A REVIEW- LIVING WITH BUTTERFLY SKIN DISEASE

About Authors:
Mohd. Yaqub Khan*, Poonam Gupta, Bipin Bihari, Vinod Kumar Singh, Sanjay Kumar Yadav, Aparna Misra
Saroj Institute of Technology & Management,
Ahimamau P.O. Arjunganj Sultanpur Road, Lucknow -226002
*khanishaan16@yahoo.com

Abstract
Epidermolysis bullosa(EB) is an inherited connective tissue disease causing blisters in the skin and mucosal membranes, with an incidence of 1/50,000. Its severity ranges from mild to lethal. The skin is extremely fragile: minor mechanical friction or trauma will separate the layers of the skin and form blisters. People with this condition have an increased risk of cancers of the skin, and many will eventually be diagnosed with it as a complication of the chronic damage done to the skin. The skin has three layers; the outermost layer is the epidermis, and the middle layer is the dermis. In individuals with healthy skin, there are protein anchors between the layers that prevent them from moving independently from one another (shearing). In people born with EB, these top skin layers lack the protein anchors that hold them together, and any action that creates friction between them (like rubbing or pressure) will create blisters and painful sores. Sufferers of EB have compared the sores with third-degree burns. Current clinical research at the University of Minnesota has included a bone marrow transplant to a 2-year-old child who is one of 2 brothers with EB. Sulforaphane, a compound found in broccoli, was found to reduce blistering in a mouse model to the point where affected pups could not be identified visually, when injected into pregnant mice (5 µmol/day = 0.9 mg) and applied topically to newborns (1 µmol/day = 0.2 mg in jojoba oil).

REFERENCE ID: PHARMATUTOR-ART-1806

INTRODUCTION
Epidermolysis Bullosa is a rare genetic condition in which the skin, and sometimes the mucous membranes (such as the lining of the mouth), blister in response to mild friction or trauma. A genetic defect prevents the layers of the skin from adhering properly. Blisters form as the layers of the skin split apart in response to friction or trauma¹.This condition is not contagious. An estimated 1 out of every 50,000 Americans is born with some form of EB. The disorder occurs in every racial and ethnic group throughout the world and affects both sexes equally. There are three main forms of inherited EB:

EB Simplex, Junctional EB and Dystrophic EB.
These different subtypes are defined by the depth of blister location within the skin layers.

* Epidermolysis bullosa(EB) is an inherited connective tissue disease causing blisters in the skin and mucosal membranes, with an incidence of 1/50,000. Its severity ranges from mild to lethal.

* The skin has three layers; the outermost layer is the epidermis, and the middle layer is the dermis. In individuals with healthy skin, there are protein anchors between the layers that prevent them from moving independently from one another (shearing). In people born with EB, these top skin layers lack the protein anchors that hold them together, and any action that creates friction between them (like rubbing or pressure) will create blisters and painful sores. Sufferers of EB have compared the sores with third-degree burns.²

EPIDEMIOLOGY

An estimated 50 in 1 million live births are diagnosed with EB, and 9 in 1 million are in population.
Approximately 92% are epidermolysis bullosa simplex (EBS)
5% are dystrophic epidermolysis bullosa (DEB)
1% are unctional epidermolysis bullosa (JEB),

2% are unclassified.The disorder occurs in every racial and ethnic group throughout the world and affects both sexes.³

Classification

Epidermolysis bullosa simplex (EBS)⁴

Generalized epidermolysis bullosa simplex (Koebner variant of generalized epidermolysis bullosa simplex)
Localized epidermolysis bullosa simplex (Weber-Cockayne variant of generalized epidermolysis bullosa simplex)
Epidermolysis bullosa herpetiformis (Dowling-Meara epidermolysis bullosa simplex)
Epidermolysis bullosa simplex of Ogna
Epidermolysis bullosa simplex with muscular dystrophy
Epidermolysis bullosa simplex with mottled pigmentation

