Dressings are a vital component of wound care in EB, and, although the ideal dressing is yet to be developed, there exist a variety of options that can be tailored to each individual patient and even to individual wounds, based on local availability, cost, relative efficacy, and personal preference 27,29. Nonadherent dressings are often preferred given the fragile nature of EB skin and to reduce the risk of infections. Dressings should be changed daily after gentle skin cleansing (Fig. 13) 4.
Systemic antibiotics are required for wounds with frank infection. The choice of antibiotic should be guided by culture. Purulent wounds may be irrigated with a variety of bacteriostatic or bactericidal solutions such as normal saline, dilute potassium permanganate, or 0.25% acetic acid 40. The use of antimicrobial emollient lotions such as benzalkonium chloride or chlorhexidine is also an option in selected cases 33.
Much of this altered growth is a result of impaired absorption of amino acids and other nutrients across damaged intestinal mucosal surfaces and the loss of blood and serum through open wounds on the skin, coupled with increased catabolism (analogous to what is observed in patients with severe cutaneous burns) and decreased oral intake [a reflection of the presence of painful lesions within the oral cavity and esophagus, structural alterations in either primary (as in JEB) or secondary (as in RDEB) teeth or their absence, and discomfort from severe constipation] 31. The risk of malnutrition is more prevalent in the severe forms of EB, most notably in RDEB-severe generalized and JEB-H, although it is also observed in children with EBS-DM, JEB non-Herlitz, and RDEB generalized other 41. These patients have also been shown to have protein and caloric deficiencies, as well as variable deficiency in several vitamins and/or micronutrients, including vitamins B6, B12, C, and D, as well as zinc and selenium 42,43. Anemia is usually multifactorial in these children, reflecting combinations of iron deficiency (through poor gastrointestinal absorption and increased loss of iron through the skin), decreased lifespan of erythrocytes, and other physiologic factors that contribute to the microcytic hypochromic anemia termed ‘anemia of chronic disease’ 10. As these patients age, many also develop osteoporosis and osteopenia. Maximizing nutrition is of vital importance for promoting growth and development, optimizing wound healing, and improving the quality of life 44.
Some children are able to take in sufficient calories and proteins by frequent oral feedings of nutritional supplements high in calories, protein, and micronutrients 45. For those unresponsive to high caloric oral feedings, gastrostomy placement and enteral feeding are the next option. Gastrostomy feedings have been shown to improve both growth and nutrition in EB patients 46. However, chronic nasogastric tube feeding is not part of the armamentarium of therapy in EB patients because of the risk of erosions arising within the nasopharynx or esophagus. Similarly, infusions of highly concentrated nutritional supplements through percutaneous indwelling catheters are not employed because of the risk of recurrent and potentially life-threatening septicemia, usually bacterial, in the setting of widespread nonhealing cutaneous wounds 31.
Growth charts must be closely monitored. A nutritionist or dietitian who is experienced with EB can help optimize the child’s nutritional status.
The extracutaneous features associated with the different subtypes of EB and their relative frequency were reviewed by Fine et al. 46. The most serious complication in EB, especially in RDEB, is the development of cutaneous derived SCC. Ninety percent are projected to develop at least one SCC and nearly 80% to die from metastatic SCC by 55 years, making it the leading cause of death in EB. Basal cell carcinoma arose almost exclusively in patients with generalized EBS-DM, with a 43.6% cumulative risk of occurrence by age 55. The cumulative risk for melanoma in those with generalized severe RDEB is 2.1% by age 12, although none of those tumors recurred following conventional excision 47. Hence, monitoring for cutaneous malignancies is vital especially in RDEB and generalized JEB. Dedicated skin checks are recommended every 3–6 months at 10 years of age, and at 3-month intervals on and after age 16 31. Serial digital photography can facilitate documentation of changing skin lesions. A body chart (available on the DebRA UK website at: http://www.debra.org.uk/) may also be useful in recording the progressive history of a patient’s SCC 48. Because of the development of erosions in gastrointestinal, respiratory, and genitourinary tracts, EB patients, particularly DEB, have the tendency to develop strictures that could be life threatening if undetected. Because of repeated scarring, pseudosyndactyly of the fingers and toes occurs. Pseudosyndactyly is the most debilitating sequelae of RDEB 4. Preventive wrapping of individual fingers with tension in the web space is recommended, beginning in infancy, in an attempt to preserve function for as long as possible. There is also variable ocular, endocrinologic, hematologic, renal, cardiac, and dental complications that need to be monitored. In our EB clinic, generalized RDEB and JEB patients are scheduled to be seen every 3 months by a multispecialty team with full skin examination and photography in an effort to detect SCCs early.
