The Etiology of Atopic

Herbert B. Allen

The Etiology of Atopic

Dermatitis Herbert B. Allen Drexel University Department of Philadelphia Pennsylvania USA

ISBN 978-1-4471-6544-6 ISBN 978-1-4471-6545-3 (eBook) DOI 10.1007/978-1-4471-6545-3 Springer London Heidelberg New York Dordrecht

Library of Congress Control Number: 2014954441

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Springer is part of Springer Science+Business Media (www.springer.com) Dr. Samuel Moschella is a clinical dermatologist who has been called a “dean” of dermatology and “the dermatologist’s dermatologist.” He has incredible recall of diseases he has seen (and there are not many he has not seen), and an incredible ability to integrate the skin fi ndings into a patient’s pathobiology. I vividly remember him diagnosing an elderly patient’s ichthyosis and integrating it into her apathetic hyperthyroidism, and another patient who looked like she had scleroderma, but he showed that she had porphyria. Sam is a retired captain in the US Navy Medical Corps and, as such, took special interest in the Navy residents and dermatologists. He made our training in leprosy at the USPHS Hospital at Carville, Louisiana, memorable. Further, any meeting where he is present will be much more informative because of his comments. I had picked up Sam in center city Philadelphia, and we were on our way to a funeral for Captain Bernett L. Johnson, Jr., MC, USN (Ret), when the discussion of my thoughts on eczema occurred. Bernie was my chairman when I was a resident at the Naval

Hospital in Philadelphia and Sam was his chairman when he was in training. Regarding eczema, I offered, “I think it may be due to because of the close association with sweating.” Sam replied, “All the docs at NYU felt the same way.” He mentioned Marion Sulzberger, Rudy Baer, and Al Kopf, all of whom were legendary dermatologists. Sometime after the funeral I was able to link Sulzberger and eczema and found his seminal article and the photograph of the occluded sweat duct. Sulzberger had it right, but he did not have many probes with which to pursue the story. Sixty years later, we did, and this book is the outcome. Once again, thanks, Sam.

Fig. 1 The author (left ) with Dr. Moschella (right ) on Dr. Moschella’s 90th birthday Pref ace

Originally, I considered calling this book Heresy , because all of the concepts con- tained herein are somewhat heretical to the current considerations and understand- ing of the pathogenesis of eczema. “Heresy,” from the Greek αίρεση, originally meant “choice”; however, with transformation through the centuries, the word now implies the opposite. True, “heresy” is predominantly thought to have religious con- notations; but, applied somewhat more loosely, the term can be used to describe opposition to any securely held beliefs or “dogmas,” if you will. It is in such a spirit that the word is utilized in this work. Sulzberger started it all in 1947 [1]. He observed an occluded sweat duct in a patient with eczema (Fig. 6.1 ). This occlusion was present in the outermost portion of the acrosyringium in the area where the sweat is released on the surface of the stratum corneum. By way of review, sweat is generated in the eccrine glands in the deep dermis, travels through the dermis in a straight duct, and traverses the epidermis via a coiled section called the acrosyringium. Sulzberger believed this occlusion in the acrosy- ringium played a signifi cant role in eczema (Fig. 1), but he lacked probes with which to pursue the concept further. Sulzberger was studying anhidrosis that arose in the tropics during World War II, a condition often severe enough to cause heat prostration that lasted 6 weeks or longer. The primary cause of this disorder was profound miliaria, but he observed that the sweat ducts were occluded not only in patients with miliaria but also in the patient in Fig. 1 with eczema, and in a second patient with seborrheic eczema. (A photomicrograph of that observation in seborrheic eczema was not present.) Fast forward 25 years to the observations of Hölzle and Kligman [2], who showed occlusion of the acrosyringium in patients with miliaria. The occlusions consisted of periodic acid–Schiff (PAS)-positive material (PAS stains polysaccharide- containing molecules) and bacteria. After creating the disorder with heat and occlu- sion, Hölzle and Kligman convincingly showed sweat-duct occlusion in 80 % of the ducts in miliaria before the rash appeared. Shortly thereafter, Mowad et al. [3], in considering the occlusion of the sweat ducts in miliaria noted by Hölzle and Kligman [2], found that the only easily

vii viii Preface

Fig. 1 Anatomy of the Spiralled eccrine sweat apparatus with duct eccrine gland (coil) in the deep dermis, the straight portion of the duct in the mid dermis, and the Epidermis acrosyringium in the epidermis Straight dermal duct Coiled Dermis dermal duct