Junctional epidermolysis bullosa (JEB)⁵

Junctional epidermolysis bullosa gravis (Epidermolysis bullosa lethalis, Herlitz disease, Herlitz epidermolysis bullosa, Lethal junctional epidermolysis bullosa)
Mitis junctional epidermolysis bullosa
Generalized atrophic benign epidermolysis bullosa
Cicatricial junctional epidermolysis bullosa
Junctional epidermolysis bullosa with pyloric atresia

Dystrophic epidermolysis bullosa (DEB) ⁶

Dystrophic epidermolysis bullosa
Dominant dystrophic epidermolysis bullosa (Cockayne-Touraine disease)
Recessive dystrophic epidermolysis bullosa (Hallopeau-Siemens variant of epidermolysis bullosa)

Other genetic ⁷

OMIM	Name	Locus	Gene
609638	epidermolysis bullosa, lethal acantholytic	6p24	DSP

Other ⁸

Epidermolysis bullosa acquisita

THE AUTOANTIGENS OF EBA
Type VII collagen, the main constituent of anchoring fibrils, was identified as the autoantigen of EBA. Anchoring fibrils are thought to anchor the epidermis and its underlying basement membrane zone to the papillary dermis. Type VII collagen is composed of three identical a-chains, each consisting of a 145-kDa central collagenous triple helical portion, flanked by a large 145-kDa amino terminal noncollagenous domain (NC1), and a smaller 34-kDa carboxy-terminal non-collagenous domain (NC2). In the extracellular space, type VII collagen molecules form anti-parallel tail-to-tail dimers stabilized by disulfide bonding through a small carboxy-terminal overlap (NC2), while a fragment of the NC2 domain is proteolytically removed. Several dimers aggregate laterally to form the unique cross-banded structure, namely, anchoring fibrils, which comprise anti-parallel dimers and contain NC1 domains at both ends, locating in the lamina densa and forming semicircular loops visible by electron microscope⁹. Previous studies have established that the major antigenic epitopes of type VII collagen are located within the NC1 domain of type VII collagen. The autoimmune nature of EBA and the pathogenic relevance of antibodies against type VII collagen are supported by the following compelling evidence. Patients’ autoantibodies to type VII collagen were shown to recruit and activate leukocytes ex vivo resulting in dermal–epidermal separation in cryosections of human skin. Recently, two different animal models of EBA were established: The disease can be induced in mice by injection of autoantibodies against type VII collagen into mice, when passively transferred into mice. In this ‘‘passive’’ EBA model, skin lesions develop in all strains of mice investigated so far. Subepidermal blisters can also be induced in mice by immunization with a recombinant fragment of the murine NC1 domain (GSTmCOL7C). Disease development in this ‘‘active’’ model is restricted to certain strains of mice; for example, SJL. Both models duplicate the clinical, histological and immunological features seen in patients with EBA. Furthermore, complement activation and infiltration of granulocytes into the skin are required for blister formation in experimental EBA. Although mechanisms of tissue damage and blister formation in EBA are not fully understood, mechanisms by which EBA autoantibodies are thought to be initiated by the binding of the autoantibodies to antigenic sites, most commonly located within the NC1 domain of type VII collagen. Subsequently, complement is activated by the Fc-portion of autoantibodies, leading to the recruitment of neutrophils, which release reactive oxygen species, ultimately resulting in subepidermal blister formation¹⁰. EBA patients have a decrease in normally functioning anchoring fibrils secondary to an abnormality in theirimmune system in which they produce ‘‘pathogenic’’ autoantibodies against type VII collagen.