As this devastating disease can isolate the affected individual and their respective families, ongoing psychosocial support is a vital part of management. Loss of self-esteem and worth, inability to cope, and severe depression have been documented in EB children and adults, especially in those with the more severe types in well-studied cohorts 49. Caring for an EB patient also takes a toll on the well-being of their caregivers, as much time and energy is required. The more severe the EB subtype, the more time, effort, and expense that go into his/her care, putting profound strain on their relationship with their partner, their workplace, their extended families, and even other children in the family who may feel an imbalance in the attention given to them and the affected child 49,50. Quality of life measurements should be incorporated in routine and continuing patient care 31. When properly validated, they can reflect disease severity and capture outcomes of therapeutic intervention 51. It is important that the medical team recognize psychosocial issues, as they can influence medical decision making. Good partnership between the patient, family, and medical staff is vital in providing optimal care given the nature of this disease.
Over the years, research in EB has been directed toward finding a way to correct the molecular defect. Although several approaches are promising, most still need further data to prove their safety and effectiveness in the clinical setting.
Revertant mosaicism is a naturally occurring genetic phenomenon that results in the correction or rescue of a mutation 52. Revertant mosaicism is not rare and has been reported in genodermatoses such as EB 53, ichthyosis 54, and, most recently, in Kindler syndrome 55. It is believed to occur focally, leading to isolated patches of normal skin within predominantly affected (mutated) areas 31. The natural occurrence of reverted cells in vivo obviates the need for other methods of mutational correction, such as the use of potentially genotoxic retroviral vectors 54. Thus, the optimization of revertant mosaicism as natural gene therapy using the patient’s own naturally corrected cells has been the focus of translational research in recent times. If successful, the technique has the potential to significantly impact the treatment of many genetic diseases. One report of application of this revertant cell therapy was in a patient with proven revertant mosaic non-Herlitz JEB grafted with revertant autologous keratinocytes 56. Although the said procedure did not produce any functional improvement, as the graft had a low number of revertant cells (<3%), if it can be improved and modified it has the potential as future therapy for genodermatoses, not just in EB.
A number of laboratories have demonstrated that it is possible to functionally correct EB keratinocytes in vitro by insertion, facilitated by the use of retrovirus, of wild-type DNA encoding for the gene mutated in that specific EB subtype 31. In 2006, Mavillo et al.57 harvested keratinocytes from a patient with non-Herlitz JEB having a mutation within the LAMB3 gene, transduced those cells with a retroviral vector expressing LAMB3 cDNA, grew them into sheets, and then transferred them back to a small area of skin on this patient. Subsequent development of clinically and immunohistochemically normal human skin with over several years of follow-up of no further blistering was seen within the grafted site. However, to strengthen the evidence, additional patients have to be treated in this manner. This effort has been limited because of regulatory issues that have arisen in Europe regarding such therapy.
Although it holds some promise, there are technical and regulatory issues with gene therapy through ex-vivo correction of EB keratinocytes that need to be addressed before it becomes a practical and viable approach.
For autosomal dominant EB, its dominant-negative mutations require that the mutated gene be somehow turned off to allow cells to function normally. A variety of techniques have been explored in vitro, and include, but are not limited to, RNA interference, oligonucleotide-mediated gene correction, and antisense technology 58. Although intriguing, these techniques are associated with a number of inherent practical limitations, most notably efficiency 31.
Another novel molecular technique actively being explored in selected EB subtypes involves the use of spliceosome technology 58. However, there continue to be insufficient data on whether this long-term approach will be practical for application in the treatment of disease.
Research involving topical application or local or intravenous injection of purified type VII collagen has been performed in animal models of RDEB 59–61. Purified type VII collagen was injected into the mouse tail vein in one mouse model of RDEB, resulting in wild-type protein homing to the blistered sites, leading in wound healing 62. In a more recent conditional knockout mouse model, similar results were achieved, confirming the validity and potential utility of such a therapeutic approach 63. A phase I clinical trial is being organized at the University of Southern California to formally study the safety of local injections of purified collagen VII into chronic RDEB wounds 31.
