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Received Date : 28-Aug-2013 Revised Date : 22-Apr-2014 Accepted Date : 20-May-2014 Article type
: Clinical and laboratory investigations
Epidermolysis Bullosa Acquisita: A Retrospective Analysis of 12 Patients Evaluated in Four Tertiary Hospitals in Spain
Running head: Epidermolysis Bullosa Acquisita First Multicentric Spanish Study P. Iranzo1, J.E. Herrero-González2, J.M. Mascaró-Galy1, R. Suárez-Fernández3, A. España4
Dermatology Departments: Hospital Clínic, Barcelona1; Hospital del Mar, Barcelona2; Hospital Gregorio Marañón, Madrid3 and University Clinic of Navarra, Pamplona4
Funding sources: none Conflicts of interest: none declared The study did not require ethical approval
Bulleted statements What is known: Epidermolysis bullosa acquisita is caused by autoantibodies against type VII collagen. The inflammatory variant is difficult to differentiate from other autoimmune subepidermal bullous diseases.
This article is protected by copyright. All rights reserved. What is new: We observed an elevated incidence of neoplasia. Among responders, benefit with dapsone is seen with doses less than 100mg/day; higher doses are associated with higher side effects without further profit. Rituximab is effective in refractory cases. Response to this drug can be delayed.
Corresponding author: Pilar Iranzo Dermatology Department, Hospital Clínic, Barcelona c/ Villarroel 170, 08036 Barcelona SPAIN Tel: +34 93 2275400. Ext. 2422 Fax: +34 93 2275438 e-mail: [email protected] Abstract Background: Epidermolysis bullosa acquisita is an exceedingly rare subepidermal blistering disease caused by antibodies against type VII collagen. Large series of patients summarizing the clinical and immunological features of this disease are scarce. Objetive: To analyze the clinical and immunopathological characteristics, treatment responses and outcomes of 12 patients with epidermolysis bullosa acquisita from four tertiary Hospitals in Spain. Methods: Extensive retrospective review of clinical charts.
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Results: The mean age of onset was 48 years and the mean diagnosis delay was 20.75 months. Classical phenotype occurred in 41.6% cases, inflammatory in 41.6% and mixed in 16.6% of the patients. Mucosal involvement was present in 75%. Linear IgG deposition along the basement membrane zone was constantly present on direct immunofluorescence examination. Indirect immunofluorescence study was positive in 66.6% of the cases. Frequently associated diseases were: neoplasms (25%), inflammatory bowel disease (25%), hepatitis C virus infection (16.6%) and thyroid dysfunction (16.6%). Therapeutic responses were variable. Limitations: Retrospective study and small sample. Diagnostic tests were possibly modified by previous treatments.
Conclusions: Prevalence of neoplasms was similar to this of inflammatory bowel disease. Multicentric prospective studies including a large number of patients are required for a better knowledge and management of this disease. Key words: Epidermolysis bullosa acquisita, subepidermal autoimmune blistering disease, type VII collagen autoantibodies.
Introduction Epidermolysis bullosa acquisita (EBA) is a chronic subepidermal autoimmune blistering disease characterized by IgG autoantibodies against type VII collagen1. Originally described by Elliot in 18952, in 1971 Roenigk established the diagnostic criteria based on the presence of spontaneous or trauma-induced
This article is protected by copyright. All rights reserved. blisters, arising in the adulthood without a family history of blistering disease, after the exclusion of all other bullous diseases3. In subsequent years, clinical, immunohistological, immunoelectron microscopical and serological features were described4-9. There are two main clinical subtypes of EBA: a classical non inflammatory mecano-bullous type with trauma-induced blisters that heal with scarring and milia formation, and an inflammatory type, resembling other subepidermal autoimmune blistering diseases such as bullous pemphigoid (BP)5, mucous membrane pemphigoid (MMP)10, Brunsting-Perry cicatricial pemphigoid11 antilamininỴ 1 pemphigoid or linear IgA disease12. The clinical presentation may change throughout evolution, and features of both subtypes may coexist in the same patient (mixed type). The estimated incidence of EBA is 0.26 cases per million people (5% of subepidermal blistering diseases) 13, 14. The real incidence is not well established. As the knowledge of other clinical variants different from classical subtype has been described and diagnostic tools have been improved, an increasing number of EBA inflammatory cases have been reported. Probably, inflammatory forms have been sometimes misdiagnosed as other subepidermal autoimmune blistering diseases. Disease onset typically occurs between the fourth and fifth decades, but it may appear from early childhood to elderly. EBA is associated with the haplotype HLA-DR2, with HLA-DRB1*13 in Koreans and with HLA-DRB1*15:03 in black patients of African descent15, 16. EBA has an unknown etiology, however there is strong evidence to support the pathogenic role of IgG autoantibodies against type VII collagen, including the
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induction of neonatal EBA by vertical transfer of maternal antibodies, some ex vivo studies and passive transfer or active animal experimental models17, 18-20. These antibodies have been also detected in bullous systemic lupus erythematosus21. The aim of our study is to analyze the clinical and laboratory profile, treatment and outcome of 12 patients diagnosed of EBA at four tertiary Hospitals in Spain.
Material and Methods Patients details
The study sample included 12 patients attending the autoimmune blistering disease units of 4 tertiary Hospitals in Spain from 1985 to 2012. The proposed criteria for diagnosis of EBA8, 22-24 are detailed in Table 1. In our series just patients fulfilling all the proposal criteria were included. Demographic and clinical data were retrospectively recorded from clinical charts. EBA was clinically classified into the next phenotypes: classical non inflammatory, inflammatory (the rest), or mixed forms. Cutaneous lesions were considered mild if the body surface area involved was less than 10%, and severe in the remaining cases Mucosal involvement was assessed by oral, genital and ophthalmologic examination. Otoscopic and endoscopic nose and throat examination was performed in 4 patients and gastrointestinal endoscopy in 2 patients.
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Diagnosis
In all cases diagnosis was made by clinical, histological and IF features. ELISA for anti-type VII collagen antibodies and Westernblotting was performed in 7 and 5 patients, respectively; immunomapping with collagen IV was performed in 2 cases and IIF on collagen VII knock-out skin substrate and fluorescent overlay antigen mapping in 1 case each.
Definitions
We used the definitions of remission proposed by Kim et al25, adapted from the definition of remission in pemphigus of the International Pemphigus Committee26 “Complete Remission (CR) off Therapy”: absence of new and/or established lesions for at least two months without treatment. “Complete Remission on Therapy (CRT)”: absence of new lesions while the patient is receiving minimal therapy. “Minimal Therapy”: less than or equal to 8 mg/day of methylprednisolone (or equivalent) with or without adjuvant therapy including dapsone and colchicine for at least two months. “Partial Remission (PR) off Therapy”: transient new lesions that heal within one week without treatment, for at least two months. “Partial Remission on Minimal Therapy (PRT)”: transient new lesions that heal within one week while the patient is receiving minimal therapy.
