Abridged from the

Dermatology Progress in Foundation Dermatology

Editor: Alan N. Moshell , MD.

Atopic Dermatitis: Recent Trends in Pathogenesis and Therapy

Kevin D. Cooper Immunodermatology Unit, Department of Dermatology, Universiry of Michigan Medical School; and Ann Arbor Veterans Administration Medical Center, Ann Arbor, Michigan, U .S.A.

Emerging concepts in the areas related to the pathogenesis Conventional therapy remains the mainstay of atopic der­ and treatment of atopic dermatitis are reviewed. In particular, matitis management; however, new therapies based upon the recent findings have revealed several key steps in the mainte­ above concepts are being tested in clinical trials. Although nance of a vicious circle of spongiotic dermatitis associated the difficulty of objectively grading AD lesional activity and with elevated T -lymphocyte activation, hyperstimulatory the high placebo response of AD patients hampers the inter­ Langerhans cells, defective cell-mediated immunity, and pretation of many reports, several types of approaches are B-cell IgE overproduction. The discovery of specific IgE­ coming into focus. The effectiveness of cyclosporinA, which binding structures on Langerhans cells provides a mechanism targets T-cell activation and antigen presentation, indicates for Langerhans cells to capture and present IgE-targeted al­ that additional agents with such activity should be effective, lergens to allergen-specific T cells. Furthermore, certain mi­ and verifies the criticality of these cells in AD pathogenesis. crobial allergens that tend to preferentially elicit IgE-type Therapy with biologic response modifiers, such as interferon responses also elicit a T-cell response dominated by the IgE­ gamma or thymopentin, is oriented toward normalization of inducing lymphokine interleukin 4. Repeated stimulation by imbalanced immune responsiveness, rather than direct sup­ activated Langerhans cells appears to induce just such a re­ pression of the immune system. The mechanism of action of sponse. Abnormal biochemical responsiveness and mediator and toxicities of Chinese herbal mixtures require further in­ release by AD monocytes, mast cells, and eosinophils also vestigation, but may reveal hitherto unconsidered avenues. participate in the sustainment or initiation of such a vicious Other recent therapeutic trials have focused on reduction of circle, and contribute directly to the dermatitis as well. De­ trigger factors, such as house dust mite exposure, foods, and velopments in the areas of neuropeptides, genetics, microbial the abnormal epidermal lipid barrier to irritation. Key words: superantigens, and cytokine networks in the skin also appear IgE/immunology/T lymphocytes/a ntigens. ] Invest Dermatol to have promise in providing a rational link between immune 102:128-137, 1994 defects and the inflammatory events in AD.

ecent a~vances in the pathog,eneSiS of atopic dermatitis ment. Many concepts of pathogenesis are currently being explored, are leadmg to novel forms of therapies for this disease, as evidenced by the activity in the field of atopic dermatitis; among which can have enormous impact, not only on the life approximately 4000 publications that are currently available on of the patient, but also on his or her family. An under­ atopic dermatitis, over 1000 have been published just since 1989. standing of these developments and the underlying For a treatment of this previolls literature, the reader is referred to biologyR is critical to successful physician utilization of our cllrrently several wide-ranging articles that review materials prior to 1989 in available agents and newer agents that are currently under develop- greater depth than the current manuscript [1-4].

Reprint requests to: Dr. Kevin D. Cooper, Immunodermatology Unit, Abbreviations: ELAM, endothelial leukocyte adhesion molecule; MF­ Universiry of Michigan, R5548 Kresge IjCampus Box 0530, Ann Arbor, CTCL, mycosis fungoides - rype cutaneous T -cell lymphoma; VIP, vasoac_ MI48109. tive intestinal peptide; PDE, phosphodiesterase.

Copyright © 1994 Dermatology Foundation, 1560 Sherman Avenue, Evanston, Illinois 60201 128 VOL. 102, NO. 1 JANUARY 1994 ATOPIC DERMATITIS 129

GENETICS cyte IL-l can induce ELAM-l and ICAM-l [26), and T-cell inter­ leukin 4 (IL-4) can potentiate ELAM-l (27). Thus T-cell activation Atopic dermatitis is clearly a genetic disorder. The inherited abnor­ can lead to enhanced adhesiveness of the microvasculature, either mality appears to be carried in the immune system; atopic dermatitis directly through lymphokine release, or indirectly through the re­ and antigen-specific IgE reactivity has been transferred into a nona­ lease of mast cell-degranul ating factors [28], which in turn leads to topic bone-marrow transplantation recipient from an atopic derma­ enhanced binding and extravasation of leukocytes into the lesional titis donor [6,7). The promise of gene therapy as a future approach milieu, and further increasing the likelihood of additional T-cell for atopic dermatitis is evidenced by the observation that the eczema activation. ofWiskott-Aldrich syndrome cleared following successful engraft­ ment of a nonatopic bone marrow (8). However, progress on identi­ Keratinocytes Keratinocytes in lesional atopic dermatitis exhibit fyi ng the gene for atopic dermatitis is limited [9,10]. evidence of cytokine or lymphokine modulation. In some cases CLINICAL IMMUNOLOGY ICAM-l can be visualized on epidermal keratinocytes [23,29], al ­ though not universally [18]' and almost always in the absence of Abnormalities in the immune system known to be associated with HLA-DR (17), indicating that interferon gamma (IFN-y) is not atopic dermatitis include an increased susceptibility to viral and likely to be the inducing lymphokine. CD36 and CDla, and even fungal infections, microbes normally handled by T cel ls generated IgE, have been observed on atopic dermatitis epidermal keratino­ by the delayed-type hypersensitivity (DTH) arm of the immune cytes, f~~the~ testimony to tl~e abnormal cytokine milieu of atopic system. Consonant with such susceptibility, patients are frequently dermatitis sklJ1 [30,31]. Studies on epidermal cytokine production anergic upon intradermal DTH testing. Because atopic dermatitis are limited in atopic dermatitis but abnormalities in IL-l (3 2) and patients exhibit generally normal ill lIitro proliferative blood T -cell IL-8 [33] have been noted. responses to the same antigens to which