Coiled gland culturable skin bacterium capable of causing anhidrosis (and thus capable of occlud- ing ducts) was biofi lm-producing Staphylococcus epidermidis. This biofi lm, or “slime,” as it was (and still is) called, is composed of extracellular polysaccharide substance. This would readily stain positive with PAS, as the authors demonstrated (Fig. 2 ). Thus, without demonstrating it directly, these authors developed a compel- ling thesis for the pathogenesis of miliaria. Heat and sweating allow for the prolif- eration of S. epidermidis and its biofi lm; these occlude the sweat ducts and cause miliaria. Heat and sweating also allow for the production of biofi lms by other staphylococci. Fast forward 25 more years to a discussion I was having with Dr. Samuel Moschella: I told him I was thinking that might be related to mili- aria. Both diseases were pruritic and both were worsened by sweating. The “occlu- sion” part of the story was well developed for miliaria but had been more diffi cult to elucidate for eczema. I ruminated that given that the most common form of eczema was “fl exural,” perhaps this apposition of two surfaces rendered enough occlusion to produce clinical disease. Dr. Moschella related that Sulzberger and the great New York University School held this theory 50 years ago, but it had been bypassed over time. Hence, back to Sulzberger (who led that school) I went, armed this time with many new probes, and the hypothesis that subclinical miliaria causes atopic dermatitis. In our studies, we have substantiated this hypothesis with many differ- ent protocols. These protocols have included microbiologic cultures, assays, and direct visual- izations of the S. epidermidis organism and its biofi lm taken from lesional skin in patients with atopy. We have performed these studies with conventional microscopy with resolution to 100× and confocal microscopy with resolution to 600×. We have also found many other staphylococcal species, all of which were capable of produc- ing biofi lms in our cultures of the skin lesions of atopic dermatitis [4]. Pathology from lesions has shown an acrosyringium occluded with PAS-positive material together with the spongiosis that is the hallmark feature of this disease. Gram-positive bacteria are present in the ducts as well [5]. One of the more exciting Preface ix

Fig. 2 Mowad’s observations from 1995. Sweat duct in miliaria occluded with PAS-positive material. These were the same pathology fi ndings as noted by Hölzle and Kligman in 1978 [2]. (From Mowad et al. [3]; with permission)

fi ndings in this endeavor was in the immunology of the specimens. Unlike the situ- ation in normal skin, where Toll-like 2 receptors are found in the basal zone, these receptors are noted around the ducts in the stratum corneum in the areas of occlu- sion [4]. Toll-like receptors are the fi rst responders in the immune system. Considering the ductal occlusion that Sulzberger, and now we, have observed, Eishi’s observations [6] in sweating and eczema fi t better with Hölzle and Kligman than with Eishi’s theory that there is faulty innervation of sweat glands in eczema. To wit, she noted an 80 % reduction in inducible sweat in her observations in lesional eczema, and Hölzle and Kligman noted a similar 80 % reduction in the number of occluded sweat ducts in miliaria. With respect to genetics, a defect in the fi laggrin gene is the leading candidate for culpability as it has been demonstrated in 50 % or more of patients with atopic dermatitis. A fi laggrin defect results in ichthyosis vulgaris, a cutaneous disorder in which eczema is commonly seen. However, we have treated numerous patients with eczema who have X-linked ichthyosis and lamellar ichthyosis, both of which have genetic derangements that are distinct from the fi laggrin gene. Further, at its most basic level, the fi laggrin gene helps to make a healthy stratum corneum. It is perhaps then not so curious that many other disease states that also involve a disruption of the stratum corneum mimic the appearance and behavior of eczema. These include seborrheic dermatitis, in which the stratum corneum may contain Malassezia yeasts, and tinea pedis, in which a dermatophyte may disrupt the outer envelope. Dermatologists and pediatricians treat eczema very well, ordinarily with -containing topical agents. It is intriguing to me that aggressive mois- turization and cautious bathing will in most instances prevent future fl ares of the disease; the need for topical corticoids would then be limited to any fl ares that do occur. Thus, instead of addressing the bacterial component of the disease, which x Preface initiates the whole process, care of the stratum corneum (which is under genetic control) is exceedingly important. Diseases in which eczema occurs in conjunction with a completely unrelated disorder have shown occluded sweat ducts on our histopathologic examinations. These include Meyerson’s nevus, which reveals a nevus and eczema in the same biopsy, and Doucas Kapetanakis-type pigmented purpuric dermatosis, which shows eczema along with capillaritis. The occluded sweat ducts in these conditions con- tain PAS-positive material that we believe represents biofi lms, inasmuch as eczema is an integral part of the combination. Though at fi rst glance heretical, all of these fi ndings are easily reproducible and can be addressed successfully. The structure of this book takes the following format:

