formation, dyskeratotic keratinocytes, vacuolar change of the basilar epidermis and epidermal exocytosis of inflammatory cells (PNP). Skin biopsy of perilesional skin or mucosa (up to 1?cm from a recent lesion), put into a cryotube for transportation in a cylinder of liquid nitrogen, or in saline (delivery?<?36?h) or Michel's fixative for DIF analysis: IgG and/or C3 deposits at the surface of epidermal/epithelial keratinocytes. The epithelial cell surface staining for in vivo IgG deposition is normally granular or linear as observed by DIF examination. Epithelial cell surface deposits can sometimes be associated with linear deposits of IgG or C3 along the dermal?epidermal junction, suggestive of PNP, or pemphigus erythematosus, or the coexistence of pemphigus and pemphigoid. In specialized laboratories, plucked hairs can be utilized for DIF for the diagnosis of pemphigus. IIF examination of patient? serum on monkey oesophagus or human skin to search for autoantibodies against surface proteins of epidermal keratinocytes. The smooth and reticular staining pattern is also referred to as ?chicken wire?, ?honeycomb? or ?fishnet-like?. IIF microscopy based on cells that recombinantly express Dsg 1 and Dsg 3 on the cell surface (Biochip; Euroimmun). In case of atypical presentation, suspected PNP, or the suspicion of an unrelated autoimmune bullous disorder, additional immunopathological tests may be performed, such as IIF microscopy on rat bladder and/or immunoblot/immunoprecipitation. Detection of anti-Dsg1 (PF/mucocutaneous PV) and/or anti-Dsg3 IgG autoantibodies (Abs) (mucosal PV) by ELISA (Table?1). The detection of anti-Dsg IgG autoantibodies by ELISA is positive in more than 95% of cases. In general, ELISA values correlate with the extent and/or activity of disease (see remark above and prognostic value for relapse, helping to guide treatment). It is recommended to make the diagnosis of PV/PF on the following findings: Compatible clinical picture plus positive DIF examination If DIF examination is negative, it is recommended to repeat the biopsy for DIF microscopy. If a new biopsy is not available, or still negative, it is recommended to make the diagnosis of pemphigus in patients with: Compatible clinical picture plus corresponding typical histological picture of acantholysis plus significant positive IIF on monkey oesophagus: (4.2???1.3). In this particular case, the presence of a typical histological picture of acantholysis is absolutely necessary to exclude an erythema multiforme major. Compatible clinical picture and histopathology plus serum reactivity against recombinant Dsg 1 and/or 3 by ELISA or IIF on cells that express recombinant Dsg1/Dsg3 (4.7???0.8). In case of atypical clinical features (i.e. progressive stomatitis, lichenoid or erythema multiforme-like skin lesions), the diagnosis of PNP must be considered. Lesional histopathology frequently shows dyskeratosis and a lichenoid interface dermatitis in addition to acantholysis. DIF examination may reveal linear staining of IgG/C3 at the dermal?epidermal junction in addition to intercellular staining of the epithelium. IIF examination of serum on rat bladder shows cell surface staining of epithelial cells, corresponding to reactivity against plakin proteins. Immunoblot with epidermal extracts shows IgG against envoplakin (210?kDa) and periplakin (190?kDa), Dsg3 (130?kDa), and more rarely Dsg1 (160?kDa). Anti-desmocollin Abs can be occasionally detected, usually in association with anti-envoplakin Abs (Table?1) (4.6???1.2). Alpha-2-macroglobulin-like-1 (A2ML-1, 170?kDa) can only be detected under non-denaturing condition?non-reducing condition. Immunoblot with extracts from cultured keratinocytes reveals IgG against envoplakin (210?kDa), periplakin (190?kDa) and desmoplakin I/II (210 and 250?kDa). Immunoprecipitation with keratinocyte extracts is not performed in clinical practice. It can reveal IgG autoantibodies against envoplakin (210?kDa) and periplakin (190?kDa), Dsg3 (130?kDa), Dsg1 (160?kDa), desmocollins, desmoplakins I and II, BP230/BPAG1, plectin (500?kDa) and alpha-2-macroglobulin-like-1 (A2ML-1, 170?kDa) (4.6???1.5). It is recommended to perform the following investigations before treatment is initiated: (4.8???0.9) Complete