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Results Demographics and clinical
The mean age of onset was 48 years (range 19-90), median 55.5 years, 5 (41.6%) females and 7 (58.4%) males from which 10 patients were Caucasian and 2 Hispanic. The mean time from disease onset to diagnosis was 20.75 months (range 1-72), median 11 months. The mean follow up period (until December 2012) was 45.1 months, median 34 months (range 5-144) (Table 2). Antinuclear antibodies (ANA) were positive in 3 cases (25%), one of them with positive anti SS-A/ Ro antibodies; we counted a total of 5 neoplasms in 3 patients (25%); 3 patients (25%) had a previous diagnosis of inflammatory bowel disease (IBD); Hepatitis C virus (HCV) infection occurred in 2 patients (16.6%); thyroiditis in other 2 patients (16.6%); 3 patients (25%) with inflammatory EBA (patients 3, 4, 7) presented with other associated autoimmune diseases (Table 2). The clinical subtype of EBA was classical in 5 cases (41.6%) (Fig 1), inflammatory in other 5 (41.6%) (Fig 2), one of them resembling BrunstingPerry cicatricial pemphigoid (Fig 3) and mixed in the remaining 2 (16.6%). Most of the classical forms occurred in the eldest patients. Patient 9 (with a mixed phenotype) was lost for follow-up during 1 year and later he was attended again with a classical phenotype, after having received systemic corticosteroids in his country of origin. Cutaneous involvement was mild in 50% of the cases and severe in the remaining 50% (Table 2).
This article is protected by copyright. All rights reserved. Mucosal involvement occurred in 9 cases (75%); oral mucosa was involved in all of them; genital in 3, ocular in 2, nose in 2, pharynx and larynx in 1, and esophageal was affected in 1 more (Table 2). Ocular involvement consisted of conjunctival blistering and minimal conjunctival scarring (patients 2 and 5). Nail dystrophy was present in 2 cases; patient 6 presented a total shedding of few nails and distal plate dystrophy (Fig 1), while patient 9 had a minimal nail plate dystrophy. Pathological, immunological and other laboratory findings
Histopathological examination revealed subepidermal detachment in all cases (Fig 4). Inflammatory infiltrates were of variable degree: scarce or absent in patients with the classical presentation (Fig 4a), in contrast BP-like cases with a mixed infiltration of neutrophils and eosinophils in a superficial perivascular distribution, interstitial, or both, and at the dermal tips (Fig 4b). Leucocytoclasia was observed in 2 cases and eosinophilic spongiosis in 2 other specimens (Table 3). Direct immunofluorescence examination (DIF) revealed lineal IgG deposits at the basement membrane zone (BMZ) (Fig 5 a) in all cases, with C3 deposition coexisting in 11 of them (Fig 5 b). IgA staining was evident in 3 and IgM, in 2 patients. We were not able to correlate any isotype with either clinical phenotype or therapeutic response. These deposits were located at the dermal side of the artificially induced blister in all the 6 cases where salt-split-skin DIF was performed (Fig 6).
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IIF examination was negative in 4 out of 12 patients. An antinuclear pattern was appreciated in 1 case. IIF on salt-split skin was performed in 9 cases, with negative results in 3 and with antibodies binding to dermal side in 6 patients. ELISA for collagen VII was positive in 3 out of 7 performed cases and immunoblotting analysis in 5 out of 6 analyzed cases (Table 3). In 2 of the 3 remaining cases in which we failed to detect anti collagen VII antibodies, an userrated pattern was appreciated (Fig 5 a), and the case with nonspecific pattern the diagnosis was confirmed by immunomapping.
Therapy and evolution
Treatment is detailed in Table 4. Corticosteroids were given in 11 patients (most of them preceding EBA diagnosis) with doses ranging from 25 to 60 mg/ day of prednisone (or equivalent). None of them attained a CR. Doses superior to 15 mg/day were necessary to control disease activity. Prednisone dose could be tapered to 5 mg/ day in monotherapy without further flare in patient 4. In 7 patients dapsone (doses 50-150 mg/day) was given along with steroids, 2 of whom achieved CR and 2, PR. Adverse effects occurred in 2 cases, both with doses >100 mg. Colchicine was given to 6 patients achieving 2 PR and 2 CR [as monotherapy in 1 case, along intravenous immunoglobulins (IGIV) in the other]. The only adverse effect was diarrhea in 3 patients. IVIG associated to prednisone, colchicine and dapsone were administered in the more refractory 5 cases, resulting in 3 PR, 1 CR and 1 CRT.
This article is protected by copyright. All rights reserved. Patient 5 was treated with Infliximab associated to methotrexate. Both medications were suppressed for progressive worsening. An excellent response was obtained with rituximab (RTX) in 2 cases; patient 5 (treated with 2 cycles of rituximab 7 months after infliximab discontinuation) response started 8 months after the last dose, and was sustained after 36 months of follow up. The efficacy of cyclosporin was difficult to evaluate. There was no response in 1 case. Response was not evaluable in patient 2 [she died 15 days after starting treatment, due to pulmonary thromboembolism (PTE)]. Patient 8 was previously treated with this drug for Crohn’s disease. Azathioprine was used in 3 patients without efficacy. Overall, we achieved 2 CR, 5 CRT and 3 PRT (Table 4). Mean time to CR was 29.5 months (range 22-37) and 33 months to CRT (range 2-120). Exitus occurred in 3 patients. The causes of death were metastatic pulmonary adenocarcinoma in 2 patients (one of them in CR, and the other one in PRT) and 1 of PTE.
Discussion EBA is an unusual subepidermal autoimmune blistering disease with heterogeneous clinical manifestations. There are only a few series including more than 10 patients
25, 27-29
.
There was a higher incidence in males, without a significant difference in gender regarding the classical and inflammatory phenotypes. Classical forms mostly
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occurred in older patients, probably as a result of the evolution of inflammatory types after treatment as we observed in patient 9. Several systemic diseases and neoplasms may be associated with EBA. However, since EBA is a rare disease, most of these reports are anecdotic. IBD has been the most frequently reported association, with Crohn’s disease (CD) being described in 30% EBA patients. This association is possible due to the expression of type VII collagen in both human colon and in the sublamina densa of the epidermal BMZ30, leading to a cross reaction to the same antigen in different tissues. Supporting this hypothesis, the presence of autoantibodies against type VII collagen has been demonstrated in more than 60% of IBD patients. Nevertheless, the absence of skin blistering in the majority of IBD patients could be explained by different subclasses of autoantibodies against type VII collagen, mainly IgG1 and IG4 subclasses in EBA in contrast to a predominant IgG3 response in IBD. This fact suggests that progression towards skin blistering disease is associated with either the generation of IgG1 and IgG4 autoantibodies against type VII collagen or by the development of antibodies to different epitopes of collagen VII. Furthermore, a lower magnitude of the type VII collagen antibody response in IBD compared to EBA may not exceed the threshold needed to trigger skin inflammation resulting in blistering31. The onset of IBD preceded EBA in all the 3 patients of our series, as previously described32. Gastrointestinal symptoms were carefully evaluated in anamnesis, but routine colonoscopy or intestinal histopathological examinations were not performed. This fact might explain the low incidence of IBD in our patients. ANA were present in 3 patients, none of them fulfilling criteria for systemic lupus erythematosus.