Chapter 1 Clinical presentations We present clinical photographs of the main varieties of eczema: facial-extensor, fl exural, and nummular. We also show the recently described –like eczema as well as , Doucas Kapetanakis disease, Meyerson’s nevus, dyshidrosis, seborrheic dermatitis, axillary granular parakeratosis, and tinea pedis. Occasional photos show small papules or papulovesicles, adjacent to the larger plaques, which we believe are the primary lesions of the disease. These represent the occlusion of the ducts, the hallmark feature of this disease.

Chapter 2 Microbiology The major new fi nding in this work is not the presence of staphylococci on the skin in eczema; it is the discovery of what these organisms are doing. They are all geneti- cally capable of forming biofi lms, which they do in the eccrine sweat ducts. The biofi lms form there because, when in contact with salt or water or both, the organ- isms make biofi lms to protect themselves. Cultures taken from eczema lesions (and controls) grew many different species of staphylococci, including (42 %) and Staphylococcus epidermidis (20 %). The ability of the organisms to form biofi lms was documented by XTT assays, cultures on Congo red media, and gene analysis by PCR. Confocal microscopy showed the presence of biofi lms in lesional skin, as did Gram staining of skin scrapings. All the organisms were multi- drug resistant and 60 % were methicillin-resistant S. aureus (MRSA) or methicillin- resistant S. epidermidis (MRSE).

Chapter 3 Pathology The new fi ndings in pathology relate to the occlusion of eccrine sweat ducts with biofi lms made by staphylococci. These biofi lms were visualized on periodic acid–Schiff (PAS), which stains extracellular polysaccharide substance, and Congo red staining, which stains for amyloid, which makes up the infrastructure of the biofi lms. The standard pathologic features, such as spongiosis, were noted as expected. In the disorders not previously considered eczema, instead of the gene causing derangement of the stratum corneum, yeasts were noted in the stratum cor- neum in seborrheic dermatitis, granules in axillary parakeratosis, and dermato- phytes in tinea pedis. Preface xi

Chapter 4 Immunology The new fi ndings in immunology relate to the identifi cation of Toll-like receptor 2 (TLR2) in the proximal stratum corneum and upper epidermis adjacent to the bio- fi lm-occluded sweat ducts. This indicates that TLR2 is activated because its control location is in the epidermal basal zone. The pathways resulting from this activation include the MyD88 pathway and the PAR2 (protease-activating receptor 2) path- way. The end results of these pathways are well known and involve spongiosis, the most common pathological fi nding, and pruritus, the most common clinical fi nding in eczema.

Chapter 5 Genetics The genetics of eczema has focused on the fi laggrin gene, which has been found in more than 50 % of patients. Eczema has been noted with other gene defects as well, including steroid sulfatase and transglutaminase 1. The genetic link to eczema is making a faulty stratum corneum, and the genes in question do precisely that. This then forms the genetic component of the double-hit phenomenon, and couples with the environmental hit (staphylococcal-derived biofi lms occluding sweat ducts). In addition, anything that disrupts the stratum corneum, such as yeasts, can behave as does the genetic defect. We have also found the gene IcaD in the staphylococci that confers the ability to make biofi lms.

