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Pemphigus Foliaceus

Pemphigus foliaceus is an autoimmune disorder of an unknown etiology. In this condition, the host’s immune system produces antibodies that bind and neutralize epidermal desmosomes, adhesion molecules that connect keratinocytes. Without these desmosome anchors, the keratinocytes separate into sheets and layers, resulting in superficial cutaneous blisters and erosions. There are several types of pemphigus disease. Pemphigus foliaceus is limited to the skin.


Presentation

Blisters (flaccid vesicles and bullae) [13] may be a rare finding on examination. The blisters rupture easily because the superficial skin overlying the blisters is quite thin. A positive Nikolsky sign implies an acantholytic condition and is found when exfoliation occurs when rubbing the healthy skin. This was discovered in 1896 by Dr. Piotr Nikolsky [1]. Bullous pemphigoid forms blister between the epidermis and dermis which result in a thicker skin and are negative for Nikolsky sign. Also, in PF there is little to no involvement of the mucous membranes where pemphigus vulgaris affects the skin and mucous membranes.

Well-demarcated, erythematous, crusted lesions are more common. These lesions are very superficial. Blisters and crusts are found on the upper torso early in the disease and spread to the face and scalp. Mucosal involvement is a rare finding. The blisters are usually painless but the open lesions may cause a focal, burning pain. These symptoms are usually not debilitating. The pemphigus erythematosus variant tends to affect the malar region of the face.

Constitutional Symptom
  • In patients with autoimmune bullous disease, the development of new skin pain or new constitutional symptoms, change in primary morphology, rapid disease progression, or failure to respond to appropriate therapies should prompt the clinician to consider[ncbi.nlm.nih.gov]
Hemophilia A
  • Acquired hemophilia A (AHA) is a rare coagulation disorder with a high mortality rate, caused by anti-factor VIII immunoglobulin G antibodies leading to spontaneous severe hemorrhages into skin, muscles or soft tissues.[ncbi.nlm.nih.gov]
Blister
  • Blisters (flaccid vesicles and bullae) may be a rare finding on examination. The blisters rupture easily because the superficial skin overlying the blisters is quite thin.[symptoma.com]
  • […] antibodies coordinately contribute to blister formation in PF.[ncbi.nlm.nih.gov]
  • Pemphigus foliaceus is an autoimmune blistering disease (bullous disorder) of the skin.[en.wikipedia.org]
Nikolsky's Sign
  • Bullous pemphigoid forms blister between the epidermis and dermis which result in a thicker skin and are negative for Nikolsky sign.[symptoma.com]
  • Nikolsky's sign was positive. Prior to present consultation, he had taken prednisolone 40 mg tablet, once a day along with supportive therapy with which he had only partial relief.[e-ijd.org]
  • The mucosal membranes were respected (fig 1 ), and Nikolsky’s sign was positive. Histological studies of a lesion showed splitting of the upper epidermis.[adc.bmj.com]
  • Blisters tend to form when the skin is rubbed ( Nikolsky sign ).[dermnetnz.org]
Eczema
  • A 55-year-old woman presented after a four-year history of impetiginized eczema that was distributed over her face, scalp, chest, and back and a recent diagnosis of breast cancer.[ncbi.nlm.nih.gov]
  • Type I (3) Drug Eruption (56) Erythrodermia, Primary (1) Nummular Eczema (50) Pemphigus Seborrhoicus (13) Psoriasis Vulgaris, Chronic Stationary Type (72) Psoriatic Erythroderma (8) Sezary Syndrome (15) Staphylococcal Lyell's Syndrom (8) Subacute Cutaneous[dermis.net]
  • This may easily be mistaken for more common problems such as eczema or fungal infections or seborrhoeic dermatitis, but does not respond to treatments for these conditions. It may spread to the body and become painful.[dermcoll.edu.au]
  • Skin blisters are rarely intact, more often presenting with “cornflake crust” erosions that can be mistaken for impetigo, seborrheic dermatitis, tinea capitis, or eczema (Figure 1). Figure 1. Superficial crusted erosions of pemphigus foliaceus.[clinicaladvisor.com]
Koebner Phenomenon
  • BACKGROUND: The Koebner phenomenon, also known as the isomorphic response, is the development of preexisting skin disease following trauma to uninvolved skin. Various cutaneous disorders have been described to arise at surgical wounds and scars.[ncbi.nlm.nih.gov]

Workup

If pemphigus foliaceus is suspected, there are a variety of diagnostic studies that may be performed. However, these tests are rather invasive and require skin biopsies or blood samples. The biopsies are evaluated histologically and by direct immunofluorescence (DIF).