blood count; Creatinine, blood electrolytes; Transaminases, gamma GT, alkaline phosphatase; Total serum protein, albumin; Fasting serum glucose; Hepatitis B, C and HIV; Serum IgA (in case of intravenous immunoglobulin (IVIG) treatment); G6PD activity, bilirubin and reticulocytes (in case of treatment with dapsone) Thiopurine methyltransferase (TPMT) activity (in case of treatment with azathioprine) Ocular examination to exclude glaucoma and cataract It may be recommended to perform the following investigations before treatment is initiated: (4.8???1.2) Chest X-ray (in case of elevated risk of tuberculosis) Quantiferon test or PPD (in case of elevated risk of tuberculosis). Abdominal sonography ? HCG to exclude pregnancy in females of childbearing age; Osteodensitometry prior to glucocorticoid treatment; Usually begins with oral mucosal lesions: buccal and/or gingival painful, persisting erosions which interfere with eating. Less common are non-cicatricial ocular lesions, and nasal, laryngeal, oesophageal, genital and anal erosions are also possible. Cutaneous involvement (which may appear several weeks or months after the first appearance of mucosal lesions) presents with flaccid bullae with clear content, developing on non-erythematous skin quickly transforming into postbullous erosions. The lesions may be localized or generalized and predominate at seborrhoeic areas (chest, face, scalp, interscapular region) and mechanically stressed regions as well as on the extremities. The disease is usually not associated with major pruritus. Fingernail involvement is possible. It is recommended to assess the following aspects: The extent of skin and mucous membrane lesions, the degree of mucosal damage and functional impairment (dysphagia, dysphonia, weight loss, impairment of vision, dyspareunia). It is recommended to quantify the extent of skin and mucosal lesion using one of the two validated scoring systems: the Pemphigus Disease Area Index (PDAI) or the Autoimmune Bullous Skin Intensity and Severity Score (ABSIS) (4.5???1.0).21,22 The patient's general condition and co-morbidities are as follows: Bodyweight. Arterial blood pressure. General condition, co-morbidities (neoplastic, cardiovascular, musculoskeletal, diabetes, etc.). The majority of authors do not recommend performing the classical Nikolsky?s sign, considering that there are other tools to measure disease activity, and that it is not necessary to induce new lesions in patients who already have skin erosions. Usually begins with oral mucosal lesions: buccal and/or gingival painful, persisting erosions which interfere with eating. Less common are non-cicatricial ocular lesions, and nasal, laryngeal, oesophageal, genital and anal erosions are also possible. Cutaneous involvement (which may appear several weeks or months after the first appearance of mucosal lesions) presents with flaccid bullae with clear content, developing on non-erythematous skin quickly transforming into postbullous erosions. The lesions may be localized or generalized and predominate at seborrhoeic areas (chest, face, scalp, interscapular region) and mechanically stressed regions as well as on the extremities. The disease is usually not associated with major pruritus. Fingernail involvement is possible. Cutaneous involvement: transient, flaccid bullae or puff pastry-like exfoliation transforming into crusty erosions in seborrhoeic skin areas (chest, scalp, face, interscapular region). More extensive cutaneous involvement in sporadic and endemic pemphigus foliaceus (?Fogo Selvagem?, Brazilian pemphigus, Tunisian pemphigus). No mucosal involvement. To be suspected in the context of concomitant malignancy, particularly non-Hodgkin's lymphoma, chronic lymphocytic leukaemia, thymoma or Castleman?s disease. In not all cases, the underlying malignancy has been diagnosed at the time of diagnosis. Moreover, the symptoms of PNP can precede the malignancy. Mucosal involvement: initially limited cheilitis and/or ulcerative stomatitis, persisting painful erosions which lead to severe dysphagia. Cicatricial conjunctivitis, keratitis and genital involvement are common. Pharyngeal involvement is possible; the nasal cavity and oesophagus can also be affected leading to