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Detlef Zillikens - One of the best experts on this subject based on the ideXlab platform.
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Anti-p200 Pemphigoid
Journal of the American Academy of Dermatology, 2014Co-Authors: S. Goletz, Detlef Zillikens, Takashi Hashimoto, Enno SchmidtAbstract:Anti-p200 Pemphigoid is a rare subepidermal blistering skin disease. Patients' autoantibodies label the dermal side of 1 mol/L NaCl-split human skin by indirect immunofluorescence microscopy and recognize a 200-kd protein by immunoblotting of human dermal extract. Clinically, anti-p200 Pemphigoid is characterized by tense blisters and vesicles, erosions, and urticarial plaques, closely resembling bullous Pemphigoid and the inflammatory variant of epidermolysis bullosa acquisita. Recently, 90% of anti-p200 Pemphigoid sera were shown to recognize laminin γ1. The C-terminus of laminin γ1 was identified as an immunodominant region and in its recombinant form was used by immunoblotting and enzyme-linked immunosorbent assay for the serologic diagnosis of this disease. Subsequent ex vivo and in vivo studies were, however, unable to show pathogenic activity of antilaminin γ1 antibodies. Both patients' sera and sera depleted from antilaminin γ1 antibodies induced subepidermal splitting in an ex vivo model of autoantibody-mediated leukocyte-dependent neutrophil activation. Antilaminin γ1 antibodies appear to be useful biomarkers that will further facilitate the diagnosis of anti-p200 Pemphigoid. The true identity of the pathogenetically relevant autoantigen of this disease, which may either be a yet unknown isoform of laminin γ1 or even another 200-kd protein of the dermoepidermal junction, still needs to be elucidated.
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Pemphigoid diseases pathogenesis diagnosis and treatment
Autoimmunity, 2012Co-Authors: Michael Kasperkiewicz, Detlef Zillikens, Enno SchmidtAbstract:Pemphigoid diseases (including bullous Pemphigoid, mucous membrane Pemphigoid, Pemphigoid gestationis, linear IgA dermatosis, lichen planus Pemphigoides, and anti-p200 Pemphigoid) are a subgroup of autoimmune bullous skin diseases characterized by an autoantibody response toward structural components of the hemidesmosome resulting in subepidermal blistering. By the use of different in vitro systems and experimental animal models, the pathogenic relevance of these autoantibodies has been demonstrated. Recent advances in the understanding of autoantibody responses have led to novel diagnostic tools and a more differentiated therapeutic approach for these disorders. This review covers the most recent understanding of the pathophysiology, diagnosis, and treatment of this group of autoimmune diseases.
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rituximab for treatment refractory pemphigus and Pemphigoid a case series of 17 patients
Journal of The American Academy of Dermatology, 2011Co-Authors: Michael Kasperkiewicz, Detlef Zillikens, Iakov Shimanovich, Ralf Ludwig, Christian Rose, Enno SchmidtAbstract:Background Rituximab has been increasingly used in autoimmune blistering dermatoses, mainly in pemphigus. However, only a few larger case series are available on this subject and information on the efficacy of retreatment with rituximab during relapses is lacking. Objective We sought to determine efficacy and adverse effects of adjuvant rituximab. Methods Seventeen patients with refractory autoimmune blistering dermatoses (pemphigus vulgaris [PV], n = 8; pemphigus foliaceus [PF], n = 2; bullous Pemphigoid [BP], n = 2; mucous membrane Pemphigoid, n = 5) were treated 4 times with rituximab at an individual dose of 375 mg/m 2 in weekly intervals or twice with 1000 mg 2 weeks apart. Six of 8 patients with a relapse after this regimen received rituximab again twice with 1000 mg in a 2-week interval. Results All lesions cleared in 14 patients (7 PV, two PF, two BP, 3 mucous membrane Pemphigoid), whereas partial healing was found in 3 others (one PV, two mucous membrane Pemphigoid). Relapses occurred in 8 patients (5 PV, two PF, one BP). Retreatment with rituximab again resulted in complete (two PV, one PF, one BP) or partial (two PV) remission. Serious side effects associated with rituximab were not observed. Limitations Rituximab has been combined with various other immunosuppressive or immunomodulatory treatments. Conclusion Adjuvant rituximab is effective and well tolerated not only in patients with pemphigus but also with Pemphigoid. Efficacy and safety of rituximab are maintained when it is readministered during relapses.
