How to Tell the Difference Between Nummular Eczema and Ringworm
It’s often difficult to distinguish between nummular eczema and ringworm, so it’s always best to be evaluated by a dermatologist, say experts.
Published On: Nov 30, 2022
Last Updated On: Jan 3, 2023
Over the past five years, a new era of treatment options for atopic dermatitis (AD) has emerged, with multiple new therapies obtaining FDA approval. This treatment revolution has been made possible by a deepening understanding of the complex biology underlying AD and the many skin and immune system contributors to disease onset and progression. Dr. Emma Guttman, MD, PhD of Mount Sinai University said, “The biggest advance in treating AD has been the advent of the first monoclonal antibody treatment (dupilumab) in March 2017 followed by enthusiasm from pharmaceutical companies to develop more drugs for AD.” Currently, nearly 100 biologics, small molecule inhibitors and topical agents have been or are being developed to target specific immune-regulating pathways and better manage the wide-ranging impacts of AD.1
These advances in science are also providing insights into the ‘why’ behind what patients have long known: that the course and experience of AD is simultaneously similar and different between individuals and that one treatment will not work for everyone.2 There is hope that being able to unravel and identify the varying underlying biology of AD will lead to the ability to leverage personalized medicine. Immunologists, skin biologists, neurobiologists, bioinformaticists and computer scientists are currently working together to try to understand how AD differs from patient to patient. This article will cover what researchers have discovered about biological variations among people with AD, called endotypes, and how these endotypes may one day be used to guide health decisions for each AD patient.
Physicians have historically classified AD based on things like age of disease onset, location and severity of disease and clinical appearance of the skin.3 Together these clinically recognizable features are called a disease phenotype. Research is newly shedding light on additional AD characteristics that can be differentiated biologically by looking at factors including genetics, which immune cells are activated and where in the skin or blood they are located, which immune signals (cytokines) are being released by cells and what the skin looks like under the microscope after taking a biopsy.4 Some of these characteristics could eventually become biomarkers to aid diagnosis, predict disease course or risk of co-occurring conditions (such as food allergy, asthma, etc) and/or guide treatment selection. For example, in other chronic diseases such as diabetes, blood level of A1C, a biomarker, is used to predict future risk of diabetes as well as determine treatment responsiveness and disease progression. However, unlike diabetes, AD currently lacks skin or blood biomarkers that can be routinely used in the clinical practice setting, which means there is no specific test that can be utilized to guide care. The availability of one or more biomarkers for AD could be helpful to screen patients at high risk of AD before disease appears (for example if a child is born into a family with a history of AD), help assess disease severity and help inform more individualized treatment decisions.4
Dr. Amy Paller, MD, of Northwestern University said, “Accumulating data suggest that there are different endotypes, some of which have been helpful for making predictions about AD. For example, a patient with filaggrin1 or 2 mutations has a tendency toward earlier onset of disease, more persistent disease and a greater association with other atopic conditions.” The ability to classify AD based on genetics first emerged in 2009 when a novel technique called Genome Wide Association Studies allowed genetic screening of large numbers of individual patients to find out which genes were altered in populations of people with a specific disease compared to those without. These studies were followed by others that sequenced the genetic material from individual AD patients to determine which genes were altered and how they were altered.5 The filaggrin gene, which is important for setting up and maintaining the skin barrier, was found to be associated with AD patients of European and Asian descent.5 However, filaggrin is less commonly altered in patients of African descent, indicating that alterations in this gene only partially explain AD pathogenesis.6 Scientists also investigated which genes associated with AD were “read” or expressed at the RNA level, which can then make functioning proteins (a gene or DNA is read by cellular machinery which makes RNA which is then coded using building blocks into a protein which can carry out work inside a cell). Scientists found that levels of the RNA that make several proteins important for skin barrier function and the immune system were expressed at different levels in humans with and without AD, and in lesional compared to non-lesional skin of AD patients.5 Collectively, these studies indicate that AD is a complex disease with many different changes in genes and gene expression, not just a single gene change.
Using various research approaches, scientists have also discovered that there are different types of immune profiles of AD in children vs. adult patients and in patients from different races and ethnicities.7,8 This means that the presence of different types of immune cells, like TH cells (T helper), differ between patients. For example, adults with AD have activated immune pathways called TH22, TH17 and TH1 while children with AD have lower levels of TH1 activation.8 Likewise, AD patients of European descent in the United States have been shown to have higher TH2/TH22 activation and lower expression of the TH1/ TH17 pathway, as well as low expression of barrier proteins filaggrin and loricrin in the skin, while African Americans have a different level of TH1/ TH17 activity that may cause their AD phenotype to appear more like psoriasis, which is a TH17 driven disease.8 While more research is needed in this area, these differences in immune pathways again highlight the multiple contributors to AD, yet indicate a future opportunity to target AD therapies based on an understanding of what pathways are increased or predominate in a particular individual.