phagodynia. Cutaneous polymorphic lesions with symptoms resembling mild lichen planus-like to graft-versus-host disease-like, erythema multiforme-like, bullous pemphigoid-like or pemphigus vulgaris-like eruption. Palmar involvement is common. Pulmonary involvement (alveolitis, bronchiolitis obliterans, pulmonary fibrosis) is a characteristic and life-threatening complication. It is recommended to document the following points: Specify the time of first onset of symptoms. Specify functional symptoms, i.e. pain, pruritus, intensity of dysphagia, ocular and ENT symptoms, dysuria, anogenital problems and weight loss. Record haematological, oncologic, endocrine, cardiovascular and infectious medical history to search for risk factors of oral corticosteroid treatment and evolving complications of immunosuppressive therapy. Evaluate anticipated pregnancy, actively practiced contraception (especially if immunosuppressive treatment is being considered). Ask for recent drug intake which may potentially induce pemphigus, such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, beta-blockers, cephalosporins, phenylbutazone, pyritinol, thiopronine and rifampicin. D-penicillamine, which was classically involved in drug-induced pemphigus, is almost no longer used. It may be considered whether to discontinue ACE inhibitors, angiotensin receptor blockers, beta-blockers, cephalosporins, phenylbutazone, pyritinol and thiopronine in the case of a clear temporal association between the occurrence of pemphigus lesions and the drug intake. Evaluation of the impact on quality of life using validated questionnaires, e.g. DLQI, and/or the ABQOL and TABQOL questionnaires specific for autoimmune bullous diseases may be considered (4.2???1.2). Check for updated vaccination. Inquire about a possible trip in a country in which vaccination with a live vaccine is required (to perform this vaccination before using immunosuppressive treatment.) It is recommended to assess the following aspects: The extent of skin and mucous membrane lesions, the degree of mucosal damage and functional impairment (dysphagia, dysphonia, weight loss, impairment of vision, dyspareunia). It is recommended to quantify the extent of skin and mucosal lesion using one of the two validated scoring systems: the Pemphigus Disease Area Index (PDAI) or the Autoimmune Bullous Skin Intensity and Severity Score (ABSIS) (4.5???1.0).21,22 The patient's general condition and co-morbidities are as follows: Bodyweight. Arterial blood pressure. General condition, co-morbidities (neoplastic, cardiovascular, musculoskeletal, diabetes, etc.). The majority of authors do not recommend performing the classical Nikolsky?s sign, considering that there are other tools to measure disease activity, and that it is not necessary to induce new lesions in patients who already have skin erosions. Usually begins with oral mucosal lesions: buccal and/or gingival painful, persisting erosions which interfere with eating. Less common are non-cicatricial ocular lesions, and nasal, laryngeal, oesophageal, genital and anal erosions are also possible. Cutaneous involvement (which may appear several weeks or months after the first appearance of mucosal lesions) presents with flaccid bullae with clear content, developing on non-erythematous skin quickly transforming into postbullous erosions. The lesions may be localized or generalized and predominate at seborrhoeic areas (chest, face, scalp, interscapular region) and mechanically stressed regions as well as on the extremities. The disease is usually not associated with major pruritus. Fingernail involvement is possible. Cutaneous involvement: transient, flaccid bullae or puff pastry-like exfoliation transforming into crusty erosions in seborrhoeic skin areas (chest, scalp, face, interscapular region). More extensive cutaneous involvement in sporadic and endemic pemphigus foliaceus (?Fogo Selvagem?, Brazilian pemphigus, Tunisian pemphigus). No mucosal involvement. To be suspected in the context of concomitant malignancy, particularly non-Hodgkin's lymphoma, chronic lymphocytic leukaemia, thymoma or Castleman?s disease. In not all cases, the underlying malignancy has been diagnosed at the time of diagnosis. Moreover, the symptoms of PNP can precede