Chapter 6 Physiology The new fi nding in the physiology of eczema is decreased sweat on the skin surface as a consequence of the occlusion of the sweat ducts by staphylococcal biofi lms. From the literature, directly measured sweat on the skin in eczema was equivalent to that in miliaria, correlating with our hypothesis that eczema is subclinical mili- aria. As in miliaria, application of heavy duty moisturizers markedly lessens the impact of the ductal occlusions. How this happens is unknown.

Chapter 7 Treatment The mainstay of treatment of eczema is topical corticoids. Depending on the presen- tation, mild, moderate, potent, or superpotent agents may be chosen. In mild to moderate cases, topical calcineurin inhibitors may be used. Gentle treatment of the skin is essential, and the use of soap must be sharply curtailed. Aggressive moistur- ization is exceedingly important, and these skin care practices must be continued after the topical corticoids are stopped. Topical antibacterial measures, such as bleach baths, may be useful if followed by immediate moisturization; other topical antibacterial agents may be tried. The prescribed skin care relates directly to care of the stratum corneum; thus it impacts the genetic portion of the disease. If the patient continues appropriate skin care, the “environmental hit” in the disease no longer needs attention. Thus, the genetic portion of the disease is being treated by nonge- netic means.

Chapter 8 Diseases in which eczema is a secondary component (Meyerson’s nevus and Doucas Kapetanakis pigmented purpuric dermatosis) Eczema is known to be a feature of Doucas Kapetanakis disease and Meyerson’s nevus. Employing the microbiological, pathological, and immunopathological tests xii Preface from the preceding chapters, we have shown that these diseases truly are eczema, with assay fi ndings similar to atopic eczema. The main features were culture posi- tivity for staphylococci, biofi lm-occluded sweat ducts, and Toll-like receptor 2 (TLR2) activation adjacent to the ductal occlusions. The fi ndings of the other dis- eases (pigmented purpura in Doucas Kapetanakis and melanocytic nevus in Meyerson’s nevus) were present.

Chapter 9 Diseases with occluded sweat ducts other than eczema (tinea pedis, axillary granular parakeratosis, and seborrheic dermatitis) Seborrheic dermatitis, axillary granular parakeratosis, and tinea pedis have all been considered distinct dermatitides. However, we have found staphylococci and bio- fi lm-occluded ducts in all these diseases and Toll-like receptor 2 (TLR2) activation in seborrheic dermatitis and tinea pedis. (We did not examine for this in the others.) These are all the same features of atopic eczema, so we now consider them simi- larly. In all these diseases, we have cultured biofi lm-producing staphylococci and have shown biofi lm-occluded sweat ducts on pathology. We have also shown TLR2 activation at the site of the occlusion in tinea pedis and seborrheic dermatitis. We postulate that the dermatophyte in tinea pedis, the yeasts in seborrheic dermatitis, and the granules in axillary granular parakeratosis lead to a defective stratum cor- neum similar to the effect of the gene in eczema.

Chapter 10 The story of eczema in pictures Presented here are clinical photographs, routine cultures, Congo red cultures, assays for biofi lm production (XTT, PCR for biofi lm-making genes), lesion scrapings for biofi lms, routine biopsies, periodic acid–Schiff (PAS)-stained biopsies, Congo red– stained biopsies, tissue scrapings for confocal microscopy and for Gram staining, Toll-like receptor 2 (TLR2) immunopathology preparations, and photographs show- ing the impact of treatment.

Chapter 11 Epilogue: a comparison of psoriasis and eczema – both caused by bacteria, but neither an infection The epilogue presents a comparison between eczema and psoriasis. We believe both are caused by bacteria, although neither is an infection.