they exhibit cutaneous anergy (11), the immune defect appears skin limited, and the pa­ Shared Features of Atopic DerlIlatitis and Cutaneous T-Cell tients are not considered to be systemically immunosuppressed. LYlIlpholIla (CTCL) The high CD4: CD8 ratios in lesional Atopic dermatitis patients are, however, deficient in their ability to atopic dermatitis can be as high as that in the mycosis fungoides engage the mechanisms leading to allergic contact dermatitis, form of CTCL (MF-CTCL) [34,35]. Combined with exocytosis of w hich also depends upon the generation of antigen-specific T cells. activated lymphocytes into the epidermis, the distinction of MF­ Thus, in a careful quantitative study, atopic dermatitis patients were CTCL from ac tive, chronic atopic dermatitis is difficult. The de­ definitely shown to exhibit an impaired ability to become contact gree of spongiosis in relation to the pattern of infiltration and other sensitized to dinitrochlorobenzene (DNCB) (12). Impaired sensiti­ features is usually sufficient to make the distinction, but spongiosis zation appears to be proportional to the disease severity at the time and epidermotropism can be altered by the presence of topical corti­ of immunization [13]. These findings explain the clinical observa­ costeroids, so biopsy of patients withdrawn from steroids is pre­ tions that patients with atopic dermatitis develop contact allergic ferred . CTCL can arise in patients with severe atopic dermatitis l36] dermatitis less frequently than nonatopic subjects (14). However, (unpublished observations), and CTCL can appear as a spongiotic because of their heavy exposure to topical medications, atopic der­ dermatitis in its early stages, so the differential diagnosis can be matitis patients often do exhibit reactivity to contact allergens. The highly relevant. most common allergens for atopic dermatitis patients include fra­ Langerhans Cells Lesional skin of atopic dermatitis shares addi­ grance-mix, balsam of Peru, and neomycin, which can be compo­ tional abnormal features with CTCL; both exhibit increased num­ nents of these topical agents, as well as nickel [15), so patch testing bers of dermal Langerhans cells [37]' as well as epidermal Lan­ can be a useful clinical maneuver in discovering trigger factors that gerhans cells of abnormal phenotype, and hyperstimulatory can be removed. antigen-pres~nting.a.ctivity. Such Langerhans cells abnormally ex­ In addition to cell-mediated immune defects of the T cell arm, press CDlb (111 addltlon to CDla) and CD36, and are able to induce defects in monocyte and neutrophil chemotaxis and phagocytosis activation of resting T cells from the same individual in the absence are present [2], and may be implicated in susceptibility to bacterial of any added antigen [38 ,3~ ] . Thus, the normal compartmentaliza­ infection, in particular, Staphylococcus aurellS. tion of LC phenotype that 1S maintained in normal skin (epidermal IMMUNOPATHOLOGY LC-high CDla, absent CDlb, absent CD36; dermal LC-Iow CDla, positive CDlb, absent CD36) [40] is replaced by a single Infiltrating Leukocytes Increased numbers of lymphocytes, milieu characteristic of atopic dermatitis in which both epidermal monocyte/macrophages, and fully granulated mast cells (16) are and dermal LC express the same phenotype: CDla and CDlb are present in atopic dermatitis lesions. The lymphocytes within atopic both expressed simultaneously at high levels, and in concert with dermatitis lesions are predominantly of the CD4 + helper cell phe­ positive CD36 expression [38]. Additional evidence for a markedly notype, with a mean CD4: CD8 ratio of7: 1 [17]. A subset ofT cells modulated LC population in lesional atopic dermatitis skin is the appears to undergo intralesional activation, as evidenced by their abnormal expression of the interpenetrating reticulum cell marker expression of IL-2 receptors (CD25) [18,19)' and the majority ex­ RFD-l, a molecule normally reserved for dendritic antigen­ press HLA-DR (a class II major histocompatibility complex mole­ presenting cells of the T-cell area of lymph nodes [19], and the cule), which is another, less labile, marker ofT-cell activation. The binding of easily detectable levels of 19E on the Langerhans cells CD4 + T lymphocytes are of the memory subset (indicating surface. previous encounter with antigen) [20] and express high levels of the The abnormal status of atopic dermatitis Langerhans cells may be x c skin-homing Sialyllewis / lectin ligand for the endothelialleuko­ of significance in both the maintenance of the dermatitis and the tilt cyte adhesion molecule 1 (ELAM-l) [21,22]. of the immune system response in atopic dermatitis toward IgE and EndotheliulIl In addition to histologically evident hypertrophy, eosinophil production with concomitant depression of DTH re­ endothelial cells in lesional atopic dermatitis skin abnormally ex­ sponses (recently reviewed in [41 D. Whereas normal Langerhans press ELAM-l (22) as well as upregulated levels of intercellular cells are unable to activate resting blood CD4+ T cells from the adhesion molecule (ICAM-l) [22,23]. Because T cells that express same individual (autologous T cells and LC) in the absence of added the highest levels of ligands for these endothelial adhesion mole­ antigens [42], atopic dermatitis lesional Langerhans cells are potent cules are those that have recently undergone activation, it is possible activators of autologous resting CD4+ T lymphocytes under such that T cells in atopic dermatitis may activate in lymphoid organs conditions [38]. In part, the reactivity is due to presentation of self (i.e., nodes) prior to landing in the skin. A number of mechanisms peptides, indicating a component of true autoreactivity [43]. The may be responsible for the enhanced adhesiveness of atopic dermati­ remaining signal could be due to presentation of processed foreign tis vasculature for leukocytes: mast cell release of tumor necrosis antigen or binding of microbial superantigen, both of which could factor (TNF) can induce ELAM-l [24,25), monocyte or keratino- result in T-cell activation in the lesion by LC themselves. The signal 130 COOPER THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

C.N.S. Inflammation \. I Neuropeptldes \ o ;;GE~ Other t Leukocyte Mediators Monocyte ... Recruitment lPD~/ J Spongiotic HOM? / Dermatitis with 1 Cell su:'~gV- :I~------'. Mediated IL-S? Immunity

