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Pemphigus

Pemphigus is a group of chronic bullous diseases.


Presentation

The characteristic symptom of pemphigus is blisters on the skin and mucous membrane. These blisters lead to ulcers creating raw open areas on the skin which increases chances of infection. Depending upon the type of pemphigus, symptoms [7] varies:

  • Pemphigus vulgaris: A patient with pemphigus vulgaris will typically present with oral blisters and ulcers. The oral mucosa is the first site to be affected in nearly 80-85% of cases and they are stubborn and persistent. Those occurring in the mouth are superficial erosions, which slowly progress to the entire mouth. There is severe pain and burning making it difficult to talk and eat. Involvement of larynx leads to hoarseness of voice. Other areas of involvement are genital areas such as vagina, labia cervix, penis, urethra and anus. The skin lesions appear as thin flaccid blisters which on rupturing, lead to painful erosion formation. Erosions tend to extend peripherally thus appear large. Most of the oral lesions are irregular, ill defined and take time to heal. There is also severe burning and stinging. If there is a widespread blistering, it can lead to fluid loss and infection which in turn can lead to scars and disfigurement. Often, in pemphigus vulgaris, the oral mucosa is the only site to be involved. Stomatitis is the main presenting feature in case of juvenile patients.
  • Pemphigus foliaceus is characterized by small crusty skin lesions which resemble corn flakes, which appear on the upper chest and face. These lessons are itchy and crusty and easily removable. When removed they leave small superficial erosions on the skin. As time progresses the lesions increases on the face, scalp and chest. Oral mucosa is spared and not affected in pemphigus foliaceus in comparison to pemphigus vulgaris.
Generalized Lymphadenopathy
  • Impaired anti-pneumococcal antibody response in patients with AIDS-related persistent generalized lymphadenopathy. Clin Exp Immunol 1987 ;68: 479 - 487 28. Anzai H, Fujii Y, Nishifuji K, et al.[doi.org]
Chills
  • Call your provider if you have been treated for PV and you develop any of the following symptoms: Chills Fever General ill feeling Joint aches Muscle aches New blisters or ulcers Amagai M. Pemphigus. In: Bolognia JL, Schaffer JV, Cerroni L, eds.[nlm.nih.gov]
  • Call your provider if you have been treated for PV and you develop any of the following symptoms: Chills Fever General ill feeling Joint aches Muscle aches New blisters or ulcers Images References Ferri FF. Pemphigus vulgaris. In: Ferri FF, ed.[ufhealth.org]
  • Call your provider if you have been treated for PV and you develop any of the following symptoms: Chills Fever General ill feeling Joint aches Muscle aches New blisters or ulcers References Amagai M. Pemphigus.[mountsinai.org]
  • Call your provider if you have been treated for PV and you develop any of the following symptoms: Chills Fever General ill feeling Joint aches Muscle aches New blisters or ulcers References Ferri FF. Pemphigus vulgaris. In: Ferri FF, ed.[umms.org]
Anemia
  • None of the patients showed any clinical sign of systemic lupus erythematosus, AIH, primary biliary cirrhosis, autoimmune atrophic gastritis, or pernicious anemia.[e-ijd.org]
  • […] mouth Crohn's disease and hemorrhagic rectal colitis – Mucocutaneous signs accompanied by abdominal pain, aphthae in oral mucosa, asthenia, weight loss, and anorexia Folic acid or Vitamin B12 deficiency – Oral pain, erythematous tongue, asthenia and anemia[jdrr.org]