Once T cells and other immune cells of various types are activated, they can send messages to one another, to keratinocytes (the main skin cells), and to nerves. The messengers produced by these immune cells are called cytokines and chemokines. Similar to immune system pathways changing during AD, research is also finding that these messengers can change throughout the progression of AD and during acute and chronic phases of the disease.9 A recent study worked to correlate clinical information based on the Investigator Global Assessment (IGA) scale (a tool for documenting AD severity) with other molecular, cellular and genetic data.10 The researchers found increased eosinophils (a type of white blood cells) associated with increased disease severity and also found levels of certain cytokines and chemokines associated with worse disease.10 Researchers in another recent study examined gene expression profiles in AD patients with high and low numbers of eosinophils and classified patients according to the level of immune dysregulation.11 Measuring eosinophils levels allowed deeper understanding of immune dysregulation and disease activity, including allowing researchers to see what immune signatures were still dysregulated after treatment with dupilumab. It is possible that this type of multi-cell or multi-molecule profiling will allow monitoring of the success of a specific AD treatment for a specific patient.11
Researchers are also examining how differences in AD phenotypes could be explained by varying exposures to allergens and environmental factors as well as the extent to which a person is colonized by Staphylococcus aureus (S. aureus) and other bacteria. These factors can all influence the extent of activation of the immune system and which immune cells become activated.12 Exposure to allergens can lead to a dramatic increase in the allergy response molecule called IgE with higher IgE associated with more allergen exposure.12 The body mounts an IgE response against S. aureus toxins, indicating that the levels of bacteria on the skin can play a role in immune imbalances in AD.12 It is important to understand how each person’s environment plays a role in their AD profile.
Researchers are working on mathematics- and computer-based methods to integrate and interpret all of these different types of data; genetic, epigenetic (what tells a gene to be expressed or not), expression (RNA), protein, lipid, microbiome, environmental, and clinical information. Clinicians, researchers, bioinformaticists and computer scientists are working in teams to solve these giant puzzles with the ultimate goal of creating a complete picture of AD for each individual.13
Most of the candidate biomarkers studied in AD have been identified using skin biopsies, which is an invasive technique that many patients and their caregivers do not want to participate in due to patient discomfort. Less invasive methods are being developed for AD biomarker assessment, such as tape strips (taking off a few top layers of skin using an adhesive in a way that does not cause pain), dried blood spots or capturing saliva.14 Dr. Paller said, “Blood tests can potentially be indicative of disease. For example, babies with AD onset in the first six months of life have markedly increased skin homing of certain T cells (immune cells) that express IL-13 and these increases are not seen in older children or older adults. There are other markers in blood like TARC that may be used for tracking disease activity.” TARC (thymus and activation-regulated chemokine), attracts TH2 T cells and strongly correlates with AD clinical severity, allowing monitoring of disease activity at baseline and along the course of treatment.15 As biomarkers emerge, it will be important to also determine the best timing for their use during the disease course, and monitor treatment response. Dr. Paller also said, “Scientists are working out how to perform large scale studies of proteins and lipids from tape strips. Studying lipids (molecules in the skin that help make the protective barrier) may help predict disease progression and response to topical and/or systemic agents with fairly inexpensive screening tools.” Tape strips have recently allowed researchers to distinguish the immune and barrier profiles that differ between atopic dermatitis and psoriasis and are rapidly becoming more standard for collecting samples for laboratory research analysis.16,17
So far none of the identified candidate biomarkers have definitively been able to distinguish who will respond to treatments such as different biologics and who will not. Successful treatment of AD has been associated by Dr. Guttman and others with decreased TH2 pathway markers and decreased TH17 pathway cytokines or chemokines. Dr. Guttman said, “We are looking for biomarkers for treatment response since some patients do not successfully respond to dupilumab. We are using serum, blood and skin, including tape stripping, which is minimally invasive, to look for more than one biomarker. Biomarkers may help us understand the mechanisms of action of a specific drug and what happens when you shut off a specific immune pathway with a drug.” Figure 1 illustrates how biomarkers and understanding of disease biology may help make treatments more specific for each patient.
Dr. Paller summarized the current state of using our understanding of AD biology to allow more personalized governing of the disease when she said, “The bottom line is we are in a strong learning phase. The future lies in developing panels of markers that can be assessed using non-invasive capturing methods, panels that will come back from the lab quickly and be predictive of helping plan for the future and choose the right medication. Tests are still very expensive, primarily used in research and there need to be large-scale studies conducted across different clinical sites to really understand subtle differences between patients and correlate these with outcomes.” There is even hope of one day being able to predict the onset of AD in the first place. This may allow targeted prevention of the disease or early intervention in AD before the other associated atopic diseases develop. With the advent of many different types of treatments for AD as well as new scientific techniques that allow much more precise measurements of important biological molecules, the future of personalized medicine for treating AD looks very hopeful.