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profibrotic phenotype of conjunctival fibroblasts from mucous membrane Pemphigoid
American Journal of Pathology, 2011Co-Authors: Detlef Zillikens, Enno Schmid, Valerie P J Saw, Ifeoma Offiah, G Galatowicz, Virginia L Calde, Julie T DanielsAbstract:Ocular mucous membrane Pemphigoid is an immunobullous disease in which excessive conjunctival fibrosis causes blindness, and the pathogenesis of scarring is incompletely understood. To establish whether profibrotic fibroblasts with an altered phenotype exist in ocular mucous membrane Pemphigoid, we compared the functional characteristics of Pemphigoid conjunctival fibroblasts to normal conjunctival fibroblasts with respect to cell division; migration; collagen contraction; matrix metalloproteinase, secretion of collagen and chemokines; and myofibroblast differentiation. We found that Pemphigoid fibroblasts showed increased cell division (P = 0.01), increased migration in serum-free medium (72 ± 18 migrated cells versus 33 ± 11, P = 0.04), increased collagen contraction in the presence of 10 ng/ml tumor necrosis factor-α, increased collagen type I secretion (P = 0.03), increased secretion of matrix metalloproteinase-3 (P = 0.03), and increased secretion of eotaxin in response to interleukin-13 (P = 0.04). Differences between Pemphigoid and normal conjunctival fibroblasts with respect to collagen contraction and MMP secretion in the presence of interleukin-13 were also observed. Together, these findings indicate that Pemphigoid conjunctival fibroblasts have a profibrotic phenotype that is maintained in vitro. No differences between Pemphigoid fibroblasts obtained from acutely inflamed versus clinically uninflamed conjunctiva were observed. Developing effective antifibrotic therapies will require understanding of the mechanisms that both induce and maintain the profibrotic phenotype.
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immunoblotting and enzyme linked immunosorbent assay for the diagnosis of Pemphigoid gestationis
Obstetrics & Gynecology, 2004Co-Authors: Cassian Sitaru, F Wojnarowska, Jenny Powell, Gerald Messer, Evabettina Brocker, Detlef ZillikensAbstract:OBJECTIVES To investigate the sensitivity of immunoblotting and enzyme-linked immunosorbent assay (ELISA) to detect autoantibodies to bullous Pemphigoid antigen 180 in patients with Pemphigoid gestationis and to correlate autoantibody serum levels with disease activity. METHODS In serum samples obtained from 44 pregnant patients before initiation of therapy and from the same number of healthy blood donors, the autoantibody reactivity was assayed by immunofluorescence microscopy on human skin sections as well as Western blot analysis and 2 different ELISAs by using recombinant forms of the immunodominant domain of BP180. In addition, ELISA reactivity with this autoantigen was assayed in 6 patients during the course of the disease, and its correlation with the clinical disease activity was estimated by applying the Spearman rank correlation test. RESULTS By indirect immunofluorescence microscopy, complement-fixing autoantibodies to the dermal-epidermal junction were found in 93% of patients' sera. By immunoblotting and ELISA, autoantibodies to bullous Pemphigoid antigen 180 were detected in 93% and 86.3% of Pemphigoid gestationis patients, respectively, but in none of the healthy controls. Serum levels of autoantibodies as detected by ELISA paralleled the patients' disease activity. CONCLUSIONS Our study shows that immunoblotting and ELISA are sensitive tools for the detection of autoantibodies to bullous Pemphigoid antigen 180 in patients with Pemphigoid gestationis. In addition, the ELISA is useful to monitor autoantibody serum levels. LEVEL OF EVIDENCE II-2
Enno Schmidt - One of the best experts on this subject based on the ideXlab platform.
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Autoimmune Subepidermal Bullous Diseases of the Skin and Mucosae: Clinical Features, Diagnosis, and Management
Clinical Reviews in Allergy & Immunology, 2018Co-Authors: Kyle T. Amber, Dedee F Murrell, Enno Schmidt, Pascal Joly, Luca BorradoriAbstract:Autoimmune subepidermal blistering diseases of the skin and mucosae constitute a large group of sometimes devastating diseases, encompassing bullous Pemphigoid, gestational Pemphigoid, mucous membrane Pemphigoid, epidermolysis bullosa acquisita, and anti-p200 Pemphigoid. Their clinical presentation is polymorphic. These autoimmune blistering diseases are associated with autoantibodies that target distinct components of the basement membrane zone of stratified epithelia. These autoantigens represent structural proteins important for maintenance of dermo-epidermal integrity. Bullous Pemphigoid (BP) is the most common subepidermal autoimmune blistering disease of the skin and mucosae. Although the disease typically presents with a generalized blistering eruption associated with itch, atypical variants with either localized bullous lesions or “non-bullous” presentations are observed in approximately 20% of patients. A peculiar form of BP typically associated with pregnancy is Pemphigoid gestationis. In anti-p200 Pemphigoid, patients present with tense blisters on erythematosus or normal skin resembling BP, with a predilection for acral surfaces. These patients have antibodies targeting the 200-kDa basement membrane protein. Epidermolysis bullosa is a rare autoimmune blistering disease associated with autoantibodies against type VII collagen that can have several phenotypes including a classical form mimicking dystrophic epidermolysis bullosa, an inflammatory presentation mimicking BP, or mucous membrane Pemphigoid-like lesions. Mucous membrane Pemphigoid (MMP) is the term agreed upon by international consensus for an autoimmune blistering disorder, which affects one or more mucous membrane and may involve the skin. The condition involves a number of different autoantigens in the basement membrane zone. It may result in severe complications from scarring, such as blindness and strictures. Diagnosis of these diseases relies on direct immunofluorescence microscopy studies and immunoserological assays. Management of affected patients is often challenging. We will here review the clinical and immunopathological features as well as the pathophysiology of this group of organ-specific autoimmune diseases. Finally, we will discuss the diagnostic approach and the principles of management in clinical practice.