  • Supervision of patients is very important during treatment due to possibility of drug toxicity as hemolytic anemia and methaemoglobinaemia. Indication of Dapsone Dermatitis herpetiformis. Erythema elevatum diutinum.[drmhijazy.com]
  • […] dry mouth Crohn’s disease and hemorrhagic rectal colitis Mucocutaneous signs accompanied by abdominal pain, aphthae in oral mucosa, asthenia, weight loss, and anorexia Folic acid or vitamin B12 deficiency Oral pain, erythematous tongue, asthenia and anemia[omicsonline.org]
  • Associated diseases There is evidence of association of PH with some diseases such as SLE, autoimmune hemolytic anemia and psoriasis and with some malignancies (prostate, esophagus) in the literature [ 11 , 97 , 98 , 99 , 100 , 101 ]. 10.[intechopen.com]
Fatigue
  • […] abdominal pain, aphthae in oral mucosa, asthenia, weight loss, and anorexia Folic acid or Vitamin B12 deficiency – Oral pain, erythematous tongue, asthenia and anemia, paresthesias in limbs, and physical problems hypochromic iron deficiency pallor, fatigue[jdrr.org]
  • […] by abdominal pain, aphthae in oral mucosa, asthenia, weight loss, and anorexia Folic acid or vitamin B12 deficiency Oral pain, erythematous tongue, asthenia and anemia, paresthesias in limbs, and physical problems Hypochromic iron deficiency Pallor, fatigue[omicsonline.org]
  • Mycophenolate mofetil (30-40 mg/kg/day divided twice daily) is generally well tolerated, although side effects of fatigue, gastrointestinal upset, and tremor are not uncommon, particularly at higher doses, and there is a small long-term risk of lymphoma[cancertherapyadvisor.com]
Painter
  • Hunt MJ, Salisbury EL, Painter DM, Lee S. Vesiculobullous Hailey-Hailey disease: successful treatment with oral retinoids. Australas J Dermatol. 1996 Nov. 37(4):196-8. [Medline]. Haley CT, Mui UN, Tyring SK.[emedicine.medscape.com]
Lymphadenopathy
  • Impaired anti-pneumococcal antibody response in patients with AIDS-related persistent generalized lymphadenopathy. Clin Exp Immunol 1987 ;68: 479 - 487 28. Anzai H, Fujii Y, Nishifuji K, et al.[doi.org]
Abdominal Mass
  • Subsequent neoplastic workup revealed an intra-abdominal mass. Our case represents a subtle, non-classic presentation of paraneoplastic pemphigus and suggests the importance of a comprehensive investigative work-up in atypical cases of pemphigus.[ncbi.nlm.nih.gov]
Aphthous Stomatitis
  • The differential diagnosis of acute herpetic stomatitis and recurrent aphthous stomatitis was suggested. Biopsy was done, and the tissue was sent for histopathological examination. The oral tissue biopsies were taken from the perilesional site.[jdrr.org]
  • Shakeri R, Zamani F, Sotoudehmanesh R, Amiri A, Mohamadnejad M, et al. (2009) Gluten sensitivity enteropathy in patients with recurrent aphthous stomatitis. BMC Gastroenterol 9: 44.[autoimmunediseases.imedpub.com]
  • The most frequent diagnoses in patients with oral lesions are recurrent aphthous stomatitis, Behçet disease, erythema multiforme, erosive lichen planus, and oral candidiasis [ 2 ].[omicsonline.org]
  • stomatitis, lichen planus should be considered in the differential diagnosis of oral lesions [ 1 ].[clinical-pediatrics-dermatology.imedpub.com]
  • […] and specific Can distinguish IgA pemphigus from other pemphigus variants and other immune-mediated skin diseases Differential Diagnosis Infectious HIV acute infection Herpes simplex viruses Coxsackievirus A16 (hand-foot-and-mouth disease) Candida spp Aphthous[arupconsult.com]
Blister