References

1. Sulzberger MB, Hermann F, Zak FG. Studies of sweating. I. Preliminary report with particular emphasis on a sweat retention syndrome. J Invest Dermatol. 1947;9(5):221–42. 2. Hölzle E, Kligman AM. The pathogenesis of miliaria rubra. Role of the resident microfl ora. Br J Dermatol. 1978;99(2):117–37. 3. Mowad CM, McGinley KJ, Foglia A, Leyden JJ. The role of extracellular polysaccharide sub- stance produced by Staphylococcus epidermidis in miliaria. J Am Acad Dermatol. 1995;33(5 Pt 1):729–33. 4. Allen HB, Vaze ND, Choi C, Hailu T, Tulbert BH, Cusack CA, Joshi SG. The presence and impact of biofi lm-producing staphylococci in atopic dermatitis. JAMA Dermatol. 2014;150(3):260–5. doi:10.1001/jamadermatol.2013.8627. Preface xiii

5. Haque MS, Hailu T, Pritchett E, Cusack CA, Allen HB. The oldest new fi nding in atopic der- matitis: subclinical miliaria as an origin. JAMA Dermatol. 2013;149(4):436–8. doi:10.1001/2013.jamadermatol.109. 6. Eishi K, Lee JB, Bae SJ, Takenaka M, Katayama I. Impaired sweating function in adult atopic dermatitis: results of the quantitative sudomotor axon refl ex test. Br J Dermatol. 2002;147(4):683–8.

Philadelphia, PA, USA Herbert Allen

Contents

1 Clinical Presentations ...... 1 2 Microbiology...... 15 3 Pathology ...... 25 4 Immunology ...... 35 5 Genetics...... 43 6 Physiology ...... 51 7 Treatment ...... 57 8 Diseases in Which Eczema Is a Secondary Component (Meyerson’s Nevus and Doucas Kapetanakis Pigmented Purpuric Dermatosis) ...... 69 9 Diseases with Occluded Sweat Ducts other than Eczema (Tinea Pedis, Axillary Granular Parakeratosis, and Seborrheic Dermatitis)...... 75 10 The Story of Eczema in Pictures...... 97 11 Epilogue: A Comparison of Psoriasis and Eczema: Both Caused by Bacteria, but Neither an Infection ...... 107

Index ...... 113

xv

Contributing Authors

The resident physicians placed and annotated the references for the sections for which they were responsible. This gave additional insight into this work. The attend- ing physicians performed the roles listed. Catherine Choi , MD , PhD Chapter 4—Immunology Christina L. Chung , MD Attending physician Editorial review Carrie Ann Cusack , MD Primary pathologist Reviewed all specimens Trisha Dasgupta , MD Chapter 9—Diseases with occluded sweat ducts other than eczema (tinea pedis, axillary granular parakeratosis, and seborrheic dermatitis) Matthew Fanelli , MD Chapter 6—Physiology Chapter 8—Diseases in which eczema is a secondary component (Meyerson’s nevus and Doucas Kapetanakis pigmented purpuric dermatosis) Chapter 9—Diseases with occluded sweat ducts other than eczema (tinea pedis, axillary granular parakeratosis, and seborrheic dermatitis) Maryam Haque , MD Chapter 3—Pathology Abby Hochberg , MD Chapter 2—Microbiology Kristin Hudacek , MD Chapter 9—Diseases with occluded sweat ducts other than eczema (tinea pedis, axillary granular parakeratosis, and seborrheic dermatitis)

xvii xviii Contributing Authors

Suresh Joshi , MD , PhD Microbiologist Performed microbiologic procedures Chapter 2—Microbiology Saurabh Lodha , MD Epilogue—A comparison of psoriasis and eczema Brett Miller , MD Epilogue—A comparison of psoriasis and eczema Swetha Narahari , MD Photo arrangement and many legends Rohit Nijhawan , MD Chapter 6—Physiology Chapter 8—Diseases in which eczema is a secondary component (Meyerson’s nevus and Doucas Kapetanakis pigmented purpuric dermatosis) Chapter 9—Diseases with occluded sweat ducts other than eczema (tinea pedis, axillary granular parakeratosis, and seborrheic dermatitis) Lauren Okon , MD Chapter 2—Microbiology Kyati Patel , MD Chapter 7—Treatment Chapter 9—Diseases with occluded sweat ducts other than eczema (tinea pedis, axillary granular parakeratosis, and seborrheic dermatitis) Ellen Nikki Pritchett , MD Chapter 3—Pathology Brittain Tulbert , MD Chapter 5—Genetics