the malignancy. Mucosal involvement: initially limited cheilitis and/or ulcerative stomatitis, persisting painful erosions which lead to severe dysphagia. Cicatricial conjunctivitis, keratitis and genital involvement are common. Pharyngeal involvement is possible; the nasal cavity and oesophagus can also be affected leading to phagodynia. Cutaneous polymorphic lesions with symptoms resembling mild lichen planus-like to graft-versus-host disease-like, erythema multiforme-like, bullous pemphigoid-like or pemphigus vulgaris-like eruption. Palmar involvement is common. Pulmonary involvement (alveolitis, bronchiolitis obliterans, pulmonary fibrosis) is a characteristic and life-threatening complication. The treatment plan for patients with pemphigus is the responsibility of an experienced dermatologist, usually a hospital-based dermatologist in a tertiary referral centre, a specialized centre or a member of a network. Other health professionals who may have supportive functions are as follows: The consultant dermatologist in general practice. The patient's general practitioner. All other specialists whose expertise is necessary, based on the patient?s general clinical condition, co-morbidities, such as internists, cardiologists, stomatologists, ophthalmologists, otorhinolaryngologists, gastroenterologists, gynaecologists, urologists, proctologists, rheumatologists, oncologists and psychologists. Health nurses in selected cases in which home care is required and applicable, e.g. elderly or disabled patients with residual mucosal or skin lesions following hospitalization Dietician, physiotherapist Nurse specialist/practitioner It is recommended that a dermatologist experienced in the management of pemphigus is involved in setting up the initial treatment plan. It is recommended that other health professionals (as listed above) are involved in the management of the patient according to the sites of involvement, disease severity, co-morbidities and complications. The initial clinical examination should seek basic evidence for the diagnosis of pemphigus, as well as screening for co-morbidities. To confirm the clinical diagnosis of pemphigus. To search for risk factors, severity factors and potential co-morbidities based on history and initial clinical evaluation. To specify the type of initial involvement (skin, mucosa) and its extent. To evaluate the prognosis depending on the age of the patient, and general condition. To measure extent and distribution of the lesions by Autoimmune Bullous Skin Intensity and Severity Score (ABSIS) or Pemphigus Disease and Area Index (PDAI). To measure the impact on patients? quality of life using dermatology-specific score (DLQI) and tools specific for autoimmune blistering diseases (ABQOL, TABQOL).19,20 To start treatment expecting to achieve disease control and complete remission as soon as possible. The treatment plan for patients with pemphigus is the responsibility of an experienced dermatologist, usually a hospital-based dermatologist in a tertiary referral centre, a specialized centre or a member of a network. Other health professionals who may have supportive functions are as follows: The consultant dermatologist in general practice. The patient's general practitioner. All other specialists whose expertise is necessary, based on the patient?s general clinical condition, co-morbidities, such as internists, cardiologists, stomatologists, ophthalmologists, otorhinolaryngologists, gastroenterologists, gynaecologists, urologists, proctologists, rheumatologists, oncologists and psychologists. Health nurses in selected cases in which home care is required and applicable, e.g. elderly or disabled patients with residual mucosal or skin lesions following hospitalization Dietician, physiotherapist Nurse specialist/practitioner It is recommended that a dermatologist experienced in the management of pemphigus is involved in setting up the initial treatment plan. It is recommended that other health professionals (as listed above) are involved in the management of the patient according to the sites of involvement, disease severity, co-morbidities and complications. It is recommended to document the following points: Specify the time of first onset of symptoms. Specify functional