Enlightened Therapy of the Disorders of Cornification (2004)

Peter M. Elias, MD, Mary L. Williams, MD, University of California, San Franciso, CA

Dr. Peter Elias Dr. Mary Williams
Towards Enlightened Therapeutics for Ichthyosis
Treatment of the ichthyoses and related disorders, in which a thickened or other wise abnormal stratum corneum (SC) (outermost, non-living skin layer) is a key component, has traditionally focused on the dual goals of: 1) removing scale to improve appearance; and 2) enhancing SC moisturization to improve pliability and comfort. For the most part, these treatments have been neither diseasespecific nor based upon new knowledge about disease pathogenesis. For example, the same therapies often are used for both ichthyoses associated with increased scale retention, such as recessive X-linked ichthyosis (RXLI), and for hyperproliferative disorders, such as non-bullous congenital ichthyosiform erythroderma (CIE). In addition to variable effectiveness, in some instances these therapies can be counterproductive. For example, treatments that peel off the SC may "overshoot the mark" and result in decreased function (e.g., decreased frictional resistance (blisters) that can occur with retinoid treatment of epidermolytic hyperkeratosis (EHK)).

Treatment, in an era of "enlightened therapeutics," should attempt to correct the underlying defect. When this goal is neither possible nor practical, treatments can still be deployed to address the underlying pathophysiology of the disorder. Unfortunately, the first principle (i.e., correction of the primary or underlying genetic defect) remains an unattained goal, because gene therapy is still in its infancy. Yet, it is possible to apply current understanding of disease pathogenesis towards disease-specific therapy that should be both more appropriate and more effective.
During the past two decades, the underlying genetic causes of the inherited disorders of cornification have been largely deciphered. The causative defects have been surprisingly broad, and include not only inborn errors of lipid (fat) metabolism, but also mutations that affect epidermal structural proteins, as well as defects in cellular communication, signaling or proliferation (see table). Yet, because a wide variety of defects lead to scaling, only a few, final common pathways account for disease pathogenesis. In other words, the epidermis can either: a) fall apart (as it does in epidermolysis bullosa simplex, EHK, and Netherton syndrome); b) it can apoptose ('kill off a bad cell', as it does in Darier disease); and/or c) it can become hyperkeratotic (thickened and scaly, as it does by definition in not only the ichthyoses, but even psoriasis). Hyperkeratosis, in turn, can arise through either a delay in desquamation (shedding), and/or as a consequence of increased epidermal cell production (hyperplasia). However, only in a few instances is the hyperkeratosis due solely to a failure to desquamate (i.e., a retention hyperkeratosis, as in RXLI). Most commonly, there is a component of epidermal hyperproliferation,as well. Therefore, understanding the biology of both desquamation and epidermal hyperplasia, as well as their causes and consequences, is critical in designing appropriate therapies for these disorders. Recent advances in knowledge of SC function and its metabolic regulation have provided insights into the pathogenesis of several of the ichthyoses, with potential new therapeutic implications.


Overview of Stratum Corneum (SC)Function and the Mechanism of Scaling The SC is composed of multiple layers (normally 12-15 layers) of cells (corneocytes). Corneocytes are specialized to provide a tough, yet flexible barrier to mechanical injury. Since they are devoid of nuclei and other organelles they are considered 'dead.'  These cells are filled with keratin filaments, as well as amino acids and other small molecules derived from the breakdown of filaggrin, a protein that surrounds the keratin filaments. A highly cross-linked protein shell, the cornified envelope, surrounds the corneocyte, which together with keratin filaments accounts for both the flexibility and mechanical resilience of the SC. It is the presence of small, intracellular filaggrin-breakdown products that render the corneocyte capable of absorbing and binding water.

Surrounding the corneocytes are lipids (fats) organized into membrane stacks (lamellar bilayers). These membranes derive from lamellar bodies (LB). LB are small packages inside the outer epidermal cells that secrete their lipid contents into the intercellular spaces, between the corneocytes, just as the SC is forming. These water-repellant lipids waterproof the skin, preventing loss of excess body fluids into the dry, external atmosphere. They also block the entry of potentially toxic chemicals, environmental antigens, and microbes into the body.