  • Skin biopsies are required from two sites: A perilesional biopsy and a biopsy from an affected region. The perilesional skin should be adjacent to the biopsied lesion. The inflamed skin may result in the destruction of autoantibody deposits and result in a false-negative study [14].
  • Patient serum may also be analyzed using enzyme-linked immunosorbent assay (ELISA) or indirect immunofluorescence [15].

Diagnosis of PF is based on three criteria. No one condition is sufficient for diagnosis.

  1. History and physical exam.
  2. Histopathological findings of the affected skin biopsy and perilesional biopsy.
  3. The presence of autoantibodies in a biopsy of the affected skin by DIF or via indirect immunofluorescent studies of the patient’s serum.

Treatment

Pemphigus disease is rare. There is insufficient evidence to develop a consensus in regards to treatment guidelines. Many treatment regimens are based on small case studies or physician experience.

The first line of intervention is least invasive: rest, stress reduction, and a thorough medication review. Any medication that is a potential trigger (especially sulfa drugs) should be discontinued and replaced with a different class of medication. Also, any blisters and open sores should be dressed appropriately. Antibiotics may be prophylactically administered to any blisters or ulcers to prevent infection.

If the condition is widespread or severe the patient may require admission to a hospital to stabilize their condition. Severity is determined by the ratio of blistered or ulcerated skin to the amount of healthy tissue. Critical cases are rare, but in these cases, the first line medical treatment is oral prednisolone dosed at 1mg/kg/day. The administration of high doses of corticosteroids for prolonged periods of time will result in detrimental side effects including hyperglycemia, insulin resistance, leukocytosis, and osteoporosis. These conditions must be anticipated and managed. Alternatively, steroid sparing agents can be used to minimize the negative effects of prolonged, high-dose steroids.

No single medication has been shown to be superior to others. Drug choice will depend on a variety of factors including severity of the condition, past medical history, and the physician’s medical judgment.

Options include agents such as:

Prognosis

Generally, patients with pemphigus foliaceus have a good prognosis, if the disease is adequately controlled. Spontaneous remission is possible; however, patients usually require long-term immunosuppression [12]. Patients with incomplete treatment (i.e., those who have multiple remissions) can develop a more aggressive disease. This process is called disease-hardening, where an indolent disease becomes aggressive and resistant to treatment.

Etiology

The exact mechanism of PF is not known. Autoantibodies against desmosome result in the pathognomonic blisters. Immunoglobulin type G (IgG) is the most common antibody involved in most cases of PF. In immunoglobulin A (IgA) pemphigus foliaceus, the pathologic autoantibodies are comprised mainly of the immunoglobulin type A. Research is underway to clarify the mechanism that leads to autoantibody creation. In photo-induced PF the loss of intracellular connections is enhanced by autoantibodies and neutrophils with a strong affinity to radiation damaged epidermal tissue [10]. Environmental factors are likely involved in the disease course as well. Pesticides, pharmaceuticals (especially sulfa drugs), hormones, infectious agents, malignancy, radiation (therapeutic radiation), and stress increase risk of developing the disease [11]. Additionally, endemic pemphigus foliaceus appears to have an antigen trigger with an arthropod vector. The prevalence of antibodies against desmoglein-1 is high in people residing in endemic areas of Brazil, but disease onset is preceded by an elevated and sustained antibody response due to an unknown environmental factor.

Genetic factors also play a role in the disease. Haplotypes DRB1*0102 and 0404 carry an increased risk of developing pemphigus foliaceus. There is an increased risk of developing FS in HLA-DRB1 haplotypes, especiallyDRB1*0404, 1402, 1406, and 1401. Drug-induced pemphigus foliaceus can be seen with the use of penicillamine [4], nifedipine, captopril, enalapril and nonsteroidal anti-inflammatory drugs (NSAIDs). Discontinuation of the offending medications results in remission of the condition in 50% of cases.