symptoms, i.e. pain, pruritus, intensity of dysphagia, ocular and ENT symptoms, dysuria, anogenital problems and weight loss. Record haematological, oncologic, endocrine, cardiovascular and infectious medical history to search for risk factors of oral corticosteroid treatment and evolving complications of immunosuppressive therapy. Evaluate anticipated pregnancy, actively practiced contraception (especially if immunosuppressive treatment is being considered). Ask for recent drug intake which may potentially induce pemphigus, such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, beta-blockers, cephalosporins, phenylbutazone, pyritinol, thiopronine and rifampicin. D-penicillamine, which was classically involved in drug-induced pemphigus, is almost no longer used. It may be considered whether to discontinue ACE inhibitors, angiotensin receptor blockers, beta-blockers, cephalosporins, phenylbutazone, pyritinol and thiopronine in the case of a clear temporal association between the occurrence of pemphigus lesions and the drug intake. Evaluation of the impact on quality of life using validated questionnaires, e.g. DLQI, and/or the ABQOL and TABQOL questionnaires specific for autoimmune bullous diseases may be considered (4.2???1.2). Check for updated vaccination. Inquire about a possible trip in a country in which vaccination with a live vaccine is required (to perform this vaccination before using immunosuppressive treatment.) It is recommended to assess the following aspects: The extent of skin and mucous membrane lesions, the degree of mucosal damage and functional impairment (dysphagia, dysphonia, weight loss, impairment of vision, dyspareunia). It is recommended to quantify the extent of skin and mucosal lesion using one of the two validated scoring systems: the Pemphigus Disease Area Index (PDAI) or the Autoimmune Bullous Skin Intensity and Severity Score (ABSIS) (4.5???1.0).21,22 The patient's general condition and co-morbidities are as follows: Bodyweight. Arterial blood pressure. General condition, co-morbidities (neoplastic, cardiovascular, musculoskeletal, diabetes, etc.). The majority of authors do not recommend performing the classical Nikolsky?s sign, considering that there are other tools to measure disease activity, and that it is not necessary to induce new lesions in patients who already have skin erosions. Usually begins with oral mucosal lesions: buccal and/or gingival painful, persisting erosions which interfere with eating. Less common are non-cicatricial ocular lesions, and nasal, laryngeal, oesophageal, genital and anal erosions are also possible. Cutaneous involvement (which may appear several weeks or months after the first appearance of mucosal lesions) presents with flaccid bullae with clear content, developing on non-erythematous skin quickly transforming into postbullous erosions. The lesions may be localized or generalized and predominate at seborrhoeic areas (chest, face, scalp, interscapular region) and mechanically stressed regions as well as on the extremities. The disease is usually not associated with major pruritus. Fingernail involvement is possible. Cutaneous involvement: transient, flaccid bullae or puff pastry-like exfoliation transforming into crusty erosions in seborrhoeic skin areas (chest, scalp, face, interscapular region). More extensive cutaneous involvement in sporadic and endemic pemphigus foliaceus (?Fogo Selvagem?, Brazilian pemphigus, Tunisian pemphigus). No mucosal involvement. To be suspected in the context of concomitant malignancy, particularly non-Hodgkin's lymphoma, chronic lymphocytic leukaemia, thymoma or Castleman?s disease. In not all cases, the underlying malignancy has been diagnosed at the time of diagnosis. Moreover, the symptoms of PNP can precede the malignancy. Mucosal involvement: initially limited cheilitis and/or ulcerative stomatitis, persisting painful erosions which lead to severe dysphagia. Cicatricial conjunctivitis, keratitis and genital involvement are common. Pharyngeal involvement is possible; the nasal cavity and oesophagus can also be affected leading to phagodynia. Cutaneous polymorphic lesions with symptoms resembling mild lichen planus-like to graft-versus-host disease-like, erythema multiforme-like, bullous