In the lower SC, specialized protein structures, called corneodesmosomes (CD), span the intercellular spaces at regular intervals, forming links or welds between adjacent corneocytes. Normally, CD are progressively degraded as corneocytes move outward through the SC, allowing invisible shedding of corneocytes as single cells. The progressive loss of CD is achieved by one or more protein-digesting enzymes (serine proteases), which in turn, are regulated (kept in an inactive state) by a family of serine protease inhibitors. The desquamatory proteases are also packaged in lamellar bodies and co-delivered to the SC intercellular spaces along with membrane lipids (fats). Thus, SC retention can occur either when the serine proteases are excessively inhibited (as in X-linked ichthyosis), or when insufficient proteases are secreted (as in ichthyoses characterized by reduced secretion of lipids and enzymes, as in Harlequin ichthyosis and CIE). In contrast, absence of a key regulatory serine protease inhibitor (LEKTI 1), as occurs in Netherton's syndrome, can lead to premature shedding (thinning) of SC, with a potentially devastating loss of barrier function.

Desquamation normally results from the repeated, mild mechanical frictions of everyday life. It is enhanced during bathing, when corneocytes first hydrate and swell, followed by dehydration and shrinking. Both friction and swelling/shrinkage weaken intercellular attachments in the SC. Therefore, SC retention can occur when corneocytes are unable to attract water osmotically (as occurs in ichthyosis vulgaris due to a deficiency in filaggrin breakdown products).

Although the SC is 'dead'; it nevertheless functions as an exquisite biosensor, sending signals to lower skin layers in response to changes in humidity or external trauma. Because permeability barrier function is so critical for survival, it is not surprising that the underlying skin layers are closely attuned to SC function. Any acute or sustained insult that results in barrier compromise, stimulates homeostatic repair responses, including both increased synthesis and secretion of lipids and a mitogenic stimulus to the underlying living cell layers of the epidermis ("Make more lipid! Make more cells!"). These repair responses are signaled by: 1) changes in epidermal ion gradients (i.e., calcium and other ions normally are concentrated in the upper epidermis; barrier perturbations flush away this gradient, thus signaling fat and enzyme secretion) and; 2) release/activation of molecules, called cytokines (e.g., IL-1a, IL-1b, TNFa), that, among other functions, recruit white blood cells that cause inflammation, initiating a downstream cytokine cascade that can lead to both epidermal hyperplasia and inflammation. Since the barrier is abnormal in several ichthyoses, these signals continue to be sent, resulting in the erythoderma (red skin) and hyperplasia(thickened skin).

Application of Enlightened Therapeutics to Specific Disorders of Cornification
Ichthyosis vulgaris: While the genetic basis for this relatively common disorder remains to be elucidated, the net result is a marked deficiency in the protein, filaggrin. The decrease in filaggrin, in turn, leads to a marked reduction in the levels of waterholding, metabolites within the corneocyte, resulting in an inability to hydrate the SC normally. The flexural sparing that is so typical for this disorder reflects the increased hydration of these body regions, resulting in normalization of shedding. Although a specific replacement formulation is not available, use of humectant-containing moisturizers, such as urea and/or glycerol-containing creams, represent logical strategies in this disorder (Table, page 6). However, a limiting factor in the treatment of ichthyosis vulgaris can be the common co-occurrence of atopic dermatitis,which renders the patient more vulnerable to some potentially-irritating topical humctants (in such cases, therefore, alphahydroxy acids should be avoided).

Recessive X-linked ichthyosis (RXLI): This not-uncommon, X-linked trait is caused by a deficiency of the enzyme, steroid sulfatase, causing an accumulation of one of its substrates, cholesterol sulfate, and a deficiency of its product, cholesterol, in the extra-lamellar membranes of the SC. While this lipid (fat) imbalance leads to a minor abnormality in barrier function, the predominant clinical issue in RXLI is impaired shedding. SC retention in RXLI can be attributed to a direct inhibitory effect of the excess cholesterol sulfate on the serine protease enzymes that digest corneodesmosomes. This disorder responds relatively well to treatment with alphahydroxy acids, which accelerate shedding of outer SC. Cholesterol-containing emollients also improve the scaling abnormality. Hence, an ideal treatment might combine an alpha-hydroxy acid with a barrier repair formulation that is enriched in, or dominated by, cholesterol (Table, page 6).