IL-4 =='L. Eosinophilia IgE ~ ® .~-----.-"" P.ovale? ~ " Figure 1. Overview of interacting inflammatory mechanisms in atopic dermatitis. APCs, in particular hyperstimulatory Langerhans cells, present antigens to T cell s and induce intralesional T cell activation, lymphokine production, and spongiotic dermatitis. The antigens may be focused on those targeted by IgE (i.e., house dust mite (HOM) or P. Ova /e), because of Fe binding ofIgE on Langerhans ce ll s, or the antigens may be self peptides, or staph super-antigens (Staph Super Ag) . An abnormal balance of neuropeptides in atopic dermatitis skin would appear to favorT -cell activation. Although uncommon in many skin diseases, TH2 cells are prese nt in lesional atopic dermatitis skin. Their production of IL-4 may help promote the hyper IgE of atopic dermatitis, and their putative production of IL-5 may be responsible for eosinophilia in atopic dermatitis. THl cells are also present, but their relative role may be diminished by the overproduction of PGE (selectively inhibitory for THl cells) by abnormal monocytes with elevated cAMP phosphodiesterase. THl ce ll s may also be selectively inhibited by TNF released from mast ce lls which are easily triggered in atopic dermatitis, possibly in response to T-cell-derived histamine-releas­ ing factor (a putative lymphokine). The diminished role ofTHl in AD is theorized to result in less gamma interferon (IFN) inhibition ofTH2 cell s, which, in turn, act to inhibit THl expansion and cell-mediated immunity. Lymphokines and cytokines induce endothelial adhesion molecules and leukocyte recruit­ ment, further propagating the cycle.

for autoreactive T-cell stimulation by lesional epidermis does not immune responses dominated by the Thl subset, which produces arise from keratinocytes themselves presenting antigen or superan­ large amounts of IFNy, along with IL-2, TNF, and other, less spe­ tigen, because depletion ofleukocytes (leaving all the keratinocytes cific lymphokines, but Thl cells produce very little IL-4, IL-5, and behind) totally removes the stimulus for T-cell activation [38]. An IL-lO [46,56]. Thl cells mediate DTH responses, and mice who important concept has recently emerged that CD4 + T cells repeat­ develop strong Th 1 responses handle microbes requiring DTH re­ edly stimulated with activated (cultured) LC differentiate into T sponses, like Leishmania, quite effectively [57,58]. This feature may lymphocytes that produce high amounts of IL-4 and negligible be related to the ability ofThl responses to recruit monocytes and IFNy [44,45]. Such Tcells are termed "TH2" and exist in a dynamic activate macrophages at sites of intracellular infections, and to in­ opposition with "TH 1" type T cells, which produce IFNy, but little duce cytolytic T lymphocytes [59] . IL-4, IL-5, or IL-I0 [46]. Other strains of mice tend to develop a Th2-dominated response; Because IL-4 induces IgE synthesis and the expression of recep­ these mice do not handle Leishmania well, but are very effective at tors for IgE on cells, a positive feedback loop might be operative in handling intestinal parasites, such as NiJ?postrongyloides, which atopic dermatitis, which is linked to allergic responses. In this con­ the Thl-generating mice handle poorly l5 8,60,61]. Th2 cells, in cept, IgE directed toward certain allergens is passively bound to contrast to Th 1 cells, make large amounts ofIL-4, IL-5, and IL-I0, Langerhans cells, the IgE captures selected allergens (e.g., dust mite and very little IFNy [46,62]. IL-4 is a potent inducer of B-cell IgE or pollens), which are then internalized and processed by the LC for production, IL-5 induces eosinophilia, and IL-I0 depresses DTH presentation to T lymphocytes, which in turn are influenced to be of responses, possibly at the antigen-presenting cell level [63,64]. All the IL-4 (Th2) type, further boosting IgE production. The evidence of these features are manifested in the atopic dermatitis state, but for this hypothesis is as follows. Langerhans cells and dendritic may be useful in dealing with helminths (alternatively, helminths dermal cells in atopic dermatitis (and other high-IgE states) [47] may have evolved to elicit an immune response that allows their have detectable levels ofIgE on their surface [48 - 50], particularly survival [59,60]). Both the Th 1 and the Th2 responses tend to be in eczematous skin [51]. This appears to occur by absorption of self-amplifying and inhibitory to the recipropical subset, such that circulating IgE onto a specific receptor for the Fc portion of the IgE IL-4 inhibits THl-type responses and IFNy inhibits Th2-type re­ molecule (Fc epSilon R I) [52- 541 and via lectin-like IgE-binding sponses [65,66]. In humans, Th2 responses appear to dominate over molecules [48]. That the surface IgE might skew the type of anti­ Thl responses in diseases such as lepromatous leprosy (which ex­ gens presented by Langerhans cells is evidenced by findings that plains the poor handling of organisms in these patients) [67], in atopic dermatitis Langerhans ce ll s could only present house dust all ergic (lgE-associated) disorders [59]. and in the Sezary syndrome mite antigen if the Langerhans cells was surface IgE positive [55], variant of cutaneous T-cell lymphoma [68]. Conversely, diseases and that Langerhans cells pre-incubated with antigen-specific IgE with IFNy-producing T cells (Thl-type response) include allergic could present that antigen if it were then ava il ab le to the Langer­ contact dermatitis [69], tuberculoid leprosy [67], and psoriasis hans cel ls [48]. [70 -72]. Atopic dermatitis patients exhibit reduced ability to generate lMMUNOREGULATION IFNy l73 - 75], a situation that could be improved by blocking the T-Cell Subsets: Thl and Th2 In mice, CD4+ T lymphocytes activity oflL-4 in the culture [73], or by removing monocytes [75]. have been class ified according to their profile of lymphokines that Atopic dermatitis T cel ls appear particularly responsive to IL-4 [76], they release upon activation. Certain strains of mice tend to generate possibly related to their elevated levels ofIL-4 receptor mRNA [77]. VOL. 102. NO.1 JANUARY 1994 ATOPIC DERMATITIS 131