  • The characteristic symptom of pemphigus is blisters on the skin and mucous membrane. These blisters lead to ulcers creating raw open areas on the skin which increases chances of infection.[symptoma.com]
  • Morphologically it is characterized by acantholysis and intraepidermal blister formation Group of chronic blistering diseases characterized histologically by acantholysis and blister formation within the epidermis Pemphigus is an autoimmune disorder in[icd9data.com]
  • About 50% of people with this condition first develop painful blisters and sores in the mouth. This is followed by skin blisters. Skin sores may come and go.[nlm.nih.gov]
  • On the other hand, subepidermal blister formation in bullous pemphigoid has been believed to be complement-dependent. Therefore, the role of IgG4 autoantibodies on blister formation in bullous pemphigoid remains controversial.[ncbi.nlm.nih.gov]
  • Presentation General features Skin lesions: [ 3 ] Skin blisters are flaccid rather than tense. Intact blisters may not be found. Lesions can extend easily and become large. Blisters appear on normal or erythematous skin.[patient.info]
Eruptions
  • Although the precise mechanism of this cutaneous eruption is unknown, clinicians should be alert for this potentially serious complication and evaluate all cutaneous eruptions developing during and after radiotherapy.[ncbi.nlm.nih.gov]
Nikolsky's Sign
  • Different types of Nikolsky’s sign: Marginal Nikolsky’s sign : Erosion of perilesional skin on the application of pressure is called marginal Nikolsy s sign. This sign is 69 % sensitive in detecting PV.[lecturio.com]
  • Theoretically, the blisters should demonstrate a positive Nikolsky's sign , in which the skin sloughs off from slight rubbing, but this is not always reliable.[en.wikipedia.org]
  • Although clinically rare, affected skin displays "Nikolsky's Sign" which means that bullae easily extend into adjacent skin when lateral pressure is placed.[pathwaymedicine.org]
  • This is called a positive Nikolsky sign. A skin biopsy is often done to confirm the diagnosis. Severe cases of pemphigus may need wound management, similar to the treatment for severe burns.[nlm.nih.gov]
  • […] blisters and erosions on trunk, face, scalp, and proximal limbs, positive Nikolsky sign Pemphigus vegetans – intertriginous and oral with involvement of tongue (cerebriform tongue) Flaccid bullae and erosions (Neumann type) Pustules (Hallopeau type)[arupconsult.com]
Alopecia
  • KEYWORDS: Sjögren's syndrome; alopecia areata; pemphigus; psoriasis; systemic lupus erythematosus[ncbi.nlm.nih.gov]
  • […] deficiency pallor, fatigue, cephalalgias, vertigo, buzzing in the ears, irritability, insomnia, concentration problems, sensitivity to cold, anorexia, and nausea Enteropathic acrodermatitis – loss of taste and smell, sight problems, intense diarrhea, alopecia[jdrr.org]
  • (Flaccid Bullae) Fig.283-1 Pemphigus (Nicoklysk's signe ve) Fig. 283-2 Pemphigus vulgaris(infected bullae) Fig.283 Pemphigus vulgaris Fig.283-4 Pemphigus-Subungual bullae Fig. 283-5 Pemphigus vulgaris Fig.283-2 Pemphigus of the scalp and cicatricial alopecia[drmhijazy.com]
  • […] iron deficiency Pallor, fatigue, cephalalgias, vertigo, buzzing in the ears, irritability, insomnia, concentration problems, sensitivity to cold, anorexia and nausea Enteropathic acrodermatitis Loss of taste and smell, sight problems, intense diarrhea, alopecia[omicsonline.org]
Photosensitivity
  • Additionally, as in all photosensitive disorders, patient education on the use of sunscreens, protective clothing, and sun-smart behaviors is a cornerstone of therapy. Pérez-Pérez ME, Avalos-Díaz E, Herrera-Esparza R.[emedicine.com]