The Autosomal Recessive Congenita Ichthyoses: This genetically heterogeneous (mixed) group is characterized by a congenital onset of generalized scaling. It includes patients with a deficiency of epidermal transglutaminase 1, resulting in classic Lamellar Ichthyosis, and patients with Non-Bullous Congenital Ichthyosiform Erythroderma (CIE). Although the basis for CIE phenotypes differs, some patients display mutations in two enzymes of fatty acids metabolism (lipooxygenases). All these patients display a hyperproliferative epidermis with variable scaling and erythroderma (redness). The hyperproliferative state is secondary in most, if not all, instances to abnormalities in the quantity or quality of intercellular membrane lipids (fats), resulting in a barrier abnormality. The barrier defect, in turn, results in the release of signals that stimulate hyperproliferation and inflammation. In many instances, fats are not fully secreted, but remain entombed within corneocytes. Failure to secrete fats and enzymes leads not only to a deficiency in lamellar membranes, but also to decreased rates of corneodesmosome breakdown (decreased shedding). In Harlequin Ichthyosis, the most severe entity in this group of diseases, these problems are present in their most extreme form, due to a virtual absence of both intercellular fats and enzymes. The ideal treatment, based upon pathogenic considerations, would include a barrier repair formulation, combined with a serine protease, and/or short-term therapy with an oral retinoid, since retinoids promote shedding of corneodesmosomes (Table, page 6).

Epidermolytic Hyperkeratosis (EHK): EHK is caused by a mutation in one of the keratins (K1, K10 or K2e) that are normally expressed in the outer, nucleated cell layers of the epidermis. These are called dominant- negative disorders, meaning that the mutant keratin pairs with a normal keratin, thereby interfering with the normal function of the keratin network within the cell. Normally, these keratins form protein filaments (cables) that loop between the cell membrane and the nucleus. Disruption of these cables produces a cell that is poorly resistant to mechanical trauma, and therefore were susceptible to trauma (blistering). Moreover, the abnormal keratins also interfere with the delivery of fats and enzymes into the intercellular spaces of the SC. Hence, instead of secretion into the intercellular domains, the fats and enzymes largely remain entombed within corneocytes in the SC. Thus, the pathophysiology is similar to CIE phenotypes (i.e., deficiency in both intercellular lipids and defective corneodesmosome proteolysis), but in the case of EHK, these features are combined with a increased fragility, and a tendency to blister. The challenge here is to devise a strategy that both restores barrier function, while stimulating sloughing of outer corneocytes, without promoting further fragility in the underlying epidermis (a common problem with retinoids). Although no currently available treatments meet all of these challenges, a combination of strategies is helpful in EHK.

Netherton syndrome: Netherton syndrome presents the opposite problem of ichthyosis. Although clinically scaly, there is typically a reduced number of layers of SC, due to unopposed enzyme (serine protease) activity due to the absence of a serine protease inhibitor, LEKTI 1, resulting from mutations in the SPINK 5 gene. Agents that remove scale (e.g., keratolytics such as the alpha-hydroxy acids and oral retinoids) have no role to play in the management of this disorder, and may further aggravate this disease. An atopic-like dermatitis and anaphylactic reactions to foods are another feature of this recessive trait. But immunosuppressants such as tacrolimus are hazardous due to the increased risk for systemic absorption and toxicity across an impaired barrier. The ideal topical therapy, instead, would be a barrier repair formulation, combined with a serine protease inhibitor, a combination that does not yet exist on the market.

Treatment of the ichthyoses can be frustrating cornification, based upon increased understanding of disease pathogenesis. Our suggestions should be modified as new information About disease causes and pathogenesis becomes available, and as new products Become available. Clearly, there is a gap currently between what we understand about these conditions and what we can offer patients as treatments. Yet, the approach outlined here can provide a model framework against which therapies can be devised and assessed. While we may not be able to eradicate the problem, we can instead focus efforts on those aspects of the disease that are most bothersome, and through a therapeutic partnership with your physician, it should be possible to help ichthyosis patients to achieve a comfortable, and more functional state.

Reprinted from Clinics in Dermatology, Volume 21, Mary L. Williams, MD, and Peter M. Elias, MD, "Enlightened Therapy of the Disorders of Cornification," pp. 269- 273, with permission from Elsevier.

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