This article is protected by copyright. All rights reserved. There are few reports on associated neoplasm33-37. The high incidence of cancer observed in the present study has not been described in past published series. However, the relationship between EBA and the neoplasm in our patients does not suggest a paraneoplastic disease: 3 of the 5 neoplasms were under control before EBA onset; in patient 3, pulmonary adenocarcinoma was diagnosed during follow-up; in patient 1, the tumor occurred after CR of EBA. None of them had been previously treated with immunosuppressive agents that could play a role in cancer induction. Patients 3 and 4 with two neoplasms each had other associated autoimmune pathologies. Therefore, we hypothesize whether crossreactivity between common epitopes in tumoral cells and dermal type VII collagen could play a trigger role in the synthesis of autoantibodies and induction of EBA. Chronic hepatitis C infection has been linked to multiple extrahepatic and autoimmune diseases including 3 cases of EBA36, 37. HCV infection was associated in 2 of our patients series, this relationship is difficult to assess due to the small number of cases and the high prevalence of HVC infection in Spain. Upper digestive endoscopy, otoscopic and endoscopic nose and throat examination were performed only in symptomatic patients, so subclinical involvement may have been mislead. Nail loss, milia formation and atrophic scarring only occurred in classical forms and scarring alopecia in the patient with Brunsting- Perry like EBA patient (Fig 3). It is difficult to assert the cause of death in patient 2. Cyclosporin thrombogenicity has been demonstrated both in vivo and in vitro, it manifested mostly with pulmonary embolisms and deep venous thromboses38. In addition, corticosteroid therapy can induce hypercoagulability. Thromboembolismis an
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uncommon but recognized complication of IBD that occurs in 1.3–6.4% of all such patients, nevertheless there is no report to date of EBA associated to thromboembolic events 39. Vodegel et al24 described the importance of DIF pattern in EBA diagnosis: besides a true linear pattern, a u-serrated staining pattern is observed in EBA and an n-serrated staining in other subepidermal immunobullous diseases. Buijsrogge27 reported a triple yield of EBA diagnosis with serration pattern analysis than when only one positive serological criterion was used. Unfortunately, in our series this pattern was rarely appreciable when we tried to reproduce this technique. Lehman et al40 suggest a practical diagnostic algorithm for subepidermal autoimmune bullous disease with the relative cost and availability of laboratory tests. We propose an initial therapeutic protocol similar to Kim et al
25
and Ishii et al
41
:an initial prednisone dosage below 0.5 mg/kg combined with colchicine 1-2 mg/ day and/or dapsone 25-100 mg/day. Prednisone dosage can be gradually tapered, once disease control is achieved. In refractory cases, IVIG or RTX should be considered. Multicentric, multidisciplinary prospective studies including a large number of patients are mandatory for a better knowledge and management of this disease.
Acknowledgments We are grateful to Dr C Sitaru (University of Freiburg, Germany) for performing ELISA-collagen VII study, and to Dr A Guilabert (Hospital Asil de Granollers, Barcelona, Spain) for immunoblot analysis.
This article is protected by copyright. All rights reserved. References 1-Woodley DT, Briggamann RA, O´Keefe EJ et al. Identification of the skin basement –membrane autoantigen in epidermolysis bullosa acquisita. N Eng J Med 1984; 310:1007-13 2-Elliot GT. Two cases of epidermolysis bullosa. J Cutan Genitourin Dis 1895; 13:10-18 3-Roenigk HH Jr, Ryan JG, Bergfeld WF. Epidermolisys bullosa acquisita: report of three cases and review of al published cases. Arch Dermatol 1971; 103:1-10 4-Ritcher BJ; McNut NS. The spectrum of epidermolisis bullosa acquisita. Arch Dermatol 1979; 115:1325-8 5-Gammon WR, Briggaman RA, Wheeler CE Jr. Epidermolisys bullosa acquisita presenting as an inflammatory bullous disease. J Am Dermatol 1982; 7:382-7 6-Kushniruk W. The immunopathology of epidermolysis bullosa acquisita. Can Med Assoc J 1973; 108:1143-6 7- Nieboer C, Boorsma DM, Woderman MJ, Kalsbeek GL. Epidermolysis bullosa acquisita: Immunofluorescence, electron micoscopic and immunoelectron microscopic studies in four patients. Br J Dermatol 1980; 102:383-92 8-Yaoita H, Briggaman RA, Lawley TJ et al. Epidermolysus bullosa acquisita: Ultrastuctural and immunological Studies. J Invest Dermatol 1981; 76:288-92 9-WoodleyDT, Burgeson RE, Lunstrun G et al. The epidermolysis bullosa acquisita antigen is the globular carboxyl terminus of type VII procollagen. J Clin Invest 1988; 81:683-7
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10- Dahl MG. Epidermolysis bullosa acquisita a sign of cicatricial pemphigoid? Br J Dermatol 1979; 101:475-84. 11- Kurzhals G, Stolz W, Meurer M et al. Acquired epidermolysis bullosa with the clinical feature of Brusnsting-Perry cicatricial bullous pemphigoid. Arch Dermatol 1991; 127:391-5 12- Zambruno G, Manca V, Kanilakis J et al. Linear IgA bullous dermatosis with autoantibodies to a 290 kd antigen of anchoring fibrils. J Am Acad Dermatol 1994; 31:884-8 13-Bernard P, Vaillant L, Labeille B et al. Incidence and distribution of subepidermal autoinmune bullous skin diseases in three French regions. Arch Dermatol 1995; 131: 48-52 14-Zhu XJ, Niimi Y, Bystrin JC. Epidermolysys bullosa acquisita. Incidence in patients with basement membrane zone antibodies. Arch Dermatol 1990; 126:171-4 15-Lee CW, Kim SC, Han H. Distribution of HLA class II alleles in Korean patients with epidermolysis bullosa acquisita. Dermatology 1996; 193:328-9. 16- Zumelzu C, Le Roux-Villet C, Loiseau P et al. Black patients of African descent and HLA-DRB1*15:03 frequency overrepresented in epidermolysis bullosa acquisita. J Invest Dermatol 2011; 131:2386-93 17-Abrams ML, Smidt A, Benjamin L et al. Congenital Epidermolysys bullosa acquisita. Vertical transfer of maternal autoantibody from mother to infant. Arch Dermatol 2011; 147:337-41
This article is protected by copyright. All rights reserved. 18-Sitaru C, Kromminga A, Hashimoto T et al. Autoantibodies to type VII collagen mediate Fcgamma-dependent neutrophil activation and induce dermalepidermal separation in cryosections of human skin. Am J Pathol 2002; 161:301–11. 19- Sitaru C, Mihai S, Otto C et al. Induction of dermal-epidermal separation in mice by passive transfer of antibodies specific to type VII collagen. J Clin Invest 2005; 115:870–8. 20-Ludwig RJ. Model systems duplicating epidermolysis bullosa acquisita: A methodological review. Autoimmunity 2011; 45:102–10. 21- Herrero-González JE, Mascaró JM Jr, Herrero C et al. Autoantibodies from patients with BSLE inducing recruitment of leukocytes to the dermoepidermal junction and subepidermal splits in cryosections of human skin. Arch Dermatol. 2006; 142:1513-6. 22- Hallel-Halevy D, Nadelman C, Chen M, Woodley DT. Epidermolysis bullosa acquisita: update and review. Clin Dermatol. 2001; 19 12-8 23- Rishu Gupta, BS, David T. Woodley, Mei Chen. Epidermolysis bullosa acquisita. Clin Dermatol 2012; 30:60–9 24- Vodegel RM, L, Jonkman MF, Pas HH, de Jong MD. U-serrated immunodeposition pattern differentiates type VII collagen targeting bullous diseases from other subepidermal bullous autoimmune diseases. Br J Dermatol 2004; 151:112-8 25- Kim JH, Kim YH, Kim SC. Epidermolysis bullosa acquisita: a retrospective clinical analysis of 30 cases. Acta Derm Venereol 2011; 91:307–12.