Lesional skin of patients with allergic conjunctivitis and atopic der­ currently understood. Reduced numbers of lymphocytes bearing matitis clearly contain T cells of the Th2 type [55.78-84J. Of the LFA-3 receptor, CD2, have been documented for years, with particular interest was that a high percentage (10-47%) ofTh2 cell the most consistent reduction being found within a subset that ex­ clones grown from lesional atopic dermatitis skin appeared to be presses CD8 and Fc receptors for IgG (reviewed in [3] and [1 J) , and specific for a house dust mite antigen [80] or for grass pollens [82]. that may represent a reduction in a CD2 + natural killer-type cell This phenomenon was also quite pronounced in epicutaneous patch subset [93,100]. Whether this reduction is due to the extreme sensi­ tests to aeroallergens [80 - 83J. In one study the frequency of Derma­ tivity of natural killer cells to topical steroid applications is not yet tophagoides pteronyssimls- reactive T-cell clones was estimated to be clear [101]. 0.4 - 2.7%. and 42% of the clones were found to be of the Th2 type Alterations in CD4/CD8 ratios are also detectable in atopic der­ [85]; in another study. all of the clones were reactive to the inciting matitis (reviewed in [1,3,84]), but the ratio can be found to be either aeroallergen. and 70% were of the Th2 type [86]. Why such high elevated or reduced, which I believe relates to how the "small lym­ percentages of T cells are reactive to these aeroallergens is unclear: phocytes" are electronically separated from the "large monocytes"; antigen-induced enrichment of antigen-specific T cells is the fa­ in atopic dermatitis this separation is not distinct as it is in normals, vored hypothesis, but self-antigen cross-reactivity (autoimmune likely because of the above-described selective shifts of normall y molecular mimicry), or superantigen-like stimulatory properties of small lymphocytes into the "monocyte-sized" cell cluster follow­ the extracts, or a selection due to the cloning procedure must also be ing enlargement upon activation. Thus, the lymphocyte ratios can held as possibilities. be altered by how the cells are chosen for analysis. In a recent stud y Despite the clear presence ofTh2-type T cells, the lesional skin of that reported both small and large cell data, the CD4/CD8 ratio was patients with atopic dermatitis also contains IFNy-producing (Th 1- minimally changed among the small lymphocytes and markedly like) T-cell clones [59,79]; their antigen specificity remains un­ reduced among the large cells, due primarily to an increase in known. The actual frequency of Th 1 and Th2 cells in lesions, and CD8 + CDl1b+ cells and a decrease of CD4+ cells [93J. their relative roles in initiating or maintaining the dermatitis, will Modulation of the Immune Response by Abnormal Mono­ be the focus of much work in coming years. However, the identifi­ cytes in Atopic Dermatitis The T-cell activation that occurs as cation ofTh2 cells in atopic dermatitis blood and skin has formed a a result of hyperstimulatory Langerhans cells in patients with atopic rational basis for therapeutic intervention with recombinant human dermatitis appears to be influenced by several factors. A current IFNy, which should be inhibitory to such cells, in patients with hypothesis is that the profile of lymphokines produced by the acti­ atopic dermatitis [87]. vated T cells is "tilted," resulting in the unique constellation of atopic dermatitis features that eventuate in spongiotic dermatitis, Other T-Cell Abnormalities Depressed DTH and cell-me­ hyperimmunoglobulinemia of IgE, depressed cell-mediated immu­ diated immunity (CMI) in atopic dermatitis may be related to more nity, tendency to respiratory allergy, and eosinophilia. Recent work than the Th 1 /Th2 imbalance concept, and there may be many more by Hanifin el ai, described below, has begun to shed light on how ramifications of Th 1/Th2 imbalance than are currently appre­ abnormally functioning monocytes with an impaired ability to rec­ ciated. Alternatively, a Th 1/Th2 imbalance may be the result of a ognize immunoregulatory signals can affect the nature of T-cell serious underlying immunoregulatory abnormality. For instance, differentiation. transforming growth factor beta (TGF/f), a potent immunosuppres­ Peripheral blood mononuclea r cells, and particularly monocytes, sive cytokine and tissue regulator, favors the activation ofTh2 over from patients with atopic dermatitis produce elevated levels of pros­ Th 1 cells [60]. Depressed CMI could also be related to a shift of the taglandin E2 (PGE2) [75,102]. Although normal CD4+ cells do primary site of T-cell activation from the regional lymph node to not adjust to external PGE2 by raising their cyclic adenosine mono­ the skin; dendritic antigen-presenting cells in atopic dermatitis phosphate (cAMP) phosphodiesterase, atopic dermatitis CD4 + T lymph nodes demonstrate abnormal morphology and reduced in­ cells do, resulting in a marked reduction in atopic dermatitis T-cell terdigitation with T lymphocytes [88]. However, the sera of atopic cAMP levels [103]. Thus, atopic dermatitis monocyte restriction of dermatitis patients clearly displays evidence of ongoing and signifi­ atopic dermatitis T-cell IFNy lymphokine secretion appears due to cant T-cell activation in some location by the elevated levels of both a disordered level of PGE2 production by atopic dermatitis soluble IL-2 receptors [89,90] and CD8 molecules [91]. The dem­ monocytes and an abnormal response on the part of atopic dermati­ onstration of IL-2 receptor bearing T cells in lesional atopic derma­ tis T cells to the PGE2 [75J . titis skin [19] strongly suggests that the skin is a major source of the Because PGE2 can inhibit THl IFNy, but not TH2 IL-4, PGE shed IL-2 receptors in the serum of these patients. oversecretion can tip the balance of the immune response in favor of Activated lymphocytes spill out of their tissue sites and are detect­ a TH2 response [104] . The ability of a cAMP phosphodiesterase able in the blood of patients with atopic dermatitis. In addition to inhibitor with beneficial clinical activity in atopic dermatitis [105] release of activated CD4 + cells [92J, enlarged (activated) B cells and to reduce atopic dermatitis ill I,ilro IgE secretion by blood mononu­ enlarged CD8+ Cllb+ T cells (putative suppressors) are found clear cells [106] could now be interpreted such that the inhibitor increased in the blood of patients with AD [93], indicating selective may make atopic dermatitis T-cell IFNy less susceptible to inhibi­ circulation of these activated lymphocyte subsets. Indeed, some pa­ tion by atopic dermatitis monocyte PGE2. PGE2 can also act di­ tients have CD8 + T suppressor cells that, upon removal, can be rectly on B cells to enhance IgE production [104J. Thus, monocytic shown to have been restraining the atopic dermatitis