History

Fact Explanation
Skin lesions Pemphigus is an autoimmune blistering disease. [2] Desmosomes are cell–to-cell adhesion junctions mainly in the epithelia that functions to mediate cell adhesion and anchorage for intermediate filaments via their cytoplasmic plaque. Desmosomes are made up of desmogleins (Dsg)1 and desmocollins (Dsc). [1] Pathogenesis of the condition is related to the autoantibodies acting against desmoglein 3 (Dsg3) causing loss of cell–to-cell adhesion of keratinocytes in the basal and immediate suprabasal layers of stratified squamous epithelia. Proteases release from keratinocytes, may also contributing to the disease formation. [1] Pemphigus is manifesting as a life-threatening, blistering disease of the skin and mucous membranes. [2]
Blisters and bullae There may be flaccid blister, sorrounding skin may be reddish in colour at times. Flaccid, thin-walled bullae, may arise on normal-appearing or erythematous skin. Clear fluid within the blister amy become hemorrhagic, turbid, or even seropurulent. Postinflammatory hyperpigmentation may be seen and scaring is infrequent. [5] Occasionally they can appear as multiple pustules in the body. [6]
Involvement of mucous membrane Mucosal involvement is common in pephigus and oral lesions occur in majority of patients. [1] They appear as painful erosions. Intact blisters are rare. [5]
Associated features There may be associated pain, and sometimes itching around the lesions. [5]
Thirst, reduced urine output These may be the features of dehydration. Both loss of fluid through skin lesions and avoidance of food and fluids due to the mucous membrane lesions leads to dehydration. [1]
Delayed wound healing Proteins are an essential component in wound healing. Loss of proteins via the skin lesions [1] may cause deficit of body proteins.
Risk to the life This is a life threatening condition without timely treatment. [2] Large areas of erosion in the skin and mucous membranes leads to massive fluid and electrolyte loss, which can be exaggerated by the reduced fluid intake. Skin lesions are also prone to infections, which contribute to mortality. [1]
Neonatal pemphigus Mothers with active lesions who deliver a baby might transfer the disease to the infant. [1] Passively transferred maternal IgG is gradually catabolized, causing the the recovery of the infant. [2]
History of drug use Drug-induced pemphigus vulgaris has been documented with drugs such as penicillamine, captopril, [5] cephalosporin, pyrazolones, nonsteroidal anti-inflammatory drugs (NSAIDs). [4]
History of infections, neoplasms, and radiation These factors are known to cause remissions. [5]
Pathological fractures, bone pain, visual problems and recurrent infectoions Osteoporosis, avascular necrosis, HPA-axis suppression, cataract, cushingoid features, myopathy, mood changes, and immunosuppression may be the complications of long term immunosupressive treatment. [3]
References
  1. KOCH PJ, MAHONEY MG, ISHIKAWA H, PULKKINEN L, UITTO J, SHULTZ L, MURPHY GF, WHITAKER-MENEZES D, STANLEY JR. Targeted Disruption of the Pemphigus Vulgaris Antigen (Desmoglein 3) Gene in Mice Causes Loss of Keratinocyte Cell Adhesion with a Phenotype Similar to Pemphigus Vulgaris J Cell Biol [online] 1997 Jun 2, 137(5):1091-1102 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2136216
  2. AMAGAI M, HASHIMOTO T, SHIMIZU N, NISHIKAWA T. Absorption of pathogenic autoantibodies by the extracellular domain of pemphigus vulgaris antigen (Dsg3) produced by baculovirus. J Clin Invest [online] 1994 Jul, 94(1):59-67 [viewed 25 September 2014] Available from: doi:10.1172/JCI117349
  3. VAISHNANI JB, BOSAMIYA SS. PEMPHIGUS: ACTIVE OR INACTIVE? Indian J Dermatol [online] 2009, 54(2):186-188 [viewed 25 September 2014] Available from: doi:10.4103/0019-5154.53173
  4. Drug induced bullous eruptions. Br Med J (Clin Res Ed) [online] 1981 Feb 7, 282(6262):421-422 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1504280
  5. GLEAVES TR, CATHER JC, MENTER A. Oral erosions and cutaneous bullae Proc (Bayl Univ Med Cent) [online] 2005 Jan, 18(1):71-73 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1200701
  6. YANG Y, LIN M, HUANG SJ, MIN C, LIAO WQ. A RARE PRESENTATION OF PEMPHIGUS VULGARIS AS MULTIPLE PUSTULES Indian J Dermatol [online] 2010, 55(3):293-295 [viewed 25 September 2014] Available from: doi:10.4103/0019-5154.70675