Workup

Blisters and ulcers occur in a number of conditions thus diagnosis is difficult to reach in case of pemphigus. A skin specialist will be required to take a complete medical history and for examination of skin and mucosa [7]. Clinically, on examination one will see typical blisters and ulcers on the skin and oral mucosa, apart from that rubbing a patch of normal skin near the affected area with a cotton swab will result in peeling of top layers of skin. This is known as Nikolsky sign and is usually positive in case of pemphigus.

Skin biopsy can be done and will reveal the typical acantholytic cells embedded within the blisters just in the superficial layers of the epidermis. The internal structure of all blisters shows intracellular edema and separation of epidermal cells to produce spaces and clefts. Histopathology helps to differentiate the various types of pemphigus. Certain cases may show eosinophilic spongiosis prior to blistering.

Blood tests can be done to detect the antibodies in circulation, desmoglein antibodies. Patients show elevated levels of these antibodies when pemphigus is initially diagnosed. This blood test is the indirect immunofluorescence test. Levels of antibodies fluctuate as symptoms improve and patient becomes better. Skin biopsy staining by direct immunofluorescence reveals antibodies and is a confirmatory test for pemphigus. Various types of pemphigus are distinguished based on the level of epidermis involved and the type of antibodies circulating in the body.

Cytopenia
  • Rituximab in the treatment of refractory autoimmune cytopenias in adults. Haematologica 2005 ;90: 1273 - 1274 31. Pijpe J, van Imhoff GW, Spijkervet FK, et al.[doi.org]

Treatment

The faster the treatment is started, the lesser are the chances of infections and complications. The approach towards pemphigus is mainly medications and in extreme cases, hospitalization [8]. The aim of initiating medications soon is to prevent further blister formation and enable healthy healing of previously existing lesions. In medications, corticosteroids are mainly used to control and suppress the immune system. The main steroid used is prednisone which should be used with caution and care. Prolonged usage of this steroid can have serious side effects such as increase in sugar, weight gain, bone damage and higher risk of infections. Immunosuppressants such as azathioprine [9], methotrexate can also be given to suppress immune system from damaging own body. For concurrent infections antibiotics, antivirals or antifungals can be given.

Widespread pemphigus vulgaris requires hospital admission as the sores and blisters are so severe that a high risk of superadded infection is possible. Severe sepsis can spread to the entire body and lead to death. Along with medications, fluid balance is maintained through IV fluids along with intravenous feeding since eating is painful due to sores and ulcers. Skin and wound care is vital for healthy healing and preventing secondary infection. Plasmapheresis is also done to reduce the levels of antibodies in the blood circulation.

With the above treatment outlined, patients have shown good results and a decrease in most of the symptoms. Though chances of relapse is quite common due to which certain patient need to continue medications for a longer period [10].

Prognosis

With the advent of systemic steroid therapy, the outlook of this life threatening condition has improved. If treatment is not given, pemphigus is fatal and complications common. Due to corticosteroids, the mortality rate [6] has decreased considerably. The most common complications which lead to death are infection, in case of pemphigus vulgaris they spread all over the body especially in the elderly patients. In these cases, high doses of steroids need to be given to suppress the immune system.

Hospitalization may be required in cases of severe blistering, special care has to be taken of the skin to prevent widespread secondary infection. Antibiotics may be prescribed for these infections along with dressing of open skin areas. Prognosis mainly depends upon the extent of spread of the disease and is worse in pemphigus vulgaris. Healing in most cases is without scarring unless secondary infection supervenes which can also lead to sepsis.

Etiology

Pemphigus is a rare autoimmune disorder. In pemphigus, the immune system produces antibodies against desmoglein, which is a protein which glues the cells of the epidermis together as a result the building blocks of the epidermis called keratinocytes that get damaged and fall apart or become flaccid. This leads to collection of fluid between the dermal layers, resulting in erosions and blisters of the skin.

The exact reason as to why the immune system behaves like this is still not known. Thus, the exact triggering factor of the immune system that leads to production of autoantibodies remains unclear. Recent investigations and research suggest a combination of genetic [3] and environmental factors in the etiology of this autoimmune disease. Certain medications can cause pemphigus to occur such as cephalosporins, penicillin and others, but it usually resolves once medication stopped.

Various types of pemphigus:

  • Pemphigus vulgaris is the most common occurring variant wherein blister and sore formation occur on the skin and mucous membranes, mainly the oral mucosa. Here, the erosions and blisters are deep and highly painful. Peeling of skin occurs due to the extent of blistering and fragility of skin. Healing occurs, but with residual brown spots may be seen. These brownish spots remain for few months. Scarring is never seen.
  • Pemphigus foliaceus is a more infrequent type of pemphigus. Blistering and oral ulcers are absent. They appear first on the face, scalp and chest. They are painless, but itchy. Pemphigus foliaceus differs from pemphigus vulgaris in the superficial nature of its erosions. The vesicles in pemphigus foliaceus are roofed, thin and rupture easily and hence, difficult to find.
  • Pemphigus vegetans is characterized by blisters in the groin and genital area. This is a subtype of pemphigus vulgaris.
  • Paraneoplastic pemphigus is a very rare condition which occurs in people suffering from various types of cancer. Blisters and erosions occur in mouth, lips, eyes and eyelids. This disorder also produces antibodies, but a different type of in comparison to the other variant. This type of pemphigus can cause scarring of the eyes and eyelids and can also affect the lungs.