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Laboratory Diagnosis and Clinical Profile of Anti-p200 Pemphigoid
JAMA dermatology, 2016Co-Authors: Joost M. Meijer, Enno Schmidt, Gilles F H Diercks, Hendri H. Pas, Marcel F JonkmanAbstract:Importance Anti-p200 Pemphigoid is a rare subepidermal autoimmune blistering disease characterized by autoantibodies against a 200-kDa protein in the basement membrane zone. Anti-p200 Pemphigoid is probably often misdiagnosed because of low availability of diagnostic assays and expertise and classified as bullous Pemphigoid or epidermolysis bullosa acquisita. Objective To clinically characterize patients with anti-p200 Pemphigoid, identified by using indirect immunofluorescence microscopy on skin substrates deficient in type VII collagen and laminin-332 (knockout analysis), to validate this technique by immunoblot with dermal extract, and to incorporate direct immunofluorescence serration pattern analysis in the diagnostic algorithm. Design, Setting, and Participants This was a retrospective study performed from January 2014 to June 2015 with biobank patient materials and clinical data for the period 1998 to 2015 from the single national referral center on autoimmune bullous diseases. Patients were selected based on a dermal side binding on 1-mol/L salt (sodium chloride)-split human skin substrate by indirect immunofluorescence microscopy, not diagnosed epidermolysis bullosa acquisita or anti–laminin-332 mucous membrane Pemphigoid. Main Outcomes and Measures Indirect immunofluorescence microscopy knockout analysis was performed and diagnosis of anti-p200 confirmed by immunoblot with dermal extract. Clinical, histological, and immunological findings were registered. Autoantibodies against laminin γ1 were determined by immunoblot. Results Twelve patients with anti-p200 Pemphigoid (7 male and 5 female; mean age, 66.6 years) were identified using the indirect immunofluorescence microscopy knockout analysis. Direct immunofluorescence microscopy showed a linear n-serrated IgG deposition pattern along the basement membrane zone in 9 of 11 patients. The diagnosis was confirmed by immunoblot showing autoantibodies against 200-kDa protein in dermal extract in 12 of 12 patients. Autoantibodies against recombinant laminin γ1 were detected by immunoblot in 8 of 12 patients. Remarkable similarities were seen in clinical features with predominantly tense blisters on hands and feet, resembling dyshidrosiform Pemphigoid. Mucosal involvement was seen in 6 (50%) of the patients. Conclusions and Relevance Predominance of blisters on hands and feet may be a clinical clue to the diagnosis of anti-p200 Pemphigoid. Direct immunofluorescence microscopy serration pattern analysis and indirect immunofluorescence microscopy knockout analysis are valuable additional techniques to facilitate the diagnosis of anti-p200 Pemphigoid.
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Anti-p200 Pemphigoid
Journal of the American Academy of Dermatology, 2014Co-Authors: S. Goletz, Detlef Zillikens, Takashi Hashimoto, Enno SchmidtAbstract:Anti-p200 Pemphigoid is a rare subepidermal blistering skin disease. Patients' autoantibodies label the dermal side of 1 mol/L NaCl-split human skin by indirect immunofluorescence microscopy and recognize a 200-kd protein by immunoblotting of human dermal extract. Clinically, anti-p200 Pemphigoid is characterized by tense blisters and vesicles, erosions, and urticarial plaques, closely resembling bullous Pemphigoid and the inflammatory variant of epidermolysis bullosa acquisita. Recently, 90% of anti-p200 Pemphigoid sera were shown to recognize laminin γ1. The C-terminus of laminin γ1 was identified as an immunodominant region and in its recombinant form was used by immunoblotting and enzyme-linked immunosorbent assay for the serologic diagnosis of this disease. Subsequent ex vivo and in vivo studies were, however, unable to show pathogenic activity of antilaminin γ1 antibodies. Both patients' sera and sera depleted from antilaminin γ1 antibodies induced subepidermal splitting in an ex vivo model of autoantibody-mediated leukocyte-dependent neutrophil activation. Antilaminin γ1 antibodies appear to be useful biomarkers that will further facilitate the diagnosis of anti-p200 Pemphigoid. The true identity of the pathogenetically relevant autoantigen of this disease, which may either be a yet unknown isoform of laminin γ1 or even another 200-kd protein of the dermoepidermal junction, still needs to be elucidated.
