Abstract

INTRODUCTION

Pemphigus is the name of a group of autoimmune pathological entities characterized by the formation of intraepithelial blisters in the skin and/or mucosa. It is histologically characterized by the formation of intraepidermal blisters and by the presence of deposits of immunoglobulin G (IgG) on the surface of keratinocytes. The presence of intraepidermal blisters results in loss of integrity of intercellular fixations caused by acantholysis, which means loss of adhesion between epithelial Malpighi cells. Autoantibodies act in desmosemes leading to loss of intercellular adhesion.¹1. Amormino SAF, Barbosa AAM. Pênfigo Vulgar: Revisão de Literatura e relato de caso clínico. R Periodontia. 2010;20:47-52.^,22. Sampaio SAP, Rivittu EA. Erupções Vésico-Bolhosas. In: Sampaio SAP, Rivitti EA. Dermatologia. São Paulo: Artes Médicas Ltda; 2007. p. 301-30.

The two major clinical forms of this disease are pemphigus vulgaris (PV) and pemphigus foliaceus (PF) - and its variant, endemic pemphigus foliaceus (EPF) or Fogo Selvagem - and differ between each other in terms of clinical, histologic, epidemiological and serological characteristics.³3. Sánchez-Perez J, García-Díez A. Pénfigo. Actas Dermosifiliogr. 2005;96:329-56. Less frequent forms include: drug-induced pemphigus, pemphigus herpetiformis, paraneoplastic pemphigus, and immunoglobulinA pemphigus.⁴4. Adriano AR, Gomes Neto A, Hamester GR, Nunes DH, Di Giunta G. Pemphigus vegetans induced by use of enalapril. An Bras Dermatol. 2011;86:1197-200.

5. Marini MA, Parra LS, Casas JG. Pénfigo herpetiforme: presentación de un caso y revisión de la literatura. Arch Argent Dermatol. 2004;54:103-8.

6. Zhu X, Zhang B. Paraneoplastic pemphigus. J Dermatol.2007;34:503-11.^-77. Funakoshi T, Lunardon L, Ellebrecht CT, Nagler AR, O'Leary CE, Payne AS. Enrichment of total serum IgG4 in patients with pemphigus. Br J Dermatol.2012;167:1245-53.

PV is considered the most common and most severe type of pemphigus and begins with oral lesions appearing as aphtous ulcers or lesions and subsequently affects the skin, with the onset of vesicles and flaccid blisters containing clear or turbid fluid throughout the tegument (Figure 1). In PV, IgG autoantibodies are directed against a group of transmembrane adhesion proteins located in desmosomes and named desmogleins (Dsg), more specifically their subtypes 1 and 3 (cutaneo-mucous form) and 3 (mucous form), which leads to acantholysis in the suprabasal spinous layer.²2. Sampaio SAP, Rivittu EA. Erupções Vésico-Bolhosas. In: Sampaio SAP, Rivitti EA. Dermatologia. São Paulo: Artes Médicas Ltda; 2007. p. 301-30.^,33. Sánchez-Perez J, García-Díez A. Pénfigo. Actas Dermosifiliogr. 2005;96:329-56.^,88. Cunha PR, Barraviera SRCS. Autoimmune bullous dermatoses. An Bras Dermatol. 2009;84:111-24.

PF is characterized by superficial blisters that break easily, eruptions, erythematous areas, crusts, and scales not affecting the mucosa (Figure 2).

Intradermal acantholysis occurs in the granular layer. The antigen for PF is known to be Dsg 1, which is highly expressed in the upper spinous layers.⁸8. Cunha PR, Barraviera SRCS. Autoimmune bullous dermatoses. An Bras Dermatol. 2009;84:111-24. PF may be subdivided into two clinical forms: the classical one, also known as Cazenave's disease, which is rare and occurs sporadically throughout the world; and the endemic one (EPF), or Fogo Selvagem, which occurs mainly in South America, especially in rural areas from Southeastern and Midwestern Brazil, and shows a great proportion of familial cases, particularly affecting young adults and children. Evidence indicates that a mosquito of the genus Similium (popularly known as black fly) may the environmental triggering factor for autoimmune response in EPF.²2. Sampaio SAP, Rivittu EA. Erupções Vésico-Bolhosas. In: Sampaio SAP, Rivitti EA. Dermatologia. São Paulo: Artes Médicas Ltda; 2007. p. 301-30.^,99. Rocha-Alvarez R, Ortega-Loayza AG, Friedman H, Campbell I, Aoki V, Rivitti EA, et al. Endemic pemphigus vulgaris. Arch Dermatol.2007;143:895-9.^,1010. Campbell R, Reis V, Aoki V, Cunha P, Hans Filho G, Alves G et al. Endemic pemphigus foliaceus / fogo selvagem. An Bras Dermatol. 2001;76:13-33.