IMMUNOBLOT ANALYSIS
Sera from patients with EBA recognize the 290-kDa protein, or its immunodominant region, the NC1 domain, by immunoblotting with normal human dermal extracts. Immunoblot analysis with extracts of human epidermis or cultured keratinocytes and fibroblasts is usually negative. A sensitive enzyme-linked immunosorbent assay for the detection of autoantibodies to type VII collagen using recombinant protein is also available¹¹. Some cases of a subepidermal blistering disease with autoantibodies against more than two antigens have been reported. EBA also sometimes complicates other subepidermal autoimmune bullous diseases, for example, against anti-laminin anti-bullous pemphigoid and anti-p-200 antigen. At present, clinical features, and histological and immunofluorescence findings are not useful to distinguish between each other. Immunoblot analysis and other molecular biological studies are necessary to further characterize these complicated subepidermal autoimmune bullous diseases. Moreover, the relationship between the antigenic reactivity of these autoantibodies and their prognostic significance needs to be elucidated by more precise analyses.¹²

CLINICAL PRESENTATIONS OF EB
Bullae can be initiated on skin or mucous membranes at sites of trauma or pressure and on rupturing they leave painful erosion which heals with scar formation. Bullae can occasionally develop spontaneously. Fingers are destroyed with resorption of phalanges, and hands become unsightly and club-shaped. This disorder is often associated with extracutaneus complications such as nutritional deficiencies, recurrent infections and motor disabilities. Nutritional problems are the consequence of restricted nutritional intake, chronic constipation and increased whole-body protein turnover, probably caused by chronic non-healing wounds and infections¹³. Oral mucosal scarring and contracture due to minor trauma such as toothbrushing, can lead to tongue-tie, obliteration of the sulci, limited opening, lingual depapillation and atrophy of the palatal folds. During blistering and subsequent cicatrization, epithelial cells become entrapped and give rise to milium cysts, particularly in the hard palatal mucosa. Areas of leukoplakia and oral squamous cell carcinoma (OSCC) have also been reported, affecting mainly the lingual mucosa. All three main types of EB produce oral defects. Abnormal enamel development is a common feature, including thin enamel and localized or generalized hypoplasia. Structural abnormalities include fine or coarse pitting defects, or thin or uneven enamel which may also lack prismatic structure¹⁴. The amelodentinal junction may also be smooth. The mineral and chemical composition of dental enamel in EB however, is no different from normal and does not predispose the teeth to caries, although the prevalance of dental caries is significantly increased in individuals with junctional EB and recessive EB, probably due to lack of oral cleansing. There is no direct relationship between the extent of oral blistering and caries experience. The salivary flow rate has been investigated and no difference found between EB individuals and controls.¹⁵

DIAGNOSIS
The evaluation of any patient suspected of having EB should begin with a detailed history, including mapping of the family pedigree. A typical history includes spontaneous blister formation in areas of frequent trauma from birth or early infancy. Nonmolecular laboratory tests for the diagnosis include transmission electron microscopy (TEM), immunofluorescence antigen mapping and immunohistochemical staining with EB-specific monoclonal antibodies. With advances in molecular biology, the underlying gene defects and linkage of various forms of EB with certain genes provide a basis for direct mutation detection and indirect linkage analysis in affected families. First-trimester prenatal diagnosis using DNA from chorionic villi and amniotic fluid can provide the diagnosis as early as 10 weeks gestation¹⁶. Direct methods include Southern blotting and restriction enzyme analysis, allele-specific hybridization and polymerase chain reaction amplification. Indirect methods include DNA polymorphism. ¹⁷

Addressing nutritional support in EB

The 2 main factors responsible for compromised nutrition are:-
Oral, oro-pharyngeal, oesophageal and gastrointestinal complications (ulceration with or without stricture) which limit nutritional intake. Hyper-metabolism promoted by external skin lesions with loss of blood and serous fluid, leading to increased protein turnover and heat loss particularly when associated with infection.¹⁸

INTERACTIONS BETWEEN CAUSES AND EFFECTS OF INADEQUATE NUTITIONAL INTAKE IN SEVERE EB ^{19, 20}

Aims of nutritional support (modify in cases of HJEB) ^{21, 22}
• To alleviate under nutrition and the stresses of feeding
• To minimize nutritional deficiencies
• To optimize growth
• To optimize bowel function
• To optimize immune status
• To optimize wound healing
• To promote pubertal development