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Pemphigoid diseases pathogenesis diagnosis and treatment
Autoimmunity, 2012Co-Authors: Michael Kasperkiewicz, Detlef Zillikens, Enno SchmidtAbstract:Pemphigoid diseases (including bullous Pemphigoid, mucous membrane Pemphigoid, Pemphigoid gestationis, linear IgA dermatosis, lichen planus Pemphigoides, and anti-p200 Pemphigoid) are a subgroup of autoimmune bullous skin diseases characterized by an autoantibody response toward structural components of the hemidesmosome resulting in subepidermal blistering. By the use of different in vitro systems and experimental animal models, the pathogenic relevance of these autoantibodies has been demonstrated. Recent advances in the understanding of autoantibody responses have led to novel diagnostic tools and a more differentiated therapeutic approach for these disorders. This review covers the most recent understanding of the pathophysiology, diagnosis, and treatment of this group of autoimmune diseases.
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rituximab for treatment refractory pemphigus and Pemphigoid a case series of 17 patients
Journal of The American Academy of Dermatology, 2011Co-Authors: Michael Kasperkiewicz, Detlef Zillikens, Iakov Shimanovich, Ralf Ludwig, Christian Rose, Enno SchmidtAbstract:Background Rituximab has been increasingly used in autoimmune blistering dermatoses, mainly in pemphigus. However, only a few larger case series are available on this subject and information on the efficacy of retreatment with rituximab during relapses is lacking. Objective We sought to determine efficacy and adverse effects of adjuvant rituximab. Methods Seventeen patients with refractory autoimmune blistering dermatoses (pemphigus vulgaris [PV], n = 8; pemphigus foliaceus [PF], n = 2; bullous Pemphigoid [BP], n = 2; mucous membrane Pemphigoid, n = 5) were treated 4 times with rituximab at an individual dose of 375 mg/m 2 in weekly intervals or twice with 1000 mg 2 weeks apart. Six of 8 patients with a relapse after this regimen received rituximab again twice with 1000 mg in a 2-week interval. Results All lesions cleared in 14 patients (7 PV, two PF, two BP, 3 mucous membrane Pemphigoid), whereas partial healing was found in 3 others (one PV, two mucous membrane Pemphigoid). Relapses occurred in 8 patients (5 PV, two PF, one BP). Retreatment with rituximab again resulted in complete (two PV, one PF, one BP) or partial (two PV) remission. Serious side effects associated with rituximab were not observed. Limitations Rituximab has been combined with various other immunosuppressive or immunomodulatory treatments. Conclusion Adjuvant rituximab is effective and well tolerated not only in patients with pemphigus but also with Pemphigoid. Efficacy and safety of rituximab are maintained when it is readministered during relapses.
Luca Borradori - One of the best experts on this subject based on the ideXlab platform.
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Autoimmune Subepidermal Bullous Diseases of the Skin and Mucosae: Clinical Features, Diagnosis, and Management
Clinical Reviews in Allergy & Immunology, 2018Co-Authors: Kyle T. Amber, Dedee F Murrell, Enno Schmidt, Pascal Joly, Luca BorradoriAbstract:Autoimmune subepidermal blistering diseases of the skin and mucosae constitute a large group of sometimes devastating diseases, encompassing bullous Pemphigoid, gestational Pemphigoid, mucous membrane Pemphigoid, epidermolysis bullosa acquisita, and anti-p200 Pemphigoid. Their clinical presentation is polymorphic. These autoimmune blistering diseases are associated with autoantibodies that target distinct components of the basement membrane zone of stratified epithelia. These autoantigens represent structural proteins important for maintenance of dermo-epidermal integrity. Bullous Pemphigoid (BP) is the most common subepidermal autoimmune blistering disease of the skin and mucosae. Although the disease typically presents with a generalized blistering eruption associated with itch, atypical variants with either localized bullous lesions or “non-bullous” presentations are observed in approximately 20% of patients. A peculiar form of BP typically associated with pregnancy is Pemphigoid gestationis. In anti-p200 Pemphigoid, patients present with tense blisters on erythematosus or normal skin resembling BP, with a predilection for acral surfaces. These patients have antibodies targeting the 200-kDa basement membrane protein. Epidermolysis bullosa is a rare autoimmune blistering disease associated with autoantibodies against type VII collagen that can have several phenotypes including a classical form mimicking dystrophic epidermolysis bullosa, an inflammatory presentation mimicking BP, or mucous membrane Pemphigoid-like lesions. Mucous membrane Pemphigoid (MMP) is the term agreed upon by international consensus for an autoimmune blistering disorder, which affects one or more mucous membrane and may involve the skin. The condition involves a number of different autoantigens in the basement membrane zone. It may result in severe complications from scarring, such as blindness and strictures. Diagnosis of these diseases relies on direct immunofluorescence microscopy studies and immunoserological assays. Management of affected patients is often challenging. We will here review the clinical and immunopathological features as well as the pathophysiology of this group of organ-specific autoimmune diseases. Finally, we will discuss the diagnostic approach and the principles of management in clinical practice.