In the Brazilian Amazon, one of the first effective reports on pemphigus described seven clinical cases diagnosed with PF in Pará state, where several countryside towns had mining areas that attracted a great number of migrants coming from other Brazilian states, especially from the Midwest region. Only one of the reported cases of pemphigus came from Pará state, and the others came from Goiás state, where the disease in acknowledgedly endemic.¹¹11. Silva D, Freire EPS. Pênfigo Foliáceo no Estado do Pará: estudo dos primeiros casos. R. Ci Bio. 1965; 3:15-25. From 1994 to 2004, 61 histologically confirmed cases of pemphigus were reported at a dermatology referral service in Belém, capital city of Pará state, 30 of which were cases of PF and 31 of PV. Additionally 55.56% of patients presented with the generalized form of the disease.¹²12. Rocha BNS, Oliveira CMM, Unger DAA. Estudo retrospectivo dos casos de pênfigo (foliáceo e vulgar) diagnosticados no Serviço de Dermatologia da Universidade Federal do Pará/Fundação Santa Casa de Misericórdia do Pará no período de julho de 1994 a julho de 2004. An Bras Dermatol. 2005;80:S77-188.

Other 10 cases of PF in the Brazilian Amazon were reported in Amazon state, including patients from riverside municipalities, but there was no evidence of familial and endemic outbreaks.¹³13. Talhari S, Fernandes G, Alecrin WD. Pênfigo foliáceo sul-americano no Estado do Amazonas. Estudo de 10 casos. An Bras Dermatol. 1975;50:49-52. In the Peruvian Amazon, studies indicate the occurrence of endemic areas of PF and PV, where the disease presents with histopathological, clinical and epidemiological characteristics similar to those described in Brazil.¹⁴14. Galarza C, Ortega-Loayza AG, Ramos W, Hurtado J, Lindo G, Ávila J, et al. Pénfigo foliáceo endémico y pénfigo vulgar en pacientes de edad pediátrica enUcayali. Dermatol Peru. 2004;14:99-103.^.1515. Ramos W, Chacon GR, Galarza C, Gutierrez EL, Smith ME, Ortega-Loayza AG. Endemic pemphigus in the Peruvian Amazon: epidemiology and risk factors for the development of complications during treatment. An Bras Dermatol.2012;87:838-45.

Treatment for pemphigus is primarily performed with systemic corticosteroids and should ideally be prescribed by a physician experienced in immunosupressive therapy at a daily dose of 1 to 2 mg of prednisone per kilo of weight, or the equivalent dose of another corticosteroid. The combination of corticosteroids with imunossupressants (azathioprine, cyclophosphamide, methotrexate, mycophenolate mofetil) has shown good results in controlling the disease, which allowed to reduce the dose of corticosteroid. When there is an associated bacterial lesion, systemic antibiotic therapy is also implemented. Clinical and laboratory control should be constant, in order to evaluate both disease evolution and undesired effects of corticosteroid therapy. A multiprofessional intervention is recommended to improve the quality of life of pemphigus patients.¹⁰10. Campbell R, Reis V, Aoki V, Cunha P, Hans Filho G, Alves G et al. Endemic pemphigus foliaceus / fogo selvagem. An Bras Dermatol. 2001;76:13-33.^,1616. Risso M, Villalpando KT, Pinho MN, Pallotta Filho R. Pênfigo vulgar: relato de caso clínico. Rev Gaúcha Odontol. 2011;59:515-20.

17. Timóteo RP, Marques LS, Bertoncello D. Physiotherapy intervention promotes better quality of life for individuals with pemphigus. Rev Soc Bras Med Trop.2010;43:580-3.

