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bullous pemphigoid; parapemphigus

Autoimmune disorder characterized by a chronic vesiculobullous dermatitis. (Also see cicatricial pemphigoid) Etiology: 1) autoantibody to antigens on the surface of basal keratinocytes extending into the lamina lucida of the epidermal basement membrane 2) complement activation 3) attraction of neutrophils & eosinophils 4) may be drug-induced [7] - furosemide, antibiotics Epidemiology: 1) two age groups: children & individuals 60-80 years of age 2) no sex preference 3) most common autoimmune bullous disease - up to 4.3 cases/100,000/year Pathology: 1) neutrophils in single file at dermal-epidermal junction 2) neutrophils, eosinophils & lymphocytes in papillary dermis 3) subepidermal bullae - regeneration of the bullae floor - no acantholysis 4) IgG & C3 deposits along the epidermal basement membrane - IgG directed against BP180 & BP230 [3] 5) C3 deposits along the epidermal basement membrane may occur in the absence of IgG 6) loss of dermal-epidermal adherence 7) electron-microscopy: a) junctional cleavage (split in lamina lucida of epidermal basement membrane) b) immunoelectron microscopy: deposition of IgG at the lamina lucida & hemidesmosomes * histopathology images [18,20,21] Genetics: - associated with defects in COL17A1 (BP180) Clinical manifestations: 1) lesions often begin as prodromal intense pruritus or erythematous urticaria resembling erythema multiforme with evolution to tense bullae in weeks to months - thus patients may present with urticaria [10] - lesions are not painful - tense bullae & prurtitus often presenting symptoms [26] 2) bullae may arise in normal or erythematous skin 3) bullae do not rupture easily (tense, not flaccid) - bullae do not coalesce when they do break [7] 4) lesions may be localized or generalized & scattered 5) distribution: axillae, medial thighs & groin, abdomen, flexor aspect of forearms, lower legs (often 1st involved) 6) in the elderly, most common on the trunk, limbs & flexural surfaces 7) mucous membrane involvement a) mouth, anus, vagina, conjunctiva [3,14] b) less common & less severe & painful than pemphigus (uncommon [3]) c) present in ~ 1/3 of patients [7] d) ~ 20%, rare in drug-induced pemphigoid [7] e) generally does not present with oral lesions 8) other patients may present with prurigo nodularis-like lesions [10] 9) Nikolsky sign is negative [3] * images [18,22] Laboratory: 1) epidermal basement membrane IgG Ab in serum detected by indirect immunofluorescence in 70% of patients a) ELISA using antibodies to bullous pemphigoid autoantigen-2 (COL171A, BP180) [6], see anti-basement membrane antibody b) check titer before discontinuing immunosuppressive therapy [6] c) titers do not correlate with course of disease d) anti BP230 (gene on 6p) [homology with desmoplakin] e) anti BP180 (gene on 10q) [transmembrane protein] f) routine serum testing had been performed with monkey esophagus as substrate t) sensitivity increased by use of NaCl-split human skin as substrate 1] antibodies localize to epidermal side of substrate or occasionally both epidermal & dermal side of substrate 2] in epidermolysis bullosa aquisita, antibodies localize only to dermal side of substrate h) the major subclass of antibody is IgG4 2) eosinophilia 3) skin biopsy: a) direct immunofluorescence testing of perilesional skin b) histopathology of lesional skin [3] c) immunoelectron microscopy 4) see ARUP consult [8] Differential diagnosis: 1) pemphigus 2) erythema multiforme 3) dermatitis herpetiformis - clustered fragile vesicles break down quickly - leaves small erosions on the elbows, knees, or buttocks - intensely pruritic - does not involve the oral mucosa 4) epidermolysis bullosa aquisita Complications: - not associated with increased risk of malignancy [17] - not associated with increased mortality [5] - 6-fold increase in mortality [9] - 5-fold increase in cardiovascular mortality [24] Management: 1) oral glucocorticoid alone or combined with azathioprine a) prednisone: start 50-100 mg PO QD b) methylprednisolone 0.5 mg/kg/day with taper 2) azathioprine a) 150 mg PO QD for remission b) 50-100 mg PO QD for maintenance 3) mycophenolate 2 g/day may be used in combination with glucocorticoid [4] 4) cyclophosphamide 5) rituximab 500 mg infused weekly for 4 weeks in conjunction with prednisolone 0.5 mg/kg/day tapered rapidly [3,16] 6) intravenous immune globulin [3] 7) dapsone 100-150 mg PO QD for milder cases 8) topical steroids for very mild cases & for local recurrences 9) tetracycline with or without nicotinamide may be of benefit

Interactions

disease interactions

Related

bullous pemphigoid antigen 1; trabeculin-beta; hemidesmosomal plaque protein; dystonia musculorum protein (DST, BPAG1, DMH, DT, KIAA0728) cicatricial pemphigoid (benign mucous membrane pemphigoid) dermatitis herpetiformis; Duhring-Brocq disease epidermolysis bullosa aquisita erythema multiforme pemphigus vesicular lichen planus