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characterization of the anti bp180 autoantibody reactivity profile and epitope mapping in bullous Pemphigoid patients
Journal of Investigative Dermatology, 2004Co-Authors: Giovanni Di Zenzo, Luca Borradori, Fabiana Grosso, Michela Terracina, Feliciana Mariotti, Ornella De Pita, Katsushi Owaribe, Alessandro Mastrogiacomo, Francesco Sera, Giovanna ZambrunoAbstract:Bullous Pemphigoid is a subepidermal bullous disease of skin and mucosae associated with autoantibodies to BP180. To characterize the humoral response to BP180, we generated a random BP180 epitope library displayed on lambda bacteriophage. After validation of the library by epitope mapping of three BP180-specific monoclonal antibodies, 15 novel or known BP180 epitopes were identified using 10 bullous Pemphigoid serum samples. Fifty-seven bullous Pemphigoid and 81 control sera were then assayed against the selected epitopes. Thirty-one out of 57 (54%) bullous Pemphigoid sera reacted with at least an additional antigenic site other than the NC16A, within the extracellular (37%) and intracellular (28%) domains of BP180. In addition, the reactivity with extracellular epitopes of BP180 contained within the residue stretches 508-541 and 1331-1404 appeared to be related to the presence of both skin and mucosal involvement. Finally, a preliminary analysis of the epitope pattern in the disease course indicated that bullous Pemphigoid patients exhibit a specific reactivity pattern, and that binding to intracellular epitopes of BP180, in addition to NC16A, may be detectable at an early clinical stage. Our findings provide novel insights into the pathophysiology of bullous Pemphigoid and show the potential of the utilized approach as a tool for a rapid diagnosis of bullous Pemphigoid patients and their management.
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severity and phenotype of bullous Pemphigoid relate to autoantibody profile against the nh2 and cooh terminal regions of the bp180 ectodomain
Journal of Investigative Dermatology, 2002Co-Authors: Silke C Hofmann, Michael Hertl, Sybille Thomauszynski, Angelika Stauber, Gerold Schuler, Thomas Hunziker, Philippe Bernard, Corinna Koebnick, Luca BorradoriAbstract:Bullous Pemphigoid, the most common autoimmune subepidermal bullous disorder, is associated with autoantibodies targeting antigenic sites clustered within the extracellular domain of BP180. To investigate epitope and subclass specificity of autoantibodies in bullous Pemphigoid, we developed an enzyme-linked immunosorbent assay utilizing baculovirus-expressed recombinant forms of the NH2- and COOH-terminal regions of the extracellular domain of BP180 and examined sera obtained from patients with active bullous Pemphigoid (n=116) and controls (n=100). Ninety-three (80%) and 54 (47%) of the 116 bullous Pemphigoid sera recognized the NH2- and COOH-terminal regions, respectively, of the extracellular domain of BP180. Detailed analysis demonstrates that (i) this novel enzyme-linked immunosorbent assay is highly specific (98%) and sensitive (93%) as 108 of 116 bullous Pemphigoid sera reacted with at least one of the baculovirus-derived recombinants, (ii) in active bullous Pemphigoid, autoantibodies against the NH2-terminus of the extracellular domain of BP180 were predominantly of the IgG1 class, whereas a dual IgG1 and IgG4 response to this region was related to a more severe skin involvement, (iii) autoreactivity against both the NH2- and COOH-terminal regions was more frequently detected in patients with mucosal lesions, and (iv) levels of IgG (and IgG1) against the NH2-terminal, but not against the COOH-terminal portion of the extracellular domain of BP180, reflected disease severity indicating that autoantibodies against the NH2-terminus are critical in the pathogenesis of bullous Pemphigoid. In conclusion, this novel enzyme-linked immunosorbent assay represents a highly sensitive and specific assay for rapid diagnosis of bullous Pemphigoid and related disorders and may provide predictive parameters for the management of bullous Pemphigoid patients.