pemphigoid-like or pemphigus vulgaris-like eruption. Palmar involvement is common. Pulmonary involvement (alveolitis, bronchiolitis obliterans, pulmonary fibrosis) is a characteristic and life-threatening complication. Clinical presentation (see 2.3) Histopathology Direct immunofluorescence (DIF) examination of a perilesional skin or mucosal biopsy Serological detection of autoantibodies against epithelial cell surface by indirect immunofluorescence (IIF) and/or enzyme-linked immunosorbent assay (ELISA Dsg1 and Dsg3). It is recommended to perform the following investigations for the diagnosis: A lesional biopsy for histopathology A perilesional biopsy for DIF examination Serology Preferentially, a 3- to 5-mm punch biopsy of a recent (<24?h) vesicle or 1/3 of the peripheral portion of a blister and 2/3 perilesional skin (placed in 4% formaldehyde solution) should be taken for routine histopathological analysis: intraepidermal suprabasal acantholysis in PV or acantholysis at the granular layer in PF. Epidermal acantholysis, suprabasal cleft formation, dyskeratotic keratinocytes, vacuolar change of the basilar epidermis and epidermal exocytosis of inflammatory cells (PNP). Skin biopsy of perilesional skin or mucosa (up to 1?cm from a recent lesion), put into a cryotube for transportation in a cylinder of liquid nitrogen, or in saline (delivery?<?36?h) or Michel's fixative for DIF analysis: IgG and/or C3 deposits at the surface of epidermal/epithelial keratinocytes. The epithelial cell surface staining for in vivo IgG deposition is normally granular or linear as observed by DIF examination. Epithelial cell surface deposits can sometimes be associated with linear deposits of IgG or C3 along the dermal?epidermal junction, suggestive of PNP, or pemphigus erythematosus, or the coexistence of pemphigus and pemphigoid. In specialized laboratories, plucked hairs can be utilized for DIF for the diagnosis of pemphigus. IIF examination of patient? serum on monkey oesophagus or human skin to search for autoantibodies against surface proteins of epidermal keratinocytes. The smooth and reticular staining pattern is also referred to as ?chicken wire?, ?honeycomb? or ?fishnet-like?. IIF microscopy based on cells that recombinantly express Dsg 1 and Dsg 3 on the cell surface (Biochip; Euroimmun). In case of atypical presentation, suspected PNP, or the suspicion of an unrelated autoimmune bullous disorder, additional immunopathological tests may be performed, such as IIF microscopy on rat bladder and/or immunoblot/immunoprecipitation. Detection of anti-Dsg1 (PF/mucocutaneous PV) and/or anti-Dsg3 IgG autoantibodies (Abs) (mucosal PV) by ELISA (Table?1). The detection of anti-Dsg IgG autoantibodies by ELISA is positive in more than 95% of cases. In general, ELISA values correlate with the extent and/or activity of disease (see remark above and prognostic value for relapse, helping to guide treatment). It is recommended to make the diagnosis of PV/PF on the following findings: Compatible clinical picture plus positive DIF examination If DIF examination is negative, it is recommended to repeat the biopsy for DIF microscopy. If a new biopsy is not available, or still negative, it is recommended to make the diagnosis of pemphigus in patients with: Compatible clinical picture plus corresponding typical histological picture of acantholysis plus significant positive IIF on monkey oesophagus: (4.2???1.3). In this particular case, the presence of a typical histological picture of acantholysis is absolutely necessary to exclude an erythema multiforme major. Compatible clinical picture and histopathology plus serum reactivity against recombinant Dsg 1 and/or 3 by ELISA or IIF on cells that express recombinant Dsg1/Dsg3 (4.7???0.8). In case of atypical clinical features (i.e. progressive stomatitis, lichenoid or erythema multiforme-like skin lesions), the diagnosis of PNP must be considered. Lesional histopathology frequently shows dyskeratosis and a lichenoid interface dermatitis in addition to acantholysis. DIF examination may reveal linear staining of IgG/C3 at the dermal?epidermal junction in addition to intercellular staining of the epithelium. IIF examination of serum on rat bladder shows cell surface staining of