18. Moleri AB, Jordão MB, Ribeiro DMC, Moreira LC. Lesões Orais do Pênfigo Vulgar: a importância do Diagnóstico Precoce. Acta Sci. Med. 2008;1:72-9.^-1919. Murrell DF, Dick S, Ahmed AR, Amagai M, Barnadas MA, BorradoriL, et al. Consensus statement on definitions of disease, end points, and therapeutic response for pemphigus. J Am Acad Dermatol. 2008;58:1043-6.

Knowledge on pemphigus has grown considerably in recent years. With the purpose of standardizing scientific definitions on the management of the disease, the International Pemphigus Committee established some criteria to be used in clinical practice.¹⁹19. Murrell DF, Dick S, Ahmed AR, Amagai M, Barnadas MA, BorradoriL, et al. Consensus statement on definitions of disease, end points, and therapeutic response for pemphigus. J Am Acad Dermatol. 2008;58:1043-6. Disease activity is considered controlled when the existing lesions start to heal and the formation of new lesions stops. Therapy remission is defined as the absence of lesions for at least 2 months during minimum therapy, represented either by a dose of prednisone lower than or equal to 10 mg/day or by the use of adjuvant immunosuppresive therapy for at least 2 months. Remission without therapy occurs when patients not using any systemic therapy are free of lesions for at least 2 months. Recurrence occurs when patients develop three or more new lesions per month that do not heal spontaneously in 1 week. In cases of recurrence or treatment failure, alternative treatments with new combinations may provide some benefit.

The aim of this paper was to evaluate the epidemiological profile and the clinical evolution of patients with PV and PF admitted to a referral hospital for pemphigus cases in Pará state from 2003 to 2010.

PATIENTS AND METHODS

A cross-sectional, observational, descriptive study was conducted based on the direct analysis of the medical records of patients admitted to Hospital Fundação Santa Casa de Misericórdia do Pará (FSCMPA), city of Belém, Northern Brazil from 2003 to 2010 due to histologically confirmed PV and PF. All the 20 cases of pemphigus reported in the dermatology service of the institution during this period were included in the study. Epimiological aspects, disease history, symptomatology, intercurrent diseases, treatment, and clinical evolution were reviewed. The study was approved by the Research Ethics Committee of the institution under decision no. 002/11.

To perform the statistical analysis, categorical variables were compared between themselves based on contingency tables using the Pearson chi-square test. The Fisher's exact test was used when at least one expected frequency was lower than five. Statistical significance was set at p-value below 0.05.

RESULTS

No significant differences were found between patients from PV and PF groups in terms of gender, age, time from onset to diagnosis, length of hospital stay, and evolution. With regard to gender, there was a statistical trend (p = 0.0948) of PF to affect males (75%) and of PV to affect females (66.7%).

The age group most affected by PV was from 22 to 59 years (83.4%), while no pediatric patient, four adult patients (up to 59 years), and four elderly patients (above 60 years) were diagnosed with PF. The time elapsed from the onset of the first signs and symptoms of the disease to the diagnosis was higher than 1 month and lower than 1 year in 75% of cases in patients from both groups.

Length of hospital stay was higher than 1 month and lower than 3 months in 50% of patients from both groups, and a satisfactory evolution (improvement of clinical symptoms) was achieved in most cases (Table 1). Disease recurrence after previous remission was reported in four of the patients discharged with clinical improvement, but they did not require readmission. However, two PV patients and one PF patient required only one readmission, and one PF patient required more than one readmission.

Oral immunosuppressive therapy regimens used to threat these patients included from monotherapy with prednisone to regimens combining steroids with azathioprine or azathioprine and dapsone (Table 2). Clinical support measures, symptomatic treatment specific for each case, and antibiotic therapy for cases of associated secondary infection were also implemented in the management of pemphigus patients.

Four patients from the study sample died, three of which were diagnosed with PV and one with PF, and developed sepsis with infection in different sites at some point of the treatment (Table 3).