Epidemiology

Worldwide, pemphigus foliaceus is a rare disease. However, there are geographic pockets with much higher incidence rates of the endemic variant of the disease. Areas of Tunisia in North Africa have shown an incidence rate of 6.7 new cases per million each year [5]. Maso Grosso do Sul in Brazil has multiple foci of endemic PF and a prevalence of approximately 3% [6]. Colombia and Peru also some of the other endemic areas [7]. The average age of non-endemic PF ranges from 40 to 60 years of age. Fogo selvagem affects a younger population in the second or third decade of life [8]. Sporadic and endemic PF affect men and women equally. Also, all races and ethnicities are affected about equally.

Sex distribution
Age distribution

Pathophysiology

The mechanism of pemphigus foliaceus involves IgG (mainly the IgG4 subtype) autoantibodies that bind specifically to desmoglein-1 (160 kd), a glycoprotein structural component of desmosomes [9]. These desmosomes are mainly expressed in the granular layer of the epidermis. The mechanism of desmosome destruction and acantholysis induction may involve phosphorylation of intracellular proteins. Complement activation does not play a role in PF.

Prevention

There is no proven method to prevent pemphigus foliaceus at this time.

Summary

Pemphigus is a group of skin diseases that result in the formation of blisters. There are two main types: pemphigus foliaceus (PF) and pemphigus vulgaris. Pemphigus should not be confused with bullous pemphigoid which also results in skin blisters. PF is an autoimmune disorder of the skin and is characterized acantholysis, the loss of cellular adhesions between adjacent keratinocytes in the epidermis. Without the adhesion molecules, layers and sheets of superficial cells split away from each other and form shallow pockets that fill up with fluid and form blisters. These blisters are often very fragile. The superficial skin overlaying the blisters is easily lost, resulting in the formation of shallow erosions.

Endemic pemphigus foliaceus or fogo selvagem (FS) (wild fire in Portuguese) was thought to be only found in the river valleys of rural Brazil. The disease has since been found in other parts including Colombia, El Salvador, Paraguay, and Peru and most recently in Tunisia. Endemic pemphigus foliaceus displays a distinctive epidemiology suggestive of a disorder triggered by an infectious insect-borne agent and immunopathologic findings of pemphigus. The endemic variant also exists in El Bagre and has a similar presentation and histology to Pemphigus erythematosus, also known as Senear-Usher syndrome, but occurs in an endemic fashion [2] [3].

Patient Information

Pemphigus diseases are autoimmune diseases affecting the skin and/or mucous membranes. They are rare outside endemic areas. Environmental and genetic factors are involved with the diseases progression. Pemphigus foliaceus is a relatively benign form of pemphigus that is limited to the skin.

What causes this disease?

Pemphigus foliaceus occurs when the immune system produces autoantibodies that recognize and bind to a specific adhesion molecule (desmosomes) in the skin. These molecules hold the top layers of the skin (epidermis) together. The autoantibodies damage the desmosomes which allow the skin to separate in sheets. Fluid fills these gaps and forms superficial blisters. A normal immune system will not attack the skin. As found in many autoimmune diseases, both environmental and genetic factors may play a role in pathogenesis. Taking medications that contain sulfur can increase the risk of developing this condition. Parasitic infection, especially in the young, can also cause the disease. Other triggers include stress, sunburn, and radiation therapy.

What are the symptoms of pemphigus foliaceus?

The key finding in pemphigus foliaceus is shallow, superficial blisters of the skin. A similar condition, pemphigus vulgaris, involves the skin and the mucous membranes (mouth, eyelids, etc.). Patients with pemphigus foliaceus are usually in good health despite the blisters. The small fluid-filled, superficial blisters usually form on the chest first and then the face and scalp. The blisters rupture very easily because they form in the upper layers of the epidermis and leave behind superficial erosions. These lesions produce a burning, painful sensation and form a scaly crust with a red base. The subtype pemphigus erythematosus only affects the malar portion of the face and may be confused with lupus erythematosus.

How is the condition diagnosis?