epithelial cells, corresponding to reactivity against plakin proteins. Immunoblot with epidermal extracts shows IgG against envoplakin (210?kDa) and periplakin (190?kDa), Dsg3 (130?kDa), and more rarely Dsg1 (160?kDa). Anti-desmocollin Abs can be occasionally detected, usually in association with anti-envoplakin Abs (Table?1) (4.6???1.2). Alpha-2-macroglobulin-like-1 (A2ML-1, 170?kDa) can only be detected under non-denaturing condition?non-reducing condition. Immunoblot with extracts from cultured keratinocytes reveals IgG against envoplakin (210?kDa), periplakin (190?kDa) and desmoplakin I/II (210 and 250?kDa). Immunoprecipitation with keratinocyte extracts is not performed in clinical practice. It can reveal IgG autoantibodies against envoplakin (210?kDa) and periplakin (190?kDa), Dsg3 (130?kDa), Dsg1 (160?kDa), desmocollins, desmoplakins I and II, BP230/BPAG1, plectin (500?kDa) and alpha-2-macroglobulin-like-1 (A2ML-1, 170?kDa) (4.6???1.5). It is recommended to perform the following investigations before treatment is initiated: (4.8???0.9) Complete blood count; Creatinine, blood electrolytes; Transaminases, gamma GT, alkaline phosphatase; Total serum protein, albumin; Fasting serum glucose; Hepatitis B, C and HIV; Serum IgA (in case of intravenous immunoglobulin (IVIG) treatment); G6PD activity, bilirubin and reticulocytes (in case of treatment with dapsone) Thiopurine methyltransferase (TPMT) activity (in case of treatment with azathioprine) Ocular examination to exclude glaucoma and cataract It may be recommended to perform the following investigations before treatment is initiated: (4.8???1.2) Chest X-ray (in case of elevated risk of tuberculosis) Quantiferon test or PPD (in case of elevated risk of tuberculosis). Abdominal sonography ? HCG to exclude pregnancy in females of childbearing age; Osteodensitometry prior to glucocorticoid treatment; To facilitate this process, a writing group, i.e. PJ, BH, AP, SU, DZ, MH and ES, appointed by the Autoimmune blistering diseases task force of the EADV wrote the first version of the updated guidelines following two telephone conferences. Thereafter, all 62 members of the EADV Autoimmune blistering diseases task force (notation group) were invited to assign scores (ranging from 0 to 5 according to the increasing degree of consensus) to each of the recommendations statements using the syntax shown below. This process identified the statements of major agreement or disagreement. Indicated major statements were then voted upon, and the degree of consensus was indicated for all statements. Based on the marks of the notation group, the writing group then prepared a second and a third version of the guidelines, until each of the statements was given a mark >4 by the voting group. In this process, a consensus meeting was held during the annual meeting of the EADV in Madrid, Spain, September 2019. The manuscript was then reviewed by the different European patient organizations. The revised version of the guideline was finally passed to the European Dermatology Forum (EDF) for final consensus. Grade of recommendation Syntax Strong recommendation Is recommended Recommendation May be recommended Recommendation pending May be considered Negative recommendation Is not recommended Pemphigus encompasses a group of life-threatening autoimmune bullous diseases characterized by flaccid blisters and erosions of the mucous membranes and/or skin.1?5 The severity of the disease is based on its progressive course which is accompanied by an increased body catabolism with loss of body fluids and proteins and secondary bacterial and viral infections which may lead to sepsis and cardiac failure. Before the advent of systemic corticosteroids, pemphigus was almost always fatal within two years after making the diagnosis. Pathophysiologically, the underlying intraepithelial blister formation is caused by IgG autoantibodies against the desmosomal adhesion proteins, desmoglein 3 (Dsg 3) and/or desmoglein 1 (Dsg1), on the cell surface of epidermal keratinocytes.5,6 Pemphigus is rare, and its incidence has been estimated to about 2 new patients per 1 million inhabitants per year in Central Europe.7,8 Two main clinical variants are known, pemphigus vulgaris (PV) and pemphigus