Epidermolysis Bullosa

 

Welcome to PT 635 Pathophysiology of Complex Patient Problems This is a wiki created by and for the students in the School of Physical Therapy at Bellarmine University in Louisville KY. Please do not edit unless you are involved in this project, but please come back in the near future to check out new information!!

Original Editors - Cody Mumaw and Rachel Kirchgessner from Bellarmine University's Pathophysiology of Complex Patient Problems project.

Top Contributors - Rachel Kirchgessner, Cody Mumaw, Elaine Lonnemann, 127.0.0.1, WikiSysop, Lucinda hampton, Evan Thomas and Kim Jackson  

Definition/Description

       Epidermolysis bullosa (EB) consists of a rare group of genetically determined skin fragility disorders, categorized by blistering skin and mucosa in response to little or no apparent trauma, with some forms leading to substantial morbidity and increased mortality. The fragility of skin and mucosa within this disease is due to defects in structural proteins within the epidermis, specifically at the epidermal-dermal junction, that cause a deficiency of cellular structures that normally stabilize the adhesion of the epidermis. These, in turn, result from abnormalities in the genes encoding various proteins that define EB into specific categories. Accordingly, EB has been classified into three major different subtypes based on mode of inheritance, location of lesions, and clinical features which include the following three major forms: EB simplex (EBS), junctional EB (JEB), and dystrophic EB (DEB). These three different subtypes are based on the level of blistering of the skin, although the classification of EB continues to evolve with recognition of up to 30 clinical subtypes.

Prevalence

       All types and subtypes of EB are rare. Estimates of prevalence and incidence of EB have been endeavored by many different sampling techniques in numerous populations worldwide, but the most accurate and up to date epidemiological data is derived from the National EB registry (NEBR) from the USA. This registry is a cross-sectional and longitudinal epidemiological study of patients diagnosed with EB across the entire U.S. Over 16 years (1986-2002), 3,300 patients were identified, enrolled, classified, characterized, and followed for outcomes. Among this study, the overall incidence and prevalence of inherited EB, within the United States, is approximately 19.60 per one million live births and 8.22 per one million population, respectively.  When analyzing the different classifcations of EB,  the incidence and prevalence rates for EB simplex are 10.75 and 4.65, for junctional EB are 2.04 and 0.44, for dystrophic EB recessive type are 2.04 and 0.92, and dystrophic EB dominant type are 2.86 and 0.99.   

Associated Co-morbidities

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Medications

       Currently no drugs are known to correct the primary molecular effects in EB. Recently, the use of topical opiates for pain management has been proven to reduce the need for powerful systemic analgesia. Amitriptyline, as well, has also been found to be useful in both children and adults in reducing pain. As far as systemic treatment, no agents thus so far have proven to be effective in controlling blisters in patients diagnosed with EB. Along with this, prolonged use of corticosteroids is contraindicated because of the high risk of complications associated with this drug. No other medication, including phenytoin and tetracycline, have improved the blistering or epithelial disadhesion in EB. Thus, there is no current reliable clinical trial evidence for any type of treatment with medication.

Diagnostic Tests/Lab Tests/Lab Values

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Etiology/Causes

With epidermolysis bullosa, the fragility of skin and mucosa in which erosions occur because of slight mechanical trauma are inadvertently the result of defects in structural proteins within the epidermis. These, in turn, occur because of abnormalities in the genes encoding these various proteins.  Subsequently, EB has been classified into three major subtypes that include their own genetic abnormalities:

EB simplex

• In EB simplex, the gene that helps make keratin, a fibrous protein in the top layer of skin, is faulty. Though it does not cause scarring, this subtype causes blister cleavage to occur within the epidermis . 

Junctional EB

• In junctional EB, defects in the basement membrane, specifically laminins, cause blister cleavage below the epidermis but above the basal lamina. This in turn, causes tissue separation and blistering in this deep layer of skin. 

Dystrophic EB

• In dystrophic EB, collagen VII mutations affect the anchoring fibrils and cause dermal blisters below the basal lamina within the papillary dermis. Because of this mutation layers of the skin don’t join properly. This type can be either dominant or recessive. 

Systemic Involvement

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Medical Management (current best evidence)

Currently there is no effective therapy or cure for EB.  Listed below is medical management that was proven to be the most effective in managing EB.

Preventing blisters

• Avoidance of aggravating factors for blistering remains the backbone of management. Measures to reduce these factors by using heat and humidity to lower the threshold for blistering are important.

Nursing Care

• Also deemed important is successful management through nursing care. Mother should be educated to nurse their children on thick foam pads to prevent them from inducing blisters from unnecessary trauma. As for older children, they should be educated upon certain precautions of using adhesive tapes, sphygmomanometer cuffs, tourniquets, and other instruments that may shear their skin or mucous membranes. The adhesions should be cleaned sterile saline and afterwards covered with nonadherant dressings. Because there is a risk of development of antibiotic resistant bacteria, topical antibiotics are usually avoided. Constipation needs to managed with a sufficient amount of fiber as well as stimulant laxatives. Balloon dilation is also required for esophageal strictures. 

Dental Care

• Good dental hygiene is vital for patients with EB, as regular visits to the dentist are recommended. This should be initiated as quickly as tooth eruption and oral mucosal involvement begins. In order to maintain function good oral hygiene, crown placements, and tooth implants should be maintained to preserve function. 

Dietary Care

• Lack of vitamins and trace metals are common with patients who receive gastrostomy feeding. It is important to do regular nutritional evaluations with patients who have EB as well as give provide them with dietary advice and appropriate supplementation. 