Examination

Fact Explanation
Blisters in the skin and mucous membranes Earliest change is the detachment of the epithelium just above the basal cells. [1] There are flaccid, thin-walled bullae,[3] and blisters which arises on an erythematous base on healthy skin or filled with clear fluid. Blisters can be either intact or ruptured. There can be large erosions with the shedding of the epithelium.
Oral lesions There will be large, flaccid, superficial bullae/erosions in the mouth, involving tongue. There can be shallow erosions on oral mucosa and desquamative gingivitis. [3]
Nikolsky sign Nikolsky's sign is elicited by applying lateral pressure on the blister it self or perilesional skin or normal appearing skin that result in removal of upper layer of epidermis. [2] There are two types of Nikolsky's sign, wet Nikolsky's sign in base of skin is moist, glistening, and exudative, and dry Nikolsky's if the base of eroded skin is relatively dry after removal of the epidermis. [2] Active disease is manifested by wet Nikolsky's sign, and re-epithialization is manifested by a dry Nikolsky's sign.
Asboe-Hansen sign Asboe-Hansen sign is elicited by applying gentle pressure on an intact bulla that forces the fluid to spread under the skin away from the site of pressure. [3]
Hyperpigmentation There can be postinflammatory associated occasionally with true scarring. [3]
Secondary bacterial infections Lesions are more prone to colonization with microbes causing secondary bacterial infections. [1]
Features of dehydration : sunken eyes, reduced skin turgor, dry skin and mucous membranes Loss of fluid through the skin lesions and avoidance of food and fluids due to the mucous membrane lesions causes dehydration. [1]
Cataract, cushingoid features, myopathy, mood changes These features are due to the drugs used for the treatment, such as steroids. These adverse effects are particularly seen when using over a long period of time. [2]
References
  1. KOCH PJ, MAHONEY MG, ISHIKAWA H, PULKKINEN L, UITTO J, SHULTZ L, MURPHY GF, WHITAKER-MENEZES D, STANLEY JR. Targeted Disruption of the Pemphigus Vulgaris Antigen (Desmoglein 3) Gene in Mice Causes Loss of Keratinocyte Cell Adhesion with a Phenotype Similar to Pemphigus Vulgaris J Cell Biol [online] 1997 Jun 2, 137(5):1091-1102 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2136216
  2. VAISHNANI JB, BOSAMIYA SS. PEMPHIGUS: ACTIVE OR INACTIVE? Indian J Dermatol [online] 2009, 54(2):186-188 [viewed 25 September 2014] Available from: doi:10.4103/0019-5154.53173
  3. GLEAVES TR, CATHER JC, MENTER A. Oral erosions and cutaneous bullae Proc (Bayl Univ Med Cent) [online] 2005 Jan, 18(1):71-73 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1200701