TABLE 1: Main complications affecting nutritional status in different EB types ^{23, 24, 25, 26}

EB type	Complications affecting nutritional status
Weber-Cockayne EB simplex (EBS WC)	Lesions usually confined to feet and hands, especially in hot weather, often severely limiting mobility. Frequently painful defecation with/without constipation.
Dowling-Meara EB simplex (EBS DM)	Generalized blistering tending later to become more confined to hands and feet. Feeding problems often severe in infancy, especially gastro-oesophageal reflux (GOR) but generally resolve before teenage. Often painful defecation with/without constipation.
Herlitz junctional EB (HJEB)	Recurrent moderate to severe lesions. Dental pain due to abnormal tooth composition. Laryngeal and respiratory complications. Good initial weight gain usually followed by profound failure to thrive; possible protein-losing enteropathy. Opioid analgesia often exacerbates constipation. Massive sepsis and respiratory complications are usual causes of death. Survivors often profoundly anaemic with osteoporosis /osteopenia consequent to immobility and possibly to malabsorption.
Non-Herlitz junctional EB NHJEB)	Recurrent mild to severe lesions. Dental pain due to abnormal tooth composition. Possible protein-losing enteropathy. Osteoporosis/osteopenia when immobility compromised.
Junctional EB with pyloric atresia (PA)	Mild to severe lesions. PA. Usually fatal in infancy, but there are exceptions.
Dominant dystrophic EB (DDEB)	Usually mild lesions. May have oral and oesophageal involvement. Anal erosions/fissures can cause painful and reluctant defecation with/without constipation.
Recessive dystrophic EB (RDEB)	When severe, recurrent skin lesions heal poorly with generalised scarring and contractures. Internal contractures cause microstomia, dysphagia and oesophageal strictures. Digits fuse in severe generalized type. Anal erosions/fissures cause painful and reluctant defaecation with/ without constipation. Some develop inflammatory bowel disease/colitis. Refractory anaemia. Osteoporosis/ osteopenia in less mobile patients.

TABLE 2: Nutritional interventions associated with particular EB types ^{27, 28, 29, 30, 31}

EB type	Nutritional interventions
Weber-Cockayne EB simplex (EBS WC)	Due to reduced mobility and activity, advice on weight maintenance/reduction may be required. Age-appropriate fibre (and fluid) intakes.
Dowling-Meara EB simplex (EBS DM)	As for RDEB (see below) in early years, but gastrostomy placement rarely necessary. Catch-up in weight often occurs around adolescence and excess weight gain leads to exacerbation of foot lesions and further reduction in activity and mobility. If so, advice on weight maintenance/reduction required. Age-appropriate fibre (and fluid) intakes.
Herlitz junctional EB (HJEB)	As for RDEB in terms of global supplementation, but with intention of improving quality of life rather than quantity. Intervention has no impact on prognosis. Unlike RDEB, gastrostomy placement not generally appropriate as may result in very poor healing around entry site, skin break- down and leakage of gastric contents. Specialised formula feeds and exclusion diets have been used experimentally with patients with suspected protein-losing enteropathy.
Non-Herlitz junctional EB NHJEB)	Global supplementation (as for RDEB) usually required except in mild cases. Specialised formula feeds and exclusion diets have been used experimentally with patients with suspected protein-losing enteropathy.
Dominant dystrophic EB (DDEB)	Intervention generally not indicated other thanage-appropriate fibre (and fluid) intakes.
Recessive dystrophic EB (RDEB)	Global supplementation usually required except in mild cases. Oesophageal dilatation +/- gastrostomy feeding often indicated. Specialised formula feeds and exclusion diets have been used experimentally with patients with suspected inflammatory bowel disease/colitis.