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26- Murrell DF, Dick S, Ahmed AR et al. Consensus statement on definitions of disease, end points, and therapeutic response for pemphigus. J Am Acad Dermatol 2008; 58:1043–6. 27- Buijsrogge JJ, Diercks GF, Pas HH, Jonkman MF. The many faces of epidermolysis bullosa acquisita after serration pattern analysis by direct immunofluorescence microscopy. Br J Dermatol 2011; 165:92-8 28- Delgado L, Aoki V, Santi C et al. Clinical and immunopathological evaluation of epidermolysis bullosa acquisita. Clin Exp Dermatol 2010; 36:12–18 29- Marzano AV, Cozzani E, Fanoni D et al. Diagnosis and disease severity assessment of epidermolysis bullosa acquisita by ELISA for anti-type VII collagen autoantibodies: an Italian multicentre study. Br J Dermatol 2013; 168:80-4 30- Chen M, O’Toole EA, Sanghavi J et al. The epidermolysis bullosa acquisita antigen (type VII collagen) is present in human colon and patients with Crohn’s disease have autoantibodies to type VII collagen. J Invest Dermatol 2002; 118:1059–64. 31- Hundorfean G, Neurath MF, Sitaru C. Autoimmunity against type VII collagen in inflammatory bowel disease. J. Cell. Mol. Med. 2010; 14:2393-403 32- Reddy H, Shipman AR, Wojnarowska F. Epidermolysis bullosa acquisita and inflammatory bowel disease: a review of the literature. Clin Exp Dermatol 2013; 38:225-9
This article is protected by copyright. All rights reserved. 33-Busch JO, Sticherling M. Epidermolysis bullosa acquisita and neuroendicrine pancreatic cancer-coincidence or pathogenetic relationship? J Dstch Dermatol Ges 2007; 5:916-8 34- Etienne A, Ruffieux P, Didierjean L, Saurat JH. Epidermolysis bullosa acquisita and metastatic cancer of the uterine cervix. Ann Dermatol Venereol 1998; 125:321–3. 35- Radfar L, Fatahzadeh M, Shahamat Y, Sirois D. Paraneoplastic epidermolysis bullosa acquisita associated with multiple myeloma. Spec Care Dentist 2006; 26:159–63. 36 +-Shook BA, Wells MJ, Rapini RP, Cobos E. Epidermolysis bullosa acquisita occurring in 2 patients with hepatitis C. J Am Acad Dermatol 2006; 54:888-91 37-Thiery S, Misery L, Chossegros P et al. Epidermolyse bulleuse acquise et hepatite virale C. Ann Dermatol Venereol 1998; 125:264-7. 38- Burke JF, Pirsch JD, Ramos EL et al. Long-term efficacy and safety of cyclosporine in renal-transplant recipients. N Engl J Med 1994; 331: 358–63. 39- Conlan MG, Haire WD, Burnett DA. Prothrombotic abnormalities in inflammatory bowel disease. Dig Dis Sci 1989; 34:1089–93 40- Lehman JS, Camilleri MJ, Gibson LE. Epidermolysis bullosa acquisita: concise review and practical considerations. Int J Dermatol 2009; 48:227-35 41-Ishii N, Hamada T, Dainichi T et al. Epidermolysis bullosa acquisita: What´s is new. J Dermatol 2010; 37: 220-230
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Figure Legends Fig 1- Classical mecano-bullous phenotype: multiple milia cysts over the back of the hand, nail plate lost and dystrophy (patient 7 after IVIG therapy) Fig 2- Inflammatory phenotype: extensive urticarial plaques over the trunk with eroded bulla Fig 3- Scarring alopecia in Brunsting-Perry pemphigoid-like presentation Fig 4- Hematoxylin and eosin: a) Classical subtype: subepidermal blister with scarce infiltrate. b) Immflamatory subtype: subepidermal blister with dermal infiltrates of neutrophils and eosinophils Fig 5- Direct immunofluorescence microscopy of perilesional skin: a) linear basement membrane zone IgG deposition with u-serrated pattern. b) complement basement membrane zone deposition Fig 6 -Direct immunofluorescence on salt split skin: IgG autoantibodies binding to dermal side of split
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Table 1: Criteria Diagnosis of EBA8, 22-24 1. A bullous disorder within the defined clinical spectrum 2. Lack of family history of a bullous disorder 3. Subepidermal blister in histological examination 4. DIF: Immunoglobulin deposits at dermal-epidermal junction 5. IEM: IgG deposits within the lower lamina densa and/or sublamina densa zone at the dermal-epidermal junction of perilesional skin 6. Alternative laboratory tests for item 5 included indirect or direct SSSI*, IIF using substrate deficient inbasement membrane molecules, Western blotting, FOAM, and ELISA, U-serrated pattern on DIF DIF: direct inmmunofluorescence. ELISA: enzyme-linked immunosorbent assay. FOAM: fluorescent overlay antigen mapping. IIF:Indirect inmmunofluorescence. SSS: salt skin split. *SSSI assay may not be conclusive in the differentiation of true CP from EBA when clinical presentation is CP-like.
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Table 2: Demographic and Clinical Characteristics
Patient/ Gender/ Diagnosis Race
Age*
Delay**
1 Cauc
M/ 73
12
2 Cauc
F/ 72
1
3 Lat. Am
F/ 32
72
ASOCIATED DISEASES
Clinical
Neoplasia
Other
Phenotype
Pulmonary ac
MGUS, HCV,DM 2, Thalasemia, COPD
Classical
BSA Mucosal/ %
10 Or, Oc
Inflammatory
>10
Cervix and pulmonary ac
Haemolytic anemia, ANA+
MM, ac mama, eccrine poroma
Hypothyroidism, optical neuritis, rhinitis, COPD, Inflammatory lichen planus, ANA+
Or, G;Ph, L
4 Cauc
F/ 64
3
5 Cauc
M/ 28
60
Thyroiditis, CD
Inflammatory Br-P
10 Or/ Yes
7 Cauc
F/ 19
6
8 Cauc
M/ 34
5
UC
9 Lat. Am
M/ 59
8
10 Cauc
M/ 52
11 Cauc 12 Cauc
Arthritis, ANA+, Inflammatory Ro+
10 Or, Es
Inflammatory
10 Or/ Yes
24
Depression
Classical
M/ 90
10
COPD
Classical
10 Or
UC
Received Date : 28-Aug-2013 Revised Date : 22-Apr-2014 Accepted Date : 20-May-2014 Article type
: Clinical and laboratory investigations
Epidermolysis Bullosa Acquisita: A Retrospective Analysis of 12 Patients Evaluated in Four Tertiary Hospitals in Spain
Running head: Epidermolysis Bullosa Acquisita First Multicentric Spanish Study P. Iranzo1, J.E. Herrero-González2, J.M. Mascaró-Galy1, R. Suárez-Fernández3, A. España4
Dermatology Departments: Hospital Clínic, Barcelona1; Hospital del Mar, Barcelona2; Hospital Gregorio Marañón, Madrid3 and University Clinic of Navarra, Pamplona4
Funding sources: none Conflicts of interest: none declared The study did not require ethical approval
Bulleted statements What is known: Epidermolysis bullosa acquisita is caused by autoantibodies against type VII collagen. The inflammatory variant is difficult to differentiate from other autoimmune subepidermal bullous diseases.