patient's series PGE2 overproduction may represent an important factor in CD4 + proliferative response to herpes simplex virus [94]. the tilt of the atopic dermatitis immune response toward a "TH2- Despite the evidence of in llivo activated T cells in atopic dermati­ like" immune lymphokine pattern. tis, blood mononuclear cells of atopic dermatitis patients often ex­ hibit slight reductions in their ability to be stimulated in vitro. In Monocytes Monocytes are present in increased numbers in th e addition to the above-mentioned reductions in IFNy production, lesional skin of atopic dermatitis patients [19,1 07J, and may thereby atopic dermatitis patients release less IL-l [32,95]' TNF [96], and account for the elevated levels ofPGE series prostaglandins detecta­ IL-2 [97], and proliferate less briskly, possibly due to the selective ble in atopic dermatitis skin [108J. Besides elevated PGE produc­ inhibitory effect on CD4+ T cells of prostaglandin E overproduc­ tion, atopic dermatitis monocytes are abnormally primed for super­ tion by atopic dermatitis monocytes [98]. Decreased proliferation by oxide production [109], additional evidence of ;n ";"0 activation. atopic dermatitis T cells may also reflect the tendency of patients The abnormal state of atopic dermatitis mOllocytes may be due to with atopic dermatitis to demonstrate reduced lymphocyte counts the elevated level of activation ofT lymphocytes [19,38,89] and the in general [93]; in at least one case, erythrodermic flares are asso­ monocyte response to stimulation by T-cell lymphokines [110]. ciated with CD4+ lymphocytopenia [99] . However, atopic dermatitis monocytes may exist in an abnormal Subtle alterations in the proportions of immunoregulatory sub­ functional state as a consequence of th eir profound elevation of sets are present in the blood of atopic dermatitis patients that are not cAMP phosphodiesterase levels [111] and elevated adenyl ate cyclase 132 COOPER THE JOURNAL OF INVESTIGATIVE DERMATOLOGY levels [112]. This abnormality is independent of lesional activity finding likely related to the high prevalence of atopy in the general and is present even in the cord blood of infants of atopic parents population. [113], leading to the speculation that this defect in atopic dermatitis monocyte membrane proteins may be linked to the genetic defect(s) House Dust Mites There seems to be no question that patients responsible for atopic dermatitis susceptibility, and that cAMP with atopic dermatitis have a high frequency of IgE antibodies that phosphodiesterase levels may be useful as a diagnostic test for atopic detect house dust mite antigens and that the skin and blood of at dermatitis [114] . least some patients also harbor T cells that can recognize house dust mite antigens when presented by appropriate antigen-presenting Mast Cells/Basophils Evidence has existed for many years that cells (recently reviewed in [84]). These findings generally occur in atopic dermatitis patients experience intermittent mast degranula­ patients who demonstrate a positive epicutaneous "patch" test to tion (see previous reviews). cAMP agonists (PGE, adrenergic dust mite antigens. Because dust Inites are ubiquitous, it is attractive agents, histamine) in normals exert a down-modulatory tone on to postulate that either aeroallergens or epicutaneous exposure can mast cell or basophil degranulation; an alteration in responsiveness initiate immunologic events that exacerbate the dermatitis. In fact, to such agents due to an elevated level of cAMP phosphodiesterase there is a positive correlation between the magnitude of exposure to in atopic cells may playa role in the excessive releasibiliry ofbaso­ dust mites and the frequency of disease [134]. However, although phils in atopic dermatitis patients [115] and mast cells in atopic dogs dust mites are known to have a more favorable growth rate under l116]. The ability of substance P, a neuropeptide released by cutane­ damp conditions than dry conditions, the association was indepen­ ous nerves, to degranulate cutaneous mast cells [117] provides an­ dent of the presence of domestic humidity. Thus, these authors other mechanism for mast cell histamine release that may be highly hypothesize that the association between high densities of mites and relevant in explaining the close relationship of psychic stress to atopic dermatitis may be related to differences in lipid composition cutaneous inflammation in atopic dermatitis. of the shed squames on which the mites feed, or perhaps on the In addition to the well-appreciated effects of mast cell products amount of squame available [134]. on inflammation and itching, the products of mast cells have also A cornerstone of the work implicating dust mite antigens as a been implicated in the epidermal hyperplasia of atopic skin [118]. trigger in atopic dermatitis has been the development of an epicu­ Furthermore, mast cell release may be a contributing factor in the taneous patch test to detect a subset of patients with atopic dermati­ "tilt" of the atopic dermatitis T-cell response toward Th2 because tis that have such reactivity. In many instances investigators use tape of their ability to release TNF [24]. TNFa inhibits the growth of stripped or somewhat abraded skin to obtain positive reactions. The Thl IFNy-producing T-cell clones, but not atopic dermatitis skin lack of standardized preparations and methods of application is the infiltrating Th2 (IL-4-producing) T-cell clones [81]. Indeed, likely cause of variations in the literature with regard to the fre­ plasma TNF levels are elevated in the serum of patients with atopic quency of atopic dermatitis patients with positive tests. In one re­ dermatitis, and the levels are tightly correlated with plasma hista­ cent study, the authors varied both the type of allergen and the state mine [119] . of the skin being patch tested; they found positive patch tests in Eosinophils High eosinophil counts are common in atopic der­ 40- 50% of atopic dermatitis patients and favored a simple applica­ matitis [120]. Whether this is due to the concomitant production of tion on healthy appearing skin [135]. In another comparative study, IL-5 by Th2 cells .in atopic dermatitis remains to be established. non-specific reactions due to tape stripping, fixation tape, or patch­ However, the eosinophils are acutely regulated and undergo activa­ test occlusion were observed in up to 80%, with specific reactions tion in correlation with disease