Clinical Evidence: Internal Factors

Introduction

With delineated evidence gathered from laboratory studies at the immunologic and molecular levels to implicate external contributing factors of atopic dermatitis (see Chapter 11, Chapter 12, Chapter 13, Chapter 14, Chapter 15, Chapter 16, Chapter 17 ), we now examine the internal factors from the perspective of clinical evidence. Although clinical evidence is not as robust as that collected through the immunologic or molecular level of investigation, it nevertheless provides a supporting documentation from a unique angle. Clinical evidence provides a sense of reality, a sense of living proof, so to speak. In fact, any medical theory or purely laboratory-based research result unsupported by clinical evidence will be deemed invalid for the actual disease.

The Oxford Living Dictionaries defines the term as “relating to the observation and treatment of actual patients rather than theoretical or laboratory studies… (of a disease or condition) causing observable and recognizable symptoms.” The term is defined in Merriam-Webster ( ) as “of, relating to, or conducted in or as if in a clinic: such as a: involving direct observation of the patient or b: based on or characterized by observable and diagnosable symptoms.” Clinical evidence therefore is data gathered from the clinical observations or clinical studies.

To collect clinical evidence, we gather all the data relating to the symptoms and signs of what we can observe, obtain, and measure about and from actual patient encounters, rather than by theoretic consideration, speculation, or purely laboratory investigation. Nevertheless, laboratory data are also part of the supporting evaluation of clinical data and of documenting clinical evidence. One simple example is the clinical evaluation of early clinical failure of treatment of a gram-negative bacteria sepsis (bloodstream infection). To collect clinical evidence accurately and correctly, the clinical investigators must first establish that all these patients indeed have bloodstream infection by gram-negative bacteria documented by results of blood culture, a laboratory method. In addition, the clinical researchers must measure many parameters to develop a set of criteria for determining the predictors for early clinical failure. These parameters would include “purely clinical data” such as blood pressure, respiratory rate, altered mental status, but they would also include “laboratory data” such as white blood cell count. Together, these data provide the valuable predictors for early clinical failure on treatment for gram-negative sepsis ( ). Similarly, to collect clinical data and to document clinical evidence in relation to development of atopic dermatitis, some laboratory-generated information, such as serum level of immunoglobulin E (IgE), bacterial culture results, skin histopathology report, genetic mutation information in skin barrier protein, immunologic status, and other clinically supportive laboratory data, is also included. The following discussions delineate some reasons to suggest that internal factors play a significant role in atopic dermatitis development.

Skin barrier defect is not synonymous with atopic dermatitis

One of the reasonable arguments against external factor as the sole contributor for atopic dermatitis goes like this: If the cause of atopic dermatitis is exclusively external, then it should naturally follow that in those patients with skin barrier defect, the resulting easy entry of the offending substance (pathogens or allergens) into the skin should, eventually, lead to development of chronic immune reactions in all patients. Therefore we should find that all patients with skin barrier defect should eventually develop atopic dermatitis when they reach adulthood. Is this conclusion supported by clinical evidence? The answer is a definite no. Outside-in dysregulation leads to atopic dermatitis, but apparently not in all cases.

Not all patients with filaggrin gene mutation develop atopic dermatitis

Filaggrin, one of the major skin barrier proteins that form a protective layer at the stratum corneum level of the skin, is now well documented to be defective, due to genetic mutation, in patients affected by an ichthyosis condition termed ichthyosis vulgaris, with a documented reduction in thickness of granular layer of the epidermis under electron microscopy ( ; ). In addition, filaggrin mutation in ichthyosis vulgaris causes various abnormal structure organization in the epidermis, including perinuclear retraction of keratin filaments, impaired loading of lamellar body contents, nonuniform extracellular distribution of secreted organelle contents, and abnormal lamellar bilayer architecture. These structural abnormalities predictably link to the functional defect, such as increased transepidermal water loss, an objective indicator of defective skin barrier function ( ). If an external factor is the only component needed to induce atopic dermatitis, one would expect that sooner or later all patients affected by ichthyosis vulgaris will develop atopic dermatitis, as our reason goes. However, this does not seem to be the clinical finding. First, it is now clear that not all patients affected with ichthyosis vulgaris develop atopic dermatitis, and this fact is well documented by reports published in different parts of the world ( ; ; ; ). A study showed that even with compound heterozygosity (biallelic filaggrin null mutation), some patients affected by ichthyosis vulgaris do not develop the atopic dermatitis disease ( ). In a study report published in 2009, there is a significantly higher number of antigen presenting cells (CD1a+ Langerhans cells) present in the nonlesional epidermis of ichthyosis vulgaris patients affected with atopic dermatitis than those patients unaffected with atopic dermatitis. Thus the finding of this study suggests that an immunologic factor other than or in addition to epidermal barrier defect may account for the atopic dermatitis development ( ).