DISCUSSION

Epidemiological data on pemphigus are still limited. The worldwide incidence of the disease ranges from 0.75 to 14 cases/1.000.000 inhabitants per year, depending on location, and tends to be higher in countries at lower latitudes.²⁰20. Hahn-Ristic K, Rzany B, Amagai M, Bröcker EB, Zillikens D. Increased incidence of pemphigus vulgaris in southern Europeans living in Germany compared with native Germans. J Eur Acad Dermatol Venereol. 2002;16:68-71.^,2121. Kulthanan K, Chularojanamontri L, Tuchinda P, Sirikudta W, Pinkaew S. Clinical features and course of pemphigus in Thai patients. Asian Pac J Allergy Immunol. 2011;29:161-8. PF cases have shown a significant increase over the last century in geographic areas in Brazil and worldwide, due to its endemic form, and have experienced apparent epidemiological changes, which resulted in an increase in the incidence of PV cases even in regions considered traditionally endemic for PF, with the percentage of PV cases reaching 91.15% in a sample of 1,560 pemphigus patients.²²22. Gonçalves GAP, Brito MMC, Salathiel AM, Ferraz TS, Alves D, Roselino AMF. Incidence of pemphigus vulgaris exceeds that of pemphigus foliaceus in a region where pemphigus foliaceus is endemic: Analysis of a 21-year historical series. An Bras Dermatol. 2011;86:1109-12.^,2323. Abdolsamadi HR, Abdollahzadeh S, BakianianVaziri P, Beheshti A, Shafigh E, Vahedi M. Epidemiology of Pemphigus in Tehran, Iran: A 20-Year Retrospective Study. J Dent Res Dent Clin Dent Prospects. 2007;1:108-13

The incidence of pemphigus cases diagnosed in Pará state has shown to be low, although the presence of these bullous lesions in this region is beyond question. From 1954 to 1970, 15,803 medical records were searched for the bullous lesions studied back then (including cases of PV, PF, Hailey-Hailey pemphigus, and Düring-Brocq dermatitis), showing an incidence of only 1.7 in a total of 1,000 diseases diagnosed. At that time, when all forms of pemphigus were still believed to have a possible endemic involvement, it was stated that "the cases of pemphigus vulgaris [studied] affected patients who have always lived in Belém" and therefore were away from the so-called "pemphigus areas", a term used to refer to the Midwestern region of Brazil, which concentrates the greatest number of cases of EPF.¹⁰10. Campbell R, Reis V, Aoki V, Cunha P, Hans Filho G, Alves G et al. Endemic pemphigus foliaceus / fogo selvagem. An Bras Dermatol. 2001;76:13-33.^,2424. Silva D, Brito AC. Incidência dos pênfigos e dermatite de Duhring-Brocq no Pará. An Bras Dermatol. 1971;46:31-4.

Patients' distribution according to age and gender differs from country to country. In a Thai study, the percentage of females was found to be as twice as high as that of males both in PV and PF patients. However, similar to what was observed in our study, some papers indicate a predominance of females among PV patients and of males among PF patients.¹²12. Rocha BNS, Oliveira CMM, Unger DAA. Estudo retrospectivo dos casos de pênfigo (foliáceo e vulgar) diagnosticados no Serviço de Dermatologia da Universidade Federal do Pará/Fundação Santa Casa de Misericórdia do Pará no período de julho de 1994 a julho de 2004. An Bras Dermatol. 2005;80:S77-188.^,1515. Ramos W, Chacon GR, Galarza C, Gutierrez EL, Smith ME, Ortega-Loayza AG. Endemic pemphigus in the Peruvian Amazon: epidemiology and risk factors for the development of complications during treatment. An Bras Dermatol.2012;87:838-45.^,2525. Wohl Y, Brenner S. Pemphigus in Israel - an epidemiologic analysis of cases in search of risk factors. Isr Med Assoc J. 2003;5:410-2.^.2626. Cheung HC. Pemphigus foliaceus: a clinical studyof 32 cases in Hong Kong. H.K. Dermatol Venereol Bull. 2004;12:126-32.

The time elapsed from onset of symptoms and diagnosis was less than 1 month in 20% of PV and PF patients, and between 1 month and 1 year in 75% of patients with both forms of the disease. In most patients, the disease has a gradual onset, with skin lesions evolving for weeks or months. A smaller number of patients present with a more acute onset, with extensive bullous lesions affecting large areas of tegument.⁸8. Cunha PR, Barraviera SRCS. Autoimmune bullous dermatoses. An Bras Dermatol. 2009;84:111-24. Cases of acute systemic involvement are related to the most severe forms of the disease and require more prolonged length of hospital stay.