Epidemiology

This is a rare disorder with an overall prevalence [4] of approximately 4.2 cases reported per million every year in the US. Overall, in the world one to ten new cases are reported per one million people. The data regarding the epidemiology of this condition is very limited and scarce. The incidence and prevalence rates are different across various parts of the globe. It affects people of all castes and races, but people of Mediterranean, Jewish, Middle East and Indian descent seem to have a higher risk which could be due to some genetic reason.

Pemphigus affects both sexes equally and usually occurs around 50-60 years of age; though nowadays, certain pediatric cases have been noted. The symptom presentation of pediatric cases is similar, but not common. No socioeconomic factors are involved. This disease is said to have a genetic predisposition and this trait seems to run in certain types of families. There are certain genes in the MHC complex on chromosome 6 which seem to be seen in people with this condition. This is a not an infectious disease and cannot be transmitted from person to person.

Sex distribution
Age distribution

Pathophysiology

Acantholysis is the primary pathological feature of pemphigus. The separation of the keratinocytes in the epidermis leads to cleft formation which becomes bigger to form blisters and later merge to form ulcers. Histopathology [5] reports of pemphigus vulgaris always show separation of epidermal keratinocytes leading to an intraepithelial vesicle formation.

The various types of pemphigus are always accompanied by circulating autoantibodies which are basically intercellular antibodies against the antigen proteins on the keratinocytes cell surfaces. The immunological aspect of this condition is very well understood with the exact role of antibodies. Antibodies against desmoglein protein are widely found in the patients of pemphigus especially desmoglein 3 in pemphigus foliaceus since this protein is abundantly found in superficial a layers of epidermis and desmoglein 1 in vulgaris as this is found in lower layers of epidermis. These autoantibodies can be detected in the circulation by indirect immunofluorescence and recently specific ELISAs are used for detection.

Prevention

Primary prevention of pemphigus is not possible due to its immunological origin. Being an autoimmune disorder, there is no way to prevent this disease. Secondary prevention to avoid exacerbation of pemphigus should be followed by all patients suffering from this disorder. Certain precautionary steps should be followed such as:

  • Avoid activities which can harm or damage the skin and mucous membrane.
  • Refrain from eating highly spicy food as it can aggravate ulcers and blisters. Soft bristle toothbrushes should be used for oral care. Oral care should be maintained to prevent any kind of infection or dental decay.
  • Sun protection creams should be used to protect affected areas from ultraviolet exposure.
  • Careful and hygienic care of wound and blisters.
  • Use of soothing and calming lotions for skin.
  • Recent research suggests the role of stress on dermatological conditions. Emotional stress or worry can indirectly aggravate these conditions.

Summary

Pemphigus is a group of immunological disorders characterized by formation of recurrent vesicles or blisters which break out on the skin and mucocutaneous areas such as lining of mouth and genital area. Pemphigus is not a common condition and occurs due to lysis of the binding spines of a protein known as desmoglein that holds together the cells of the epidermis. Autoantibodies are formed against this protein which results in the lysis of these cells. Such keratinocytes, called acantholytic cells, are found within the bullae of the patients. This leads to formation of intraepidermal bullae and consequently ulcers and erosions due to their rupture. Young and middle aged adults are affected and extensive oozing erosions may lead to fluid, electrolyte and protein loss. The different types in this group of autoimmune disorders are pemphigus vulgaris [1], pemphigus foliaceus, paraneoplastic pemphigus and other variants. About 70% individuals are affected by pemphigus vulgaris and each of these variants is characterized histologically by a different layer of epidermis being affected.