foliaceus (PF). The pathogenic role of anti-desmoglein 1 and 3 IgG has been clearly established since the injection of patients? sera or affinity-purified IgG from pemphigus sera into neonatal mice reproduces clinically and immunopathologically the cardinal symptoms of pemphigus within 24?h.1,5. In most patients, disease activity is closely correlated with serum levels of desmoglein-reactive autoantibodies.9,10 Due to its rarity, only few randomized controlled trials (RCT) are available in pemphigus, most of them limited by the low numbers of patients enrolled and the lack of statistically significant differences between the study groups. A few studies compared different doses of prednisone/prednisolone, i.v. corticosteroid pulses versus placebo, azathioprine versus mycophenolate mofetil, and the use of adjuvant treatment with methotrexate, cyclosporine, cyclophosphamide or high-dose intravenous immunoglobulins.11,12. The combination of systemic corticosteroids (prednisone/prednisolone, 1.0?1.5?mg/kg/day) and potentially corticosteroid-sparing immunosuppressive drugs, mostly azathioprine and mycophenolate mofetil, was regarded as standard first-line therapy by most clinicians.13 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 literature.14 Rituximab has first been used to treat severe forms (recalcitrant or relapsing types) and later as first-line treatment reaching complete remissions in 80?90% of patients.15?18 Recently, a randomized controlled trial with newly diagnosed patients with PV and PF showed that 89% of patients assigned to the rituximab group achieved complete remission off therapy versus 34% of patients assigned to treatment with prednisone alone.18 Additionally, prednisone could be stopped after only 6?months of treatment in around 70% of patients initially treated with rituximab, leading to a twofold decrease in the number of severe treatment side-effects.18 For this reason, the Autoimmune blistering diseases task force of the European Academy of Dermatology and Venereology (EADV) has initiated a thorough update of the previous guidelines for the management of patients with pemphigus.13 To facilitate this process, a writing group, i.e. PJ, BH, AP, SU, DZ, MH and ES, appointed by the Autoimmune blistering diseases task force of the EADV wrote the first version of the updated guidelines following two telephone conferences. Thereafter, all 62 members of the EADV Autoimmune blistering diseases task force (notation group) were invited to assign scores (ranging from 0 to 5 according to the increasing degree of consensus) to each of the recommendations statements using the syntax shown below. This process identified the statements of major agreement or disagreement. Indicated major statements were then voted upon, and the degree of consensus was indicated for all statements. Based on the marks of the notation group, the writing group then prepared a second and a third version of the guidelines, until each of the statements was given a mark >4 by the voting group. In this process, a consensus meeting was held during the annual meeting of the EADV in Madrid, Spain, September 2019. The manuscript was then reviewed by the different European patient organizations. The revised version of the guideline was finally passed to the European Dermatology Forum (EDF) for final consensus. Grade of recommendation Syntax Strong recommendation Is recommended Recommendation May be recommended Recommendation pending May be considered Negative recommendation Is not recommended The Autoimmune blistering diseases Task Force of the European Academy of Dermatology and Venereology (EADV) has initiated a throughout update of the guideline for the management of patients with pemphigus.
UN SDGs
This output contributes to the following UN Sustainable Development Goals (SDGs)
-
SDG 3 Good Health and Well-being
Research Areas and Centers
- Academic Focus: Center for Infection and Inflammation Research (ZIEL)
Fingerprint
Dive into the research topics of 'Updated S2K guidelines on the management of pemphigus vulgaris and foliaceus initiated by the european academy of dermatology and venereology (EADV)'. Together they form a unique fingerprint.Cite this
- APA
- Author
- BIBTEX
- Harvard
- Standard
- RIS
- Vancouver