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detection of igg autoantibodies in the sera of patients with bullous and gestational Pemphigoid elisa studies utilizing a baculovirus encoded form of bullous Pemphigoid antigen 2
Journal of Investigative Dermatology, 1998Co-Authors: Claudia Haase, Lioba Budinger, Luca Borradori, Carole Yee, Hans F Merk, Kim B Yancey, Michael HertlAbstract:Autoantibodies against the extracellular domain of bullous Pemphigoid antigen 2 (BPAG2) are thought to play a key role in the pathogenesis of bullous Pemphigoid and their detection may thus be of diagnostic and prognostic value. The aim of this study was to develop a standardized enzyme-linked immunosorbent assay utilizing the baculovirus-derived protein BV13 (extracellular domain of BPAG2 devoid of 68 amino acids at the C terminus linked to glutathione-S-transferase and 6x His tag) to detect BPAG2-specific autoantibodies. For the enzyme-linked immunosorbent assay, nickel agarose affinity-purified BV13 protein was incubated with sera from patients with bullous Pemphigoid (n = 39), gestational Pemphigoid (n = 10), and pemphigus vulgaris/ pemphigus foliaceus (PV/PF; n = 15), or normal human sera (NHS; n = 18). Nickel affinity-purified proteins from wild-type baculovirus-infected insect cells served as a control. A positive enzyme-linked immunosorbent assay value was defined as reactivity (ODBV13 - ODWT) < mean reactivity + SD of the negative control sera (PV/PF; NHS). Thirty-five of 39 bullous Pemphigoid sera and 10 of 10 gestational Pemphigoid sera were reactive to BPAG2 compared with none of 15 PV/PF sera and one of 18 NHS (sensitivity, 91.8%; specificity, 97%). Of 16 BPAG2-reactive sera in the enzyme-linked immunosorbent assay, only six were BPAG2-reactive in the western blot, whereas 14 sera immunoprecipitated BPAG2 from extracts of epidermal keratinocytes. The enzyme-linked immunosorbent assay utilizing an eukaryotic BPAG2 protein thus seems to be highly sensitive and specific in the detection of BPAG2-specific antibodies and, hence, may be useful in the diagnosis of bullous autoimmune diseases, such as bullous Pemphigoid and gestational Pemphigoid.
Marcel F Jonkman - One of the best experts on this subject based on the ideXlab platform.
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table_1.docx
2018Co-Authors: Aniek Lamberts, Marcel F Jonkman, Jorrit B Terra, Ilona H. Euverman, Barbara HorváthAbstract:IntroductionRituximab (RTX) is a monoclonal antibody targeting CD20, a transmembrane protein expressed on B cells, causing B cell depletion. RTX has shown great efficacy in studies of pemphigus vulgaris, but data of Pemphigoid diseases are limited.ObjectiveTo assess the effectiveness and safety of RTX in Pemphigoid diseases.MethodsThe medical records of 28 patients with Pemphigoid diseases that were treated with RTX were reviewed retrospectively. Early and late endpoints, defined according to international consensus, were disease control (DC), partial remission (PR), complete remission (CR), and relapses. Safety was measured by reported adverse events.ResultsPatients with bullous Pemphigoid (n = 8), mucous membrane Pemphigoid (n = 14), epidermolysis bullosa acquisita (n = 5), and linear IgA disease (n = 1) were included. Treatment with 500 mg RTX (n = 6) or 1,000 mg RTX (n = 22) was administered on days 1 and 15. Eight patients received additional 500 mg RTX at months 6 and 12. Overall, DC was achieved in 67.9%, PR in 57.1%, and CR in 21.4% of the cases. During follow-up, 66.7% patients relapsed. Repeated treatment with RTX led to remission (PR or CR) in 85.7% of the retreated cases. No significant difference in response between Pemphigoid subtypes was found. IgA-dominant cases (n = 5) achieved less DC (20 vs. 81.3%; p = 0.007), less PR (20 vs. 62.5%; p = 0.149), and less CR (0 vs. 18.8%; p = 0.549) compared to IgG-dominant cases (n = 16). Five severe adverse events and three deaths were reported. One death was possibly related to RTX and one death was disease related.ConclusionRTX can be effective in recalcitrant IgG-dominant Pemphigoid diseases, however not in those where IgA is dominant.