This article is protected by copyright. All rights reserved. What is new: We observed an elevated incidence of neoplasia. Among responders, benefit with dapsone is seen with doses less than 100mg/day; higher doses are associated with higher side effects without further profit. Rituximab is effective in refractory cases. Response to this drug can be delayed.
Corresponding author: Pilar Iranzo Dermatology Department, Hospital Clínic, Barcelona c/ Villarroel 170, 08036 Barcelona SPAIN Tel: +34 93 2275400. Ext. 2422 Fax: +34 93 2275438 e-mail: [email protected] Abstract Background: Epidermolysis bullosa acquisita is an exceedingly rare subepidermal blistering disease caused by antibodies against type VII collagen. Large series of patients summarizing the clinical and immunological features of this disease are scarce. Objetive: To analyze the clinical and immunopathological characteristics, treatment responses and outcomes of 12 patients with epidermolysis bullosa acquisita from four tertiary Hospitals in Spain. Methods: Extensive retrospective review of clinical charts.
This article is protected by copyright. All rights reserved.
Results: The mean age of onset was 48 years and the mean diagnosis delay was 20.75 months. Classical phenotype occurred in 41.6% cases, inflammatory in 41.6% and mixed in 16.6% of the patients. Mucosal involvement was present in 75%. Linear IgG deposition along the basement membrane zone was constantly present on direct immunofluorescence examination. Indirect immunofluorescence study was positive in 66.6% of the cases. Frequently associated diseases were: neoplasms (25%), inflammatory bowel disease (25%), hepatitis C virus infection (16.6%) and thyroid dysfunction (16.6%). Therapeutic responses were variable. Limitations: Retrospective study and small sample. Diagnostic tests were possibly modified by previous treatments.
Conclusions: Prevalence of neoplasms was similar to this of inflammatory bowel disease. Multicentric prospective studies including a large number of patients are required for a better knowledge and management of this disease. Key words: Epidermolysis bullosa acquisita, subepidermal autoimmune blistering disease, type VII collagen autoantibodies.
Introduction Epidermolysis bullosa acquisita (EBA) is a chronic subepidermal autoimmune blistering disease characterized by IgG autoantibodies against type VII collagen1. Originally described by Elliot in 18952, in 1971 Roenigk established the diagnostic criteria based on the presence of spontaneous or trauma-induced
This article is protected by copyright. All rights reserved. blisters, arising in the adulthood without a family history of blistering disease, after the exclusion of all other bullous diseases3. In subsequent years, clinical, immunohistological, immunoelectron microscopical and serological features were described4-9. There are two main clinical subtypes of EBA: a classical non inflammatory mecano-bullous type with trauma-induced blisters that heal with scarring and milia formation, and an inflammatory type, resembling other subepidermal autoimmune blistering diseases such as bullous pemphigoid (BP)5, mucous membrane pemphigoid (MMP)10, Brunsting-Perry cicatricial pemphigoid11 antilamininỴ 1 pemphigoid or linear IgA disease12. The clinical presentation may change throughout evolution, and features of both subtypes may coexist in the same patient (mixed type). The estimated incidence of EBA is 0.26 cases per million people (5% of subepidermal blistering diseases) 13, 14. The real incidence is not well established. As the knowledge of other clinical variants different from classical subtype has been described and diagnostic tools have been improved, an increasing number of EBA inflammatory cases have been reported. Probably, inflammatory forms have been sometimes misdiagnosed as other subepidermal autoimmune blistering diseases. Disease onset typically occurs between the fourth and fifth decades, but it may appear from early childhood to elderly. EBA is associated with the haplotype HLA-DR2, with HLA-DRB1*13 in Koreans and with HLA-DRB1*15:03 in black patients of African descent15, 16. EBA has an unknown etiology, however there is strong evidence to support the pathogenic role of IgG autoantibodies against type VII collagen, including the
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induction of neonatal EBA by vertical transfer of maternal antibodies, some ex vivo studies and passive transfer or active animal experimental models17, 18-20. These antibodies have been also detected in bullous systemic lupus erythematosus21. The aim of our study is to analyze the clinical and laboratory profile, treatment and outcome of 12 patients diagnosed of EBA at four tertiary Hospitals in Spain.
Material and Methods Patients details
The study sample included 12 patients attending the autoimmune blistering disease units of 4 tertiary Hospitals in Spain from 1985 to 2012. The proposed criteria for diagnosis of EBA8, 22-24 are detailed in Table 1. In our series just patients fulfilling all the proposal criteria were included. Demographic and clinical data were retrospectively recorded from clinical charts. EBA was clinically classified into the next phenotypes: classical non inflammatory, inflammatory (the rest), or mixed forms. Cutaneous lesions were considered mild if the body surface area involved was less than 10%, and severe in the remaining cases Mucosal involvement was assessed by oral, genital and ophthalmologic examination. Otoscopic and endoscopic nose and throat examination was performed in 4 patients and gastrointestinal endoscopy in 2 patients.
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Diagnosis
In all cases diagnosis was made by clinical, histological and IF features. ELISA for anti-type VII collagen antibodies and Westernblotting was performed in 7 and 5 patients, respectively; immunomapping with collagen IV was performed in 2 cases and IIF on collagen VII knock-out skin substrate and fluorescent overlay antigen mapping in 1 case each.
Definitions
We used the definitions of remission proposed by Kim et al25, adapted from the definition of remission in pemphigus of the International Pemphigus Committee26 “Complete Remission (CR) off Therapy”: absence of new and/or established lesions for at least two months without treatment. “Complete Remission on Therapy (CRT)”: absence of new lesions while the patient is receiving minimal therapy. “Minimal Therapy”: less than or equal to 8 mg/day of methylprednisolone (or equivalent) with or without adjuvant therapy including dapsone and colchicine for at least two months. “Partial Remission (PR) off Therapy”: transient new lesions that heal within one week without treatment, for at least two months. “Partial Remission on Minimal Therapy (PRT)”: transient new lesions that heal within one week while the patient is receiving minimal therapy.