What are nutritional requirements in EB? ^{32, 33}
This is one of the most frequently asked questions in EB management. It is also one of the most difficult to answer due to:-
• The complex, multi-system, inflammatory, infection-prone nature of the disease
• The variability of disease severity of patients even with the same EB sub-type
• The variability over time of individual patient’s requirements as a reflection of age, extent of skin lesions, presence of infection, need for catch-up growth etc
• The difficulties associated with estimating desirable weight gain when height is compromised as a result of pain, joint contractures and osteoporosis
• The difficulties associated with conducting clinical trials in such small patient numbers

The impact of nutrition on mobility in EB
When weight centile deviates upwardly by more than 2 centiles from the height centile, the EB child may be less mobile and more wheelchair dependent. However, maintenance of a balance between mobility, growth and nutritional status is vital, as these 3 aspects are inter-related and inter-dependant³⁴. Lack of weight bearing exercise and significant wheelchair dependency compounds the low bone mass often seen in severe EB16. Increased bone pain and fractures lead to further reliance on a wheelchair. Conversely, children who remain abnormally light may fail to attain puberty and to benefit from its associated protective hormonal effect on bone health. Work is on going to investigate best practice in this area.³⁵

TABLE 3: Biochemical and haematological investigations in EB children; suggested investigations and sampling frequencies ^{36, 37, 38, 39, 40, 41}

6 – 12 monthly	Yearly	1 – 2 yearly
Urea and electrolytes	Vitamin B1	Vitamin E
Creatinine	Carnitine
Calcium, phosphate (+/- Vitamin D3)	Vitamin B12
Total protein, albumin	Folate
Alkaline phosphatase
Zinc, selenium
Serum iron, ferritin, full blood count
Hypochromic red blood cell
Transferrin receptors
Mean corpuscular volume (MCV)
Reticulocytes, red cell folate
Erythrocyte sedimentation rate (ESR)
Free erythrocyte protoporphyrin (FEP)

CLINICAL COURSE AND TREATMENT OPTIONS
* Recent research has focused on changing the mixture of keratins produced in the skin. There are 54 known keratin genes, 28 types I intermediate filament genes and 26 types II, which work as heterodimers. If a drug can shift the balance of production toward an intact keratin gene, symptoms can be reduced.⁴²

* Sulforaphane, a compound found in broccoli, was found to reduce blistering in a mouse model to the point where affected pups could not be identified visually, when injected into pregnant mice (5 µmol/day = 0.9 mg) and applied topically to newborns (1 µmol/day = 0.2 mg in jojoba oil).⁴³

There is no specific therapy for EB. Traditionally, treatment has been both supportive and preventive. Common strategies include wound management, nutritional support, infection control and patient education. Topical steroids and topical antibiotics frequently are used to promote healing and prevent secondary infection of blisters. Oral tetracycline therapy may be beneficial for patients with EBS. Dapsone and low-dose prednisolone appear to be very effective in EBA. ⁴⁴

Performing oral hygiene is difficult because of the poor ability to grip and hold a toothbrush. Children with EB should be actively encouraged to use fluoride supplements and 0.2% chlorhexidine gluconate either as a mouth rinse or a spray. Retention of the teeth by preventive measures is essential as dentures cannot be tolerated or even retained. Patients with EB should be seen on a regular basis to reduce bacterial plaque accumulation. Periodic follow-ups are also necessary due to the potential for malignant transformation. Although there is no cure for EB, many complications can be minimized or avoided through early intervention. In all cases, treatment of EB is directed toward the symptoms and is largely supportive. This care should focus on prevention of infection, protection of the skin against trauma, attention to nutritional deficiencies and dietary complications, minimization of deformities and contractures, and the need for psychological support for the entire family. Many persons with milder forms have minimal symptoms and may require little or no treatment. All children with EB need special skin care. Families develop a daily routine of inspecting the skin and taking necessary action. In the mildest forms of EB, this will involve identifying new blisters, draining them and keeping the affected area clean⁴⁵. In the most severe forms, where large areas of the body are affected with numerous new blisters daily, care is very time consuming, often taking hours each morning and/or evening. This may involve soaking off dressings which have stuck to wounds, draining blisters, bathing and applying ointments and several layers of non-adherent dressings.