Molecular Therapy

• Gene therapy is probable to become a reality sometime in the future. With gene therapy, there are two broad principles-ex vivo and in vivo. Ex vivo is a specific type of gene therapy uses cultured cells such as keratinocytes, specifically from the affected individuals, which are propagated and transduced in culture to re-express the gene that is malfunctioning in the patients. Contrarily, in vivo gene introduces the transgene directly into the target tissue by either direct injection of the genetic material into the skin or mucous membranes or by topical application. The objective of molecular therapy is to replace one of the two mutant alleles in recessive forms of EB by introducing one normal allele into somatic cells.  The first successful gene therapy for EB was reported by Michele De Luca. With this, areas of skin on the anterior thighs of an adult male patient with junctional EB were “cured” by transplanting genetically modified epidermal sheets grown in culture with a total of 500cm2 on both legs. “These epidermal sheets taken from palm biopsies and transfected ex vivo with a retroviral expressing normal lamina 5-3 which were grown from the patient’s own laminin 5-3-chain-deficient epidermal stem cells. De Luca’s team is now planning the replacement of big proportion of the patient’s skin surface with this genetically modified skin. These current advances in molecular genetics has allowed prenatal and preimplantation genetic diagnosis to be possible, broadening many options with patients in management of EB. 
  
  

Physical Therapy Management (current best evidence)

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Differential Diagnosis

       The size or validity of the differential diagnosis presented with a child or adult with blistering of the skin is most certainly a reflection of the level of training and expertise of the physician. In almost all situations the diagnosis of EB should be apparent to a dermatologist, with only a marginal number of cases needing more of wide-ranging differential diagnoses before tissue confirmation. 

Pemphigus vulgaris
       Pemphigus vulgaris (PV) is a rare autoimmune, intraepithelial, blistering disease that is associated with a very encumbering quality of life. PV is characterized by autoantibodies against desmoglein 3 and desmoglein 1 of keratinocytes. It clinically, however, is characterized by extensive blisters that affect the skin and mucous membranes.  This is found in the mucous membrane in 95% of cases (oral, pharyngeal, esophageal, nasal, and genital), followed by skin lesions, crusting, and purple stains on the anterior chest, back, and abdomen, with oral lesions being common as well. Characteristics of these blisters include a diameter consisting of millimeters to centimeters that is isolated or in groups that appear to be fragile and flaccid, breaking in eroded areas, becoming bloody and wet, and covered with bloody crusting. Areas such as the face, scalp, neck, sternum, armpit, groin and periumbicals may experience a burning sensation.
The treatment goal of PV is to prevent new blister formation, heal old wounds, and eventually complete the tapering of treatment. As of now, there has been been no treatment strategy for PV according to the international consensus. The best treatment strategy for PV remains unclear as higher quality RCTs are needed in the future to explore other unstudied interventions. 

Bullous systemic lupus erythematosus
       Bullous systemic lupus erythematosus (BSLE) is a rare and distinct subtype of SLE, occurring mostly in the third decade. This subepidermal blistering disease occurs in patients that have been diagnosed with systemic lupus erythematosus (SLE), with a low occurrence of only 1%. Clinically, patients diagnosed with BSLE present with a rapid, widespread small vesicles or large tense blisters that are filled with fluid. These lesions may affect the trunk and limbs, or even face and mucous membranes, involving any area of the body. Diagnosis of BSLE includes the following: a past diagnosis of SLE based on American College Criteria (ACR), presence of vesicles and bullae most commonly located in sun-exposed sites, histopathology findings, and deposition of immunoglobulins at the basement membrane zone. Patient evaluation is critical, as a prompt diagnosis may prevent further SLE complications and change the prognosis and method to treatment.
In regards to treatment for BSLE, dapsone, corticosteroids, and/or immunosuppressant’s are the first treatment options to consider. If symptoms do not go away rituximab might be appropriate to consider. 

Bullous Pemphigoid
       Bullous pemphigoid (BP), idiopathic in origin, is the most common autoimmune subdermal blistering disease of the skin and mucous membranes, occurring from antibodies directed against the proteins BPAG1 and BPAG2. This disease is most commonly seen in elderly individuals and is characterized with blistering of the skin as well as intense pruritus.  Systemic corticosteroids, prednisone, in doses of 1 mg/kg/day, with dose tapering according to the therapeutic control of disease was shown to be the treatment of choice with the highest level of evidence for BP. 

Dyshidrotic eczema
       Dyshidrotic eczema is a chronic, recurrent skin disease that effects the palms and soles symmetrically. It often is a very intense and painful condition that can have a very devastating impact on quality of life. Although the etiology is unclear, dyshidrotic eczema is often triggered by emotional stress, smoking, seasonal changes, fungal infections, atopy, nickel allergy, hyperhidrosis, and intravenous immunoglobulin therapy.  Much like many other types of eczema, this is a benign chronic inflammatory disease that may occur at intervals of 3 to 4 weeks for months or years, or even progress to longer irregular intervals. Dyshidrotic eczema has no impact on survival as well as very few effective treatment options.

Linear IgA Bullous Dermatosis
       Linear IgA Bullous Dermatosis (LAD) is an autoimmune, chronic bullous disease affecting mainly young children and adults. Sub-epithelial blister formation with neutrophils along the basement membrane zone are typically histological characteristic features in LAD.
Childhood onset LAD is characterized by vesicles and bulla mainly around the mouth, eyes, lower abdomen, thighs, buttocks, genitals, wrists, and ankles. Subjective symptoms range mild pruritus to severe burning. The adult onset form presents with lesions on the trunk and occasionally head and limbs. The most often used treatment modalities in both children and adults are corticosteroids, dapsone, and sulpapyridine. 

Case Reports/ Case Studies

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Resources

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Recent Related Research (from Pubmed)

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References

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