activity. Eosinophils degenerate in occurring in only 30% of atopic dermatitis patients. Almost all of atopic dermatitis skin [121], presumably releasing the polypeptide these reactions occurred in patients with extremely high serum IgEs crystalloid core of the eosinophil granule, termed major basic pro­ [136]. Careful use of this test is therefore required. However, the tein. This/rotein is distributed extensively in atopic dermatitis immunoreactivity that occurs after initiation of such a test has re­ dermis, an is also capable of degranulating mast cells (reviewed in vealed significant useful information. Presentation of house dust [1] and [3]). The eosinophil cationic protein is also useful as a marker antigen via specific IgE bound to Langerhans cells has been demon­ of eosinophil activity in vivo; eosinophil cationic protein levels are strated, as described above [55], and an antibody to house dust mite elevated in atopic dermatitis serum [89,122,123], providing further antigen has even been used to visualize the antigen in positive patch evidence for eosinophil involvement in atopic dermatitis. Interest­ tests by immunoelectron microscopy in epidermal and dermal Lan­ ingly, eosinophilia was the most sensitive blood element to treat­ gerhans cells [137]. ment with IFNy [87,93] and cyc1osporin A [124]. In addition to dust mites, other airborne allergens, such as tree and grass pollens, have been used in occlusive chamber-scarification TRIGGER FACTORS patch tests to elicit contact sensitivity -like delayed-in-time re­ Early recognition of the presence of trigger factors can allow earlier sponses in patients with atopic dermatitis. Although such special appropriate intervention and less severe exacerbations, and thus are testing may be able to elicit atopic dermatitis -like cutaneous in­ an important part of clinical management. Patients usually learn flammation under these controlled circumstances, it still is ex­ early in life that wool (lanolin) and harsh detergents are irritating to tremely unusual for allergen desensitization to provide any benefit their skin. A recent study has documented that the skin of atopic for the dermatitis of atopic dermatitis. Another ubiquitous antigen, dermatitis patients demonstrates a statistically significantly higher which has been found to elicit reactions in patients with atopic increase in skin thickness (by ultrasound) in response to exposure to dermatitis under chamber-scarification patch tests is PityrosponlPl/ sodium !auryl sulfate, as compared to controls [125]. Whether this is ova Ie. Large molecular weight antigenic substances from P. ollale due to the abnormalities in epidermal lipid metabolism, in particular (greater than 60 kD) have been found to induce lymphocyte prolif­ elevated free arachidonic acid, of patients with atopic dermatitis eration in atopic dermatitis patients with positive patch test to [126] or abnormally low levels of ceramides in the stratum corneum P. ovale extracts [138]. IgE antibodies against P. ol/ale were found in of atopic dermatitis patients [127] or to defective conversion of two of three atopic dermatitis patients, particularly in those with linoleic acid [128] remains to be determined. Other contributory lesions predominantly in the seborrheic areas, the area of highest factors include various microbes and psychic stress. Under rare cir­ prevalence of P. ol/ale [139] in young adults. Whether this commOn cumstance, triggers can include dietary foods, aeroallergens [129], lipophilic yeast is truly pathogenic, or whether these findings and ultraviolet [130]. Contact urticaria to raw foods [131], or con­ merely reflect the propensity of atopic dermatitis patients to develop tact allergens, i.e., dermatitis, but mainly extrinsic contact irritant IgE-dominated responses to microbial and aeroallergens is currently dermatitis is responsible for the high incidence of hand dermatitis. unclear. Several studies have documented that 80-85% of patients with The mechanism by which Staphylococcus aureus can trigger atopic occupational hand epidermis had coexisting atopy [132,133], a dermatitis flares might be one of several things. Staphylococcal cell VOL. 102, NO.1 JANUARY 1994 ATOPIC DERMATITIS 133

wall products (teichoic acid and peptidoglycan), as well as a staphy­ (neuropeptide Y and tyrosine hydroxylase). Markers of sensory lococcal secreted superantigen, entero-toxin B, can stimulate pe­ nerve fibers (calcitonin gene-related peptide and substance P) also ripheral blood lymphocytes, and, particularly in combination with showed a somewhat increased density of fibers [149]. IL-4, can lead to a pronounced increase in IgE synthesis and FeIgE The total skin content of neuropeptides is beginning to be ex­ receptor expression [140]. Staphylococcal superantigens also have plored. Two groups have found elevated vasoactive intestinal poly­ the capacity to activate large classes of T cells, regardless of their peptide (VIP) in lesional skin of atopic dermatitis [150,151], and in antigen specificity, because they are able to bridge the linkage be­ one study this was associated also with a reduction in the level of tween the class II major histocompatibility complex molecule on substance P [152]' Because VIP and substance P are somewhat in the antigen-presenting cell and the T-cell receptor without having dynamic opposition with regard to their immunomodulatory ef­ to be processed and presented by the antigen-presenting cell. In this fects, an imbalance of VIP over substance P may participate in the scenario, staphylococcal superantigens released into the epidermis impaired immunologic responses of atopic dermatitis skin. In con­ would find a way onto class II major histocompatibility complex­ trast to substance P, which is stimulatory for lymphocyte prolifera­ positive Langerhans cells or dermal DR + cells, and could thereby tion and monocyte cytokine production, VIP is inhibitory to lym­ cause a marked stimulation of several classes of T cells that have phocyte proliferation and natural killer cell activity [152]. It is been non-specifically recruited into the lesion. This hypothesis is tempting to speculate that the observed imbalances in the neurocu­ consistent with our findings that Langerhans cells exclusively carry taneous innervation in atopic dermatitis are related to abnormal the autostimulatory signal for autologous T lymphocytes in atopic vasoactive cutaneous responses in atopic dermatitis [153,154] and dermatitis [38]. However, this cannot