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Laboratory Diagnosis and Clinical Profile of Anti-p200 Pemphigoid
JAMA dermatology, 2016Co-Authors: Joost M. Meijer, Enno Schmidt, Gilles F H Diercks, Hendri H. Pas, Marcel F JonkmanAbstract:Importance Anti-p200 Pemphigoid is a rare subepidermal autoimmune blistering disease characterized by autoantibodies against a 200-kDa protein in the basement membrane zone. Anti-p200 Pemphigoid is probably often misdiagnosed because of low availability of diagnostic assays and expertise and classified as bullous Pemphigoid or epidermolysis bullosa acquisita. Objective To clinically characterize patients with anti-p200 Pemphigoid, identified by using indirect immunofluorescence microscopy on skin substrates deficient in type VII collagen and laminin-332 (knockout analysis), to validate this technique by immunoblot with dermal extract, and to incorporate direct immunofluorescence serration pattern analysis in the diagnostic algorithm. Design, Setting, and Participants This was a retrospective study performed from January 2014 to June 2015 with biobank patient materials and clinical data for the period 1998 to 2015 from the single national referral center on autoimmune bullous diseases. Patients were selected based on a dermal side binding on 1-mol/L salt (sodium chloride)-split human skin substrate by indirect immunofluorescence microscopy, not diagnosed epidermolysis bullosa acquisita or anti–laminin-332 mucous membrane Pemphigoid. Main Outcomes and Measures Indirect immunofluorescence microscopy knockout analysis was performed and diagnosis of anti-p200 confirmed by immunoblot with dermal extract. Clinical, histological, and immunological findings were registered. Autoantibodies against laminin γ1 were determined by immunoblot. Results Twelve patients with anti-p200 Pemphigoid (7 male and 5 female; mean age, 66.6 years) were identified using the indirect immunofluorescence microscopy knockout analysis. Direct immunofluorescence microscopy showed a linear n-serrated IgG deposition pattern along the basement membrane zone in 9 of 11 patients. The diagnosis was confirmed by immunoblot showing autoantibodies against 200-kDa protein in dermal extract in 12 of 12 patients. Autoantibodies against recombinant laminin γ1 were detected by immunoblot in 8 of 12 patients. Remarkable similarities were seen in clinical features with predominantly tense blisters on hands and feet, resembling dyshidrosiform Pemphigoid. Mucosal involvement was seen in 6 (50%) of the patients. Conclusions and Relevance Predominance of blisters on hands and feet may be a clinical clue to the diagnosis of anti-p200 Pemphigoid. Direct immunofluorescence microscopy serration pattern analysis and indirect immunofluorescence microscopy knockout analysis are valuable additional techniques to facilitate the diagnosis of anti-p200 Pemphigoid.
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bullous Pemphigoid as pruritus in the elderly a common presentation
JAMA Dermatology, 2013Co-Authors: Christiaan V Bakker, Hendri H. Pas, Jorrit B Terra, Marcel F JonkmanAbstract:IMPORTANCE In the literature, patients with bullous Pemphigoid have been reported to have itch without blisters. Clinical observations in these patients have varied from eczematous or urticarial to papular or nodular skin lesions. Here we investigated the spectrum of clinical variants. OBSERVATIONS Fifteen patients with itch without blisters had immunopathologic findings of bullous Pemphigoid. Mean age at diagnosis was 81.7 years. No blistering occurred during the mean 2.2 years of follow-up. Mean delay of diagnosis was 2.8 years. Clinical symptoms were heterogeneous: pruritus sine materia (no primary skin lesions), eczematous, urticarial, papular, and/or nodular skin lesions were seen. Treatment with potent topical corticosteroids or methotrexate sodium led to remission in 11 patients. CONCLUSIONS AND RELEVANCE Itch without skin lesions can be the only symptom of bullous Pemphigoid. Therefore, it is important to include serologic and direct immunofluorescence in the diagnostic algorithm of itch. We propose the unifying term pruritic nonbullous Pemphigoid for all patients with immunopathologic findings of bullous Pemphigoid, itch, and no blisters.
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inflammatory variant of epidermolysis bullosa acquisita with igg autoantibodies against type vii collagen and laminin α3
Archives of Dermatology, 2000Co-Authors: Marcel F Jonkman, Kim B Yancey, Jacqueline Schuur, F Dijk, K Heeres, Marcelus C J M De Jong, Jan Van Der Meer, Hendri H. PasAbstract:Background: The inflammatory variant of epidermolysis bullosa acquisita (EBA) may clinically closely resemble bullous or cicatricial Pemphigoid. Patients with inflammatory EBA have IgG autoantibodies against type VII collagen. Patients with anti-epiligrin cicatricial Pemphigoid have IgG autoantibodies against laminin 5. Observation: We describe a patient with inflammatory EBA exhibiting nonscarring oral and vaginal involvement. Indirect immunofluorescence using skin substrate lacking an epidermal basement membrane molecule, direct immunoelectron microscopy, immuno-blot, and immunoprecipitation studies revealed the simultaneous presence of circulating IgG autoantibodies against type VII collagen and laminin alpha 3. A final diagnosis of EBA was based on the sublamina densa level of blister formation. Conclusion: This case illustrates the clinical and immunological overlap between EBA and anti-epiligrin cicatricial Pemphigoid, a unique finding that may have developed as a consequence of epitope spreading.
Hendri H. Pas - One of the best experts on this subject based on the ideXlab platform.