Another recently reported finding of enhanced expression of genes related to xenobiotic metabolism occurred only in the nonlesional skin of patients with atopic dermatitis, not in those patients with ichthyosis vulgaris, which also supports the notion that factors other than skin barrier defect of filaggrin may be involved in the development of atopic dermatitis. Specifically, investigators found that the genes involved in the processing of pollutants, endocrine disruptors, and xenobiotics, particularly glucuronidation, were substantially upregulated in the skin of atopic dermatitis patients but not in that of ichthyosis vulgaris patients. Glucuronidation is a chemical process that converts the less biologically active form of glucuronides to reactive metabolite acylglucuronides ( ). In other words, detoxification genes are highly activated in atopic dermatitis. Importantly, these enhancements exhibited in the skin of patients affected with atopic dermatitis, with or without filaggrin gene mutation, further reduce the importance of filaggrin gene mutation as a sole triggering factor for atopic dermatitis. These investigators suggested that an inflammatory triggering of local metabolism of noxious molecules might be the key factor that could transform a subinflammatory skin to an overt inflamed skin observed in atopic dermatitis ( ).

Not all atopic dermatitis patients have an identifiable filaggrin gene mutation

Conversely, we can ask the question from the opposite direction: Do all patients affected by atopic dermatitis have the mutation of major skin barrier protein filaggrin? The answer is, again, no ( ; ; ; ; ; ; ; ). An early study based in Japan indicates that only a little over 20% of atopic dermatitis patients carry some form of filaggrin gene mutations ( ). A subsequent study in Japanese atopic dermatitis patients reveals that just 25% of patients carry one or more filaggrin mutations ( ), significantly lower than the high percentage (near 50%) of mutation present in European atopic dermatitis patients ( ; ). Similarly, in a study of Singaporean patients with atopic dermatitis, only 20% carry one or more filaggrin gene mutations ( ). Further, filaggrin mutations occur in Han Chinese atopic dermatitis patients with an overall rate of 31% ( ; ). Among African patients affected by both atopic dermatitis and ichthyosis vulgaris, a study documents that only 22% of these patients carry heterozygous filaggrin mutation ( ). In a study of Korean patients with atopic dermatitis, the investigators discovered that only 68 among the 1110 atopic dermatitis patients have filaggrin mutations (6.1%): 18 patients have the heterozygous 3321 delA mutations, 49 patients have the heterozygous, and 1 patient has the homozygous p.K4022X mutations ( ). Another study of Korean atopic dermatitis showed that four filaggrin null mutations (3321 delA, K4022X, S3296X, and S2889X) were detected in only 16% of the 70 tested patients ( ).

Not surprisingly, patients with filaggrin mutations tend to have poorer skin hydration, earlier disease onset, and more severe atopic dermatitis ( ). Overall, approximately 10% to 50% of patients in different cohorts affected by atopic dermatitis harbor mutations at different regions of the filaggrin gene ( ; ). The next logical question to ask is: Do those atopic dermatitis patients who have no filaggrin gene mutation have genetic mutations of other skin barrier proteins such as loricrin or involucrin? Barrier dysfunctions due to yet-to-be-discovered mutations of those nonfilaggrin barrier proteins, if existed, may account for the external triggering factor in atopic dermatitis. At the present time, however, we do not have the answer, and there is no literature report as of June 2020. This question is important to answer as it would help decipher whether atopic dermatitis is a pure inside-out or outside-in process, or a combination of both. The following paragraphs will examine the internal immune milieu of patients affected by atopic dermatitis.

Th2 immune type correlates with inside-out dysregulation in atopic dermatitis