Pemphigus vulgaris affects oral mucosa which leads to severe pain and burning while eating or talking. Inability to eat food further aggravates electrolyte imbalance and leads to hypoproteinemia. Untreated and extensive disease leads to debility and death. Pemphigus foliaceus differs from vulgaris by being superficial in nature and sparing the mucosa, though if pemphigus foliaceus is left untreated, it can lead to erythema and even be fatal. Earlier this condition had a high mortality rate, but with the advent of steroids and immunosuppressants, results of this blistering disorder are much better. This rare autoimmune disorder [2] responds to high doses of systemic steroid therapy with an extended tapering over many months or even years. Pulse therapy with steroids is known to reduce the side effects of these medications.

Patient Information

Pemphigus is a rare group of skin disorders wherein severe blisters and ulcers appear in the skin and mucous membranes of the mouth, nose, throat, eyes and even genital areas. Pemphigus usually has many types with pemphigus vulgaris being the most common variant. The exact cause is not known, but since it is an autoimmune disorder, interplay of genetic and environmental factors has been suggested. In this disorder, the body's own immune system starts producing antibodies against healthy tissue and body cells. The immune system similar to how it fights germs and bacteria, wrongly starts damaging healthy cells and tissues. Certain races and ethnics are more prone to this condition and affects both sexes equally. The median age of onset of this disease is usually 50-60 years.

Clinical symptoms of pemphigus are blisters and ulcers on the healthy skin, which tend to rupture oozing out fluid. There may be severe burning and stinging pain. Due to rupture, secondary infection is also quite common if proper care is not taken. If you observe painful blisters and ulcers on your skin, especially mouth, seek medical help immediately. Timely treatment can prevent complications and reduce duration of disorder. Consult a skin specialist who will do a complete physical as well as advice certain tests including a skin biopsy. After a diagnosis, treatment consists of steroids and steroidal creams. Strict oral care should be followed. Immunosuppressants may be given as another option instead of steroids. Certain minor changes in lifestyle such as avoidance of too spicy food, sunscreen application, oral hygiene as well as refrain from stress and emotional worry. Follow up is essential for a successful treatment.

References

Article

  1. Ayoub N. [Pemphigus and pemphigus-triggering drugs]. Ann Dermatol Venereol. 2005 Jun-Jul. 132(6-7 Pt 1):595.
  2. Ettlin DA. Pemphigus. Dent Clin North Am. 2005 Jan. 49(1):107-25, viii-ix.
  3. Leshem YA, Katzenelson V, Yosipovitch G, David M, Mimouni D. Autoimmune diseases in patients with pemphigus and their first-degree relatives. Int J Dermatol. 2011 Jul. 50(7):827-31.
  4. Pisanti S, Sharav Y, Kaufman E, Posner LN. Pemphigus vulgaris: incidence in Jews of different ethnic groups, according to age, sex, and initial lesion. Oral Surg Oral Med Oral Pathol. 1974 Sep. 38(3):382-7.
  5. Ahmed AR, Wagner R, Khatri K, et al. Major histocompatibility complex haplotypes and class II genes in non-Jewish patients with pemphigus vulgaris. Proc Natl Acad Sci U S A. 1991 Jun 1. 88(11):5056-60.
  6. Ahmed AR, Moy R. Death in pemphigus. J Am Acad Dermatol. 1982 Aug. 7(2):221-8.
  7. Venugopal SS, Murrell DF. Diagnosis and clinical features of pemphigus vulgaris. Immunol Allergy Clin North Am. 2012 May. 32(2):233-43, v-vi.
  8. Yeh SW, Sami N, Ahmed RA. Treatment of pemphigus vulgaris: current and emerging options. Am J Clin Dermatol. 2005. 6(5):327-42.
  9. Aberer W, Wolff-Schreiner EC, Stingl G, Wolff K. Azathioprine in the treatment of pemphigus vulgaris. A long-term follow-up. J Am Acad Dermatol. 1987 Mar. 16(3 Pt 1):527-33.
  10. Beissert S, Mimouni D, Kanwar AJ, Solomons N, Kalia V, Anhalt GJ. Treating pemphigus vulgaris with prednisone and mycophenolate mofetil: a multicenter, randomized, placebo-controlled trial. J Invest Dermatol. 2010 Aug. 130(8):2041-8.

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Last updated: 2019-07-11 22:39