Although many regimens have been implemented to treat pemphigus, none of them has shown to provide absolute efficacy in controlling the disease. Oral steroids represent the basic choice for the management of pemphigus at any disease stage, and their development in the last century led to a substantial improvement in the survival of all patients.²⁷27. Tirado-Sánchez A, León-Dorantes G. Treatment of pemphigus vulgaris. An overview in Mexico. Allergol Immunopathol (Madr). 2006;34:10-6. In our study, prednisone was administered in all therapy regimens for PV and PF. Drug dosage was empirically adjusted according to disease severity and reached 2 mg/kg/day as needed.

Mean time that patients used monotherapy with prednisone, from the beginning of treatment to clinical improvement, was 16 days in the PV group and 46.25 days in the PF group. An American study compared the clinical course of patients with different degrees of PV involvement when treated with monotherapy with corticosteroids at prednisone-equivalent doses. As expected, PV patients with moderate severity showed lower mortality rates (p = 0.045) compared to those with severe disease, as well extremely lower remission rates.²⁸28. Carson PJ, Hameed A, Ahmed AR. Influence of treatment on the clinical course of pemphigus vulgaris. J Am Acad Dermatol. 1996;34:645-52.

The disease was controlled by adjuvant therapy with other immunosuppressive agents, which are added as steroid saving agents.²⁹29. Cianchini G, Corona R, Frezzolini A, Ruffelli M, Didona B, Puddu P. Treatment of severe pemphigus with rituximab: report of 12 cases and a review of the literature. Arch Dermatol. 2007;143:1033-8. The patients of this study received adjuvant therapy with azathioprine and dapsone, or both drugs combined with corticosteroid. Treatment time in PV patients who required a combination of drugs was higher than that of patients receiving steroid monotherapy, which may indicate that this combination was used in cases with more severe disease expression.

In the past, the combination of corticosteroid and azatioprine was believed to represent the cure for pemphigus patients. Evidence on the best therapy regimen is still scarce, but this combination has been considered the most effective steroid saving strategy, since it may have an effect equal to or even higher than that obtained with the treatment with mycophenolate mofetil.²⁸28. Carson PJ, Hameed A, Ahmed AR. Influence of treatment on the clinical course of pemphigus vulgaris. J Am Acad Dermatol. 1996;34:645-52.^,3030. Chams-Davatchi C, Esmaili N, Daneshpazhooh M, Valikhani M, Balighi K, Hallaji Z,et al. Randomized controlled open-label trial of four treatment regimens for pemphigus vulgaris. J Am Acad Dermatol. 2007;57:622-8.^,3131. Beissert S, Werfel T, Frieling U, Böhm M, Sticherling M, Stadler Ret al. A comparison of oral methylprednisolone plus azathioprine or mycophenolate mofetil for the treatment of bullous pemphigoid. Arch Dermatol. 2007;143:1536-42. The combination of corticosteroids and azatioprine also showed a greater benefit compared to dexamethasone-cyclophosphamide pulse therapy in the treatment of pemphigus, thus reducing the need for additional therapies.³²32. Rose E, Wever S, Zilliken D, Linse R, Haustein UF, Bröcker EB. Intravenous dexamethasone- cyclophosphamide pulse therapy in comparison with oral methylprednisolone-azathioprine therapy in patients with pemphigus vulgaris: Results of a multicenter prospectively randomized study. J Dtsch Dermatol Ges. 2005;3:200-6.^,3333. Mentink LF, Mackenzie MW, Tóth GG, Laseur M, Lambert FP, Veeger NJ, et al. Randomized controlled trial of adjuvant oral dexamethasone pulse therapy in pemphigus vulgaris. PEMPULS trial. Arch Dermatol. 2006;142:570-6.

Dapsone, which is currently used as chemotherapeutic agent in many diseases such as Hansen's disease, has been considered to be useful in the treatment of pemphigus, probably because it is able to control antibody levels in pemphigus patients, but this hypothesis requires further confirmation.²⁷27. Tirado-Sánchez A, León-Dorantes G. Treatment of pemphigus vulgaris. An overview in Mexico. Allergol Immunopathol (Madr). 2006;34:10-6. The rates of overall response to dapsone when it was administered in isolation or in association with corticosteroids or immunosuppressants were 84% in mucous membrane pemphigoid and 81% in bullous pemphigoid. Hemolysis was the most common adverse effect observed.³⁴34. Gürcan HM, Ahmed AR. Efficacy of dapsone in thetreatment of pemphigus and pemphigoid: analysis of current data. Am J Clin Dermatol. 2009;10:383-96. Although dapsone plays a significant role in the treatment of pemphigus, evidence to recommend its use in PV cases is still scarce.¹⁹19. Murrell DF, Dick S, Ahmed AR, Amagai M, Barnadas MA, BorradoriL, et al. Consensus statement on definitions of disease, end points, and therapeutic response for pemphigus. J Am Acad Dermatol. 2008;58:1043-6.