Differential Diagnoses

Fact Explanation
Pemphigus foliaceus This is an autoimmune blistering disease where the humoral immune response targeting the skin causes loss of keratinocyte cell-cell adhesion in the superficial layers of the epidermal epithelium. [3] Onset is usually in the 40 to 60 years of age. [3] Females are commonly affected. [3] Lesions may have the same picture as in pemphigus, but there are no mucosal lesions. [1] Treatment is same as for pemphigus vulgaris. [1]
Paraneoplastic pemphigus Paraneoplastic pemphigus (PNP) is a condition that affects the people with underlying disorder such as neoplasm, most commonly of B cell lineage (chronic lymphocytic leukemia, non-Hodgkin’s B cell lymphoma, thymoma and Castleman disease). It is a multiorgan disorderand is an autoimmune bullous disease that presents with painful mucosal ulcerations and polymorphous skin lesions. [2] There are mucocutaneous eruptions, mucocutaneous bullous and erosive lesions in the body. There can be associated mucosal lesions as well. [1]
Dermatitis herpetiformis Dermatitis herpetiformis (DH) is a chronic bullous disease. [5] Lesions are appear on the elbows, knees, buttocks, neck, and scalp, and less commonly on the upper back, abdomen, groin, and face. [4] Unlike the pemphigus, here there is a sever itch causing eroded and crusted secondary lesions. [4] There is an erythematous papules and urticarial plaques, grouped vesicles with centrifuge growth, and tense blisters. [5] Symptoms of gluten-sensitive enteropathy such as diarrhea, steatorrhea, malabsorption with resulting anemia, metabolic bone disease, weight loss and malnutrition may occur. [5] Skin biopsy and direct immunofluorescence of perilesional skin are used to diagnose the disease. [5]
Erythema Multiforme Erythema multiforme is an immune-mediated, cindition involving the skin and mucous membranes. It is characterized by “target” lesions. [6] Mainly it affects the limbs, specifically the extensor surfaces, but can affect any where in the body, excluding mucous membranes. It is self-limited lasting less than 4 weeks. [6] Common causes include infectious organisms (herpes simplex virus types 1 and 2) , Mycoplasma pneumonia, Nonsteroidal anti-inflammatory drugs, antiepileptics, and antibiotics. [6]
References
  1. MUTASIM DF. Therapy of autoimmune bullous diseases Ther Clin Risk Manag [online] 2007 Mar, 3(1):29-40 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1936286
  2. ZENG M, ZHANG M, HU W, KONG Q, SANG H, XU X. A case of Paraneoplastic Pemphigus associated with Castleman's disease An Bras Dermatol [online] 2013, 88(6 Suppl 1):11-14 [viewed 25 September 2014] Available from: doi:10.1590/abd1806-4841.20132332
  3. JAMES KA, CULTON DA, DIAZ LA. Diagnosis & Clinical Features of Pemphigus Foliaceus Dermatol Clin [online] 2011 Jul, 29(3):405-412 [viewed 25 September 2014] Available from: doi:10.1016/j.det.2011.03.012
  4. CRIADO PR, CRIADO RF, AOKI V, BELDA W JR, HALPERN I, LANDMAN G, VASCONCELLOS C. Dermatitis herpetiformis: Relevance of the physical examination to diagnosis suspicion Can Fam Physician [online] 2012 Aug, 58(8):843-847 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418983
  5. MENDES FB, HISSA-ELIAN A, DE ABREU MA, GONçALVES VS. Review: dermatitis herpetiformis An Bras Dermatol [online] 2013, 88(4):594-599 [viewed 25 September 2014] Available from: doi:10.1590/abd1806-4841.20131775
  6. CHAN M, GOLDMAN RD. Erythema multiforme in children: The steroid debate Can Fam Physician [online] 2013 Jun, 59(6):635-636 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3681448

Investigations - for Diagnosis

Fact Explanation
Histopathology Detachment of the epithelium just above the basal cells, with no, or minimal, inflammation in an early lesion. “Row of tombstones” patternis seen due to the detached basal cells from one another while while preserving the attachment to the basement membrane. [1] Histopathology ia helpful in differentiating pemphigus vulgaris from pemphigus foliaceous, as latter will demonstrates a more superficial epidermal cleavage.
Direct immunofluorescence IgG autoantibodies to the cell surface of keratinocytes of stratified squamous epithelia are found in the skin and sera of these patients. [1] A sample from the normal-appearing perilesional skin can be used to direct immunofluorescence. It will demonstrate the deposits of antibodies and other complement. Immunoglobulin G (IgG) [2] is deposited on the keratinocytes surface in and around lesions.
Indirect immunofluorescence Indirect immunofluorescence is alsl able to detect thje pathogenic IgG autoantobodies. [1]
References
  1. KOCH PJ, MAHONEY MG, ISHIKAWA H, PULKKINEN L, UITTO J, SHULTZ L, MURPHY GF, WHITAKER-MENEZES D, STANLEY JR. Targeted Disruption of the Pemphigus Vulgaris Antigen (Desmoglein 3) Gene in Mice Causes Loss of Keratinocyte Cell Adhesion with a Phenotype Similar to Pemphigus Vulgaris J Cell Biol [online] 1997 Jun 2, 137(5):1091-1102 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2136216
  2. AMAGAI M, HASHIMOTO T, SHIMIZU N, NISHIKAWA T. Absorption of pathogenic autoantibodies by the extracellular domain of pemphigus vulgaris antigen (Dsg3) produced by baculovirus. J Clin Invest [online] 1994 Jul, 94(1):59-67 [viewed 25 September 2014] Available from: doi:10.1172/JCI117349