Figure 1: How genetics and understanding the underlying biology of a disease can lead to better distinguishing which patients will respond to which treatment. The top row shows patients with similar symptoms. On the left clinicians use their knowledge of standard clinical practice, results of clinical trials, and experience with other patients to treat the patients, only some of which respond to the treatment. On the right, a fuller understanding of the underlying biology of the disease and how patients differ from each other allows the clinician to better decide which treatment to give a specific patient, allowing each patient to ideally respond well to the different treatments based on their own personal disease biology. Figure adapted from reference 18.
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References
1. Yamamura K, Nakahara T. The Dawn of a New Era in Atopic Dermatitis Treatment. J Clin Med. 2022;11(20).
2. Cianferoni A, Annesi-Maesano I. Precision medicine in atopic diseases. Curr Opin Allergy Clin Immunol. 2019;19(6):654-664.
3. Kim J, Ahn K. Atopic dermatitis endotypes: knowledge for personalized medicine. Curr Opin Allergy Clin Immunol. 2022;22(3):153-159.
4. Moyle M, Cevikbas F, Harden JL, Guttman-Yassky E. Understanding the immune landscape in atopic dermatitis: The era of biologics and emerging therapeutic approaches. Exp Dermatol. 2019;28(7):756-768.
5. Bin L, Leung DY. Genetic and epigenetic studies of atopic dermatitis. Allergy Asthma Clin Immunol. 2016;12:52.
6. Brunner PM, Guttman-Yassky E. Racial differences in atopic dermatitis. Ann Allergy Asthma Immunol. 2019;122(5):449-455.
7. Czarnowicki T, He H, Canter T, et al. Evolution of pathologic T-cell subsets in patients with atopic dermatitis from infancy to adulthood. J Allergy Clin Immunol. 2020;145(1):215-228.
8. Nomura T, Wu J, Kabashima K, Guttman-Yassky E. Endophenotypic Variations of Atopic Dermatitis by Age, Race, and Ethnicity. J Allergy Clin Immunol Pract. 2020;8(6):1840-1852.
9. Fania L, Moretta G, Antonelli F, et al. Multiple Roles for Cytokines in Atopic Dermatitis: From Pathogenic Mediators to Endotype-Specific Biomarkers to Therapeutic Targets. Int J Mol Sci. 2022;23(5).
10. Smieszek SP, Przychodzen B, Welsh SE, et al. Genomic and phenotypic characterization of Investigator Global Assessment (IGA) scale-based endotypes in atopic dermatitis. J Am Acad Dermatol. 2021;85(6):1638-1640.
11. Mobus L, Rodriguez E, Harder I, et al. Blood transcriptome profiling identifies 2 candidate endotypes of atopic dermatitis. J Allergy Clin Immunol. 2022;150(2):385-395.
12. Leonard A, Wang J, Yu L, et al. Atopic Dermatitis Endotypes Based on Allergen Sensitization, Reactivity to Staphylococcus aureus Antigens, and Underlying Systemic Inflammation. J Allergy Clin Immunol Pract. 2020;8(1):236-247 e233.
13. Ghosh D, Bernstein JA, Khurana Hershey GK, Rothenberg ME, Mersha TB. Leveraging Multilayered “Omics” Data for Atopic Dermatitis: A Road Map to Precision Medicine. Front Immunol. 2018;9:2727.
14. Mastraftsi S, Vrioni G, Bakakis M, et al. Atopic Dermatitis: Striving for Reliable Biomarkers. J Clin Med. 2022;11(16).
15. Renert-Yuval Y, Thyssen JP, Bissonnette R, et al. Biomarkers in atopic dermatitis-a review on behalf of the International Eczema Council. J Allergy Clin Immunol. 2021;147(4):1174-1190 e1171.
16. He H, Bissonnette R, Wu J, et al. Tape strips detect distinct immune and barrier profiles in atopic dermatitis and psoriasis. J Allergy Clin Immunol. 2021;147(1):199-212.
17. Keurentjes AJ, Jakasa I, Kezic S. Research Techniques Made Simple: Stratum Corneum Tape Stripping. J Invest Dermatol. 2021;141(5):1129-1133 e1121.
18. Proper SP, Azouz NP, Mersha TB. Achieving Precision Medicine in Allergic Disease: Progress and Challenges. Front Immunol. 2021;12:720746.
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