All cases of death from our sample were related, among other comorbidities, to sepsis, which evolved to some of its complicated forms (septic shock, severe sepsis, and organ failure). In these conditions, determining markers to stratify the risk of death for hospitalized patients seems to be useful to improve diagnosis. It was found that PV patients who clinically evolved to severe sepsis or who show laboratory results with high levels of serum lactate (>4mmol/L) represented a potential risk group and may benefit from a more aggressive treatment.³⁵35. Tirado-Sánchez A, Vázquez-González D, Ponce-Olivera RM, Montes de Oca-Sánchez G. Serum lactateis a useful predictor of death in severe sepsis in patients with pemphigus vulgaris. Acta Dermatovenerol Alp Panonica Adriat. 2012;21:7-9.

In 1998, pemphigus and other bullous lesions were considered the fourth most common cause of death among all dermatological diseases in the United States.³⁶36. Cirillo N, Cozzani E, Carrozzo M, Grando SA. Urban legends: Pemphigus vulgaris. Oral Dis. 2012;18:442-58. Before the 1940s, when there was the emergence of corticosteroids, PV was almost invariably lethal.²⁸28. Carson PJ, Hameed A, Ahmed AR. Influence of treatment on the clinical course of pemphigus vulgaris. J Am Acad Dermatol. 1996;34:645-52. Currently, it is difficult to understand the real incidence of mortality for pemphigus because of the small number of studies involving a large sample of patients, the heterogeneous number and size of cohorts, and because it is not always possible to properly distinguish mortality for complications caused by PV from those caused by PF. Anyway, mortality rates range from 3.62% (only PV) to 20% (not distinguishing PV from PF).³⁷37. Scully C, Paes De Almeida O, Porter SR, Gilkes JJ. Pemphigus vulgaris: the manifestations and long-tern management of 55 patients with oral lesions. Br J Dermatol. 1999;140:84-9.^,3838. Shamsadini S, Fekri AR, Esfandiarpoor I, Saryazdi S, Rahnama Z, Zandi S, FarajzadehS. Determination of survival and hazard functions for pemphigus patients in Kerman, a southern province of Iran. Int J Dermatol. 2006;45:668-71.

Studies with large cohorts have been conducted to estimate mortality rates for pemphigus. In Iran, where the disease is highly prevalent, a prospective study with 1,206 patients found mortality rates of 6%, with sepsis representing the main cause of deaths.³⁹39. Chams-Davatchi C, Valikhani M, Daneshpazhooh M, Esmaili N, Balighi K, Hallaji Z, et al. Pemphigus: analysis of 1209 cases. Int J Dermatol. 2005;44:470-6. In Taiwan, a cohort of 853 patients showed a mortality rate of 10.3% and found that, when compared to the general population, pemphigus patients showed a significantly higher risk of death for pneumonia, sepsis, cardiovascular diseases, and peptic ulcer.⁴⁰40. Huang YH, Kuo CF, Chen YH, Yang YW. Incidence, mortality, and causes of death of patients with pemphigus in Taiwan: a nation wide population-based study. J Invest Dermatol. 2012;132:92-7.

CONCLUSIONS

This study allowed to outline some characteristics of pemphigus in Pará state, Brazilian Amazon, during a period of 8 years, showing the evolution of patients from a referral service. The number of cases diagnosed in the state are relatively small compared to other country federal units, and no familial or endemic cases were found. Disease prognosis was predominantly satisfactory, with four cases of death associated with sepsis in the study sample.

The treatment of pemphigus is still a challenging task. The choice for the best regimen for each type of patient, based on the extent of disease, patients' comorbidities, control of side effects, and facility of access to drugs, which may be expensive sometimes, makes treatment options very limited in certain cases.

REFERENCES

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