Investigations - Fitness for Management

Fact Explanation
Serum electrlytes Large areas of erosions on mucous membranes and skin due to the rapid loss of the superficial epithelia causes prevent protein and electrolyte loss from the body. [1]
Full blood count These patients are vulnerable for the secondary bacterial infections, [1] and evaluation of the leucocytosis in the bacterial infections and lymphocytosis in the viral infections may be needful.
References
  1. KOCH PJ, MAHONEY MG, ISHIKAWA H, PULKKINEN L, UITTO J, SHULTZ L, MURPHY GF, WHITAKER-MENEZES D, STANLEY JR. Targeted Disruption of the Pemphigus Vulgaris Antigen (Desmoglein 3) Gene in Mice Causes Loss of Keratinocyte Cell Adhesion with a Phenotype Similar to Pemphigus Vulgaris J Cell Biol [online] 1997 Jun 2, 137(5):1091-1102 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2136216

Investigations - Followup

Fact Explanation
IgG antibody titre Serum antibody titers can be used to monitor disease activity. [1] Higher the level may indicate the more severe disease. [2]
References
  1. GLEAVES TR, CATHER JC, MENTER A. Oral erosions and cutaneous bullae Proc (Bayl Univ Med Cent) [online] 2005 Jan, 18(1):71-73 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1200701
  2. KOCH PJ, MAHONEY MG, ISHIKAWA H, PULKKINEN L, UITTO J, SHULTZ L, MURPHY GF, WHITAKER-MENEZES D, STANLEY JR. Targeted Disruption of the Pemphigus Vulgaris Antigen (Desmoglein 3) Gene in Mice Causes Loss of Keratinocyte Cell Adhesion with a Phenotype Similar to Pemphigus Vulgaris J Cell Biol [online] 1997 Jun 2, 137(5):1091-1102 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2136216

Investigations - Screening/Staging

Fact Explanation
Indirect immunofluorescence Indirect immunofluorescence, will detect the autoantibody titer, that correlates well with the disease activity. Higher antibody titer, is associated with more severe disease. [1] Paraneoplastic pemphigus can be diagnosed by demonstration of immunoglobulin G autoantibodies to desmoglein 3 and plakins on immunofluorescence. [2]
References
  1. KOCH PJ, MAHONEY MG, ISHIKAWA H, PULKKINEN L, UITTO J, SHULTZ L, MURPHY GF, WHITAKER-MENEZES D, STANLEY JR. Targeted Disruption of the Pemphigus Vulgaris Antigen (Desmoglein 3) Gene in Mice Causes Loss of Keratinocyte Cell Adhesion with a Phenotype Similar to Pemphigus Vulgaris J Cell Biol [online] 1997 Jun 2, 137(5):1091-1102 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2136216
  2. GLEAVES TR, CATHER JC, MENTER A. Oral erosions and cutaneous bullae Proc (Bayl Univ Med Cent) [online] 2005 Jan, 18(1):71-73 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1200701