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Treatment of EBA can often be challenging and primarily consists of systemic corticosteroids, while it remains unsatisfactory, and mainly relies on immunosuppressive agents such as methotrexate, azathioprine or cyclophosphamide. Overall, treatment of EBA is difficult, despite the use of corticosteroids combined with other immunosuppressants. Furthermore, long-term immunosuppression has been shown to be associated with increased morbidity and mortality. This includes systemic infections, gastrointestinal disorders, hypertension, osteoporosis, hyperlipidemia, psychiatric disorders, moon face, diabetes mellitus and obesity. Hence, there is a need for the identification of safe and effective alternatives for the treatment modalities of EBA. If required, colchicine or other adjuvants can be added. Some cases of EBA have been identified in which colchicine treatment may be beneficial. This is often used as a first-line management because its side-effects are relatively benign compared with other therapeutic choices. Diarrhea is a common side-effect of colchicine, however, which makes it difficult for many patients to achieve a high enough dose to control the disease⁴⁶. Dapsone has been used in some EBA patients, especially when neutrophils are present in their dermal infiltrate. Recently, i.v. immunoglobulin (IVIG) is one potential promising therapy for patients with EBA, as evidence of its effectiveness and safety is increasing. A number of autoimmune bullous skin diseases have been identified in which IVIG treatment may be beneficial. A review of published work revealed that more than 10 patients with extensive treatment resistant EBA have – in most cases successfully – been treated.90–96 Recommended doses are 2 g.kg IVIG monthly until clinical improvement is achieved and no lesions are developed. Because of the limited duration of response retreatment with IVIG (several cycles) is necessary. However, experience with IVIG in patients with autoimmune skin blistering disease is limited⁴⁷. Thus, IVIG is recommended as second-line therapy in autoimmune bullous skin diseases, or for patients not responding to conventional therapy. The mode of action of IVIG in autoimmune diseases including bullous disease is far from being completely understood. In addition, the most novel treatment is the anti-CD20 monoclonal antibody, rituximab, which is a monoclonal humanized antibody directed against the B-cell-specific cell surface antigen CD20. CD20 is expressed on the cell surfaces of pre-B cells and mature B cells.⁴⁸

Rituximab is a chimeric monoclonal anti-CD20 antibody that abolishes these cells through complement- and antibody- dependent cytotoxicity and apoptosis. Thus, rituximab significantly reduces circulating B cells and antibody-producing plasma cells. Rituximab had a dramatic effect on EBA patient in a life-threatening situation. In some patients with severe widespread EBA resistant to conventional therapies were successfully treated with rituximab as adjuvant therapy. Rituximab is the newest potent therapy in severe and refractory EBA patients. Now, the regimens for these therapies are being examined worldwide. Further data and challenge are needed to establish the real potential of new treatment in EBA. In addition, there are several anti-tumor necrosis factors-(anti-TNF-a) inhibitors in the class of biological agents (such as infliximab, an anti-TNF-a chimeric monoclonal antibody) that are being considered for use in the treatment of patients with EBA. ⁴⁹

CURRENT CLINICAL RESEARCH
Universityof Minnesotahas included a bone marrow transplant to a 2-year-old child who is one of 2 brothers with EB. The procedure was successful, strongly suggesting that a cure may have been found ⁵⁰

CONCLUSIONS AND PERSPECTIVES
Considerable progress has been made in the last years regarding our understanding of the pathogenesis of EBA. The availability of animal models of EBA provides an important tool to gain further insight into the pathophysiology of the disease. Recently, several new therapeutic agents and modalities have been reported and show promise in the treatment of patients with EBA⁵¹. The multidisciplinary approach to understanding the mechanisms of central and peripheral tolerance as well as the inflammatory cascade, induced by binding of auto antibodies to type VII collagen, is leading to the more specific therapeutic strategies that counteract the chronic morbidity and mortality of this autoimmune disorder.⁵²

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