Type VII collagen is expressed by both human skin keratinocytes and fibroblasts. Normal skin fibroblasts injected intradermally have been shown to increase the formation of type VII collagen and anchoring fibrils at the dermal–epidermal junction in mice 64. A pilot study has investigated the effect of intradermal injection of autologous and allogeneic fibroblasts in five RDEB patients who had reduced or absent type VII collagen expression. Autologous injections did not lead to any increase in type VII collagen in the skin in any of the five patients, which was expected, as those cells carry mutations in the COL7A1 gene. In contrast, allogeneic unrelated-donor cultured fibroblasts were shown to produce more type VII collagen compared with autologous fibroblasts. Partially functional mutant protein deposited along the dermal–epidermal junction in patients treated with autologous fibroblasts was associated with the presence of rudimentary-appearing anchoring fibrils 65. Recent studies suggest that a subclinical immunological mechanism may induce the synthesis of heparin-binding epidermal growth factor that then upregulates the synthesis and assembly of the patient’s own mutated type VII collagen following allogeneic fibroblast injection 66–68. Intriguingly, a recent randomized phase II trial by our group comparing allogeneic cultured fibroblast injections in transport solution to transport solution injections alone in paired chronic wounds found that placebo injections healed the wounds as quickly as did the active group, but both healed significantly faster than did uninjected chronic wounds 69.
Recent studies have suggested that stem cells can be a source of cell types that contributes to the regeneration of disrupted skin in genetic skin diseases such as EB 70. Bone marrow-derived stem cells, in particular, may be induced to develop into skin cells, given the right conditions 71. The first clinical trial of allogeneic bone marrow transplantation involved seven children with RDEB 72. Improvement in wound healing and increased type VII collagen production were reported, with effects sustainable over 1 year of published follow-up after transplantation. However, two of the seven children died from complications arising from the traditional myeloablative procedures used before transplantation. Although such transplantation techniques may in the future play a significant clinical role in the treatment of RDEB, further modifications will be needed in order to improve the safety and efficacy of the procedure, before it will likely become routinely recommended by most EB experts. Strategies to lower morbidity and mortality through the use of a reduced-intensity conditioning regimen have been initiated by some groups 73. However, it is believed that even this may not completely avoid mismatch between graft and host, thus still allowing the development of graft-versus-host disease 59.
Induced pluripotent stem cells (iPSCs) are patient-specific stem cells that have the capacity to differentiate into both hematopoietic and nonhematopoietic lineages 74. Salas-Alanis et al. 75 has suggested that the use of iPSCs combined with revertant mosaic cells could produce spontaneously corrected patient-specific autologous cells, which could then be used both as circulating cells and as skin grafts. This procedure offers the advantage of avoiding problems with the use of allogeneic products that are subject to immune reactivity from the host, the need for viral vectors, as well as induction of immunosuppression to prepare the host for the grafts. iPSC technology is in the preclinical trial stage 68,76.
Two RDEB patients in Chile have been treated with intralesional injections of mesenchymal stem cells, with reported improved wound healing within the treated sites 77.
A novel class of drugs exists that can trick the body into ignoring certain stop codons that otherwise lead to premature cessation of gene translation (PTCs) and the generation of unstable foreshortened gene protein products 31. These drugs are already in clinical trials for Duchenne muscular dystrophy and cystic fibrosis 78,79. This class of drugs has great therapeutic potential for severe recessive forms of EB in which a high proportion of mutations are PTC mutations. The PTC 124 compound was reported to revert up to 100% of type VII collagen production in PTC-affected RDEB keratinocytes in preliminary work conducted by Chen, Woodley, and Bruckner-Tuderman, as presented at the DebRA International research conference EB 2009 in Vienna 59.
Thymosin B4 is a purified protein found to promote enhanced healing in induced wounds in mice and normal volunteers. A multicenter double-blind randomized placebo-controlled phase I/II clinical trial has been recently completed, assessing both the safety and clinical efficacy of the application of this small-molecular-weight protein in the healing of selected wounds in RDEB patients 80. The results are currently being analyzed.
EB is a complex disease best managed with a multidisciplinary team. As EB is associated with varied mutations leading to a variety of clinical phenotypes with different prognoses, proper identification of the specific subtype is ideal for guiding the patient and their caregivers. At present, there is still no cure, but advancement in research is paving the way.
There are no conflicts of interest.
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