General

pemphigoid

Database Correlations

OMIM correlations

References

  1. Color Atlas and Synopsis of Clinical Dermatology, Common and Serious Diseases, 3rd ed, Fitzpatrick et al, McGraw Hill, NY, 1997, pg 406-409
  2. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 166-67
  3. Medical Knowledge Self Assessment Program (MKSAP) 11, 15, 16, 17, 18. American College of Physicians, Philadelphia 1998, 2009, 2012, 2015. 2018 - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  4. Beissert S et al, A comparison of oral methylprednisolone plus azathioprine or mycophenolate mofetil for the treatment of bullous pemphigoid. Arch Dermatol 2007 Dec; 143:1536. PMID: 18087004
  5. Parker SRS et al. Mortality of bullous pemphigoid: An evaluation of 223 patients and comparison with the mortality in the general population in the United States. J Am Acad Dermatol 2008 Oct; 59:582. PMID: 18707800
  6. Bernard P et al Risk factors for relapse in patients with bullous pemphigoid in clinical remission: A multicenter, prospective, cohort study. Arch Dermatol 2009 May; 145:537. PMID: 19451497
  7. Geriatric Review Syllabus, 7th edition Parada JT et al (eds) American Geriatrics Society, 2010 - Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013
  8. ARUP Consult: Pemphigoid The Physician's Guide to Laboratory Test Selection & Interpretation https://arupconsult.com/content/pemphigoid
  9. Joly P et al. Incidence and mortality of bullous pemphigoid in France. J Invest Dermatol 2012 Aug; 132:1998. PMID: 22418872 - Naldi L et al Bullous pemphigoid: Simple measures for a complex disease. J Invest Dermatol 2012 Aug; 132:1948. PMID: 22797296
  10. Bakker CV et al. Bullous pemphigoid as pruritus in the elderly. JAMA Dermatol 2013 Jun 26 PMID: 23804286 http://archderm.jamanetwork.com/article.aspx?articleid=1699369 - Hertl M and Schmidt T. Underrecognition of the heterogeneous clinical spectrum of bullous pemphigoid. JAMA Dermatol 2013 Jun 26; PMID: 23804145 http://archderm.jamanetwork.com/article.aspx?articleid=1699364
  11. Parker SR, MacKelfresh J. Autoimmune blistering diseases in the elderly. Clin Dermatol. 2011 Jan-Feb;29(1):69-79 PMID: 21146735
  12. Kirtschig G, Middleton P, Bennett C et al Interventions for bullous pemphigoid. Cochrane Database Syst Rev. 2010 Oct 6;(10):CD002292 PMID: 20927731
  13. Di Zenzo G, Marazza G, Borradori L. Bullous pemphigoid: physiopathology, clinical features and management. Adv Dermatol. 2007;23:257-88. PMID: 18159905
  14. Saw VP, Dart JK. Ocular mucous membrane pemphigoid: diagnosis and management strategies. Ocul Surf. 2008 Jul;6(3):128-42. PMID: 18781259
  15. Schmidt E, della Torre R, Borradori L. Clinical features and practical diagnosis of bullous pemphigoid. Dermatol Clin. 2011 Jul;29(3):427-38, viii-ix. Review. PMID: 21605808
  16. Cho Y-T et al. First-line combination therapy with rituximab and corticosteroids provides a high complete remission rate in moderate-to-severe bullous pemphigoid. Br J Dermatol 2014 Dec 22; PMID: 25529394 http://onlinelibrary.wiley.com/doi/10.1111/bjd.13633/abstract
  17. Cai SCS et al. Association of bullous pemphigoid and malignant neoplasms. JAMA Dermatol 2015 Feb 11 PMID: 25671805 http://archderm.jamanetwork.com/article.aspx?articleid=2110015
  18. Raap U, Werfel T (images) IMAGES IN CLINICAL MEDICINE. Bullous Pemphigoid. N Engl J Med. 2015 Oct 22;373(17):1659. http://www.nejm.org/doi/full/10.1056/NEJMicm1500430 PMID: 26488696
  19. Ruocco E, Wolf R, Caccavale S et al Bullous pemphigoid: associations and management guidelines: facts and controversies. Clin Dermatol. 2013 Jul-Aug;31(4):400-12 PMID: 23806157
  20. Chan LS, Elston DM (histopathology images) Medscape: Bullous Pemphigoid http://emedicine.medscape.com/article/1062391-overview
  21. DermNet NZ. (histopathology images) Bullous pemphigoid pathology http://www.dermnetnz.org/pathology/bp-path.html
  22. DermNet. Skin Disease Atlas (images) Bullous Pemphigoid Photos http://www.dermnet.com/images/Bullous-Pemphigoid
  23. Schmidt E, della Torre R, Borradori L. Clinical features and practical diagnosis of bullous pemphigoid. Immunol Allergy Clin North Am. 2012 May;32(2):217-32, v. PMID: 22560135
  24. Shen WC, Chiang HY, Chen PS et al Risk of All-Cause Mortality, Cardiovascular Disease Mortality, and Cancer Mortality in Patients With Bullous Pemphigoid. JAMA Dermatol. Published online December 29, 2021. PMID: 34964804 https://jamanetwork.com/journals/jamadermatology/fullarticle/2787674
  25. NEJM Knowledge+ Dermatology
  26. Kridin K. Pemphigus group: overview, epidemiology, mortality, and comorbidities. Immunol Res. 2018;66:255-70. PMID: 29479654