Diagnosis requires two biopsies:

  • a biopsy of the lesion
  • a biopsy adjacent to the lesion (perilesional) in the unaffected skin.

A pathologist will use special stains that may show IgG autoantibodies surrounding the skin cells. Additionally, autoantibodies to desmoglein-1 can be detected in a patient’s serum.

How is pemphigus foliaceus treated?

For focal and minor cases of pemphigus foliaceus, topical corticosteroids are recommended. Widespread and severe cases require systemic corticosteroids and may also require other immunosuppressive combinations. Azathioprine, methotrexate, mycophenolate mofetil, plasma exchange, and rituximab are effective. The combination of nicotinamide 500 mg by mouth three times a day with tetracycline 500 mg by mouth four times a day may also provide relief.

References

Article

  1. Nikolski PV. Materiali K.uchenigu o pemphigus foliaceus [doctoral thesis]. Kiev. 1896.
  2. Abreu-Velez AM, Hashimoto T, Bollag WB, et al. A unique form of endemic pemphigus in northern Colombia. J Am Acad Dermatol. 2003 Oct. 49(4):599-608.
  3. Abreu-Velez AM, Beutner EH, Montoya F, Bollag WB, Hashimoto T. Analyses of autoantigens in a new form of endemic pemphigus foliaceus in Colombia. J Am Acad Dermatol. 2003 Oct. 49(4):609-14.
  4. Brenner S, Ruocco V. D-penicillamine-induced pemphigus foliaceus with autoantibodies to desmoglein-1. J Am Acad Dermatol. 1998 Jul. 39(1):137-8.
  5. Bastuji-Garin S, Souissi R, Blum L, et al. Comparative epidemiology of pemphigus in Tunisia and France unusual incidence of pemphigus foliaceus in young Tunisian women. J Invest Dermatol. 1995;104:302–305.
  6. Culton DA, Qian Y, Li N, et al. Advances in pemphigus and its endemic pemphigus foliaceus. J Autoimmun. 2008;31:311–324.
  7. Abreu-Velez AM, Hashimoto T, Bollag WB, et al. A unique form of endemic pemphigus in northern Colombia. J Am Acad Dermatol. 2003;49:599–608.
  8. Meyer N, Misery L. Geoepidemiologic considerations of auto-immune pemphigus. Autoimmun Rev. 2010;9:A379–A382.
  9. Ishii K, Amagai M, Komai A, et al. Desmoglein 1 and desmoglein 3 are the target autoantigens in herpetiform pemphigus. Arch Dermatol. 1999 Aug. 135(8):943-7.
  10. Kikuchi K, Inokuma D, Moriuchi R, Koguchi-Yoshioka H, Yasui C, Shimizu S. Exacerbation of Pemphigus Foliaceus After Electron-beam Radiation. Acta Derm Venereol. 2014 Mar 13.
  11. Ruocco V, Ruocco E. Pemphigus and environmental factors. Giornale Dermatol Venereol. 2003. 138:299-309.
  12. Colliou N, Picard D, Caillot F, et al. Long-term remissions of severe pemphigus after rituximab therapy are associated with prolonged failure of desmoglein B cell response. Sci Transl Med. 2013;5:175ra30.
  13. Santoro FA, Stoopler ET, Werth VP; Pemphigus. Dent Clin North Am. 2013 Oct;57(4):597-610. doi: 10.1016/j.cden.2013.06.002. Epub 2013 Aug 12.
  14. Mutasim DF, Adams BB. Immunofluorescence in dermatology. J Am Acad Dermatol. 2001;45:803–822.
  15. Abasq C, Mouquet H, Gilbert D, et al. ELISA testing of anti-desmoglein 1 and 3 antibodies in the management of pemphigus. Arch Dermatol. 2009;145:529-535.
  16. Gurcan HM, Ahmed AR; Efficacy of dapsone in the treatment of pemphigus open link and pemphigoid: analysis of Am J Clin Dermatol. 2009;10(6):383-96.
  17. Joly P, Mouquet H, Roujeau JC, et al. A single cycle of rituximab for the treatment of severe pemphigus. N Engl J Med. 2007;357:545-552.

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Last updated: 2019-07-11 21:14