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Results Demographics and clinical
The mean age of onset was 48 years (range 19-90), median 55.5 years, 5 (41.6%) females and 7 (58.4%) males from which 10 patients were Caucasian and 2 Hispanic. The mean time from disease onset to diagnosis was 20.75 months (range 1-72), median 11 months. The mean follow up period (until December 2012) was 45.1 months, median 34 months (range 5-144) (Table 2). Antinuclear antibodies (ANA) were positive in 3 cases (25%), one of them with positive anti SS-A/ Ro antibodies; we counted a total of 5 neoplasms in 3 patients (25%); 3 patients (25%) had a previous diagnosis of inflammatory bowel disease (IBD); Hepatitis C virus (HCV) infection occurred in 2 patients (16.6%); thyroiditis in other 2 patients (16.6%); 3 patients (25%) with inflammatory EBA (patients 3, 4, 7) presented with other associated autoimmune diseases (Table 2). The clinical subtype of EBA was classical in 5 cases (41.6%) (Fig 1), inflammatory in other 5 (41.6%) (Fig 2), one of them resembling BrunstingPerry cicatricial pemphigoid (Fig 3) and mixed in the remaining 2 (16.6%). Most of the classical forms occurred in the eldest patients. Patient 9 (with a mixed phenotype) was lost for follow-up during 1 year and later he was attended again with a classical phenotype, after having received systemic corticosteroids in his country of origin. Cutaneous involvement was mild in 50% of the cases and severe in the remaining 50% (Table 2).
This article is protected by copyright. All rights reserved. Mucosal involvement occurred in 9 cases (75%); oral mucosa was involved in all of them; genital in 3, ocular in 2, nose in 2, pharynx and larynx in 1, and esophageal was affected in 1 more (Table 2). Ocular involvement consisted of conjunctival blistering and minimal conjunctival scarring (patients 2 and 5). Nail dystrophy was present in 2 cases; patient 6 presented a total shedding of few nails and distal plate dystrophy (Fig 1), while patient 9 had a minimal nail plate dystrophy. Pathological, immunological and other laboratory findings
Histopathological examination revealed subepidermal detachment in all cases (Fig 4). Inflammatory infiltrates were of variable degree: scarce or absent in patients with the classical presentation (Fig 4a), in contrast BP-like cases with a mixed infiltration of neutrophils and eosinophils in a superficial perivascular distribution, interstitial, or both, and at the dermal tips (Fig 4b). Leucocytoclasia was observed in 2 cases and eosinophilic spongiosis in 2 other specimens (Table 3). Direct immunofluorescence examination (DIF) revealed lineal IgG deposits at the basement membrane zone (BMZ) (Fig 5 a) in all cases, with C3 deposition coexisting in 11 of them (Fig 5 b). IgA staining was evident in 3 and IgM, in 2 patients. We were not able to correlate any isotype with either clinical phenotype or therapeutic response. These deposits were located at the dermal side of the artificially induced blister in all the 6 cases where salt-split-skin DIF was performed (Fig 6).
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IIF examination was negative in 4 out of 12 patients. An antinuclear pattern was appreciated in 1 case. IIF on salt-split skin was performed in 9 cases, with negative results in 3 and with antibodies binding to dermal side in 6 patients. ELISA for collagen VII was positive in 3 out of 7 performed cases and immunoblotting analysis in 5 out of 6 analyzed cases (Table 3). In 2 of the 3 remaining cases in which we failed to detect anti collagen VII antibodies, an userrated pattern was appreciated (Fig 5 a), and the case with nonspecific pattern the diagnosis was confirmed by immunomapping.
Therapy and evolution
Treatment is detailed in Table 4. Corticosteroids were given in 11 patients (most of them preceding EBA diagnosis) with doses ranging from 25 to 60 mg/ day of prednisone (or equivalent). None of them attained a CR. Doses superior to 15 mg/day were necessary to control disease activity. Prednisone dose could be tapered to 5 mg/ day in monotherapy without further flare in patient 4. In 7 patients dapsone (doses 50-150 mg/day) was given along with steroids, 2 of whom achieved CR and 2, PR. Adverse effects occurred in 2 cases, both with doses >100 mg. Colchicine was given to 6 patients achieving 2 PR and 2 CR [as monotherapy in 1 case, along intravenous immunoglobulins (IGIV) in the other]. The only adverse effect was diarrhea in 3 patients. IVIG associated to prednisone, colchicine and dapsone were administered in the more refractory 5 cases, resulting in 3 PR, 1 CR and 1 CRT.
This article is protected by copyright. All rights reserved. Patient 5 was treated with Infliximab associated to methotrexate. Both medications were suppressed for progressive worsening. An excellent response was obtained with rituximab (RTX) in 2 cases; patient 5 (treated with 2 cycles of rituximab 7 months after infliximab discontinuation) response started 8 months after the last dose, and was sustained after 36 months of follow up. The efficacy of cyclosporin was difficult to evaluate. There was no response in 1 case. Response was not evaluable in patient 2 [she died 15 days after starting treatment, due to pulmonary thromboembolism (PTE)]. Patient 8 was previously treated with this drug for Crohn’s disease. Azathioprine was used in 3 patients without efficacy. Overall, we achieved 2 CR, 5 CRT and 3 PRT (Table 4). Mean time to CR was 29.5 months (range 22-37) and 33 months to CRT (range 2-120). Exitus occurred in 3 patients. The causes of death were metastatic pulmonary adenocarcinoma in 2 patients (one of them in CR, and the other one in PRT) and 1 of PTE.
Discussion EBA is an unusual subepidermal autoimmune blistering disease with heterogeneous clinical manifestations. There are only a few series including more than 10 patients
25, 27-29
.
There was a higher incidence in males, without a significant difference in gender regarding the classical and inflammatory phenotypes. Classical forms mostly
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occurred in older patients, probably as a result of the evolution of inflammatory types after treatment as we observed in patient 9. Several systemic diseases and neoplasms may be associated with EBA. However, since EBA is a rare disease, most of these reports are anecdotic. IBD has been the most frequently reported association, with Crohn’s disease (CD) being described in 30% EBA patients. This association is possible due to the expression of type VII collagen in both human colon and in the sublamina densa of the epidermal BMZ30, leading to a cross reaction to the same antigen in different tissues. Supporting this hypothesis, the presence of autoantibodies against type VII collagen has been demonstrated in more than 60% of IBD patients. Nevertheless, the absence of skin blistering in the majority of IBD patients could be explained by different subclasses of autoantibodies against type VII collagen, mainly IgG1 and IG4 subclasses in EBA in contrast to a predominant IgG3 response in IBD. This fact suggests that progression towards skin blistering disease is associated with either the generation of IgG1 and IgG4 autoantibodies against type VII collagen or by the development of antibodies to different epitopes of collagen VII. Furthermore, a lower magnitude of the type VII collagen antibody response in IBD compared to EBA may not exceed the threshold needed to trigger skin inflammation resulting in blistering31. The onset of IBD preceded EBA in all the 3 patients of our series, as previously described32. Gastrointestinal symptoms were carefully evaluated in anamnesis, but routine colonoscopy or intestinal histopathological examinations were not performed. This fact might explain the low incidence of IBD in our patients. ANA were present in 3 patients, none of them fulfilling criteria for systemic lupus erythematosus.