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Laboratory Diagnosis and Clinical Profile of Anti-p200 Pemphigoid
JAMA dermatology, 2016Co-Authors: Joost M. Meijer, Enno Schmidt, Gilles F H Diercks, Hendri H. Pas, Marcel F JonkmanAbstract:Importance Anti-p200 Pemphigoid is a rare subepidermal autoimmune blistering disease characterized by autoantibodies against a 200-kDa protein in the basement membrane zone. Anti-p200 Pemphigoid is probably often misdiagnosed because of low availability of diagnostic assays and expertise and classified as bullous Pemphigoid or epidermolysis bullosa acquisita. Objective To clinically characterize patients with anti-p200 Pemphigoid, identified by using indirect immunofluorescence microscopy on skin substrates deficient in type VII collagen and laminin-332 (knockout analysis), to validate this technique by immunoblot with dermal extract, and to incorporate direct immunofluorescence serration pattern analysis in the diagnostic algorithm. Design, Setting, and Participants This was a retrospective study performed from January 2014 to June 2015 with biobank patient materials and clinical data for the period 1998 to 2015 from the single national referral center on autoimmune bullous diseases. Patients were selected based on a dermal side binding on 1-mol/L salt (sodium chloride)-split human skin substrate by indirect immunofluorescence microscopy, not diagnosed epidermolysis bullosa acquisita or anti–laminin-332 mucous membrane Pemphigoid. Main Outcomes and Measures Indirect immunofluorescence microscopy knockout analysis was performed and diagnosis of anti-p200 confirmed by immunoblot with dermal extract. Clinical, histological, and immunological findings were registered. Autoantibodies against laminin γ1 were determined by immunoblot. Results Twelve patients with anti-p200 Pemphigoid (7 male and 5 female; mean age, 66.6 years) were identified using the indirect immunofluorescence microscopy knockout analysis. Direct immunofluorescence microscopy showed a linear n-serrated IgG deposition pattern along the basement membrane zone in 9 of 11 patients. The diagnosis was confirmed by immunoblot showing autoantibodies against 200-kDa protein in dermal extract in 12 of 12 patients. Autoantibodies against recombinant laminin γ1 were detected by immunoblot in 8 of 12 patients. Remarkable similarities were seen in clinical features with predominantly tense blisters on hands and feet, resembling dyshidrosiform Pemphigoid. Mucosal involvement was seen in 6 (50%) of the patients. Conclusions and Relevance Predominance of blisters on hands and feet may be a clinical clue to the diagnosis of anti-p200 Pemphigoid. Direct immunofluorescence microscopy serration pattern analysis and indirect immunofluorescence microscopy knockout analysis are valuable additional techniques to facilitate the diagnosis of anti-p200 Pemphigoid.
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bullous Pemphigoid as pruritus in the elderly a common presentation
JAMA Dermatology, 2013Co-Authors: Christiaan V Bakker, Hendri H. Pas, Jorrit B Terra, Marcel F JonkmanAbstract:IMPORTANCE In the literature, patients with bullous Pemphigoid have been reported to have itch without blisters. Clinical observations in these patients have varied from eczematous or urticarial to papular or nodular skin lesions. Here we investigated the spectrum of clinical variants. OBSERVATIONS Fifteen patients with itch without blisters had immunopathologic findings of bullous Pemphigoid. Mean age at diagnosis was 81.7 years. No blistering occurred during the mean 2.2 years of follow-up. Mean delay of diagnosis was 2.8 years. Clinical symptoms were heterogeneous: pruritus sine materia (no primary skin lesions), eczematous, urticarial, papular, and/or nodular skin lesions were seen. Treatment with potent topical corticosteroids or methotrexate sodium led to remission in 11 patients. CONCLUSIONS AND RELEVANCE Itch without skin lesions can be the only symptom of bullous Pemphigoid. Therefore, it is important to include serologic and direct immunofluorescence in the diagnostic algorithm of itch. We propose the unifying term pruritic nonbullous Pemphigoid for all patients with immunopathologic findings of bullous Pemphigoid, itch, and no blisters.
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inflammatory variant of epidermolysis bullosa acquisita with igg autoantibodies against type vii collagen and laminin α3
Archives of Dermatology, 2000Co-Authors: Marcel F Jonkman, Kim B Yancey, Jacqueline Schuur, F Dijk, K Heeres, Marcelus C J M De Jong, Jan Van Der Meer, Hendri H. PasAbstract:Background: The inflammatory variant of epidermolysis bullosa acquisita (EBA) may clinically closely resemble bullous or cicatricial Pemphigoid. Patients with inflammatory EBA have IgG autoantibodies against type VII collagen. Patients with anti-epiligrin cicatricial Pemphigoid have IgG autoantibodies against laminin 5. Observation: We describe a patient with inflammatory EBA exhibiting nonscarring oral and vaginal involvement. Indirect immunofluorescence using skin substrate lacking an epidermal basement membrane molecule, direct immunoelectron microscopy, immuno-blot, and immunoprecipitation studies revealed the simultaneous presence of circulating IgG autoantibodies against type VII collagen and laminin alpha 3. A final diagnosis of EBA was based on the sublamina densa level of blister formation. Conclusion: This case illustrates the clinical and immunological overlap between EBA and anti-epiligrin cicatricial Pemphigoid, a unique finding that may have developed as a consequence of epitope spreading.