be the entire source of stimu­ the increased itch responses that patients with atopic dermatitis lation, because a significant component of the T-cell response to self exhibit for agents such as wool fibers [155], and even a TH1/TH2 antigen-presenting cells can be removed by removing autoreactive imbalance [156]. T cells that respond to blood antigen-presenting' cells [43]. THERAPY Foods In a highly selected group of patients, patients with food Objective Assessment of Atopic Dermatitis A critical ad­ allergies and atopic dermatitis who follow an appropriate avoidance vance in the study of atopic dermatitis occurred upon the adoption diet can have substantial clinical improvement [141] and lose their of standardized diagnostic criteria. A similar effort is now needed to food hypersensitivities [142]. In certain patients in whom a careful standardize the quantitative clinical assessment tools available for history clearly implicates certain foods, ingestion of a food allergen assessing whether atopic dermatitis patients improve with a specific during challenge can lead to a pruritic, morbilliform rash, which therapy. Many clinical trials a.re riddled with subjectivity, because can become eczematous after a series of positive challenges over the quantitative assessments of severity and pruritis almost invariably course of several days [143]. How large food proteins in the diet allow subjective patient perceptions to influence the physician's could induce reactivity in the skin is not clear, but it has been assessments, whether intended or unintended. In addition, the mar­ postulated that increased intestinal permeability allows penetration gins of atopic dermatitis lesions are not distinct, like those of psoria­ of certain of these antigens such that the food antigens could be sis, so that an accurate quantitation possibly of total body surface processed by antigen-presenting cells similarly to the in vitro model involvement is very difficult, because patients have spongiosis even in which food antigens can stimulate atopic dermatitis peripheral in apparently uninvolved skin and exhibit variable degrees of xerosis blood mononuclear cells to produce high levels ofIL-2 [144]. Expo­ blending into frank scaling, which is also modified by the number of sure of carefully identified patients to the offending foods causes hours since bathing or moisturizing. The problem is further com­ their peripheral blood basophils to spontaneously release histamine, pounded by the extremely high placebo response in studies of pa­ which in turn appears dependent upon elevated production of a tients with atopic dermatitis, which can mask the detection of a histamine-releasing factor from mononuclear cells [28]. Interest­ partially effective therapy, or falsely give the impression that an ingly, avoidance of the specific food ca n result in decreased levels of ineffective approach has a response rate. There is also a problem of blood histamine-releasing factor and actual histamine release from "subsets," that is, there appear to be therapies in which a percentage atopic dermatitis basophils [28]. More generalized food-avoidance of atopic dermatitis patients receive a great deal of benefit, whereas diets do not have a good response/risk ratio; an elemental diet has others experience little benefit. been tried in children with widespread atopic dermatitis and, al­ A workshop on the subject outlined quantifiable signs and symp­ though some clinical benefit was obtainable, the patients required toms, issues regarding target site selection, and recommendations prolonged hospitalization and experienced a fall in body weight and for systemic and topical steroid washout periods [157J. Other au­ serum albumin, and, in addition, experienced a significant risk of thors have recommended weighting the extent of disease by the anaphylactic shock in over 10% of the cases [145]. Highly restricted distribution of severe and mild changes, either as a modification of (few foods) diets are extremely arduous, although beneficial for the psoriasis a.rea and severity index [158], or using a simplified and some children, but the long-term outcome does not appear to be rapid point-counting technique [159]. Methods involving portable affected by compliance or non-compliance for such a diet [146] . A data loggers for the continuous recording of itch [155] have been large follow-up cohort of 736 patients was recently evaluated at 7, developed, and actigraphic watches are availab le to monitor 11 , and 14 years of age to determine the effect of cow's milk. scratching. Ultrasound has been used to quantitate the degree of Children with an atopic family history ran the same risk of subse­ skin edema. Others have argued that simple, rapid assessments are as quent atopic disease whether they were fed formula or breast milk accurate as elaborate grading methods [160]. For the purpose of alone, as compared to cow's milk [147]. determining whether equally severe patients are entered into both Neurocutaneous Alterations As reagents for detecting and the placebo and active therapy arm of a trial, a system for estimating measuring neuropeptides have become available, it is becoming the lifelong severity of a patient's AD has been proposed [161 J. possible to visualize and quantitate these neuropeptides and the Recent Advances in Therapy nerves that carry them. A number of abnormalities in atopic derma­ titis are already becoming apparent. For instance, somatostatin-im­ UV: Although PUVA [162] and UVB alone provide a response munoreactive nerves, easily visualized in normal skin, were not rate, studies have revealed that addition of UVA to the UVB found in the skin of patients with atopic dermatitis [148]. By con­ (UVAB) provided a detectably improved therapeutic response trast, neuropeptide Y - positive dendritic cells in the epidermis are [163,164]. Interestingly, UVB is also effective at reducing Staph present in lesional atopic dermatitis skin, but not in controls [148]. aureus colonization. Subsequent studies have demonstrated the su­ Also in atopic dermatitis there was an increase in nerve fibers re­ periority of short-wave UVA (UVAII) [165J and, in particular, vealed by anti-neural filament antibody and anti-neuron specific long-wave UVA (UVAI) [1 66] over UVB. The ability oflong-wave protein 9.5 antibody, but a reduction in adrenergic-innervated fibers UVA (UVAI) to selectively reduce and transiently inactivate Lan- 134 COOPER THE JOURNAL OF INVESTIGATIVE DERMATOLOGY