This article is protected by copyright. All rights reserved. There are few reports on associated neoplasm33-37. The high incidence of cancer observed in the present study has not been described in past published series. However, the relationship between EBA and the neoplasm in our patients does not suggest a paraneoplastic disease: 3 of the 5 neoplasms were under control before EBA onset; in patient 3, pulmonary adenocarcinoma was diagnosed during follow-up; in patient 1, the tumor occurred after CR of EBA. None of them had been previously treated with immunosuppressive agents that could play a role in cancer induction. Patients 3 and 4 with two neoplasms each had other associated autoimmune pathologies. Therefore, we hypothesize whether crossreactivity between common epitopes in tumoral cells and dermal type VII collagen could play a trigger role in the synthesis of autoantibodies and induction of EBA. Chronic hepatitis C infection has been linked to multiple extrahepatic and autoimmune diseases including 3 cases of EBA36, 37. HCV infection was associated in 2 of our patients series, this relationship is difficult to assess due to the small number of cases and the high prevalence of HVC infection in Spain. Upper digestive endoscopy, otoscopic and endoscopic nose and throat examination were performed only in symptomatic patients, so subclinical involvement may have been mislead. Nail loss, milia formation and atrophic scarring only occurred in classical forms and scarring alopecia in the patient with Brunsting- Perry like EBA patient (Fig 3). It is difficult to assert the cause of death in patient 2. Cyclosporin thrombogenicity has been demonstrated both in vivo and in vitro, it manifested mostly with pulmonary embolisms and deep venous thromboses38. In addition, corticosteroid therapy can induce hypercoagulability. Thromboembolismis an
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uncommon but recognized complication of IBD that occurs in 1.3–6.4% of all such patients, nevertheless there is no report to date of EBA associated to thromboembolic events 39. Vodegel et al24 described the importance of DIF pattern in EBA diagnosis: besides a true linear pattern, a u-serrated staining pattern is observed in EBA and an n-serrated staining in other subepidermal immunobullous diseases. Buijsrogge27 reported a triple yield of EBA diagnosis with serration pattern analysis than when only one positive serological criterion was used. Unfortunately, in our series this pattern was rarely appreciable when we tried to reproduce this technique. Lehman et al40 suggest a practical diagnostic algorithm for subepidermal autoimmune bullous disease with the relative cost and availability of laboratory tests. We propose an initial therapeutic protocol similar to Kim et al
25
and Ishii et al
41
:an initial prednisone dosage below 0.5 mg/kg combined with colchicine 1-2 mg/ day and/or dapsone 25-100 mg/day. Prednisone dosage can be gradually tapered, once disease control is achieved. In refractory cases, IVIG or RTX should be considered. Multicentric, multidisciplinary prospective studies including a large number of patients are mandatory for a better knowledge and management of this disease.
Acknowledgments We are grateful to Dr C Sitaru (University of Freiburg, Germany) for performing ELISA-collagen VII study, and to Dr A Guilabert (Hospital Asil de Granollers, Barcelona, Spain) for immunoblot analysis.
This article is protected by copyright. All rights reserved. References 1-Woodley DT, Briggamann RA, O´Keefe EJ et al. Identification of the skin basement –membrane autoantigen in epidermolysis bullosa acquisita. N Eng J Med 1984; 310:1007-13 2-Elliot GT. Two cases of epidermolysis bullosa. J Cutan Genitourin Dis 1895; 13:10-18 3-Roenigk HH Jr, Ryan JG, Bergfeld WF. Epidermolisys bullosa acquisita: report of three cases and review of al published cases. Arch Dermatol 1971; 103:1-10 4-Ritcher BJ; McNut NS. The spectrum of epidermolisis bullosa acquisita. Arch Dermatol 1979; 115:1325-8 5-Gammon WR, Briggaman RA, Wheeler CE Jr. Epidermolisys bullosa acquisita presenting as an inflammatory bullous disease. J Am Dermatol 1982; 7:382-7 6-Kushniruk W. The immunopathology of epidermolysis bullosa acquisita. Can Med Assoc J 1973; 108:1143-6 7- Nieboer C, Boorsma DM, Woderman MJ, Kalsbeek GL. Epidermolysis bullosa acquisita: Immunofluorescence, electron micoscopic and immunoelectron microscopic studies in four patients. Br J Dermatol 1980; 102:383-92 8-Yaoita H, Briggaman RA, Lawley TJ et al. Epidermolysus bullosa acquisita: Ultrastuctural and immunological Studies. J Invest Dermatol 1981; 76:288-92 9-WoodleyDT, Burgeson RE, Lunstrun G et al. The epidermolysis bullosa acquisita antigen is the globular carboxyl terminus of type VII procollagen. J Clin Invest 1988; 81:683-7
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10- Dahl MG. Epidermolysis bullosa acquisita a sign of cicatricial pemphigoid? Br J Dermatol 1979; 101:475-84. 11- Kurzhals G, Stolz W, Meurer M et al. Acquired epidermolysis bullosa with the clinical feature of Brusnsting-Perry cicatricial bullous pemphigoid. Arch Dermatol 1991; 127:391-5 12- Zambruno G, Manca V, Kanilakis J et al. Linear IgA bullous dermatosis with autoantibodies to a 290 kd antigen of anchoring fibrils. J Am Acad Dermatol 1994; 31:884-8 13-Bernard P, Vaillant L, Labeille B et al. Incidence and distribution of subepidermal autoinmune bullous skin diseases in three French regions. Arch Dermatol 1995; 131: 48-52 14-Zhu XJ, Niimi Y, Bystrin JC. Epidermolysys bullosa acquisita. Incidence in patients with basement membrane zone antibodies. Arch Dermatol 1990; 126:171-4 15-Lee CW, Kim SC, Han H. Distribution of HLA class II alleles in Korean patients with epidermolysis bullosa acquisita. Dermatology 1996; 193:328-9. 16- Zumelzu C, Le Roux-Villet C, Loiseau P et al. Black patients of African descent and HLA-DRB1*15:03 frequency overrepresented in epidermolysis bullosa acquisita. J Invest Dermatol 2011; 131:2386-93 17-Abrams ML, Smidt A, Benjamin L et al. Congenital Epidermolysys bullosa acquisita. Vertical transfer of maternal autoantibody from mother to infant. Arch Dermatol 2011; 147:337-41
This article is protected by copyright. All rights reserved. 18-Sitaru C, Kromminga A, Hashimoto T et al. Autoantibodies to type VII collagen mediate Fcgamma-dependent neutrophil activation and induce dermalepidermal separation in cryosections of human skin. Am J Pathol 2002; 161:301–11. 19- Sitaru C, Mihai S, Otto C et al. Induction of dermal-epidermal separation in mice by passive transfer of antibodies specific to type VII collagen. J Clin Invest 2005; 115:870–8. 20-Ludwig RJ. Model systems duplicating epidermolysis bullosa acquisita: A methodological review. Autoimmunity 2011; 45:102–10. 21- Herrero-González JE, Mascaró JM Jr, Herrero C et al. Autoantibodies from patients with BSLE inducing recruitment of leukocytes to the dermoepidermal junction and subepidermal splits in cryosections of human skin. Arch Dermatol. 2006; 142:1513-6. 22- Hallel-Halevy D, Nadelman C, Chen M, Woodley DT. Epidermolysis bullosa acquisita: update and review. Clin Dermatol. 2001; 19 12-8 23- Rishu Gupta, BS, David T. Woodley, Mei Chen. Epidermolysis bullosa acquisita. Clin Dermatol 2012; 30:60–9 24- Vodegel RM, L, Jonkman MF, Pas HH, de Jong MD. U-serrated immunodeposition pattern differentiates type VII collagen targeting bullous diseases from other subepidermal bullous autoimmune diseases. Br J Dermatol 2004; 151:112-8 25- Kim JH, Kim YH, Kim SC. Epidermolysis bullosa acquisita: a retrospective clinical analysis of 30 cases. Acta Derm Venereol 2011; 91:307–12.