Management - General Measures

Fact Explanation
Patient education Patient should be informed about the nature of the disease, potential complications particularly secondary infections, inability to take food, dehydration and involvement of the oral cavity. [1] Psychological support is also important as they might be depressed, anxious and irritable with the disease.
Skin care Secondary infections with bacteria, can occur and lesion may progress to ulcers. Therefore appropriate skin care is important in the healing of lesions and avoidance of complications. [1] Gentle cleansing of the erosions, liberal application of antibiotic ointments or petroleum jelly, and avoidance of trauma are some measures to prevent the complications. [1]
Diet and nutrition Usually there are no dietary restrictions. But the disease may involve mucous membrane of the oral cavity [1] causing difficulty in food and water intake. Certain foods like spicy foods, tomatoes, orange juice and hard food cause more discomfort. Nutritional support is important as there is loss of proteins from the lesions. [1]
Follow up Osteoporosis risk assessment and if needed bisphosphonate for prophylaxis against osteoporosis may be valueble. [2] Opthalmological review, blood pressure check up may be needed in patients receiving steroids.
Managing the complications Complications may be either due to disease or therapy. Patients receiving long-term systemic corticosteroids are suseptible to get complications like osteoporosis, avascular necrosis, HPA-axis suppression, cataract, cushingoid features, myopathy, mood changes, and immunosuppression. [2] Secondary bacterial infections are common [3] and need appropriate wound and skin care.
References
  1. MUTASIM DF. Therapy of autoimmune bullous diseases Ther Clin Risk Manag [online] 2007 Mar, 3(1):29-40 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1936286
  2. VAISHNANI JB, BOSAMIYA SS. PEMPHIGUS: ACTIVE OR INACTIVE? Indian J Dermatol [online] 2009, 54(2):186-188 [viewed 25 September 2014] Available from: doi:10.4103/0019-5154.53173
  3. KOCH PJ, MAHONEY MG, ISHIKAWA H, PULKKINEN L, UITTO J, SHULTZ L, MURPHY GF, WHITAKER-MENEZES D, STANLEY JR. Targeted Disruption of the Pemphigus Vulgaris Antigen (Desmoglein 3) Gene in Mice Causes Loss of Keratinocyte Cell Adhesion with a Phenotype Similar to Pemphigus Vulgaris J Cell Biol [online] 1997 Jun 2, 137(5):1091-1102 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2136216

Management - Specific Treatments

Fact Explanation
Corticosteroids Prednisone and methylprednisolone may be used. Starting dose of prednisone is 1mg/kg/day divided into two or three doses and clinical remission will occur within 4–12 weeks. [1] Dose is maintained for further 6–10 weeks to prevent relapses. Dose is then gradually decreased and if there is no recurrence, maintenance dose of 5 mg daily for several years is used to prevent recurrences. [1] When the patient is having severe disease or not responding adequately to the standard dose of prednisone, either increment in dose upto 1.5 or 2 mg/kg/day until remission. or pulse-steroid therapy (intravenous methylprednisolone 1 g daily given for three consecutive days) are used. [1] Topical steroid gel (clobetasol propionate) can be used for the mucosa. [2]
Immunosuppressive drugs There are steroid-sparing immunosuppressive agents [2] such as azathioprine, mycophenolate mofetil (MMF), and cyclophosphamide that are used for the treatment of pemphigus. [1] Azathioprine is the most commonly using drug. Gastrointestinal intolerance, mild hepatotoxicity, and bone marrow suppression may be the side effects of treatment and it shoud not be used for pregnant mothers. [1] Mycofenate mofetil causes adverse effects such as gastrointestinal side effects, mild dose-related bone marrow suppression. Cyclophosphamide is an alkylating cytotoxic steroid sparing agent given as pulse therapy (1 g intravenously every four weeks). [1] Acute myelosuppressio, mucosal ulcers, alopecia, nephrotoxicity, urotoxicity (hemorrhagic cystitis), cardiotoxicity, hepatotoxicity, interstitial lung fibrosis, and toxicity in reproductive systems resulting in amenorrhea are the side effects of cyclophosphomide therapy. [1]
Intravenous immunoglobulin therapy Intravenous immunoglobulin [2] is useful in pemphigus patients who are not fully responingd to systemic steroids. It is given as an infusion of a total of 2 g/kg body weight over four or five days and that gives a rapid clinical improvement. [1]
Plasmapheresis Plasmapheresis is the withdrawal of the patient’s blood, using a filter and is effective in combination with cyclophosphamide for patients with severe disease who are unresponsive to conventional therapy. [1]
References
  1. MUTASIM DF. Therapy of autoimmune bullous diseases Ther Clin Risk Manag [online] 2007 Mar, 3(1):29-40 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1936286
  2. GLEAVES TR, CATHER JC, MENTER A. Oral erosions and cutaneous bullae Proc (Bayl Univ Med Cent) [online] 2005 Jan, 18(1):71-73 [viewed 25 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1200701