gerhans cells without inducing infiltration of inflammatory macro­ antibiotic, or sedative activities of these plants are responsible is phages into the skin [167,168] may be a factor in the improved currently under active investigation. performance of UVAI over UVB in AD. Dieta ry Lipids: Dietary modifications involving supplementation Cyclosporil1 A: Systemic immunosuppression with corticosteroids with n-3 fatty acids (including eicosapentanoic acid) slightly fa­ is clearly effective in atopic dermatitis, but oral or parenteral corti­ vored the experimental group over the control group [179]. How­ costeroids should be limited to brief courses of therapy in extremely ever, ingestion of oil of evening primrose extract (which contains severe situations, due to the significant long-term toxicity and de­ the deficient linoleic and gamma-linoleic acids), demonstrated no pendency associated with steroid use in atopic dermatitis. However, difference from a control group taking olive oil, or from a group other forms of systemic immunosuppression are being developed ingesting a combination of primrose oil and fish oil (eicosapentan­ for atopic dermatitis. Oral cyclosporin A, at a dose of 5 mg/kg/d, oic acid) (181,182]' Although studies have been performed that was highly effective in reducing disease extent and severity scores, exhibited a beneficial effect of primrose oil on atopic dermatitis and in improving itch and sleep scores in a double-blind crossover [183], a lack of effect of primrose oil was also found by others study of atopic dermatitis [158]. Although patients experienced [181,182]. nausea, abdominal discomfort, and paresthesias, and elevations of House Dust Mites: Hyposensitization with dust mite allergen was bilirubin and worsening of renal function were reported, the ad­ unsuccessful in improving atopic dermatitis [184]. Attempts to re­ verse effects were considered more tolerable than placebo [158], duce mite levels in the home and to obtain clinical benefit with this indicating high patient acceptance, despite the use of a maximal approach have been elusive [185 ,186]' including the use of natamy­ dose level. This study validates earlier open trials and case reports of cin, which kills the aspergillus on which mites feed. Vacuum clean­ the effectiveness of oral cyclosporin A for atopic dermatitis [169- ing, neither alone or in combination with natamyacin, were able to 171]. By contrast, topical cyclosporin A application does not appear reduce mite numbers sufficiently to provide clinical benefit [186]' to be particularly effective for atopic dermatitis [172,173]. Despite Patients were able to obtain benefit from mite reduction only in a the efficacy of cyclosporin A in atopic dermatitis, such therapy does hospital setting in which a room was specially treated to reduce mite not appear to reduce either intracutaneous skin tests or patch tests to density to less than three mites per meter squared. In this study, dust mite antigens [170), reducing the likelihood that cyclosporin A night-time admission to the mite free room gave 11 of 13 atopic is acting primarily to stabilize mast cells, and consistent with the dermatitis patients relief from itching and dermatitis within 2 - 3 potent ability of cyclosporin A to block Langerhans cell antigen­ weeks. presenting activity and T-cell activation in the skin [174]. Indeed, cyclosporin A therapy of atopic dermatitis patients results in a po­ Mast Cells/Phosphodiesterase: From a mast-cell-stabilizing point of tent inhibition of the hyperstimulatory Langerhans cells present in view, reports of activity of ketotifin in atopic dermatitis continue to lesional atopic dermatitis skin [175], and in a reduction of activated appear, and even topical cromolyn applied to lesions of young chil­ T cells, Langerhans cells bearing IgE, and macrophages [18]. dren improved the dermatitis [188]. Phosphodiesterase inhibition would also be expected to provide some mast cell stabilization, but 1I1te1eroll Gamma: In addition to the application of immunosup­ papaverine (which has limited phosphodiesterase activity) was pressant agents to atopic dermatitis, several agents have been re­ found to be ineffective [189,190]. However, the development of cently utilized that·have an immunomodulatory effect, rather than phosphodiesterase inhibitors specific for the cAMP phosphodiester­ strictly suppressive capacity. Recombinant interferon gamma has ase elevated in atopic dermatitis monocytes continues to be a valid been administered to patients with atopic dermatitis in a double­ option, and candidates with promising in vitro activity have been blind, placebo-controlled trial of atopic dermatitis, and found to be identified (105]. statistically significantly superior to placebo [87]. We found clinical benefit to be accompanied by a reduction in eosinophil count, al­ CONCLUSION though no reduction in serum IgE was noted [87]. Eosinophils were The activity of investigators in studying patients with atopic derma­ not the only blood element to be reduced, however; reductions in titis in part reflects an optimism that newer concepts in immuno­ the overall white blood cell count, in particular those with clinical biology can be utilized to better understand atopic dermatitis benefit, were also observed [93]. These findings confirm a phase I pathomechanisms. This enthusiasm, combined with the rapid de­ open erial, which also suggested that atopic dermatitis patients ben­ velopment of new classes of immunosuppressives, immunomodula­ efitted from IFNy therapy [176]. Although it was originally hy­ tors, and light sources, makes it likely that significant strides will be pothesized that IFNy would be of benefit for atopic dermatitis via its made in the coming decades in the understanding and treatment of ability to down regulate Th2 responses, there was no reduction in atopic dermatitis. spontaneous IgE production [176]. Thymoperltil1 : In a similar recently reported double-blind clinical REFERENCES trial, thymopentin, the active pentapeptide of a thymic hormone 1. Cooper KD: Mechanisms of atopic dermatitis. In: Norris DA (ed .). Itm"''''e with immunostimulatory potential, gave significantly better clini­ Medlan;sms in C"tan"""s Disease. Marcel Dekker, Inc., New York, 1989, Pp cal improvement than placebo in severity and pruritus at 6 weeks of 247-276 2. Hanifin JM, Cooper KD, Roth HL: Atopy and atopic dermatitis. ] Am Acad treatment [177]. 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