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26- Murrell DF, Dick S, Ahmed AR et al. Consensus statement on definitions of disease, end points, and therapeutic response for pemphigus. J Am Acad Dermatol 2008; 58:1043–6. 27- Buijsrogge JJ, Diercks GF, Pas HH, Jonkman MF. The many faces of epidermolysis bullosa acquisita after serration pattern analysis by direct immunofluorescence microscopy. Br J Dermatol 2011; 165:92-8 28- Delgado L, Aoki V, Santi C et al. Clinical and immunopathological evaluation of epidermolysis bullosa acquisita. Clin Exp Dermatol 2010; 36:12–18 29- Marzano AV, Cozzani E, Fanoni D et al. Diagnosis and disease severity assessment of epidermolysis bullosa acquisita by ELISA for anti-type VII collagen autoantibodies: an Italian multicentre study. Br J Dermatol 2013; 168:80-4 30- Chen M, O’Toole EA, Sanghavi J et al. The epidermolysis bullosa acquisita antigen (type VII collagen) is present in human colon and patients with Crohn’s disease have autoantibodies to type VII collagen. J Invest Dermatol 2002; 118:1059–64. 31- Hundorfean G, Neurath MF, Sitaru C. Autoimmunity against type VII collagen in inflammatory bowel disease. J. Cell. Mol. Med. 2010; 14:2393-403 32- Reddy H, Shipman AR, Wojnarowska F. Epidermolysis bullosa acquisita and inflammatory bowel disease: a review of the literature. Clin Exp Dermatol 2013; 38:225-9
This article is protected by copyright. All rights reserved. 33-Busch JO, Sticherling M. Epidermolysis bullosa acquisita and neuroendicrine pancreatic cancer-coincidence or pathogenetic relationship? J Dstch Dermatol Ges 2007; 5:916-8 34- Etienne A, Ruffieux P, Didierjean L, Saurat JH. Epidermolysis bullosa acquisita and metastatic cancer of the uterine cervix. Ann Dermatol Venereol 1998; 125:321–3. 35- Radfar L, Fatahzadeh M, Shahamat Y, Sirois D. Paraneoplastic epidermolysis bullosa acquisita associated with multiple myeloma. Spec Care Dentist 2006; 26:159–63. 36 +-Shook BA, Wells MJ, Rapini RP, Cobos E. Epidermolysis bullosa acquisita occurring in 2 patients with hepatitis C. J Am Acad Dermatol 2006; 54:888-91 37-Thiery S, Misery L, Chossegros P et al. Epidermolyse bulleuse acquise et hepatite virale C. Ann Dermatol Venereol 1998; 125:264-7. 38- Burke JF, Pirsch JD, Ramos EL et al. Long-term efficacy and safety of cyclosporine in renal-transplant recipients. N Engl J Med 1994; 331: 358–63. 39- Conlan MG, Haire WD, Burnett DA. Prothrombotic abnormalities in inflammatory bowel disease. Dig Dis Sci 1989; 34:1089–93 40- Lehman JS, Camilleri MJ, Gibson LE. Epidermolysis bullosa acquisita: concise review and practical considerations. Int J Dermatol 2009; 48:227-35 41-Ishii N, Hamada T, Dainichi T et al. Epidermolysis bullosa acquisita: What´s is new. J Dermatol 2010; 37: 220-230
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Figure Legends Fig 1- Classical mecano-bullous phenotype: multiple milia cysts over the back of the hand, nail plate lost and dystrophy (patient 7 after IVIG therapy) Fig 2- Inflammatory phenotype: extensive urticarial plaques over the trunk with eroded bulla Fig 3- Scarring alopecia in Brunsting-Perry pemphigoid-like presentation Fig 4- Hematoxylin and eosin: a) Classical subtype: subepidermal blister with scarce infiltrate. b) Immflamatory subtype: subepidermal blister with dermal infiltrates of neutrophils and eosinophils Fig 5- Direct immunofluorescence microscopy of perilesional skin: a) linear basement membrane zone IgG deposition with u-serrated pattern. b) complement basement membrane zone deposition Fig 6 -Direct immunofluorescence on salt split skin: IgG autoantibodies binding to dermal side of split
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Table 1: Criteria Diagnosis of EBA8, 22-24 1. A bullous disorder within the defined clinical spectrum 2. Lack of family history of a bullous disorder 3. Subepidermal blister in histological examination 4. DIF: Immunoglobulin deposits at dermal-epidermal junction 5. IEM: IgG deposits within the lower lamina densa and/or sublamina densa zone at the dermal-epidermal junction of perilesional skin 6. Alternative laboratory tests for item 5 included indirect or direct SSSI*, IIF using substrate deficient inbasement membrane molecules, Western blotting, FOAM, and ELISA, U-serrated pattern on DIF DIF: direct inmmunofluorescence. ELISA: enzyme-linked immunosorbent assay. FOAM: fluorescent overlay antigen mapping. IIF:Indirect inmmunofluorescence. SSS: salt skin split. *SSSI assay may not be conclusive in the differentiation of true CP from EBA when clinical presentation is CP-like.
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Table 2: Demographic and Clinical Characteristics
Patient/ Gender/ Diagnosis Race
Age*
Delay**
1 Cauc
M/ 73
12
2 Cauc
F/ 72
1
3 Lat. Am
F/ 32
72
ASOCIATED DISEASES
Clinical
Neoplasia
Other
Phenotype
Pulmonary ac
MGUS, HCV,DM 2, Thalasemia, COPD
Classical
BSA Mucosal/ %
10 Or, Oc
Inflammatory
>10
Cervix and pulmonary ac
Haemolytic anemia, ANA+
MM, ac mama, eccrine poroma
Hypothyroidism, optical neuritis, rhinitis, COPD, Inflammatory lichen planus, ANA+
Or, G;Ph, L
4 Cauc
F/ 64
3
5 Cauc
M/ 28
60
Thyroiditis, CD
Inflammatory Br-P
10 Or/ Yes
7 Cauc
F/ 19
6
8 Cauc
M/ 34
5
UC
9 Lat. Am
M/ 59
8
10 Cauc
M/ 52
11 Cauc 12 Cauc
Arthritis, ANA+, Inflammatory Ro+
10 Or, Es
Inflammatory
10 Or/ Yes
24
Depression
Classical
M/ 90
10
COPD
Classical
10 Or
UC
